{"paper_id":"488d0699-304b-4136-bdd2-9728eeb4b75f","body_text":"Association of circulating proteasome activity with Alzheimer’s pathology and cognitive functions in APOE ε4 carriers | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of circulating proteasome activity with Alzheimer’s pathology and cognitive functions in APOE ε4 carriers Bon Gook Koo, Ha-Eun Seo, Yejin Yun, Daegyeom Kim, Jae Myeong Kang, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8306028/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Feb, 2026 Read the published version in Alzheimer's Research & Therapy → Version 1 posted 9 You are reading this latest preprint version Abstract Background: Proteasome is a major intracellular protease complex, but the significance of circulating proteasome activity in Alzheimer’s disease (AD) is not well established. Because APOE ε4 is the strongest genetic risk factor for AD, we examined whether plasma proteasome activity is associated with AD-related pathology, neurodegeneration, and cognitive decline, focusing on APOE ε4 carriers. Methods: In this observational study, participants were classified as cognitively normal (CN), mild cognitive impairment (MCI), and dementia. All underwent 3.0-T MRI, [ 18 F]flutemetamol PET for amyloid, [ 18 F]MK-6240 PET for tau, APOE genotyping, and neuropsychological testing. Circulating proteasome activity was measured using fluorogenic substrates. Associations between proteasome activity and imaging or clinical features were assessed after stratifying by APOE ε4 status. Mediation analyses evaluated whether amyloid or tau burden indirectly linked proteasome activity with hippocampal volume or cognition. Results: A total of 148 individuals were included (58 CN, 39 MCI, 38 AD dementia, and 13 other dementia). Significant associations appeared only in APOE ε4 carriers (n = 55). Higher proteasome activity was associated with lower amyloid burden (β = − 0.142, p = 0.009), lower global tau burden (β = − 0.447, p = 0.047), and reduced tau in Braak I/II (β = − 0.460, p = 0.033) and Braak III/IV regions (β = − 0.454, p = 0.033). Proteasome activity was positively associated with hippocampal volume (β = 0.294, p = 0.001) and with cognitive performance, including MMSE (β = 2.375, p = 0.026), CDR-SOB (β = − 1.604, p = 0.005), and memory function. No significant associations were found in noncarriers. Mediation analyses showed that amyloid burden explained ~ 29% and Braak I/II tau ~ 23% of the proteasome–hippocampal volume relationship, while tau in Braak I/II and III/IV regions mediated 24–41% of the associations between proteasome activity and global cognition. Conclusions: Downregulated proteasome activity is strongly associated with amyloid burden, early tau accumulation, hippocampal atrophy, and cognitive impairment only in APOE ε4 carriers. These findings suggest that plasma proteasome activity may serve as a noninvasive marker of AD-related vulnerability in genetically at-risk individuals. Further studies are needed to clarify whether proteasome activity contributes to or results from amyloid and tau aggregation. Trial registration ■ Trial registration number: KCT0005428. Registered September 24, 2020. ■ Study subjects included in this analysis were those recruited from November 2018 onwards. (retrospectively registered) Alzheimer’s disease amyloid APOE ε4 biomarker cognition PET plasma proteasome tau Figures Figure 1 Figure 2 Figure 3 Background The ubiquitin (Ub)-proteasome system (UPS) plays a principal role in degrading misfolded and aggregation-prone proteins in cells. Given that many neurodegenerative diseases, including Alzheimer’s disease (AD), manifest with the accumulation of proteotoxic proteins, UPS dysfunction is expected to be pathologically associated with the onset and progression of these disorders [ 1 , 2 ]. For example, postmortem analyses of AD brains have revealed significantly reduced proteasome activity in the hippocampal region compared to healthy controls [ 3 , 4 ]. The 26S proteasome is the sole adenosine triphosphate (ATP)-dependent protease in the cytoplasm, consisting of two functionally distinct compartments: the catalytic complex (20S) for substrate hydrolysis and the regulatory complex (19S) for substrate recognition, processing, and translocation into the 20S chamber [ 5 ]. Notably, more than half of all proteasomes exist as a free 20S form [ 6 ]. The contribution of 20S-mediated proteolysis to global protein homeostasis, i.e., proteostasis, has been increasingly recognized, particularly in the degradation of misfolded proteins in a Ub-independent manner [ 7 , 8 ]. While intracellular proteostasis via proteolysis has been extensively studied, how extracellular proteostasis is regulated remains poorly understood. Yet, the presence of protein aggregates in the blood or cerebrospinal fluid, such as amyloid β (Aβ) and tau proteins, underscores the importance of extracellular protein quality control (PQC), especially in neurodegenerative conditions [ 9 ]. With more than one-third of protein encoding genes involved in producing membrane-bound and secreted proteins [ 10 , 11 ], extracellular PQC may be particularly critical in preventing the accumulation of misfolded proteins in the extracellular environment, where ATP is depleted. We previously observed that circulating proteasomes in human plasma predominantly exist as 20S proteasomes and that their activity is significantly reduced in patients with mild cognitive impairment (MCI) and chronic tinnitus, compared to those with tinnitus alone [ 10 ]. We also found a significant negative association between Aβ levels and circulating proteasome activity, which was not observed with other plasma enzymes. The ε4 allele of apolipoprotein E (APOE) is the strongest risk factors for late-onset AD [ 11 – 13 ]. APOE, present in lipoprotein particles in the human brain, plays critical roles in amyloid precursor protein processing, Aβ clearance, and tau phosphorylation [ 14 ]. Among the three gene variants (APOE ε2, ε3, and ε4), the ε4 isoform increases AD risk by 2- to 3-fold with one ε4 allele and up to 12-fold with two alleles [ 15 ]. While APOE ε4 appears critically implicated in Aβ and tau pathologies, the precise mechanism of how it contributes to AD risk and prognosis remains to be determined. We hypothesized that proteasomes in the circulatory system may dynamically respond to systemic stress caused by accumulated proteotoxic proteins, potentially serving as an adaptive response mechanism linked to neuropathological characteristics. In addition, APOE ε4 status strengthens the association between plasma proteasome activity and AD pathology indices. Our results indicate that circulating proteasome activity in APOE ε4 carriers reflects significant 1) Aβ and tau accumulation, 2) anatomical neurodegeneration, and 3) cognitive decline. Thus, proteasome activity may serve as a novel, noninvasive, and cost-effective biomarker for monitoring disease progression, thereby offering an earlier time window for AD prevention and therapeutic intervention. Materials and Methods Participants Participants were enrolled in a prospective cohort study conducted at the memory disorder clinic within the Department of Neurology at Gachon University Gil Medical Center. Patients with cognitive impairment, including those with MCI or dementia, were recruited through this neurology-based clinic. Community-dwelling cognitive normal (CN) individuals were recruited as control participants from volunteers engaged in aging-related research. All participants underwent the same standardized clinical evaluation by a single board-certified neurologist (Y.N.), and each completed a detailed neuropsychological assessment administered by an experienced neuropsychologist to confirm the diagnosis. We recruited a total of 180 participants composed of patients with MCI or dementia and CN individuals. They performed 3.0-Tesla MRI, [ 18 F]flutemetamol (FLUTE) and [ 18 F]MK-6240 (MK-6240) PET scans, APOE genotyping, comprehensive neuropsychological tests, and plasma collection for blood-based proteasome activity assessment. Among them, 15 individuals were excluded due to incomplete evaluation, 11 due to motion defects on PET imaging and 6 due to hemolyzed blood. The final cohorts consisted of 38 patients with AD dementia, 39 with MCI, 13 with other dementia (3 with subcortical vascular dementia, 1 with corticobasal syndrome, and 9 with amyloid-negative dementia), and 58 CN individuals. Patients with AD dementia were diagnosed according to the framework criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association [ 16 ]. AD patients with a history of other neurological or psychiatric disorders were not recruited in the study. Patients with structural abnormalities on MRI, such as cerebral, cerebellar, or brainstem infarction, intracranial hemorrhage, hydrocephalus, severe white matter hyperintensities, white matter hyperintensities associated with radiation, traumatic brain injury, tumors, multiple sclerosis, and vasculitis, were excluded. Furthermore, patients with cognitive impairment due to metabolic or systemic causes were excluded after assessment with laboratory tests, which included complete blood count, thyroid function, syphilis serology, folate levels, vitamin B12, and metabolic profile. Participants were classified as MCI according to Petersen’s criteria [ 17 ], objective cognitive decline in neuropsychological tests, indicated by a clinical dementia rating (CDR) score of 0.5, and their ability to independently perform activities of daily living at a sufficient level. CN participants were either healthy volunteers or individuals who did not exhibit objective cognitive decline, with mean z-scores within 1.5 standard deviations of age- and education-corrected norms on neuropsychological tests and a CDR score of 0. Written informed consent was obtained from all participants and their guardians (for dementia patients). This study was approved by the Institutional Review Board (IRB # GBIRB2018-350) and registered at the Clinical Research Information Service of Korea (CRIS: KCT0005428). Neuropsychological assessment All participants underwent cognitive function evaluations using the Mini-Mental State Examination (MMSE), CDR, and comprehensive neuropsychological tests, assessing attention, language, verbal and visual memory, visuospatial skills, and frontal/executive functioning. Detailed items of the comprehensive test battery have been described in the previous study [ 18 , 19 ]. For comprehensive neuropsychological test results, we used z-scores which were standardized for age and years of education. Details of the specific tests administered are provided in Supplementary Text 1. Image acquisition and quantification MR imaging acquisition and segmentation MRI scans were performed using a Magnetom Skyra 3.0-Tesla MRI scanner (Siemens, Erlangen, Germany), equipped with a 32-channel Siemens matrix head coil. We acquired 3D T1 magnetization-prepared rapid gradient echo (T1-MPRAGE): repetition time = 1,810 ms, echo time = 2.91 ms, flip angle = 9°, pixel bandwidth = 340 Hz/pixel, matrix size = 256 × 256, field of view = 250 mm, NEX = 1, total acquisition time = 3 min 37 s, voxel size = 0.49 × 0.49 × 1.0 mm 3 , and fluid attenuated inversion recovery (FLAIR): repetition time = 9,000 ms, echo time = 122 ms, flip angle = 150°, pixel bandwidth = 287 Hz/pixel, matrix size = 256 × 224, field of view = 256 mm, NEX = 1, total acquisition time = 2 min 44 s, voxel size = 0.5 × 0.5 × 2.0 mm3. 3D susceptibility weighted imaging (SWI) was conducted with TR = 40 ms and dual echo times of 13.70 ms and 30.50 ms. The flip angle was 15°, bandwidth was 120 Hz/pixel, matrix = 230 × 202, FOV = 230 mm, and NEX = 1. The scan duration was about 109 sec, with voxel dimensions of 0.8 × 0.8 × 2.0 mm³. MR imaging quantification Structural MRI processing and volumetric measurements were performed using FreeSurfer 6.0 ( www.surfer.nmr.mgh.harvard.edu ). The standard recon-all processing pipeline was applied to 3D-T1 MPRAGE images for cortical surface reconstruction and volumetric segmentation. Mean cortical thickness was calculated by averaging vertex-wise cortical thickness across bilateral hemispheres. Intracranial volume (ICV) and hippocampal volume (HV) were automatically derived using the aseg (automated segmentation) output. All segmentations were visually inspected for accuracy and manual corrections were performed, when necessary, in accordance with FreeSurfer guidelines [ 20 ]. Assessment of white matter hyperintensity volume, microbleeds and lacunes are described in the Supplementary Text 2. PET imaging acquisition All participants acquired FLUTE and MK-6240 PET scans using a Siemens Biograph 6 Truepoint PET/computed tomography (CT) scanner (Siemens, Knoxville, TN, USA) with a list-mode emission acquisition. MK-6240 scans were acquired from 70 to 90 min after the intravenous injection of 185 MBq of [ 18 F]MK-6240, which was prepared as described previously [ 21 ] with a modified method at the cyclotron facility, Gachon University. FLUTE scans were acquired from 90 to 110 min after the intravenous injection of 185 MBq of [ 18 F] FLUTE, which was purchased from Carecamp Inc. We used a low-dose CT scan for attenuation correction. PET data was reconstructed onto a 256 × 256 × 109 matrix with a voxel size of 1.3 × 1.3 × 1.5 mm 3 using a 2D ordered subset expectation maximization algorithm with 8 iterations and 16 subsets. PET quantification Individual MK-6240 and FLUTE PET images were co-registered onto individual T1 MPRAGE images using FreeSurfer. We calculated regional mean values of PET images after region-based partial volume correction using PETSurfer and acquired weighted-average values of pre-defined ROIs [ 22 , 23 ]. For amyloid PET, the cortical retention of FLUTE was quantified in AD-associated regions, including the prefrontal, superior parietal, lateral temporal, inferior parietal, occipital, anterior cingulate, mesial temporal, precuneus, and posterior cingulate cortices. FLUTE SUVR was evaluated using the pons as a reference region [ 24 ]. FLUTE images were also visually evaluated for amyloid positivity based on a standardized visual rating protocol [ 25 ]. Tau burden was quantified using MK-6240 SUVR. ROIs for MK-6240 included global MK-6240 (frontal pole, pars orbitalis, lateral orbitofrontal, pars triangularis, pars opercularis, rostral middle frontal, superior frontal, caudal middle frontal, medial orbitofrontal, superior parietal, inferior parietal, supramarginal, precuneus, cuneus, pericalcarine, lateral occipital, banks of superior temporal, inferior temporal, middle temporal, superior temporal, hippocampus, amygdala, parahippocampal, entorhinal, nucleus accumbens, caudal anterior cingulate, rostral anterior cingulate and posterior cingulate), Braak I/II (entorhinal and hippocampus regions), Braak III/IV (parahippocampal, fusiform, lingual, amygdala, inferior temporal, middle temporal, temporal pole, thalamus, caudal, rostral, isthmus, posterior cingulate and insula regions) and Braak V/VI (frontal, parietal, occipital, transverse, superior temporal, precuneus, banks of superior temporal, nucleus accumbens, caudate nucleus, putamen, precentral, postcentral, paracentral, cuneus and pericalcarine regions) [ 26 , 27 ]. Regional standardized uptake value ratios (SUVRs) of MK-6240 were computed using cerebellar gray matter as a reference region [ 28 ]. Plasma preparation and processing Whole blood was collected in two EDTA vacuum tubes from study participants between 9:00 and 10:00 AM after a 6-hour fasting period. Blood was processed independently as technical duplicates. Plasma was isolated by centrifugation at 3,000 rpm using a benchtop centrifuge for 15 min, aliquoted into 1.5 mL tubes in 0.5–1.0 mL volumes and stored at − 80 ◦ C until analyzed. Hemolytic samples were identified and discarded through visual inspection. Previous studies have confirmed that proteasome activity in plasma remains comparable across multiple freeze-thaw cycles [ 10 ]. Proteasome activity measurement Circulating proteasome activity in plasma was assessed using a standardized method employing a fluorogenic reporter substrate, succinyl-Leu-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin (suc-LLVY-AMC; Bachem, Bubendorf, Switzerland.) [ 29 , 30 ]. This peptide is cleaved by the chymotrypsin-like activity of the 20S catalytic proteasome and the fluorescence intensity from free AMC is considered as a representative measure of overall proteasome activity [ 31 ]. Briefly, 20 µL of human plasma was combined with 250 µM of suc-LLVY-AMC in an assay buffer (50 mM Tris-HCl [pH 7.5], 1 mg/mL BSA, 1 mM EDTA, 1 mM fresh ATP, and 1 mM fresh DTT) in a black 96-well plate. The hydrolysis of the fluorogenic peptides was monitored every three min at 380/460 nm (excitation/emission wavelength) at 30°C. Each sample was assayed in triplicate. All fluorescence intensities from plasma samples were normalized to those obtained in the presence of the proteasome inhibitor MG132 (10 µM), and the resulting circulating proteasome activity was expressed as relative fluorescence units (RFU). Statistical Analysis To analyze the demographics and clinical characteristics of the study population, continuous variables were assessed through group comparisons using the independent samples t-test. For nominal variables, the chi-square test or Fisher’s exact test was applied. After dividing the study participants as APOE ε4 carriers (having at least one APOE e4 allele) and noncarriers, we assessed associations of clinical variables (MMSE, CDR-SOB, mean cortical thickness, hippocampal volume, cortical FLUTE retention, global MK-6240 retention, and MK-6240 SUVR based on Braak stages) with proteasome activity using multivariable linear regression models in each group. In the linear regression models, age, sex, and years of education were included as covariates. The difference in the associations between APOE e4 carriers and noncarriers was tested by the method described elsewhere and expressed as p for intraction [ 32 ]. To examine whether amyloid or tau burden (‘M’) mediated the associations between proteasome activity (‘X’) and global cognition or hippocampal volume (‘Y’), we performed mediation analyses. Indirect effects were quantified through a series of regression models evaluating: (1) the association between X and Y, (2) the association between X and M, and (3) the joint influence of X and M on Y. After controlling for age, sex, and years of education, we derived the estimates for the indirect, direct, and total effects (direct plus indirect), as well as the percentage of the total effect explained by mediation (indirect effect/total effect × 100). Confidence intervals for the beta coefficients were obtained using non-parametric bootstrapping with 1,000 resamples. All mediation procedures were implemented in R (version 3.4.1, R Foundation) using the “mediation” package [ 33 ]. All statistical analyses were conducted using PASW Statistics 19 (SPSS Inc, Chicago, IL, USA) with a significance at p < 0.05 (two-way). Results Demographics and clinical characteristics of study population The demographics and clinical characteristics of the study population are shown in Table 1. There was no significant difference in age, sex, and years of education. In contrast, APOE ε4 carriers and noncarrier groups showed clear statistical difference in clinical diagnoses ( p = 0.002). The APOE ε4 carrier group had a higher number of AD dementia patients, while the noncarrier group included a higher proportion of CN individuals. In the APOE ε4 carrier group, the majority of participants were ε3/ε4 (n = 39, 70.9%), followed by ε4/ε4 (n = 13, 23.6%), and ε2/ε4 (n = 3. 5.5%). By comparison, the APOE ε4 noncarrier group mainly consisted of ε3/ε3 individuals (n = 76, 81.7%), with a smaller proportion of ε2/ε3 (n = 17, 18.3%). Table 1 Demographics and clinical characteristics of the study subjects Variables All participants (N = 148) APOE ε4 carrier (n = 55) APOE ε4 noncarrier (n = 93) p value CN/MCI/ADD/OD (%) 58/39/38/13 (39.2/26.4/25.7/8.8) 15/18/21/1 (27.3/32.7/38.2/1.8) 43/21/17/12 (46.2/22.6/18.3/12.9) 0.002 Age 70.80 ± 8.01 70.47 ± 7.95 70.99 ± 8.09 0.706 Sex (Female, n [%]) 97(65.5) 35(63.6) 62(66.7) 0.724 Education(year) 9.09 ± 4.25 9.58 ± 4.02 8.81 ± 4.37 0.284 APOE genotype < .001 † ε2/ε3 17 (11.5) 17 (18.3) ε3/ε3 76 (51.4) 76 (81.7) ε2/ε4 3 (2.0) 3 (5.5) ε3/ε4 39 (26.4) 39 (70.9) ε4/ε4 13 (8.8) 13 (23.6) MMSE 24.53 ± 5.09 24.18 ± 4.52 24.73 ± 5.41 0.527 CDR-SOB 2.53 ± 2.87 2.75 ± 2.46 2.39 ± 3.09 0.460 Hypertension (%) 67(45.3) 23(41.8) 44(47.3) 0.609 Diabetes mellitus (%) 44(29.7) 13(23.6) 31(33.3) 0.265 Dyslipidemia (%) 62(41.9) 27(49.1) 35(37.6) 0.227 Coronary artery disease (%) 8(5.4) 6(10.9) 2(2.2) 0.052 † History of stroke (%) 2(1.4) 0(0.0) 2(2.2) 0.530 † Amyloid Positivity (%) 64(43.2) 38(69.1) 26(28.3) < .001 Cortical FLUTE SUVR 0.5955 ± 0.27 0.7136 ± 0.24 0.5230 ± 0.27 < .001 Global MK-6240 SUVR 1.4010 ± 0.93 1.6216 ± 0.95 1.2759 ± 0.90 0.034 Mean cortical thickness (mm) 2.35 ± 0.18 2.37 ± 0.16 2.34 ± 0.19 0.346 ICV (L) 1.42 ± 0.18 1.38 ± 0.17 1.44 ± 0.19 0.052 Hippocampal volume (mL) 3.25 ± 0.48 3.10 ± 0.54 3.35 ± 0.43 0.004* WMHV (mL) 10.07 ± 11.60 9.28 ± 12.28 10.54 ± 11.21 0.523 Proteasome activity (RFU/1,000) 1.215 ± 0.56 1.239 ± 0.56 1.201 ± 0.56 0.690 Values are presented as mean ± standard deviation for continuous variables and as number (%) for nominal variables. Group comparisons were performed between the APOE ε4 carrier and noncarrier groups using an independent samples t -test for continuous variables and chi-square test for categorical variables. All group comparisons were considered significant when p < 0.05.*The assumption of equal variances was not met (Levene's test), so the results of Welch's t -test were reported. †Mean group differences were assessed by Fisher’s exact test. Abbreviations: CN, cognitive normal; MCI, mild cognitive impairment; ADD, Alzheimer’s disease dementia; OD, other dementia; MMSE, Mini-Mental State Examination; CDR-SOB, Clinical Dementia Rating-Sum Of Boxes; FLUTE, flutemetamol; SUVR, standardized uptake value ratio; ICV, intracranial volume; WMHW, white matter hyperintensity volume; RFU, Relative fluorescence units. MMSE and CDR-SOB scores did not significantly differ between APOE ε4 carrier and noncarriers. In addition, there were no significant differences in the prevalence of comorbidities, such as hypertension, diabetes, dyslipidemia, coronary artery disease, and history of stroke, between the two groups. Proteasome activity in plasma did not also differ between the groups. However, we found that hippocampal volume was significantly smaller in APOE ε4 carriers. Both cortical FLUTE retention and global MK-6240 PET retention were greater in APOE ε4 carriers than in noncarriers. Associations between circulating proteasome activity and amyloid, tau, and neurodegeneration in APOE ε4 carriers and noncarriers Among APOE ε4 carriers, higher proteasome activity was significantly associated with lower cortical amyloid burden (β = -0.142, SE = 0.052, p = 0.009) and lower global tau burden measured by MK-6240 SUVR (β = -0.447, SE = 0.219, p = 0.047) (Figs. 1A and 1B, Table 2). Regional tau deposition in Braak I/II and Braak III/IV areas also showed significant negative associations (β = − 0.460, p = 0.033; β = − 0.454, p = 0.033, respectively) (Fig. 1C and 1D). In contrast, none of these associations reached significance in APOE ε4 noncarriers. Proteasome activity was further associated with neurodegeneration in APOE ε4 carriers, as reflected by a strong positive association with hippocampal volume normalized to intracranial volume (HV/ICV; β = 0.294, SE = 0.083, p = 0.001) (Fig. 1E), whereas no such association was observed in noncarriers (β =-0.123, SE = 0.078, p = 0.119). The interaction term for APOE ε4 status was highly significant for HV/ICV ( p for interaction < 0.001), indicating that the effect of proteasome activity on hippocampal atrophy differed markedly by genetic risk. Interaction effects for tau burden were also observed, with trend-level significance in Braak I/II and Braak III/IV regions ( p for interaction = 0.060 and 0.072, respectively), suggesting that the association between proteasome activity and tau deposition is stronger in APOE ε4 carriers than in noncarriers. When APOE ε4 carriers and noncarriers were analyzed together, no significant associations were observed between proteasome activity and amyloid/tau burden or structural brain atrophy (Supplementary Table 2). Associations between circulating proteasome activity and cognitive functions in APOE ε4 carriers In APOE ε4 carriers, global cognitive functions were significantly associated with circulating proteasome activity (Table 3). MMSE scores showed a positive association (β = 2.375, p = 0.026), and CDR-SOB scores were inversely associated (β = -1.604, p = 0.005) with proteasome activity, but not in APOE ε4 noncarriers (Figs. 2A and 2B, Table 3). These group differences were statistically significant ( p for interaction = 0.014 for MMSE, p for interaction = 0.005 for CDR-SOB). In addition, memory functions were significantly correlated with proteasome activity only in APOE ε4 carriers. Verbal memory, evaluated with the Seoul verbal learning test (SVLT) delayed recall, was positively correlated (β = 0.749, p = 0.023) (Fig. 2C). Similarly, visual memory, assessed with Rey complex figure test (RCFT) recall, showed significant correlations for both immediate recall (β = 0.553, p = 0.023) and delayed recall (β = 0.514, p = 0.044) with circulating proteasome activity (Fig. 2D). No significant correlations between proteasome activity and cognitive functions were observed in APOE ε4 noncarriers. When both carriers and noncarriers were analyzed together, no significant association was observed between proteasome activity and cognitive functions (Supplementary Table 3). Table 3 Association of cognitive functions and proteasome activity Variables APOE ε4 carrier APOE ε4 noncarrier β (SE) p value β (SE) p value p for interaction MMSE 2.375(1.034) 0.026 -1.162(0.999) 0.248 0.014 CDR-SOB -1.604(0.544) 0.005 0.618(0.578) 0.288 0.005 Digit span test: forward -0.044(0.207) 0.833 0.161(0.201) 0.425 0.477 Digit span test: backward 0.097(0.219) 0.659 -0.031(0.205) 0.882 0.670 Boston Naming Test 0.637(0.351) 0.075 -0.167(0.343) 0.628 0.101 Rey Complex Figure Test-copy 0.573(0.635) 0.371 -0.089(0.651) 0.891 0.467 SVLT immediate recall 0.590(0.311) 0.063 0.217(0.302) 0.474 0.391 SVLT delayed recall 0.749(0.321) 0.023 0.143(0.301) 0.637 0.168 SVLT recognition 0.579(0.483) 0.236 0.191(0.308) 0.538 0.497 RCFT immediate recall 0.553(0.237) 0.023 -0.052(0.249) 0.837 0.079 RCFT delayed recall 0.514(0.249) 0.044 0.003(0.255) 0.991 0.151 RCFT recognition 0.589(0.343) 0.091 0.027(0.276) 0.924 0.201 COWAT animal 0.412(0.250) 0.105 0.048(0.232) 0.835 0.286 COWAT supermarket 0.413(0.297) 0.170 -0.133(0.231) 0.567 0.147 COWAT phonemic total 0.175(0.267) 0.516 -0.021(0.212) 0.921 0.566 Color-Word Stroop Test 0.401(0.310) 0.202 0.215(0.269) 0.428 0.651 Digit Symbol Coding 0.608(0.326) 0.068 0.194(0.311) 0.533 0.358 TMT-A 0.249(0.246) 0.318 -0.284(1.656) 0.864 0.750 TMT-B 1.389(0.878) 0.119 -0.507(0.957) 0.598 0.144 Values were expressed as beta coefficients and standard errors, from multivariable linear regression models adjusted for age, sex, and years of education. Abbreviations . MMSE, Mini-Mental State Examination; CDR-SOB, Clinical Dementia Rating-Sum of Boxes; SVLT, Seoul verbal language test; RCFT, Rey complex figure test; COWAT, Controlled Oral word association test; TMT, Trail making test Mediation effects of amyloid and tau burden on the associations between proteasome activity and cognitive function and hippocampal volume in APOE ε4 carriers In the mediation analysis, the associations of proteasome activity with hippocampal volume and cognitive function in APOE4 carriers were differentially mediated by amyloid and tau burden (Fig. 3, Supplementary Table 4). Cortical FLUTE SUVR significantly mediated the relationship between proteasome activity and hippocampal volume, showing a significant indirect effect ( p = 0.02) and accounting for approximately 29.3% of the total effect. Regional MK-6240 corresponding to Braak I/II demonstrated significant indirect effects for the associations of proteasome activity with hippocampal volume, MMSE, and CDR-SOB, indicating that early-stage tau burden mediates both neurodegeneration and global cognitive impairment. The proportion mediated ranged from 23% to 28% across outcomes. In contrast, regional MK-6240 corresponding to Braak III/IV significantly mediated the associations of proteasome activity with MMSE and CDR-SOB, whereas the indirect effect for hippocampal volume was not significant. Mediation proportions for these cognitive measures ranged from 30% to 41%. Discussion In this study, we found that plasma proteasome activity is significantly associated with AD–related biomarkers in individuals carrying the APOE ε4 allele, but not in noncarriers. Specifically, higher proteasome activity in APOE ε4 carriers was linked to lower amyloid and tau burden, larger hippocampal volume, and better cognitive performance (e.g., MMSE, CDR-SOB, and memory function). In sharp contrast, these correlations were absent or negligible in APOE ε4 noncarriers, suggesting that peripheral proteasome activity might reflect underlying neuropathology and cognitive decline only in individuals genetically predisposed to AD. Therefore, changes in proteasome activity may function as a genotype-specific biomarker that is potentially manifested from AD-linked proteostasis dysfunction in neurons. Mediation analysis showed that in APOE4 carriers, amyloid burden primarily mediates proteasome-related hippocampal atrophy, whereas tau burden, particularly in Braak I/II and III/IV regions, mediates the associations between proteasome dysfunction and cognitive decline. The monomeric component of proteotoxic proteins, such as Aβ and tau, major hallmarks of AD, have been identified as direct substrates for 20S proteasomes, degraded in a Ub- and ATP-independent manner [ 31 , 34 , 35 ]. These findings might be in line with clinical studies where 20S activity and levels in plasma were altered in diverse disease states [ 5 – 10 , 36 , 37 ]. Proteasome impairment in AD have been attributed to the degradation-resistant proteins, such as oligomeric Aβ and tau, that may clog the proteasome and initiate a vicious cycle producing excess aggregation-prone proteins [ 38 – 40 ]. More recently, the 20S proteasome was reported to be packaged into extracellular vesicles, delivered to recipient cells, and contributed to the degradation of excess tau proteins [ 41 ]. Overall, our finding that circulating proteasome activity is inversely associated with amyloid and tau PET signals in ε4 carriers aligns with these mechanistic models of UPS dysfunction in AD. The APOE genotype appears to modulate this activity-pathology relationship. APOE ε4 is known to enhance amyloid-related tau pathology a neuronal damage [ 42 ]. Recent quantitative proteomic analysis using humanized APOE ε4 mice also demonstrated inadequate proteasome and autophagy function, thus indicating extensively disrupted proteostasis the mouse brain [ 43 ]. Our human data parallel these findings, suggesting that ε4 impairs UPS-mediated clearance of pathological proteins, unlike ε2 or ε3 variants. This may explain why proteasome function correlates with AD pathology only in APOE ε4 carriers. Along with this notion, it seems plausible that proteasome inactivation is a central feature of neurodegeneration and that proteasome augmentation reduces related cognitive deficits [ 44 ]. The pro-inflammatory effect of APOE ε4 in the brain may further exacerbate dysregulation of proteasome pathways, although this remains to be fully elucidated [ 45 ]. Our study demonstrates that circulating proteasome activity is selectively associated with pathologic changes at the early stages of AD. Significant correlations with tau burden were confined to Braak I/II and III/IV regions, but absent in Braak V/VI, suggesting that proteasome dysfunction is preferentially linked to early tau deposition. This aligns with the Braak model, where initial tau accumulation in medial temporal regions is most closely tied to episodic memory impairment, whereas widespread neocortical tau (Braak V/VI) reflects more advanced disease. The lack of association at Braak V/VI may indicate that once tau pathology becomes widespread, systemic proteasome activity no longer tracks disease severity, possibly due to saturation of proteostasis impairment. Similarly, proteasome activity was positively correlated with hippocampal volume, but not with mean cortical thickness. Since hippocampal atrophy emerges in prodromal stages of AD, whereas diffuse cortical thinning typically manifests later, these results suggest that plasma proteasome activity reflects early medial temporal neurodegeneration rather than global cortical atrophy. The concordance of these findings with tau PET results supports the hypothesis that systemic proteasome dysfunction mirrors early, region-specific AD changes. In terms of cognition, proteasome activity was associated with MMSE, CDR-SOB and memory functions, but not with attention, language, visuospatial or executive functions. This selective relationship is consistent with the amnestic syndrome of early AD, in which memory deficits dominate before other domains decline. Taken together, our findings highlight that systemic proteasome alterations may preferentially accompany the initial cognitive and structural manifestations of AD in APOE ε4 carriers. Mediation analyses further clarified these genotype-specific relationships. In APOE ε4 carriers, amyloid burden partially mediated the association between proteasome activity and hippocampal volume, suggesting that reduced amyloid accumulation may be one pathway through which preserved proteasome function relates to medial temporal structural integrity. Moreover, tau burden played a critical and region-specific mediating role: Braak I/II MK-6240 SUVR significantly mediated the associations between proteasome activity and hippocampal volume, MMSE, and CDR-SOB, indicating that early-stage tau deposition is a key intermediary linking proteasome dysfunction to both neurodegeneration and global cognition. In contrast, Braak III/IV MK-6240 SUVR mediated only the relationships with MMSE and CDR-SOB, but not hippocampal volume, suggesting that limbic-stage tau primarily contributes to cognitive impairment rather than structural atrophy in this group. Together, these findings suggest that both amyloid and early tau burden lie on the pathway between systemic proteasome dysfunction and AD-related clinical outcomes, reinforcing the centrality of proteostasis impairment in APOE ε4 carriers. This study’s strengths lie in its rigorously characterized cohort with multimodal imaging and detailed cognitive function data, genotype stratification, and quantitative measurement of plasma proteasome activity. These design features enabled us to detect genotype-specific associations that would have been missed in pooled analyses. Clinically, plasma proteasome activity could offer a noninvasive readout of proteostatic stress in AD in APOE ε4 carriers. Previously, we have reported that proteasome activity is lower in MCI patients and that proteasome activity negatively correlates with plasma Aβ levels [ 10 ]. Current findings extend this by showing that in ε4 carriers, proteasome activity not only reflects amyloid and tau burdens but also predicts cognitive performance. This suggests that systemic decline in proteostasis may mirror synaptic dysfunction in the brain, particularly in neurons predisposed by APOE ε4-related pathologic stress. A blood-based enzymatic assay would be far more accessible and cost-effective than PET scans or CSF analyses. Thus, combining plasma proteasome measurements with APOE genotyping could help identify high-risk individuals in prodromal stages more efficiently. Limitations include the cross-sectional data, which preclude causal inference; the modest sample size, particularly of APOE ε4 carriers; and the single-center, ethnically homogeneous cohort, which may limit generalizability. While our cohort was powered to detect significant effects in ε4 carriers, replication in larger and more diverse populations is essential. In addition, we do not yet know the sequence of events at present; a longitudinal study will determine whether proteasome decline drives pathology or results from it. The origin of plasma proteasomes also remains unclear. Therefore, in a follow-up work, it would be interesting to design in vivo experiments to address these questions in AD model mice. In summary, our study reveals an APOE ε4-specific correlation between circulating proteasome activity and AD-related features, which may indicate impaired proteostasis in AD. Plasma proteasome activity therefore emerges as a promising, noninvasive biomarker for genotype-specific AD diagnosis and prognosis. Our data also underscores the therapeutic potential of proteasome-activating strategies in neurodegeneration [ 46 , 47 ]. Abbreviations Aβ Amyloid beta AD Alzheimer’s Disease APOE Apolipoprotein E ATP Adenosine Triphosphate CDR-SOB Clinical Dementia Rating Sum of Box CN Cognitively Normal CT Computed Tomography FLAIR Fluid Attenuated Inversion Recovery FLUTE Flutemetamol MCI Mild Cognitive Impairment MMSE Mini-Mental State Examination MPRAGE Magnetization-Prepared Rapid Gradient Echo MRI Magnetic Resonance Imaging NEX Number of Excitation PET Positron Emission Tomography PQC Protein Quality Control ROI Region of Interest SUVR Standardized Uptake Value Ratio SVLT Seoul Verbal Learning Test RCFT Rey Complex Figure Test Ub Ubiquitin UPS Ubiquitin Proteasome System Declarations Ethics approval and consent to participate Written informed consent was obtained from all participants and their guardians (in case of dementia patients). This study was approved by the Institutional Review Board (IRB # GBIRB2018-350) and was registered at the Clinical Research Information Service of Korea (CRIS: KCT0005428). Consent for publication Not applicable. All figures and tables included in this manuscript have been carefully reviewed. This manuscript does not contain any contents that dispose of any direct or indirect identifiers. Datasets have been fully anonymized and no identifiable personal information is presented. Availability of data and materials All original data from this manuscript are available from the corresponding author upon reasonable request. Competing interests The authors declare no conflict of interest. Funding This work was supported by grant of the Korea Healthcare Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant No: HI14C1135 to Y.N.), grants from the National Research Foundation (NRF) of Korea (RS-2021-NR059245 and RS-2023-00261784 to M.J.L..) and Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (RS-2024-00334574 to Y.N. and RS-2024-00332875 to M.J.L), and Gachon University Gil Medical Center (FRD2025-01 to Y.N.). Author contributions B.G.K.: Investigation, Writing – original draft. H.E.S.: Data curation, investigation. Y.Y.: Investigation, Methodology. D.K.: Data curation, investigation. J.M.K.: Investigation. J.C.: Formal analysis, investigation, methodology. S.Y.L.: Investigation, Methodology. Y.J.L.: Data curation, investigation. K.H.P.: Investigation. M.J.L.: Methodology, Writing – review, Supervision, Funding acquisition. Y.N.: Conceptualization, Methodology, Writing – review & editing, Supervision, Funding acquisition. All authors have given approval to the final version of the manuscript. Acknowledgements This work was supported by grant of the Korea Healthcare Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant No: HI14C1135 to Y.N.), grants from the National Research Foundation (NRF) of Korea (RS-2021-NR059245 and RS-2023-00261784 to M.J.L..) and Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, of Korea (RS-2024-00334574 to Y.N. and RS-2024-00332875 to M.J.L), and Gachon University Gil Medical Center (FRD2025-01 to Y.N.). References Rubinsztein DC. 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Ahammed SM, Wang X. Promoting proteostasis by cAMP/PKA and cGMP/PKG. Trends Mol Med. 2025;31(3):224–39. George ED, Tepe JJ. Advances in Proteasome Enhancement by Small Molecules. Biomolecules. 2021;11(12):1789. Table 2 Table 2 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files AdditionalFile20251208nyf.docx Table2.docx Cite Share Download PDF Status: Published Journal Publication published 28 Feb, 2026 Read the published version in Alzheimer's Research & Therapy → Version 1 posted Editorial decision: Revision requested 11 Jan, 2026 Reviews received at journal 09 Jan, 2026 Reviews received at journal 23 Dec, 2025 Reviewers agreed at journal 17 Dec, 2025 Reviewers agreed at journal 11 Dec, 2025 Reviewers invited by journal 10 Dec, 2025 Editor assigned by journal 10 Dec, 2025 Submission checks completed at journal 10 Dec, 2025 First submitted to journal 08 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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16:18:48\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":1066583,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eAssociations between amyloid, tau burdens and hippocampal volume and proteasome activity in APOE ε4 carriers\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eA.\\u003c/strong\\u003e A partial regression plot showing the association between proteasome activity in plasma and cortical FLUTE SUVR. \\u003cstrong\\u003eB.\\u003c/strong\\u003e A partial regression plot showing the association between proteasome activity and global MK-6240 SUVR. \\u003cstrong\\u003eC.\\u003c/strong\\u003e A partial regression plot showing the association between proteasome activity and regional MK-6240 SUVR in the brain areas for Braak I/II. \\u003cstrong\\u003eD.\\u003c/strong\\u003e A partial regression plot showing the association between proteasome activity and regional MK-6240 PET SUVR in the brain areas for Braak III/IV. \\u003cstrong\\u003eE.\\u003c/strong\\u003e A partial regression plot showing proteasome activity and hippocampal volume (HV) normalized to intracranial volume (ICV). All analyses were performed with adjustment of age, sex and years of education.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8306028/v1/2dd76e1491b45ba73eca80fe.png\"},{\"id\":98246250,\"identity\":\"2fbb0aea-bcbc-4261-9eaf-ae11627176f4\",\"added_by\":\"auto\",\"created_at\":\"2025-12-15 16:18:53\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":827616,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eAssociation between cognitive functions and proteasome activity in APOE ε4 carriers\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eA. \\u003c/strong\\u003eA partial regression plot showing the association between proteasome activity and MMSE scores. \\u003cstrong\\u003eB.\\u003c/strong\\u003e A partial regression plot showing the association between proteasome activity and clinical dementia rating-sum of boxes (CDR-SOB) scores. \\u003cstrong\\u003eC.\\u003c/strong\\u003eA partial regression plot for proteasome activity and Seoul verbal learning test (SVLT) delayed recall Z-scores. \\u003cstrong\\u003eD.\\u003c/strong\\u003e A partial regression plot for proteasome activity and Rey complex figure test (RCFT) delayed recall Z-scores. All analyses were performed with adjustment of age, sex and years of education.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8306028/v1/2a635d81cf6fabb1a6d7f0d6.png\"},{\"id\":98246129,\"identity\":\"670a5ee2-59ca-4b0f-a2a4-766a2f4c2b14\",\"added_by\":\"auto\",\"created_at\":\"2025-12-15 16:18:50\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":3456635,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eMediation effects of amyloid and tau on association between proteasome activity and neurodegeneration and cognition\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eA.\\u003c/strong\\u003e Cortical FLUTE retention, \\u003cstrong\\u003eB.\\u003c/strong\\u003e Regional MK-6240 retention in the brain regions for Braak I/II, \\u003cstrong\\u003eC.\\u003c/strong\\u003e Regional MK-6240 retention in the brain regions for Braak III/IV mediate the associations between proteasome activity hippocampal atrophy and global cognition (MMSE, CDR-SOB).\\u003c/p\\u003e\\n\\u003cp\\u003eAbbreviations, SUVR, standardized uptake value ratio; IDE, indirect effect; DE, direct effect; TE, total effect; HV, hippocampal volume; ICV, intracranial volume; MMSE, mini-mental state examination; CDR-SOB, clinical dementia rating-sum of boxes.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8306028/v1/26226311e19a9294f31a9991.png\"},{\"id\":103766385,\"identity\":\"0f0b0be0-68bd-4801-8eff-21dac2c69216\",\"added_by\":\"auto\",\"created_at\":\"2026-03-02 16:14:21\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":13303040,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8306028/v1/ed8f2999-9416-4acf-80ab-47791f81695f.pdf\"},{\"id\":98246350,\"identity\":\"52686115-e0ec-40a7-bc10-52072f1e2829\",\"added_by\":\"auto\",\"created_at\":\"2025-12-15 16:19:00\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":44187,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"AdditionalFile20251208nyf.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8306028/v1/c70441d38cf52dca24c9c2a0.docx\"},{\"id\":98246236,\"identity\":\"2ccf1a79-7414-4c8d-bc6c-4107501dd116\",\"added_by\":\"auto\",\"created_at\":\"2025-12-15 16:18:52\",\"extension\":\"docx\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":16470,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Table2.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8306028/v1/d5ac2bb376639f40323bd9fb.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Association of circulating proteasome activity with Alzheimer’s pathology and cognitive functions in APOE ε4 carriers\",\"fulltext\":[{\"header\":\"Background\",\"content\":\"\\u003cp\\u003eThe ubiquitin (Ub)-proteasome system (UPS) plays a principal role in degrading misfolded and aggregation-prone proteins in cells. Given that many neurodegenerative diseases, including Alzheimer\\u0026rsquo;s disease (AD), manifest with the accumulation of proteotoxic proteins, UPS dysfunction is expected to be pathologically associated with the onset and progression of these disorders [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. For example, postmortem analyses of AD brains have revealed significantly reduced proteasome activity in the hippocampal region compared to healthy controls [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. The 26S proteasome is the sole adenosine triphosphate (ATP)-dependent protease in the cytoplasm, consisting of two functionally distinct compartments: the catalytic complex (20S) for substrate hydrolysis and the regulatory complex (19S) for substrate recognition, processing, and translocation into the 20S chamber [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. Notably, more than half of all proteasomes exist as a free 20S form [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. The contribution of 20S-mediated proteolysis to global protein homeostasis, i.e., proteostasis, has been increasingly recognized, particularly in the degradation of misfolded proteins in a Ub-independent manner [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eWhile intracellular proteostasis via proteolysis has been extensively studied, how extracellular proteostasis is regulated remains poorly understood. Yet, the presence of protein aggregates in the blood or cerebrospinal fluid, such as amyloid β (Aβ) and tau proteins, underscores the importance of extracellular protein quality control (PQC), especially in neurodegenerative conditions [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. With more than one-third of protein encoding genes involved in producing membrane-bound and secreted proteins [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e], extracellular PQC may be particularly critical in preventing the accumulation of misfolded proteins in the extracellular environment, where ATP is depleted. We previously observed that circulating proteasomes in human plasma predominantly exist as 20S proteasomes and that their activity is significantly reduced in patients with mild cognitive impairment (MCI) and chronic tinnitus, compared to those with tinnitus alone [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]. We also found a significant negative association between Aβ levels and circulating proteasome activity, which was not observed with other plasma enzymes.\\u003c/p\\u003e \\u003cp\\u003eThe ε4 allele of apolipoprotein E (APOE) is the strongest risk factors for late-onset AD [\\u003cspan additionalcitationids=\\\"CR12\\\" citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. APOE, present in lipoprotein particles in the human brain, plays critical roles in amyloid precursor protein processing, Aβ clearance, and tau phosphorylation [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. Among the three gene variants (APOE ε2, ε3, and ε4), the ε4 isoform increases AD risk by 2- to 3-fold with one ε4 allele and up to 12-fold with two alleles [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. While APOE ε4 appears critically implicated in Aβ and tau pathologies, the precise mechanism of how it contributes to AD risk and prognosis remains to be determined. We hypothesized that proteasomes in the circulatory system may dynamically respond to systemic stress caused by accumulated proteotoxic proteins, potentially serving as an adaptive response mechanism linked to neuropathological characteristics. In addition, APOE ε4 status strengthens the association between plasma proteasome activity and AD pathology indices. Our results indicate that circulating proteasome activity in APOE ε4 carriers reflects significant 1) Aβ and tau accumulation, 2) anatomical neurodegeneration, and 3) cognitive decline. Thus, proteasome activity may serve as a novel, noninvasive, and cost-effective biomarker for monitoring disease progression, thereby offering an earlier time window for AD prevention and therapeutic intervention.\\u003c/p\\u003e\"},{\"header\":\"Materials and Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eParticipants\\u003c/h2\\u003e \\u003cp\\u003eParticipants were enrolled in a prospective cohort study conducted at the memory disorder clinic within the Department of Neurology at Gachon University Gil Medical Center. Patients with cognitive impairment, including those with MCI or dementia, were recruited through this neurology-based clinic. Community-dwelling cognitive normal (CN) individuals were recruited as control participants from volunteers engaged in aging-related research. All participants underwent the same standardized clinical evaluation by a single board-certified neurologist (Y.N.), and each completed a detailed neuropsychological assessment administered by an experienced neuropsychologist to confirm the diagnosis.\\u003c/p\\u003e \\u003cp\\u003e We recruited a total of 180 participants composed of patients with MCI or dementia and CN individuals. They performed 3.0-Tesla MRI, [\\u003csup\\u003e18\\u003c/sup\\u003eF]flutemetamol (FLUTE) and [\\u003csup\\u003e18\\u003c/sup\\u003eF]MK-6240 (MK-6240) PET scans, APOE genotyping, comprehensive neuropsychological tests, and plasma collection for blood-based proteasome activity assessment. Among them, 15 individuals were excluded due to incomplete evaluation, 11 due to motion defects on PET imaging and 6 due to hemolyzed blood. The final cohorts consisted of 38 patients with AD dementia, 39 with MCI, 13 with other dementia (3 with subcortical vascular dementia, 1 with corticobasal syndrome, and 9 with amyloid-negative dementia), and 58 CN individuals.\\u003c/p\\u003e \\u003cp\\u003ePatients with AD dementia were diagnosed according to the framework criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. AD patients with a history of other neurological or psychiatric disorders were not recruited in the study. Patients with structural abnormalities on MRI, such as cerebral, cerebellar, or brainstem infarction, intracranial hemorrhage, hydrocephalus, severe white matter hyperintensities, white matter hyperintensities associated with radiation, traumatic brain injury, tumors, multiple sclerosis, and vasculitis, were excluded. Furthermore, patients with cognitive impairment due to metabolic or systemic causes were excluded after assessment with laboratory tests, which included complete blood count, thyroid function, syphilis serology, folate levels, vitamin B12, and metabolic profile.\\u003c/p\\u003e \\u003cp\\u003eParticipants were classified as MCI according to Petersen\\u0026rsquo;s criteria [\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e], objective cognitive decline in neuropsychological tests, indicated by a clinical dementia rating (CDR) score of 0.5, and their ability to independently perform activities of daily living at a sufficient level. CN participants were either healthy volunteers or individuals who did not exhibit objective cognitive decline, with mean z-scores within 1.5 standard deviations of age- and education-corrected norms on neuropsychological tests and a CDR score of 0.\\u003c/p\\u003e \\u003cp\\u003e Written informed consent was obtained from all participants and their guardians (for dementia patients). This study was approved by the Institutional Review Board (IRB # GBIRB2018-350) and registered at the Clinical Research Information Service of Korea (CRIS: KCT0005428).\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eNeuropsychological assessment\\u003c/h3\\u003e\\n\\u003cp\\u003eAll participants underwent cognitive function evaluations using the Mini-Mental State Examination (MMSE), CDR, and comprehensive neuropsychological tests, assessing attention, language, verbal and visual memory, visuospatial skills, and frontal/executive functioning. Detailed items of the comprehensive test battery have been described in the previous study [\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e]. For comprehensive neuropsychological test results, we used z-scores which were standardized for age and years of education. Details of the specific tests administered are provided in Supplementary Text 1.\\u003c/p\\u003e\\n\\u003ch3\\u003eImage acquisition and quantification\\u003c/h3\\u003e\\n\\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eMR imaging acquisition and segmentation\\u003c/h2\\u003e \\u003cp\\u003eMRI scans were performed using a Magnetom Skyra 3.0-Tesla MRI scanner (Siemens, Erlangen, Germany), equipped with a 32-channel Siemens matrix head coil. We acquired 3D T1 magnetization-prepared rapid gradient echo (T1-MPRAGE): repetition time\\u0026thinsp;=\\u0026thinsp;1,810 ms, echo time\\u0026thinsp;=\\u0026thinsp;2.91 ms, flip angle\\u0026thinsp;=\\u0026thinsp;9\\u0026deg;, pixel bandwidth\\u0026thinsp;=\\u0026thinsp;340 Hz/pixel, matrix size\\u0026thinsp;=\\u0026thinsp;256 \\u0026times; 256, field of view\\u0026thinsp;=\\u0026thinsp;250 mm, NEX\\u0026thinsp;=\\u0026thinsp;1, total acquisition time\\u0026thinsp;=\\u0026thinsp;3 min 37 s, voxel size\\u0026thinsp;=\\u0026thinsp;0.49 \\u0026times; 0.49 \\u0026times; 1.0 mm\\u003csup\\u003e3\\u003c/sup\\u003e, and fluid attenuated inversion recovery (FLAIR): repetition time\\u0026thinsp;=\\u0026thinsp;9,000 ms, echo time\\u0026thinsp;=\\u0026thinsp;122 ms, flip angle\\u0026thinsp;=\\u0026thinsp;150\\u0026deg;, pixel bandwidth\\u0026thinsp;=\\u0026thinsp;287 Hz/pixel, matrix size\\u0026thinsp;=\\u0026thinsp;256 \\u0026times; 224, field of view\\u0026thinsp;=\\u0026thinsp;256 mm, NEX\\u0026thinsp;=\\u0026thinsp;1, total acquisition time\\u0026thinsp;=\\u0026thinsp;2 min 44 s, voxel size\\u0026thinsp;=\\u0026thinsp;0.5 \\u0026times; 0.5 \\u0026times; 2.0 mm3. 3D susceptibility weighted imaging (SWI) was conducted with TR\\u0026thinsp;=\\u0026thinsp;40 ms and dual echo times of 13.70 ms and 30.50 ms. The flip angle was 15\\u0026deg;, bandwidth was 120 Hz/pixel, matrix\\u0026thinsp;=\\u0026thinsp;230 \\u0026times; 202, FOV\\u0026thinsp;=\\u0026thinsp;230 mm, and NEX\\u0026thinsp;=\\u0026thinsp;1. The scan duration was about 109 sec, with voxel dimensions of 0.8 \\u0026times; 0.8 \\u0026times; 2.0 mm\\u0026sup3;.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eMR imaging quantification\\u003c/h3\\u003e\\n\\u003cp\\u003eStructural MRI processing and volumetric measurements were performed using FreeSurfer 6.0 (\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e\\u003ca href=\\\"http://www.surfer.nmr.mgh.harvard.edu\\\" target=\\\"_blank\\\"\\u003ewww.surfer.nmr.mgh.harvard.edu\\u003c/a\\u003e\\u003c/span\\u003e\\u003cspan address=\\\"http://www.surfer.nmr.mgh.harvard.edu\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e). The standard recon-all processing pipeline was applied to 3D-T1 MPRAGE images for cortical surface reconstruction and volumetric segmentation. Mean cortical thickness was calculated by averaging vertex-wise cortical thickness across bilateral hemispheres. Intracranial volume (ICV) and hippocampal volume (HV) were automatically derived using the aseg (automated segmentation) output. All segmentations were visually inspected for accuracy and manual corrections were performed, when necessary, in accordance with FreeSurfer guidelines [\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. Assessment of white matter hyperintensity volume, microbleeds and lacunes are described in the Supplementary Text 2.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePET imaging acquisition\\u003c/h2\\u003e \\u003cp\\u003eAll participants acquired FLUTE and MK-6240 PET scans using a Siemens Biograph 6 Truepoint PET/computed tomography (CT) scanner (Siemens, Knoxville, TN, USA) with a list-mode emission acquisition. MK-6240 scans were acquired from 70 to 90 min after the intravenous injection of 185 MBq of [\\u003csup\\u003e18\\u003c/sup\\u003eF]MK-6240, which was prepared as described previously [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e] with a modified method at the cyclotron facility, Gachon University. FLUTE scans were acquired from 90 to 110 min after the intravenous injection of 185 MBq of [\\u003csup\\u003e18\\u003c/sup\\u003eF] FLUTE, which was purchased from Carecamp Inc. We used a low-dose CT scan for attenuation correction. PET data was reconstructed onto a 256 \\u0026times; 256 \\u0026times; 109 matrix with a voxel size of 1.3 \\u0026times; 1.3 \\u0026times; 1.5 mm\\u003csup\\u003e3\\u003c/sup\\u003e using a 2D ordered subset expectation maximization algorithm with 8 iterations and 16 subsets.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003ePET quantification\\u003c/h3\\u003e\\n\\u003cp\\u003eIndividual MK-6240 and FLUTE PET images were co-registered onto individual T1 MPRAGE images using FreeSurfer. We calculated regional mean values of PET images after region-based partial volume correction using PETSurfer and acquired weighted-average values of pre-defined ROIs [\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. For amyloid PET, the cortical retention of FLUTE was quantified in AD-associated regions, including the prefrontal, superior parietal, lateral temporal, inferior parietal, occipital, anterior cingulate, mesial temporal, precuneus, and posterior cingulate cortices. FLUTE SUVR was evaluated using the pons as a reference region [\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. FLUTE images were also visually evaluated for amyloid positivity based on a standardized visual rating protocol [\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eTau burden was quantified using MK-6240 SUVR. ROIs for MK-6240 included global MK-6240 (frontal pole, pars orbitalis, lateral orbitofrontal, pars triangularis, pars opercularis, rostral middle frontal, superior frontal, caudal middle frontal, medial orbitofrontal, superior parietal, inferior parietal, supramarginal, precuneus, cuneus, pericalcarine, lateral occipital, banks of superior temporal, inferior temporal, middle temporal, superior temporal, hippocampus, amygdala, parahippocampal, entorhinal, nucleus accumbens, caudal anterior cingulate, rostral anterior cingulate and posterior cingulate), Braak I/II (entorhinal and hippocampus regions), Braak III/IV (parahippocampal, fusiform, lingual, amygdala, inferior temporal, middle temporal, temporal pole, thalamus, caudal, rostral, isthmus, posterior cingulate and insula regions) and Braak V/VI (frontal, parietal, occipital, transverse, superior temporal, precuneus, banks of superior temporal, nucleus accumbens, caudate nucleus, putamen, precentral, postcentral, paracentral, cuneus and pericalcarine regions) [\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e]. Regional standardized uptake value ratios (SUVRs) of MK-6240 were computed using cerebellar gray matter as a reference region [\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e].\\u003c/p\\u003e\\n\\u003ch3\\u003ePlasma preparation and processing\\u003c/h3\\u003e\\n\\u003cp\\u003eWhole blood was collected in two EDTA vacuum tubes from study participants between 9:00 and 10:00 AM after a 6-hour fasting period. Blood was processed independently as technical duplicates. Plasma was isolated by centrifugation at 3,000 rpm using a benchtop centrifuge for 15 min, aliquoted into 1.5 mL tubes in 0.5\\u0026ndash;1.0 mL volumes and stored at \\u0026minus;\\u0026thinsp;80\\u003csup\\u003e◦\\u003c/sup\\u003eC until analyzed. Hemolytic samples were identified and discarded through visual inspection. Previous studies have confirmed that proteasome activity in plasma remains comparable across multiple freeze-thaw cycles [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eProteasome activity measurement\\u003c/h2\\u003e \\u003cp\\u003eCirculating proteasome activity in plasma was assessed using a standardized method employing a fluorogenic reporter substrate, succinyl-Leu-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin (suc-LLVY-AMC; Bachem, Bubendorf, Switzerland.) [\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]. This peptide is cleaved by the chymotrypsin-like activity of the 20S catalytic proteasome and the fluorescence intensity from free AMC is considered as a representative measure of overall proteasome activity [\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e]. Briefly, 20 \\u0026micro;L of human plasma was combined with 250 \\u0026micro;M of suc-LLVY-AMC in an assay buffer (50 mM Tris-HCl [pH 7.5], 1 mg/mL BSA, 1 mM EDTA, 1 mM fresh ATP, and 1 mM fresh DTT) in a black 96-well plate. The hydrolysis of the fluorogenic peptides was monitored every three min at 380/460 nm (excitation/emission wavelength) at 30\\u0026deg;C. Each sample was assayed in triplicate. All fluorescence intensities from plasma samples were normalized to those obtained in the presence of the proteasome inhibitor MG132 (10 \\u0026micro;M), and the resulting circulating proteasome activity was expressed as relative fluorescence units (RFU).\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical Analysis\\u003c/h2\\u003e \\u003cp\\u003eTo analyze the demographics and clinical characteristics of the study population, continuous variables were assessed through group comparisons using the independent samples t-test. For nominal variables, the chi-square test or Fisher\\u0026rsquo;s exact test was applied. After dividing the study participants as APOE ε4 carriers (having at least one APOE e4 allele) and noncarriers, we assessed associations of clinical variables (MMSE, CDR-SOB, mean cortical thickness, hippocampal volume, cortical FLUTE retention, global MK-6240 retention, and MK-6240 SUVR based on Braak stages) with proteasome activity using multivariable linear regression models in each group. In the linear regression models, age, sex, and years of education were included as covariates. The difference in the associations between APOE e4 carriers and noncarriers was tested by the method described elsewhere and expressed as \\u003cem\\u003ep\\u003c/em\\u003e for intraction [\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eTo examine whether amyloid or tau burden (\\u0026lsquo;M\\u0026rsquo;) mediated the associations between proteasome activity (\\u0026lsquo;X\\u0026rsquo;) and global cognition or hippocampal volume (\\u0026lsquo;Y\\u0026rsquo;), we performed mediation analyses. Indirect effects were quantified through a series of regression models evaluating: (1) the association between X and Y, (2) the association between X and M, and (3) the joint influence of X and M on Y. After controlling for age, sex, and years of education, we derived the estimates for the indirect, direct, and total effects (direct plus indirect), as well as the percentage of the total effect explained by mediation (indirect effect/total effect \\u0026times; 100). Confidence intervals for the beta coefficients were obtained using non-parametric bootstrapping with 1,000 resamples. All mediation procedures were implemented in R (version 3.4.1, R Foundation) using the \\u0026ldquo;mediation\\u0026rdquo; package [\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eAll statistical analyses were conducted using PASW Statistics 19 (SPSS Inc, Chicago, IL, USA) with a significance at p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 (two-way).\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec14\\\"\\u003e\\n \\u003ch2\\u003eDemographics and clinical characteristics of study population\\u003c/h2\\u003e\\n \\u003cp\\u003eThe demographics and clinical characteristics of the study population are shown in Table\\u0026nbsp;1. There was no significant difference in age, sex, and years of education. In contrast, APOE \\u0026epsilon;4 carriers and noncarrier groups showed clear statistical difference in clinical diagnoses (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.002). The APOE \\u0026epsilon;4 carrier group had a higher number of AD dementia patients, while the noncarrier group included a higher proportion of CN individuals. In the APOE \\u0026epsilon;4 carrier group, the majority of participants were \\u0026epsilon;3/\\u0026epsilon;4 (n\\u0026thinsp;=\\u0026thinsp;39, 70.9%), followed by \\u0026epsilon;4/\\u0026epsilon;4 (n\\u0026thinsp;=\\u0026thinsp;13, 23.6%), and \\u0026epsilon;2/\\u0026epsilon;4 (n\\u0026thinsp;=\\u0026thinsp;3. 5.5%). By comparison, the APOE \\u0026epsilon;4 noncarrier group mainly consisted of \\u0026epsilon;3/\\u0026epsilon;3 individuals (n\\u0026thinsp;=\\u0026thinsp;76, 81.7%), with a smaller proportion of \\u0026epsilon;2/\\u0026epsilon;3 (n\\u0026thinsp;=\\u0026thinsp;17, 18.3%).\\u003c/p\\u003e\\u0026nbsp;\\u003ctable id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e\\n \\u003ccaption language=\\\"En\\\"\\u003e\\n \\u003cdiv\\u003eTable 1\\u003c/div\\u003e\\n \\u003cdiv\\u003e\\n \\u003cp\\u003eDemographics and clinical characteristics of the study subjects\\u003c/p\\u003e\\n \\u003c/div\\u003e\\n \\u003c/caption\\u003e\\n \\u003cthead\\u003e\\n \\u003ctr\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003eVariables\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\"\\u003e\\n \\u003cp\\u003eAll participants\\u003c/p\\u003e\\n \\u003cp\\u003e(N\\u0026thinsp;=\\u0026thinsp;148)\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\"\\u003e\\n \\u003cp\\u003eAPOE \\u0026epsilon;4 carrier\\u003c/p\\u003e\\n \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;55)\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\"\\u003e\\n \\u003cp\\u003eAPOE \\u0026epsilon;4 noncarrier\\u003c/p\\u003e\\n \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;93)\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003ep\\u003c/em\\u003e value\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/thead\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCN/MCI/ADD/OD (%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e58/39/38/13\\u003c/p\\u003e\\n \\u003cp\\u003e(39.2/26.4/25.7/8.8)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e15/18/21/1\\u003c/p\\u003e\\n \\u003cp\\u003e(27.3/32.7/38.2/1.8)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e43/21/17/12\\u003c/p\\u003e\\n \\u003cp\\u003e(46.2/22.6/18.3/12.9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.002\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAge\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e70.80\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;8.01\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e70.47\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;7.95\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e70.99\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;8.09\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.706\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eSex (Female, n [%])\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e97(65.5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e35(63.6)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e62(66.7)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.724\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eEducation(year)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e9.09\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.25\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e9.58\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.02\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e8.81\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.37\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.284\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAPOE genotype\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;\\u0026thinsp;.001\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" rowspan=\\\"5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026epsilon;2/\\u0026epsilon;3\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e17 (11.5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e17 (18.3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" rowspan=\\\"5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026epsilon;3/\\u0026epsilon;3\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e76 (51.4)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e76 (81.7)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026epsilon;2/\\u0026epsilon;4\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e3 (2.0)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e3 (5.5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026epsilon;3/\\u0026epsilon;4\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e39 (26.4)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e39 (70.9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026epsilon;4/\\u0026epsilon;4\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e13 (8.8)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e13 (23.6)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMMSE\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e24.53\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;5.09\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e24.18\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.52\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e24.73\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;5.41\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.527\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCDR-SOB\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e2.53\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.87\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e2.75\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.46\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e2.39\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;3.09\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.460\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHypertension (%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e67(45.3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e23(41.8)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e44(47.3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.609\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eDiabetes mellitus (%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e44(29.7)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e13(23.6)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e31(33.3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.265\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eDyslipidemia (%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e62(41.9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e27(49.1)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e35(37.6)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.227\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCoronary artery disease (%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e8(5.4)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e6(10.9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e2(2.2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.052\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHistory of stroke (%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e2(1.4)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0(0.0)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e2(2.2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.530\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAmyloid Positivity (%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e64(43.2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e38(69.1)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e26(28.3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;\\u0026thinsp;.001\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCortical FLUTE SUVR\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.5955\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.27\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.7136\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.24\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.5230\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.27\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;\\u0026thinsp;.001\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eGlobal MK-6240 SUVR\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e1.4010\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.93\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e1.6216\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.95\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e1.2759\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.90\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.034\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMean cortical thickness (mm)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e2.35\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.18\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e2.37\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e2.34\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.19\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.346\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eICV (L)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e1.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.18\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e1.38\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.17\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e1.44\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.19\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.052\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHippocampal volume (mL)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e3.25\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.48\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e3.10\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.54\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e3.35\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.43\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.004*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eWMHV (mL)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e10.07\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;11.60\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e9.28\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;12.28\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e10.54\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;11.21\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.523\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eProteasome activity (RFU/1,000)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e1.215\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.56\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e1.239\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.56\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e1.201\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.56\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.690\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"6\\\"\\u003e\\n \\u003cp\\u003eValues are presented as mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;standard deviation for continuous variables and as number (%) for nominal variables. Group comparisons were performed between the APOE \\u0026epsilon;4 carrier and noncarrier groups using an independent samples \\u003cem\\u003et\\u003c/em\\u003e-test for continuous variables and chi-square test for categorical variables. All group comparisons were considered significant when p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05.*The assumption of equal variances was not met (Levene\\u0026apos;s test), so the results of Welch\\u0026apos;s \\u003cem\\u003et\\u003c/em\\u003e-test were reported. \\u0026dagger;Mean group differences were assessed by Fisher\\u0026rsquo;s exact test.\\u003c/p\\u003e\\n \\u003cp\\u003eAbbreviations: CN, cognitive normal; MCI, mild cognitive impairment; ADD, Alzheimer\\u0026rsquo;s disease dementia; OD, other dementia; MMSE, Mini-Mental State Examination; CDR-SOB, Clinical Dementia Rating-Sum Of Boxes; FLUTE, flutemetamol; SUVR, standardized uptake value ratio; ICV, intracranial volume; WMHW, white matter hyperintensity volume; RFU, Relative fluorescence units.\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n \\u003c/table\\u003e\\n \\u003cp\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003eMMSE and CDR-SOB scores did not significantly differ between APOE \\u0026epsilon;4 carrier and noncarriers. In addition, there were no significant differences in the prevalence of comorbidities, such as hypertension, diabetes, dyslipidemia, coronary artery disease, and history of stroke, between the two groups. Proteasome activity in plasma did not also differ between the groups. However, we found that hippocampal volume was significantly smaller in APOE \\u0026epsilon;4 carriers. Both cortical FLUTE retention and global MK-6240 PET retention were greater in APOE \\u0026epsilon;4 carriers than in noncarriers.\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAssociations between circulating proteasome activity and amyloid, tau, and neurodegeneration in APOE \\u0026epsilon;4 carriers and noncarriers\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003eAmong APOE \\u0026epsilon;4 carriers, higher proteasome activity was significantly associated with lower cortical amyloid burden (\\u0026beta; = -0.142, SE\\u0026thinsp;=\\u0026thinsp;0.052, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.009) and lower global tau burden measured by MK-6240 SUVR (\\u0026beta; = -0.447, SE\\u0026thinsp;=\\u0026thinsp;0.219, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.047) (Figs. 1A and 1B, Table 2). Regional tau deposition in Braak I/II and Braak III/IV areas also showed significant negative associations (\\u0026beta; = \\u0026minus;\\u0026thinsp;0.460, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.033; \\u0026beta; = \\u0026minus;\\u0026thinsp;0.454, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.033, respectively) (Fig. 1C and 1D). In contrast, none of these associations reached significance in APOE \\u0026epsilon;4 noncarriers.\\u003c/p\\u003e\\n \\u003cp\\u003eProteasome activity was further associated with neurodegeneration in APOE \\u0026epsilon;4 carriers, as reflected by a strong positive association with hippocampal volume normalized to intracranial volume (HV/ICV; \\u0026beta;\\u0026thinsp;=\\u0026thinsp;0.294, SE\\u0026thinsp;=\\u0026thinsp;0.083, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.001) (Fig. 1E), whereas no such association was observed in noncarriers (\\u0026beta; =-0.123, SE\\u0026thinsp;=\\u0026thinsp;0.078, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.119). The interaction term for APOE \\u0026epsilon;4 status was highly significant for HV/ICV (\\u003cem\\u003ep\\u003c/em\\u003e for interaction\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001), indicating that the effect of proteasome activity on hippocampal atrophy differed markedly by genetic risk.\\u003c/p\\u003e\\n \\u003cp\\u003eInteraction effects for tau burden were also observed, with trend-level significance in Braak I/II and Braak III/IV regions (\\u003cem\\u003ep\\u003c/em\\u003e for interaction\\u0026thinsp;=\\u0026thinsp;0.060 and 0.072, respectively), suggesting that the association between proteasome activity and tau deposition is stronger in APOE \\u0026epsilon;4 carriers than in noncarriers.\\u003c/p\\u003e\\n \\u003cp\\u003eWhen APOE \\u0026epsilon;4 carriers and noncarriers were analyzed together, no significant associations were observed between proteasome activity and amyloid/tau burden or structural brain atrophy (Supplementary Table\\u0026nbsp;2).\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec15\\\"\\u003e\\n \\u003ch2\\u003eAssociations between circulating proteasome activity and cognitive functions in APOE \\u0026epsilon;4 carriers\\u003c/h2\\u003e\\n \\u003cp\\u003eIn APOE \\u0026epsilon;4 carriers, global cognitive functions were significantly associated with circulating proteasome activity (Table 3). MMSE scores showed a positive association (\\u0026beta;\\u0026thinsp;=\\u0026thinsp;2.375, \\u003cem\\u003ep\\u0026thinsp;=\\u003c/em\\u003e\\u0026thinsp;0.026), and CDR-SOB scores were inversely associated (\\u0026beta; = -1.604, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.005) with proteasome activity, but not in APOE \\u0026epsilon;4 noncarriers (Figs.\\u0026nbsp;2A and 2B, Table\\u0026nbsp;3). These group differences were statistically significant (\\u003cem\\u003ep\\u003c/em\\u003e for interaction\\u0026thinsp;=\\u0026thinsp;0.014 for MMSE, \\u003cem\\u003ep\\u003c/em\\u003e for interaction\\u0026thinsp;=\\u0026thinsp;0.005 for CDR-SOB). In addition, memory functions were significantly correlated with proteasome activity only in APOE \\u0026epsilon;4 carriers. Verbal memory, evaluated with the Seoul verbal learning test (SVLT) delayed recall, was positively correlated (\\u0026beta;\\u0026thinsp;=\\u0026thinsp;0.749, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.023) (Fig. 2C). Similarly, visual memory, assessed with Rey complex figure test (RCFT) recall, showed significant correlations for both immediate recall (\\u0026beta;\\u0026thinsp;=\\u0026thinsp;0.553, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.023) and delayed recall (\\u0026beta;\\u0026thinsp;=\\u0026thinsp;0.514, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.044) with circulating proteasome activity (Fig. 2D). No significant correlations between proteasome activity and cognitive functions were observed in APOE \\u0026epsilon;4 noncarriers. When both carriers and noncarriers were analyzed together, no significant association was observed between proteasome activity and cognitive functions (Supplementary Table 3).\\u003c/p\\u003e\\u0026nbsp;\\u003ctable id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e\\n \\u003ccaption language=\\\"En\\\"\\u003e\\n \\u003cdiv\\u003eTable 3\\u003c/div\\u003e\\n \\u003cdiv\\u003e\\n \\u003cp\\u003eAssociation of cognitive functions and proteasome activity\\u003c/p\\u003e\\n \\u003c/div\\u003e\\n \\u003c/caption\\u003e\\n \\u003cthead\\u003e\\n \\u003ctr\\u003e\\n \\u003cth align=\\\"left\\\"\\u003e\\n \\u003cp\\u003eVariables\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eAPOE \\u0026epsilon;4 carrier\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eAPOE \\u0026epsilon;4 noncarrier\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/thead\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u0026beta; (SE)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003ep\\u003c/em\\u003e value\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u0026beta; (SE)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003ep\\u003c/em\\u003e value\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003ep for interaction\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMMSE\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e2.375(1.034)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.026\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e-1.162(0.999)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.248\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.014\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCDR-SOB\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e-1.604(0.544)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.005\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.618(0.578)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.288\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.005\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eDigit span test: forward\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e-0.044(0.207)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.833\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.161(0.201)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.425\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.477\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eDigit span test: backward\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.097(0.219)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.659\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e-0.031(0.205)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.882\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.670\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eBoston Naming Test\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.637(0.351)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.075\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e-0.167(0.343)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.628\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.101\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eRey Complex Figure Test-copy\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.573(0.635)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.371\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e-0.089(0.651)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.891\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.467\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eSVLT immediate recall\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.590(0.311)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.063\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.217(0.302)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.474\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.391\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eSVLT delayed recall\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.749(0.321)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.023\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.143(0.301)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.637\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.168\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eSVLT recognition\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.579(0.483)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.236\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.191(0.308)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.538\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.497\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eRCFT immediate recall\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.553(0.237)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.023\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e-0.052(0.249)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.837\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.079\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eRCFT delayed recall\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.514(0.249)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.044\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.003(0.255)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.991\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.151\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eRCFT recognition\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.589(0.343)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.091\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.027(0.276)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.924\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.201\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCOWAT animal\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.412(0.250)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.105\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.048(0.232)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.835\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.286\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCOWAT supermarket\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.413(0.297)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.170\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e-0.133(0.231)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.567\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.147\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCOWAT phonemic total\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.175(0.267)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.516\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e-0.021(0.212)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.921\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.566\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eColor-Word Stroop Test\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.401(0.310)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.202\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.215(0.269)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.428\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.651\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eDigit Symbol Coding\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.608(0.326)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.068\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.194(0.311)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.533\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.358\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTMT-A\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.249(0.246)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.318\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e-0.284(1.656)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.864\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.750\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTMT-B\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e1.389(0.878)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.119\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e-0.507(0.957)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.598\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003e0.144\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n \\u003ctfoot\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"6\\\"\\u003eValues were expressed as beta coefficients and standard errors, from multivariable linear regression models adjusted for age, sex, and years of education.\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"6\\\"\\u003e\\u003cem\\u003eAbbreviations\\u003c/em\\u003e. MMSE, Mini-Mental State Examination; CDR-SOB, Clinical Dementia Rating-Sum of Boxes; SVLT, Seoul verbal language test; RCFT, Rey complex figure test; COWAT, Controlled Oral word association test; TMT, Trail making test\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tfoot\\u003e\\n \\u003c/table\\u003e\\n \\u003cp\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMediation effects of amyloid and tau burden on the associations between proteasome activity and cognitive function and hippocampal volume in APOE \\u0026epsilon;4 carriers\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003eIn the mediation analysis, the associations of proteasome activity with hippocampal volume and cognitive function in APOE4 carriers were differentially mediated by amyloid and tau burden (Fig.\\u0026nbsp;3, Supplementary Table\\u0026nbsp;4). Cortical FLUTE SUVR significantly mediated the relationship between proteasome activity and hippocampal volume, showing a significant indirect effect (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.02) and accounting for approximately 29.3% of the total effect.\\u003c/p\\u003e\\n \\u003cp\\u003eRegional MK-6240 corresponding to Braak I/II demonstrated significant indirect effects for the associations of proteasome activity with hippocampal volume, MMSE, and CDR-SOB, indicating that early-stage tau burden mediates both neurodegeneration and global cognitive impairment. The proportion mediated ranged from 23% to 28% across outcomes.\\u003c/p\\u003e\\n \\u003cp\\u003eIn contrast, regional MK-6240 corresponding to Braak III/IV significantly mediated the associations of proteasome activity with MMSE and CDR-SOB, whereas the indirect effect for hippocampal volume was not significant. Mediation proportions for these cognitive measures ranged from 30% to 41%.\\u003c/p\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn this study, we found that plasma proteasome activity is significantly associated with AD\\u0026ndash;related biomarkers in individuals carrying the APOE ε4 allele, but not in noncarriers. Specifically, higher proteasome activity in APOE ε4 carriers was linked to lower amyloid and tau burden, larger hippocampal volume, and better cognitive performance (e.g., MMSE, CDR-SOB, and memory function). In sharp contrast, these correlations were absent or negligible in APOE ε4 noncarriers, suggesting that peripheral proteasome activity might reflect underlying neuropathology and cognitive decline only in individuals genetically predisposed to AD. Therefore, changes in proteasome activity may function as a genotype-specific biomarker that is potentially manifested from AD-linked proteostasis dysfunction in neurons. Mediation analysis showed that in APOE4 carriers, amyloid burden primarily mediates proteasome-related hippocampal atrophy, whereas tau burden, particularly in Braak I/II and III/IV regions, mediates the associations between proteasome dysfunction and cognitive decline.\\u003c/p\\u003e \\u003cp\\u003eThe monomeric component of proteotoxic proteins, such as Aβ and tau, major hallmarks of AD, have been identified as direct substrates for 20S proteasomes, degraded in a Ub- and ATP-independent manner [\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e]. These findings might be in line with clinical studies where 20S activity and levels in plasma were altered in diverse disease states [\\u003cspan additionalcitationids=\\\"CR6 CR7 CR8 CR9\\\" citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e]. Proteasome impairment in AD have been attributed to the degradation-resistant proteins, such as oligomeric Aβ and tau, that may clog the proteasome and initiate a vicious cycle producing excess aggregation-prone proteins [\\u003cspan additionalcitationids=\\\"CR39\\\" citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e]. More recently, the 20S proteasome was reported to be packaged into extracellular vesicles, delivered to recipient cells, and contributed to the degradation of excess tau proteins [\\u003cspan citationid=\\\"CR41\\\" class=\\\"CitationRef\\\"\\u003e41\\u003c/span\\u003e]. Overall, our finding that circulating proteasome activity is inversely associated with amyloid and tau PET signals in ε4 carriers aligns with these mechanistic models of UPS dysfunction in AD.\\u003c/p\\u003e \\u003cp\\u003eThe APOE genotype appears to modulate this activity-pathology relationship. APOE ε4 is known to enhance amyloid-related tau pathology a neuronal damage [\\u003cspan citationid=\\\"CR42\\\" class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e]. Recent quantitative proteomic analysis using humanized APOE ε4 mice also demonstrated inadequate proteasome and autophagy function, thus indicating extensively disrupted proteostasis the mouse brain [\\u003cspan citationid=\\\"CR43\\\" class=\\\"CitationRef\\\"\\u003e43\\u003c/span\\u003e]. Our human data parallel these findings, suggesting that ε4 impairs UPS-mediated clearance of pathological proteins, unlike ε2 or ε3 variants. This may explain why proteasome function correlates with AD pathology only in APOE ε4 carriers. Along with this notion, it seems plausible that proteasome inactivation is a central feature of neurodegeneration and that proteasome augmentation reduces related cognitive deficits [\\u003cspan citationid=\\\"CR44\\\" class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e]. The pro-inflammatory effect of APOE ε4 in the brain may further exacerbate dysregulation of proteasome pathways, although this remains to be fully elucidated [\\u003cspan citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eOur study demonstrates that circulating proteasome activity is selectively associated with pathologic changes at the early stages of AD. Significant correlations with tau burden were confined to Braak I/II and III/IV regions, but absent in Braak V/VI, suggesting that proteasome dysfunction is preferentially linked to early tau deposition. This aligns with the Braak model, where initial tau accumulation in medial temporal regions is most closely tied to episodic memory impairment, whereas widespread neocortical tau (Braak V/VI) reflects more advanced disease. The lack of association at Braak V/VI may indicate that once tau pathology becomes widespread, systemic proteasome activity no longer tracks disease severity, possibly due to saturation of proteostasis impairment.\\u003c/p\\u003e \\u003cp\\u003eSimilarly, proteasome activity was positively correlated with hippocampal volume, but not with mean cortical thickness. Since hippocampal atrophy emerges in prodromal stages of AD, whereas diffuse cortical thinning typically manifests later, these results suggest that plasma proteasome activity reflects early medial temporal neurodegeneration rather than global cortical atrophy. The concordance of these findings with tau PET results supports the hypothesis that systemic proteasome dysfunction mirrors early, region-specific AD changes.\\u003c/p\\u003e \\u003cp\\u003eIn terms of cognition, proteasome activity was associated with MMSE, CDR-SOB and memory functions, but not with attention, language, visuospatial or executive functions. This selective relationship is consistent with the amnestic syndrome of early AD, in which memory deficits dominate before other domains decline. Taken together, our findings highlight that systemic proteasome alterations may preferentially accompany the initial cognitive and structural manifestations of AD in APOE ε4 carriers.\\u003c/p\\u003e \\u003cp\\u003eMediation analyses further clarified these genotype-specific relationships. In APOE ε4 carriers, amyloid burden partially mediated the association between proteasome activity and hippocampal volume, suggesting that reduced amyloid accumulation may be one pathway through which preserved proteasome function relates to medial temporal structural integrity. Moreover, tau burden played a critical and region-specific mediating role: Braak I/II MK-6240 SUVR significantly mediated the associations between proteasome activity and hippocampal volume, MMSE, and CDR-SOB, indicating that early-stage tau deposition is a key intermediary linking proteasome dysfunction to both neurodegeneration and global cognition. In contrast, Braak III/IV MK-6240 SUVR mediated only the relationships with MMSE and CDR-SOB, but not hippocampal volume, suggesting that limbic-stage tau primarily contributes to cognitive impairment rather than structural atrophy in this group. Together, these findings suggest that both amyloid and early tau burden lie on the pathway between systemic proteasome dysfunction and AD-related clinical outcomes, reinforcing the centrality of proteostasis impairment in APOE ε4 carriers.\\u003c/p\\u003e \\u003cp\\u003eThis study\\u0026rsquo;s strengths lie in its rigorously characterized cohort with multimodal imaging and detailed cognitive function data, genotype stratification, and quantitative measurement of plasma proteasome activity. These design features enabled us to detect genotype-specific associations that would have been missed in pooled analyses. Clinically, plasma proteasome activity could offer a noninvasive readout of proteostatic stress in AD in APOE ε4 carriers. Previously, we have reported that proteasome activity is lower in MCI patients and that proteasome activity negatively correlates with plasma Aβ levels [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]. Current findings extend this by showing that in ε4 carriers, proteasome activity not only reflects amyloid and tau burdens but also predicts cognitive performance. This suggests that systemic decline in proteostasis may mirror synaptic dysfunction in the brain, particularly in neurons predisposed by APOE ε4-related pathologic stress. A blood-based enzymatic assay would be far more accessible and cost-effective than PET scans or CSF analyses. Thus, combining plasma proteasome measurements with APOE genotyping could help identify high-risk individuals in prodromal stages more efficiently.\\u003c/p\\u003e \\u003cp\\u003eLimitations include the cross-sectional data, which preclude causal inference; the modest sample size, particularly of APOE ε4 carriers; and the single-center, ethnically homogeneous cohort, which may limit generalizability. While our cohort was powered to detect significant effects in ε4 carriers, replication in larger and more diverse populations is essential. In addition, we do not yet know the sequence of events at present; a longitudinal study will determine whether proteasome decline drives pathology or results from it. The origin of plasma proteasomes also remains unclear. Therefore, in a follow-up work, it would be interesting to design \\u003cem\\u003ein vivo\\u003c/em\\u003e experiments to address these questions in AD model mice.\\u003c/p\\u003e \\u003cp\\u003eIn summary, our study reveals an APOE ε4-specific correlation between circulating proteasome activity and AD-related features, which may indicate impaired proteostasis in AD. Plasma proteasome activity therefore emerges as a promising, noninvasive biomarker for genotype-specific AD diagnosis and prognosis. Our data also underscores the therapeutic potential of proteasome-activating strategies in neurodegeneration [\\u003cspan citationid=\\\"CR46\\\" class=\\\"CitationRef\\\"\\u003e46\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR47\\\" class=\\\"CitationRef\\\"\\u003e47\\u003c/span\\u003e].\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eA\\u0026beta;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Amyloid beta\\u003c/p\\u003e\\n\\u003cp\\u003eAD \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; Alzheimer\\u0026rsquo;s Disease\\u003c/p\\u003e\\n\\u003cp\\u003eAPOE\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Apolipoprotein E\\u003c/p\\u003e\\n\\u003cp\\u003eATP\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Adenosine Triphosphate\\u003c/p\\u003e\\n\\u003cp\\u003eCDR-SOB \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Clinical Dementia Rating Sum of Box\\u003c/p\\u003e\\n\\u003cp\\u003eCN\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Cognitively Normal\\u003c/p\\u003e\\n\\u003cp\\u003eCT\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Computed Tomography\\u003c/p\\u003e\\n\\u003cp\\u003eFLAIR\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Fluid Attenuated Inversion Recovery\\u003c/p\\u003e\\n\\u003cp\\u003eFLUTE\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Flutemetamol\\u003c/p\\u003e\\n\\u003cp\\u003eMCI\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Mild Cognitive Impairment\\u003c/p\\u003e\\n\\u003cp\\u003eMMSE \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp;\\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Mini-Mental State Examination\\u003c/p\\u003e\\n\\u003cp\\u003eMPRAGE\\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; Magnetization-Prepared Rapid Gradient Echo\\u003c/p\\u003e\\n\\u003cp\\u003eMRI\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Magnetic Resonance Imaging\\u003c/p\\u003e\\n\\u003cp\\u003eNEX\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Number of Excitation\\u003c/p\\u003e\\n\\u003cp\\u003ePET \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Positron Emission Tomography\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003ePQC\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Protein Quality Control\\u003c/p\\u003e\\n\\u003cp\\u003eROI\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Region of Interest\\u003c/p\\u003e\\n\\u003cp\\u003eSUVR\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Standardized Uptake Value Ratio\\u003c/p\\u003e\\n\\u003cp\\u003eSVLT \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp;\\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Seoul Verbal Learning Test\\u003c/p\\u003e\\n\\u003cp\\u003eRCFT\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; Rey Complex Figure Test\\u003c/p\\u003e\\n\\u003cp\\u003eUb\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; Ubiquitin\\u003c/p\\u003e\\n\\u003cp\\u003eUPS\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; Ubiquitin Proteasome System\\u003c/p\\u003e\\n\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWritten informed consent was obtained from all participants and their guardians (in case of dementia patients). This study was approved by the Institutional Review Board (IRB # GBIRB2018-350) and was registered at the Clinical Research Information Service of Korea (CRIS: KCT0005428).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable. All figures and tables included in this manuscript have been carefully reviewed. This manuscript does not contain any contents that dispose of any direct or indirect identifiers. Datasets have been fully anonymized and no identifiable personal information is presented.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll original data from this manuscript are available from the corresponding author upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare no conflict of interest.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis work was supported by grant of the Korea Healthcare Technology R\\u0026amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health \\u0026amp; Welfare, Republic of Korea (grant No: HI14C1135 to Y.N.), grants from the National Research Foundation (NRF) of Korea (RS-2021-NR059245 and RS-2023-00261784 to M.J.L..) and Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health \\u0026amp; Welfare and Ministry of Science and ICT, Republic of Korea (RS-2024-00334574 to Y.N. and RS-2024-00332875 to M.J.L), and Gachon University Gil Medical Center (FRD2025-01 to Y.N.).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eB.G.K.: Investigation, Writing \\u0026ndash; original draft. H.E.S.: Data curation, investigation. Y.Y.: Investigation, Methodology. D.K.: Data curation, investigation. J.M.K.: Investigation. J.C.: Formal analysis, investigation, methodology. S.Y.L.: Investigation, Methodology. Y.J.L.: Data curation, investigation. K.H.P.: Investigation. M.J.L.: Methodology, Writing \\u0026ndash; review, Supervision, Funding acquisition. Y.N.: Conceptualization, Methodology, Writing \\u0026ndash; review \\u0026amp; editing, Supervision, Funding acquisition. All authors have given approval to the final version of the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis work was supported by grant of the Korea Healthcare Technology R\\u0026amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health \\u0026amp; Welfare, Republic of Korea (grant No: HI14C1135 to Y.N.), grants from the National Research Foundation (NRF) of Korea (RS-2021-NR059245 and RS-2023-00261784 to M.J.L..) and Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health \\u0026amp; Welfare and Ministry of Science and ICT, of Korea (RS-2024-00334574 to Y.N. and RS-2024-00332875 to M.J.L), and Gachon University Gil Medical Center (FRD2025-01 to Y.N.).\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eRubinsztein DC. 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Nature. 2003;425(6959):737\\u0026ndash;41.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKeck S, et al. Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease. J Neurochem. 2003;85(1):115\\u0026ndash;22.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eThibaudeau AT, Anderson TR, Smith MD. A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers. Nat Commun, 2018. 9(1).\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFarizatto GLK, et al. Aβ42-mediated proteasome inhibition and associated tau pathology in hippocampus are governed by a lysosomal response involving cathepsin B: Evidence for protective crosstalk between protein clearance pathways. PLoS ONE. 2017;12(8):e0182895.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKim J et al. Extracellular Vesicle-Mediated Delivery of 20S Proteasomes Enhances Tau Degradation in Recipient Cells. J Extracell Vesicles, 2025. 14(5).\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSteward A, et al. ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels. JAMA Neurol. 2023;80(12):1295.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eZuniga RN, et al. Quantitative and Kinetic Proteomics Reveal ApoE Isoform-dependent Proteostasis Adaptations in Mouse Brain. PLoS Comput Biol. 2024;20(12):e1012407.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDavidson K, Pickering MA. The proteasome: A key modulator of nervous system function, brain aging, and neurodegenerative disease. Front Cell Dev Biology, 2023. 11.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKloske CM, Wilcock DM. The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer\\u0026rsquo;s Disease. Front Immunol, 2020. 11.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAhammed SM, Wang X. Promoting proteostasis by cAMP/PKA and cGMP/PKG. Trends Mol Med. 2025;31(3):224\\u0026ndash;39.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGeorge ED, Tepe JJ. Advances in Proteasome Enhancement by Small Molecules. Biomolecules. 2021;11(12):1789.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"},{\"header\":\"Table 2\",\"content\":\"\\u003cp\\u003eTable 2 is available in the Supplementary Files section.\\u003c/p\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"alzheimers-research-and-therapy\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"azrt\",\"sideBox\":\"Learn more about [Alzheimer's Research and Therapy](http://alzres.biomedcentral.com/)\",\"snPcode\":\"13195\",\"submissionUrl\":\"https://submission.nature.com/new-submission/13195/3\",\"title\":\"Alzheimer's Research \\u0026 Therapy\",\"twitterHandle\":\"@AlzheimersRes\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC/SO AJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Alzheimer’s disease, amyloid, APOE ε4, biomarker, cognition, PET, plasma, proteasome, tau\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-8306028/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-8306028/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eProteasome is a major intracellular protease complex, but the significance of circulating proteasome activity in Alzheimer’s disease (AD) is not well established. Because APOE ε4 is the strongest genetic risk factor for AD, we examined whether plasma proteasome activity is associated with AD-related pathology, neurodegeneration, and cognitive decline, focusing on APOE ε4 carriers.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eIn this observational study, participants were classified as cognitively normal (CN), mild cognitive impairment (MCI), and dementia. All underwent 3.0-T MRI, [\\u003csup\\u003e18\\u003c/sup\\u003eF]flutemetamol PET for amyloid, [\\u003csup\\u003e18\\u003c/sup\\u003eF]MK-6240 PET for tau, APOE genotyping, and neuropsychological testing. Circulating proteasome activity was measured using fluorogenic substrates. Associations between proteasome activity and imaging or clinical features were assessed after stratifying by APOE ε4 status. Mediation analyses evaluated whether amyloid or tau burden indirectly linked proteasome activity with hippocampal volume or cognition.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eA total of 148 individuals were included (58 CN, 39 MCI, 38 AD dementia, and 13 other dementia). Significant associations appeared only in APOE ε4 carriers (n = 55). Higher proteasome activity was associated with lower amyloid burden (β = − 0.142, \\u003cem\\u003ep\\u003c/em\\u003e = 0.009), lower global tau burden (β = − 0.447, \\u003cem\\u003ep\\u003c/em\\u003e = 0.047), and reduced tau in Braak I/II (β = − 0.460, \\u003cem\\u003ep\\u003c/em\\u003e = 0.033) and Braak III/IV regions (β = − 0.454, \\u003cem\\u003ep\\u003c/em\\u003e = 0.033). Proteasome activity was positively associated with hippocampal volume (β = 0.294, \\u003cem\\u003ep\\u003c/em\\u003e = 0.001) and with cognitive performance, including MMSE (β = 2.375, \\u003cem\\u003ep\\u003c/em\\u003e = 0.026), CDR-SOB (β = − 1.604, \\u003cem\\u003ep\\u003c/em\\u003e = 0.005), and memory function. No significant associations were found in noncarriers. Mediation analyses showed that amyloid burden explained ~ 29% and Braak I/II tau ~ 23% of the proteasome–hippocampal volume relationship, while tau in Braak I/II and III/IV regions mediated 24–41% of the associations between proteasome activity and global cognition.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusions:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eDownregulated proteasome activity is strongly associated with amyloid burden, early tau accumulation, hippocampal atrophy, and cognitive impairment only in APOE ε4 carriers. These findings suggest that plasma proteasome activity may serve as a noninvasive marker of AD-related vulnerability in genetically at-risk individuals. Further studies are needed to clarify whether proteasome activity contributes to or results from amyloid and tau aggregation.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTrial registration\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e■ Trial registration number: KCT0005428. Registered September 24, 2020.\\u003c/p\\u003e\\n\\u003cp\\u003e■ Study subjects included in this analysis were those recruited from November 2018 onwards. 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