Early-Onset Alzheimer’s Disease Mimicking Cognitive Progression Independent of Relapse Activity in Multiple Sclerosis: A Case Report and Diagnostic Strategy

Early-Onset Alzheimer’s Disease Mimicking Cognitive Progression Independent of Relapse Activity in Multiple Sclerosis: A Case Report and Diagnostic Strategy | 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 Case Report Early-Onset Alzheimer’s Disease Mimicking Cognitive Progression Independent of Relapse Activity in Multiple Sclerosis: A Case Report and Diagnostic Strategy Tatuya Ueno, Maki Miura, Ko Hiyama, Ren Yanagida, Iku Kinoshita, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8570961/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Cognitive impairment (CI) is a common and disabling feature of multiple sclerosis (MS) and is increasingly recognized as part of progression independent of relapse activity (PIRA). However, distinguishing MS-related cognitive PIRA from comorbid neurodegenerative disorders remains challenging, particularly in younger patients, in whom diagnostic overshadowing may delay appropriate diagnosis and management. Herein, we report a case of a patient with MS who developed rapid, memory-predominant CI. Case presentation: A 46-year-old man with long-standing MS developed rapidly progressive, memory-predominant CI that mimicked cognitive PIRA. Despite the absence of clinical relapses and limited magnetic resonance imaging (MRI) activity, cognitive decline progressed and was disproportionate to physical disability. Neuropsychological assessment revealed an early amnestic-dominant profile rather than the processing speed-predominant pattern observed in MS-related CI. Despite escalation from interferon-β1a to high-efficacy anti-CD20 therapy (ofatumumab), cognitive deterioration persisted, arguing against ongoing inflammatory disease activity as the primary cause. Longitudinal MRI showed progressive corpus callosum and parietal lobe atrophy without new white matter lesions. Single-photon emission computed tomography showed hypoperfusion in the bilateral parietal lobes, precuneus, and posterior cingulate gyrus. Cerebrospinal fluid analysis showed reduced amyloid-β1–42/1–40 with elevated phosphorylated tau levels, consistent with Alzheimer’s disease (AD) pathology. Based on the clinical course, neuropsychological profile, neuroimaging findings, and biomarker evidence, comorbid early-onset AD was identified as the predominant cause of cognitive decline. Conclusions This case highlights a critical diagnostic pitfall in MS: rapidly progressive memory-dominant CI may represent a cognitive PIRA mimic rather than MS-related progression. Therefore, clinicians should consider comorbid AD when cognitive decline is amnestic, disproportionate to physical disability, and unresponsive to high-efficacy disease-modifying therapies. Multiple sclerosis Alzheimer’s disease Progress independently of relapse activity Cognitive impairment Neurodegeneration Biomarkers Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system characterized by relapsing–remitting episodes and progressive neurodegeneration. Cognitive impairment (CI) affects approximately 34–70% of patients with MS (pwMS) ( 1 , 2 ), negatively affecting their quality of life and employment status ( 3 , 4 ). CI can occur during acute relapses; however, recent attention has focused on "progression independent of relapse activity" (PIRA), where disability worsens owing to underlying neurodegeneration, often with limited or absent overt inflammatory activity ( 4 – 7 ). Clinically, distinguishing MS-related cognitive PIRA from other neurodegenerative comorbidities is a significant challenge. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β deposition and tau accumulation ( 8 ). pwMS may develop comorbid AD owing to aging; however, establishing a diagnosis is complicated because both conditions are associated with neurodegeneration and brain atrophy. Furthermore, although AD pathology is observed occasionally in older pwMS, confirming early-onset AD (defined as onset before 65 years of age) in young pwMS is exceptionally rare ( 9 – 12 ). This scarcity often leads to "diagnostic overshadowing," where progressive CI in young patients is attributed solely to MS progression (PIRA), delaying appropriate management. Herein, we report a case of a 46-year-old man with MS who developed rapid, memory-predominant CI. The clinical course initially mimicked cognitive PIRA, although the domain-specific profile and lack of response to high-efficacy disease-modifying therapy prompted further investigation, leading to a confirmed diagnosis of comorbid early-onset AD by analyzing cerebrospinal fluid (CSF) biomarkers. Case presentation Eleven years before the current presentation, a 35-year-old Japanese male presented with dysarthria that resolved within 1 week. A year later, he was referred to our department after experiencing numbness in the right arm and hypoesthesia of the left palm. His medical history was unremarkable, with no family history of early-onset dementia. Neurological examination revealed a superficial sensory impairment in the right upper extremity. Brain magnetic resonance imaging (MRI) revealed periventricular white matter lesions. Cervical spine T2-weighted MRI showed a hyperintense intramedullary lesion at C2/3 with gadolinium enhancement on T1-weighted images (Figure 1). CSF analysis revealed 5 cells/μL, a protein concentration of 40 mg/dL, positive oligoclonal bands, and an elevated immunoglobulin index of 1.8. Based on these findings, MS was diagnosed and interferon-β1a therapy (30 μg weekly) was initiated. At age 46 years, the patient developed progressive forgetfulness that was disproportionate to his physical disability and occurred in the absence of clinical relapses or new MRI activity. At age 47 years, his Mini-Mental State Examination (MMSE) score was 29, his Montreal Cognitive Assessment-Japanese version (MoCA-J) score was 27 (memory 2/5), his Symbol Digit Modalities Test (SDMT) score was 50, and his Expanded Disability Status Scale (EDSS) score was 2.5. Brain MRI revealed a corpus callosum index (CCI) of 0.408, indicating mild atrophy (Figure 2a). Notably, early cognitive testing suggested an amnestic-predominant profile rather than the typical processing speed–dominant impairment observed in MS-related cognitive dysfunction. At age 48 years, his cognitive assessment declined further; his test scores were as follows: MoCA-J, 23 (executive function 4/4, visuospatial ability 4/4, language 4/5, attention 5/6, memory 1/5, and orientation 5/6); MMSE, 22 (orientation 9/10, immediate recall 3/3, attention and calculation 1/5, delayed recall 1/3, language 7/8, and visuospatial construction 1/1); and SDMT, 44. Subjective memory complaints had also worsened, and his EDSS score had increased to 3.5. Brain MRI demonstrated mild parietal lobe atrophy with preserved medial temporal lobe, a CCI of 0.382, and a newly emerged periventricular lesion (Figure 2b). At this stage, the cognitive decline could not be classified as definite cognitive PIRA owing to the new MRI activity, leading to a switch from interferon-β1a to ofatumumab (20 mg every 4 weeks). Despite escalation to high-efficacy anti-CD20 therapy with ofatumumab, cognitive decline progressed steadily over the next 2 years (MoCA-J, 17 [executive function 2/4, visuospatial ability 2/4, language 4/5, attention 3/6, memory 0/5, and orientation 5/6]; MMSE, 21 [orientation 8/10, immediate recall 3/3, attention and calculation 2/5, delayed recall 0/3, language 7/8, and visuospatial construction 1/1]; SDMT, 21), arguing against ongoing inflammatory disease activity as the primary cause. Brain MRI showed no new white matter lesions (Figure 2c and d). At age 51 years, his CI had become severe (MoCA-J, 10; MMSE, 14; and SDMT could not be completed because of his inability to comprehend instructions). Ambulatory function remained preserved, although his EDSS score increased to 4.0 owing to CI. Brain MRI showed no new white matter lesions but demonstrated parietal lobe atrophy, and the CCI was 0.369 (Figure 2e). The cognitive decline was initially attributed to cognitive PIRA; however, its rapid progression and memory-dominant pattern, which are atypical for secondary progressive MS (SPMS), prompted further evaluation and subsequent single-photon emission computed tomography (SPECT) imaging. The results revealed hypoperfusion in the bilateral parietal lobes, precuneus, and posterior cingulate gyrus, suggesting AD (Figure 3). CSF biomarkers showed a decreased Aβ 1-42/1-40 ratio of 0.048 (reference value: ≥0.067) and elevated phosphorylated tau (148 pg/mL; reference range: 21.5–59.0 pg/mL), consistent with positive AD biomarkers. Phenotyping of apolipoprotein E revealed the E3/E3 genotype. There were no clinical features suggestive of autoimmune encephalitis, such as seizures, psychiatric symptoms, altered consciousness, CSF pleocytosis, or contrast-enhancing cortical lesions. Based on the longitudinal clinical course and biomarker profile, comorbid young-onset AD was determined to be the predominant contributor to the progressive CI. Discussion and Conclusions This case highlights a critical diagnostic pitfall in MS: the misattribution of progressive, memory-dominant cognitive decline to PIRA, representing a cognitive PIRA mimic that delayed recognition of comorbid early-onset AD. Relapsing-remitting MS (RRMS) typically impairs processing speed, whereas progressive MS impairs memory and executive function (3, 13). Previous studies have shown that CI is more frequent and severe in SPMS than in RRMS, with broader involvement across multiple cognitive domains, including memory, in SPMS, whereas RRMS predominantly affects information processing speed (3, 14). Isolated cognitive decline occurs in a subset of neurologically stable pwMS and is often detected as a decline in SDMT scores on longitudinal testing (15). The types of CI in MS can be categorized into transient “cognitive relapse” and “PIRA” (4). In Fuchs et al.’s study (2024), cognitive PIRA was detected in 44.6% of patients, with test-specific involvement observed in SDMT (25.6%), Brief Visuospatial Memory Test-Revised (16.4%), and California Verbal Learning Test-II (20.8%) scores, indicating that reliance on SDMT alone would result in missing a substantial proportion of cognitive PIRA (5). Recently, Glanz et al. showed that SDMT-defined information processing speed can worsen independent of EDSS-based PIRA (7). Furthermore, longitudinal studies have shown that SDMT-defined cognitive decline can occur independent of clinical relapses and often without concurrent MRI activity, supporting the concept of relapse- and MRI-independent cognitive progression (6). The decline in information processing speed assessed by the SDMT is the most sensitive and commonly reported cognitive abnormality in MS. However, early involvement of memory and other cognitive domains has also been described, particularly in progressive disease courses and heterogeneous cognitive phenotypes. Accordingly, reliance on early SDMT decline alone is insufficient for etiological attribution in MS, and memory-predominant or atypical cognitive trajectories should prompt evaluation for comorbid neurodegenerative disease. Memory impairment can occur in progressive MS; however, the early preservation of processing speed with initial memory-dominant decline in this case represents an atypical cognitive trajectory, suggesting a PIRA mimic rather than MS-related progression alone (Table 1). With improvement in MS-related survival, comorbid age-related neurodegenerative diseases are gaining attention. Recent studies suggest that chronic inflammatory processes in pwMS may impair microglial function and glymphatic clearance, thereby promoting amyloid-β accumulation and accelerating AD-like pathology (12). A few previous reports have documented that pathologically confirmed AD occurs across MS subtypes and a tendency toward greater prevalence in patients with primary and SPMS (10, 11). However, most reported cases of MS with AD developed dementia after 65 years of age and reports clearly confirming comorbidities in early-onset cases remain exceedingly rare (9-12). Autopsy-based analyses have shown that AD pathology in MS emerges only in patients aged ≥65 years and is absent in younger individuals (16). In this context, early-onset AD represents a clinically important cognitive PIRA mimic. Early-onset AD commonly presents with either memory-dominant or non-amnestic phenotypes and often progresses more rapidly than late-onset AD. CI is frequently disproportionate to physical disability and is associated with posterior cortical atrophy, hypoperfusion, and an AD-specific CSF biomarker profile (17-19) (Table 1). The patient in this case showed progressive, amnesia-dominant CI beginning approximately 11 years after MS diagnosis. After initiating interferon-β1a, the patient remained relapse-free and MRI-stable for approximately 10 years; however, CI decline accelerated despite a switch to high-efficacy anti-CD20 therapy (ofatumumab). Cognitive PIRA may persist despite high-efficacy therapy; however, the lack of response suggests that MS-related inflammatory activity alone does not fully explain the progression. Neuropsychological testing revealed reduced information processing speed and marked impairment in delayed recall. This memory dysfunction exceeded the typical processing speed deficits in MS. An MRI showed corpus callosum and bilateral parietal lobe atrophy, whereas SPECT demonstrated hypoperfusion in typical AD regions (20). The decreased Aβ 1-42/1-40 ratio and elevated phosphorylated tau levels confirmed AD as the primary cause of cognitive decline (8). Distinguishing between MS-related neurodegeneration and comorbid AD is challenging but vital to prevent inappropriate escalation of immunosuppression. This case highlights the need not to assume that cognitive decline in MS is disease-related by default, especially when the domain profile is amnestic (Table 1). Rather, clinicians should consider a "cognitive PIRA mimic" and screen for comorbid neurodegeneration, particularly AD, when (1) cognitive decline is rapid and disproportionate to physical disability (EDSS); (2) the impairment is memory-predominant rather than processing speed-predominant; and (3) decline persists after escalating to high-efficacy disease-modifying therapies (DMTs). In such scenarios, integrating SPECT, CSF AD biomarker analysis, and amyloid PET can be considered to facilitate early diagnosis and appropriate management (Figure 3). In conclusion, progressive CI in pwMS should not be automatically attributed to cognitive PIRA, particularly when the decline is memory-dominant, disproportionate to physical disability, and unresponsive to high-efficacy DMTs. In such cases, comorbid neurodegenerative disorders, such as AD, should be considered and integrated evaluation using neuropsychological testing, neuroimaging, and disease-specific biomarkers is essential for accurate diagnosis and appropriate management. Abbreviations AD, Alzheimer’s disease; Aβ, amyloid-β; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; MRI, magnetic resonance imaging; MS, multiple sclerosis; PIRA, progression independent of relapse activity; SDMT, Symbol Digit Modalities Test; SPECT, single-photon emission computed tomography. Declarations Ethics approval and consent to participate: This case report was conducted in accordance with the Declaration of Helsinki. According to the policy of the ethics committee of Aomori Prefectural Central Hospital, ethical approval was waived because this study was a retrospective case report involving no experimental intervention. Written informed consent to participate was obtained from the patient and his family. Consent for publication: Written informed consent for publication was obtained from the patient. In addition, written informed consent for publication was obtained from the patient’s family as the patient developed cognitive impairment during the clinical course. Availability of data and materials: The datasets generated and/or analyzed during the current study are not publicly available due patient privacy protection but are available from the corresponding author on reasonable request Competing interests: Funding: This study did not receive any specific grants from funding agencies in the public, commercial, or nonprofit sectors. Authors’ contributions TU conceptualized and designed the study and drafted and revised the manuscript. KH revised the manuscript. RY revised the manuscript. MM revised the manuscript. IK revised the manuscript. RH revised the manuscript. AA revised the manuscript. Acknowledgements We are grateful to Taiki Ohira, Mizue Kitamura, Shiori Sato, and Yuka Kato from the Division of Clinical Psychological Support, Aomori Prefectural Central Hospital, Aomori, Japan, for their assistance with data collection. We thank Editage (https://www.editage.com) for English language editing. References De Meo E, Portaccio E, Bonacchi R, Giovannoli J, Niccolai C, Amato MP. An update on the treatment and management of cognitive dysfunction in patients with multiple sclerosis. Expert Rev Neurother. 2025;25(2):227–43. Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol. 2008;7(12):1139–51. Ruano L, Portaccio E, Goretti B, Niccolai C, Severo M, Patti F, et al. 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NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimer's Dement. 2018;14(4):535–62. Flanagan EP, Knopman DS, Keegan BM. Dementia in MS complicated by coexistent Alzheimer disease: Diagnosis premortem and postmortem. Neurology: Clin Pract. 2014;4(3):226–30. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(5):1175–89. Luczynski P, Laule C, Hsiung G-YR, Moore GW, Tremlett H. Coexistence of multiple sclerosis and Alzheimer's disease: a review. Multiple Scler Relat disorders. 2019;27:232–8. Cottrill R, Ekanayake A, Grove C, Peiris S, Corbett N, Ahmed B, et al. Alzheimer's disease (AD) in multiple sclerosis (MS): A systematic review of published cases, mechanistic links between AD and MS, and possible clinical evaluation of AD in MS. J Alzheimer's disease Rep. 2025;9:25424823251316134. Benedict RH, Zivadinov R. Risk factors for and management of cognitive dysfunction in multiple sclerosis. Nat Reviews Neurol. 2011;7(6):332–42. Planche V, Gibelin M, Cregut D, Pereira B, Clavelou P. Cognitive impairment in a population-based study of patients with multiple sclerosis: differences between late relapsing – remitting, secondary progressive and primary progressive multiple sclerosis. Eur J Neurol. 2016;23(2):282–9. Motyl J, Friedova L, Vaneckova M, Krasensky J, Lorincz B, Blahova Dusankova J, et al. Isolated Cognitive Decline in Neurologically Stable Patients with Multiple Sclerosis. Diagnostics. 2021;11(3):464. Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H. Multiple sclerosis and Alzheimer's disease. Ann Neurol. 2008;63(2):174–83. Koedam EL, Lauffer V, Van Der Vlies AE, Van Der Flier WM, Scheltens P, Pijnenburg YA. Early-versus late-onset Alzheimer's disease: more than age alone. J Alzheimer’s Disease. 2010;19(4):1401–8. van der Vlies AE, Koedam EL, Pijnenburg YA, Twisk JW, Scheltens P, van der Flier WM. Most rapid cognitive decline in APOE epsilon4 negative Alzheimer's disease with early onset. Psychol Med. 2009;39(11):1907–11. Mendez MF. Early-onset Alzheimer Disease and Its Variants. Continuum (Minneap Minn). 2019;25(1):34–51. Imokawa T, Yokoyama K, Takahashi K, Oyama J, Tsuchiya J, Sanjo N, et al. Brain perfusion SPECT in dementia: what radiologists should know. Japanese J Radiol. 2024;42(11):1215–30. Additional Declarations No competing interests reported. Supplementary Files Table1BMCNeuro2026.17.xlsx Table 1. Key features differentiating cognitive PIRA from early-onset Alzheimer’s disease as a PIRA mimic. This table summarizes the characteristic cognitive domains, progression patterns, relationships to physical disability, responses to disease-modifying therapy, imaging findings, and cerebrospinal fluid biomarkers in cognitive PIRA, early-onset Alzheimer’s disease (as a PIRA mimic), and the present case. Abbreviations: AD, Alzheimer’s disease; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; EOAD, early-onset Alzheimer’s disease; MRI, magnetic resonance imaging; PIRA, progression independent of relapse activity; SPECT, single-photon emission computed tomography. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8570961","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":576317933,"identity":"732f50b0-c2b9-4c76-bfb4-a5f118036c9d","order_by":0,"name":"Tatuya 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12:36:01","extension":"html","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":67029,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8570961/v1/793f3c942220d1dffbfb8166.html"},{"id":100683826,"identity":"2adb52fa-c3b4-4f28-ba2c-7416c7d4f06e","added_by":"auto","created_at":"2026-01-20 12:36:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1361741,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBrain and spinal cord magnetic resonance imaging at the initial presentation at the age of 36 years. \u003c/strong\u003e(a–c) Fluid-attenuated inversion recovery images show periventricular white matter lesions. (d, f) T2-weighted images of the cervical spinal cord demonstrate a hyperintense intramedullary lesion at the C2/3 level. (e, g) Gadolinium-enhanced T1-weighted images revealenhancement of the same lesion.\u003c/p\u003e","description":"","filename":"OnlineFigure1BMCNeuro2026.1.11.png","url":"https://assets-eu.researchsquare.com/files/rs-8570961/v1/90c9c4464a156af4187c5fd2.png"},{"id":100684282,"identity":"aa94778d-0d73-4958-8431-45ead6a517bb","added_by":"auto","created_at":"2026-01-20 12:41:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3924212,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFluid-attenuated inversion recovery images obtained at ages 47 (a), 48 (b), 49 (c), 50 (d), and 51 (e) years.\u003c/strong\u003e The arrow in panel b indicates a newly developed white matter lesion. No new lesions were detected after age 49 years. Throughout the entire observation period, the medial temporal lobes were relatively preserved, whereas progressive parietal lobe atrophy was evident.\u003c/p\u003e","description":"","filename":"OnlineFigure2BMCNeuro2026.1.11.png","url":"https://assets-eu.researchsquare.com/files/rs-8570961/v1/96bc0400d6eb2fc41e03e74c.png"},{"id":100684280,"identity":"3467ccf7-2ac1-46bf-869f-7e025e1cd502","added_by":"auto","created_at":"2026-01-20 12:41:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":382830,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBrain magnetic resonance imaging and cerebral perfusion imaging at the age of 51 years\u003c/strong\u003e. Three-dimensional stereotactic surface projection analysis of single-photon emission computed tomography using N-isopropyl-p-[¹²³I] iodoamphetamine showed hypoperfusion in the bilateral parietal lobes, precuneus, and posterior cingulate gyrus.\u003c/p\u003e","description":"","filename":"OnlineFigure3BMCNeuro2026.1.7.png","url":"https://assets-eu.researchsquare.com/files/rs-8570961/v1/c061f08ef8f2a6de13830787.png"},{"id":100683888,"identity":"30919da6-319c-4fce-922a-7d4da7924b63","added_by":"auto","created_at":"2026-01-20 12:37:26","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":37859,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProposed stepwise approach to cognitive decline in MS (conceptual framework).\u003c/strong\u003e This flowchart provides a conceptual framework for the evaluation of cognitive decline in multiple sclerosis and is not intended to establish a definitive diagnosis. MS-related cognitive PIRA/PIRMA remains a consideration after targeted assessment for Alzheimer’s disease and other clinically relevant PIRA mimics. Abbreviations: AD, Alzheimer’s disease; Aβ, amyloid-β; BM, biomarker; CSF, cerebrospinal fluid; CVLT-II, California Verbal Learning Test, Second Edition; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; EOAD, early-onset Alzheimer’s disease; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; MS, multiple sclerosis; PIRA, progression independent of relapse activity; PIRMA, progression independent of relapse and MRI activity; RAW, relapse-associated worsening; SDMT, Symbol Digit Modalities Test; SPECT, single-photon emission computed tomography.\u003c/p\u003e","description":"","filename":"OnlineFigure4BMCNeuro2026.1.7.png","url":"https://assets-eu.researchsquare.com/files/rs-8570961/v1/f63fed43783863f4a1f8dce0.png"},{"id":100690860,"identity":"95abc8d4-c3a7-47ed-b7d9-c2b37c2ab403","added_by":"auto","created_at":"2026-01-20 13:58:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10118806,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8570961/v1/7ffa8f5f-8218-43fa-bd36-ec14271abf9e.pdf"},{"id":100683814,"identity":"39ed1640-0e78-4548-8c05-a1561d535ffb","added_by":"auto","created_at":"2026-01-20 12:36:36","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11478,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 1. Key features differentiating cognitive PIRA from early-onset Alzheimer’s disease as a PIRA mimic\u003c/strong\u003e. This table summarizes the characteristic cognitive domains, progression patterns, relationships to physical disability, responses to disease-modifying therapy, imaging findings, and cerebrospinal fluid biomarkers in cognitive PIRA, early-onset Alzheimer’s disease (as a PIRA mimic), and the present case. Abbreviations: AD, Alzheimer’s disease; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; EOAD, early-onset Alzheimer’s disease; MRI, magnetic resonance imaging; PIRA, progression independent of relapse activity; SPECT, single-photon emission computed tomography.\u003c/p\u003e","description":"","filename":"Table1BMCNeuro2026.17.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8570961/v1/25dcdb9ec12a3a7eafd560f4.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early-Onset Alzheimer’s Disease Mimicking Cognitive Progression Independent of Relapse Activity in Multiple Sclerosis: A Case Report and Diagnostic Strategy","fulltext":[{"header":"Background","content":"\u003cp\u003eMultiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system characterized by relapsing\u0026ndash;remitting episodes and progressive neurodegeneration. Cognitive impairment (CI) affects approximately 34\u0026ndash;70% of patients with MS (pwMS) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), negatively affecting their quality of life and employment status (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). CI can occur during acute relapses; however, recent attention has focused on \"progression independent of relapse activity\" (PIRA), where disability worsens owing to underlying neurodegeneration, often with limited or absent overt inflammatory activity (\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Clinically, distinguishing MS-related cognitive PIRA from other neurodegenerative comorbidities is a significant challenge.\u003c/p\u003e \u003cp\u003eAlzheimer\u0026rsquo;s disease (AD) is a neurodegenerative disorder characterized by amyloid-β deposition and tau accumulation (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). pwMS may develop comorbid AD owing to aging; however, establishing a diagnosis is complicated because both conditions are associated with neurodegeneration and brain atrophy. Furthermore, although AD pathology is observed occasionally in older pwMS, confirming early-onset AD (defined as onset before 65 years of age) in young pwMS is exceptionally rare (\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). This scarcity often leads to \"diagnostic overshadowing,\" where progressive CI in young patients is attributed solely to MS progression (PIRA), delaying appropriate management.\u003c/p\u003e \u003cp\u003eHerein, we report a case of a 46-year-old man with MS who developed rapid, memory-predominant CI. The clinical course initially mimicked cognitive PIRA, although the domain-specific profile and lack of response to high-efficacy disease-modifying therapy prompted further investigation, leading to a confirmed diagnosis of comorbid early-onset AD by analyzing cerebrospinal fluid (CSF) biomarkers.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eEleven years before the current presentation, a 35-year-old Japanese male presented with dysarthria that resolved within 1 week. A year later, he was referred to our department after experiencing numbness in the right arm and hypoesthesia of the left palm. His medical history was unremarkable, with no family history of early-onset dementia. Neurological examination revealed a superficial sensory impairment in the right upper extremity. Brain magnetic resonance imaging (MRI) revealed periventricular white matter lesions. Cervical spine T2-weighted MRI showed a hyperintense intramedullary lesion at C2/3 with gadolinium enhancement on T1-weighted images (Figure 1). CSF analysis revealed 5 cells/μL, a protein concentration of 40 mg/dL, positive oligoclonal bands, and an elevated immunoglobulin index of 1.8. Based on these findings, MS was diagnosed and interferon-β1a therapy (30 μg weekly) was initiated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt age 46 years, the patient developed progressive forgetfulness that was disproportionate to his physical disability and occurred in the absence of clinical relapses or new MRI activity. At age 47 years, his Mini-Mental State Examination (MMSE) score was 29, his Montreal Cognitive Assessment-Japanese version (MoCA-J) score was 27 (memory 2/5), his Symbol Digit Modalities Test (SDMT) score was 50, and his Expanded Disability Status Scale (EDSS) score was 2.5. Brain MRI revealed a corpus callosum index (CCI) of 0.408, indicating mild atrophy (Figure 2a). Notably, early cognitive testing suggested an amnestic-predominant profile rather than the typical processing speed–dominant impairment observed in MS-related cognitive dysfunction.\u003c/p\u003e\n\u003cp\u003eAt age 48 years, his cognitive assessment declined further; his test scores were as follows: MoCA-J, 23 (executive function 4/4, visuospatial ability 4/4, language 4/5, attention 5/6, memory 1/5, and orientation 5/6); MMSE, 22 (orientation 9/10, immediate recall 3/3, attention and calculation 1/5, delayed recall 1/3, language 7/8, and visuospatial construction 1/1); and SDMT, 44. Subjective memory complaints had also worsened, and his EDSS score had increased to 3.5. Brain MRI demonstrated mild parietal lobe atrophy with preserved medial temporal lobe, a CCI of 0.382, and a newly emerged periventricular lesion (Figure 2b). At this stage, the cognitive decline could not be classified as definite cognitive PIRA owing to the new MRI activity, leading to a switch from interferon-β1a to ofatumumab (20 mg every 4 weeks).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDespite escalation to high-efficacy anti-CD20 therapy with ofatumumab, cognitive decline progressed steadily over the next 2 years (MoCA-J, 17 [executive function 2/4, visuospatial ability 2/4, language 4/5, attention 3/6, memory 0/5, and orientation 5/6]; MMSE, 21 [orientation 8/10, immediate recall 3/3, attention and calculation 2/5, delayed recall 0/3, language 7/8, and visuospatial construction 1/1]; SDMT, 21), arguing against ongoing inflammatory disease activity as the primary cause. Brain MRI showed no new white matter lesions (Figure 2c and d).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt age 51 years, his CI had become severe (MoCA-J, 10; MMSE, 14; and SDMT could not be completed because of his inability to comprehend instructions). Ambulatory function remained preserved, although his EDSS score increased to 4.0 owing to CI. Brain MRI showed no new white matter lesions but demonstrated parietal lobe atrophy, and the CCI was 0.369 (Figure 2e). The cognitive decline was initially attributed to cognitive PIRA; however, its rapid progression and memory-dominant pattern, which are atypical for secondary progressive MS (SPMS), prompted further evaluation and subsequent single-photon emission computed tomography (SPECT) imaging. The results revealed hypoperfusion in the bilateral parietal lobes, precuneus, and posterior cingulate gyrus, suggesting AD (Figure 3). CSF biomarkers showed a decreased Aβ\u003csub\u003e1-42/1-40\u0026nbsp;\u003c/sub\u003eratio of 0.048 (reference value: ≥0.067) and elevated phosphorylated tau (148 pg/mL; reference range: 21.5–59.0 pg/mL), consistent with positive AD biomarkers. Phenotyping of apolipoprotein E revealed the E3/E3 genotype. There were no clinical features suggestive of autoimmune encephalitis, such as seizures, psychiatric symptoms, altered consciousness, CSF pleocytosis, or contrast-enhancing cortical lesions. Based on the longitudinal clinical course and biomarker profile, comorbid young-onset AD was determined to be the predominant contributor to the progressive CI.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eThis case highlights a critical diagnostic pitfall in MS: the misattribution of progressive, memory-dominant cognitive decline to PIRA, representing a cognitive PIRA mimic that delayed recognition of comorbid early-onset AD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRelapsing-remitting MS (RRMS) typically impairs processing speed, whereas progressive MS impairs memory\u0026nbsp;and executive function (3, 13). Previous studies have shown that CI is more frequent and severe in SPMS than in RRMS, with broader involvement across multiple cognitive domains, including memory, in SPMS, whereas RRMS predominantly affects information processing speed\u0026nbsp;(3, 14). Isolated cognitive decline occurs in a subset of neurologically stable pwMS and is often detected as a decline in SDMT scores on longitudinal testing\u0026nbsp;(15). The types of CI in MS can be categorized into transient “cognitive relapse” and “PIRA”\u0026nbsp;(4). In Fuchs et al.’s study (2024), cognitive PIRA was detected in 44.6% of patients, with test-specific involvement observed in SDMT (25.6%), Brief Visuospatial Memory Test-Revised (16.4%), and California Verbal Learning Test-II (20.8%) scores, indicating that reliance on SDMT alone would result in missing a substantial proportion of cognitive PIRA\u0026nbsp;(5). Recently, Glanz et al. showed that SDMT-defined information processing speed can worsen independent of EDSS-based PIRA\u0026nbsp;(7). Furthermore, longitudinal studies have shown that SDMT-defined cognitive decline can occur independent of clinical relapses and often without concurrent MRI activity, supporting the concept of relapse- and MRI-independent cognitive progression\u0026nbsp;(6). The decline in information processing speed assessed by the SDMT is the most sensitive and commonly reported cognitive abnormality in MS. However, early involvement of memory and other cognitive domains has also been described, particularly in progressive disease courses and heterogeneous cognitive phenotypes. Accordingly, reliance on early SDMT decline alone is insufficient for etiological attribution in MS, and memory-predominant or atypical cognitive trajectories should prompt evaluation for comorbid neurodegenerative disease. Memory impairment can occur in progressive MS; however, the early preservation of processing speed with initial memory-dominant decline in this case represents an atypical cognitive trajectory, suggesting a PIRA mimic rather than MS-related progression alone (Table 1).\u003c/p\u003e\n\u003cp\u003eWith improvement in MS-related survival, comorbid age-related neurodegenerative diseases are gaining attention. Recent studies suggest that chronic inflammatory processes in pwMS may impair microglial function and glymphatic clearance, thereby promoting amyloid-β accumulation and accelerating AD-like pathology\u0026nbsp;(12). A few previous reports have documented that pathologically confirmed AD occurs across MS subtypes and a tendency toward greater prevalence in patients with primary and SPMS (10, 11). However, most reported cases of MS with AD developed dementia after 65 years of age and reports clearly confirming comorbidities in early-onset cases remain exceedingly rare (9-12).\u0026nbsp;Autopsy-based analyses have shown that AD pathology in MS emerges only in patients aged ≥65 years and is absent in younger individuals\u0026nbsp;(16). In this context, early-onset AD represents a clinically important cognitive PIRA mimic. Early-onset AD commonly presents with either memory-dominant or non-amnestic phenotypes and often progresses more rapidly than late-onset AD. CI is frequently disproportionate to physical disability and is associated with posterior cortical atrophy, hypoperfusion, and an AD-specific CSF biomarker profile (17-19)\u0026nbsp;(Table 1).\u003c/p\u003e\n\u003cp\u003eThe patient in this case showed progressive, amnesia-dominant CI beginning approximately 11 years after MS diagnosis. After initiating interferon-β1a, the patient remained relapse-free and MRI-stable for approximately 10 years; however, CI\u0026nbsp;decline accelerated despite a switch to high-efficacy anti-CD20 therapy (ofatumumab). Cognitive PIRA may persist despite high-efficacy therapy; however, the lack of response suggests that MS-related inflammatory activity alone does not fully explain the progression.\u0026nbsp;Neuropsychological testing revealed reduced information processing speed and marked impairment in delayed recall. This memory dysfunction exceeded the typical processing speed deficits in MS. An MRI showed corpus callosum and bilateral parietal lobe atrophy, whereas SPECT demonstrated hypoperfusion in typical AD regions (20). The decreased Aβ\u003csub\u003e1-42/1-40\u0026nbsp;\u003c/sub\u003eratio and elevated phosphorylated tau levels confirmed AD as the primary cause of cognitive decline (8).\u003c/p\u003e\n\u003cp\u003eDistinguishing between MS-related neurodegeneration and comorbid AD is challenging but vital to prevent inappropriate escalation of immunosuppression. This case highlights the need not to assume that cognitive decline in MS is disease-related by default, especially when the domain profile is amnestic (Table 1). Rather, clinicians should consider a \"cognitive PIRA mimic\" and screen for comorbid neurodegeneration, particularly AD, when (1) cognitive decline is rapid and disproportionate to physical disability (EDSS); (2) the impairment is memory-predominant rather than processing speed-predominant; and (3) decline persists after escalating to high-efficacy disease-modifying therapies (DMTs). In such scenarios, integrating SPECT, CSF AD biomarker analysis, and amyloid PET can be considered to facilitate early diagnosis and appropriate management (Figure 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, progressive CI in pwMS should not be automatically attributed to cognitive PIRA, particularly when the decline is memory-dominant, disproportionate to physical disability, and unresponsive to high-efficacy DMTs. In such cases, comorbid neurodegenerative disorders, such as AD, should be considered and integrated evaluation using neuropsychological testing, neuroimaging, and disease-specific biomarkers is essential for accurate diagnosis and appropriate management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAD, Alzheimer\u0026rsquo;s disease; A\u0026beta;, amyloid-\u0026beta;; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; MRI, magnetic resonance imaging; MS, multiple sclerosis; PIRA, progression independent of relapse activity; SDMT, Symbol Digit Modalities Test; SPECT, single-photon emission computed tomography.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and consent to participate:\u0026nbsp;\u003c/strong\u003eThis case report was conducted in accordance with the Declaration of Helsinki. According to the policy of the ethics committee of Aomori Prefectural Central Hospital, ethical approval was waived because this study was a retrospective case report involving no experimental intervention. Written informed consent to participate was obtained from the patient and his family.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eWritten informed consent for publication was obtained from the patient. In addition, written informed consent for publication was obtained from the patient’s family as the patient developed cognitive impairment during the clinical course.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe datasets generated and/or analyzed during the current study are not publicly available due patient privacy protection but are available from the corresponding author on reasonable request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study did not receive any specific grants from funding agencies in the public, commercial, or nonprofit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTU conceptualized and designed the study and drafted and revised the manuscript. KH revised the manuscript. RY revised the manuscript. MM revised the manuscript. IK revised the manuscript. RH revised the manuscript. AA revised the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to Taiki Ohira, Mizue Kitamura, Shiori Sato, and Yuka Kato from the Division of Clinical Psychological Support, Aomori Prefectural Central Hospital, Aomori, Japan, for their assistance with data collection. We thank Editage (https://www.editage.com) for English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDe Meo E, Portaccio E, Bonacchi R, Giovannoli J, Niccolai C, Amato MP. An update on the treatment and management of cognitive dysfunction in patients with multiple sclerosis. Expert Rev Neurother. 2025;25(2):227\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol. 2008;7(12):1139\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuano L, Portaccio E, Goretti B, Niccolai C, Severo M, Patti F, et al. Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes. Multiple Scler J. 2017;23(9):1258\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenedict RH, Amato MP, DeLuca J, Geurts JJ. Cognitive impairment in multiple sclerosis: clinical management, MRI, and therapeutic avenues. Lancet Neurol. 2020;19(10):860\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuchs TA, Schoonheim MM, Zivadinov R, Dwyer MG, Colato E, Weinstock Z, et al. Cognitive progression independent of relapse in multiple sclerosis. Mult Scler. 2024;30(11\u0026ndash;12):1468\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZiccardi S, Fuchs TA, Guandalini M, Marastoni D, Benedict RH, Calabrese M. Cognitive Progression Independent of Relapse and MRI Activity in Multiple Sclerosis. Neurol Open Access. 2025;1(1):e0005.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlanz BI, Chitnis T, Weiner HL, Healy BC. Assessment of changes in fatigue and cognitive functioning in the absence of progression independent of relapse activity. Multiple Scler Relat disorders. 2025;104:106786.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimer's Dement. 2018;14(4):535\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFlanagan EP, Knopman DS, Keegan BM. Dementia in MS complicated by coexistent Alzheimer disease: Diagnosis premortem and postmortem. Neurology: Clin Pract. 2014;4(3):226\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(5):1175\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuczynski P, Laule C, Hsiung G-YR, Moore GW, Tremlett H. Coexistence of multiple sclerosis and Alzheimer's disease: a review. Multiple Scler Relat disorders. 2019;27:232\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCottrill R, Ekanayake A, Grove C, Peiris S, Corbett N, Ahmed B, et al. Alzheimer's disease (AD) in multiple sclerosis (MS): A systematic review of published cases, mechanistic links between AD and MS, and possible clinical evaluation of AD in MS. J Alzheimer's disease Rep. 2025;9:25424823251316134.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenedict RH, Zivadinov R. Risk factors for and management of cognitive dysfunction in multiple sclerosis. Nat Reviews Neurol. 2011;7(6):332\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePlanche V, Gibelin M, Cregut D, Pereira B, Clavelou P. Cognitive impairment in a population-based study of patients with multiple sclerosis: differences between late relapsing\u0026thinsp;\u0026ndash;\u0026thinsp;remitting, secondary progressive and primary progressive multiple sclerosis. Eur J Neurol. 2016;23(2):282\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMotyl J, Friedova L, Vaneckova M, Krasensky J, Lorincz B, Blahova Dusankova J, et al. Isolated Cognitive Decline in Neurologically Stable Patients with Multiple Sclerosis. Diagnostics. 2021;11(3):464.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H. Multiple sclerosis and Alzheimer's disease. Ann Neurol. 2008;63(2):174\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoedam EL, Lauffer V, Van Der Vlies AE, Van Der Flier WM, Scheltens P, Pijnenburg YA. Early-versus late-onset Alzheimer's disease: more than age alone. J Alzheimer\u0026rsquo;s Disease. 2010;19(4):1401\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan der Vlies AE, Koedam EL, Pijnenburg YA, Twisk JW, Scheltens P, van der Flier WM. Most rapid cognitive decline in APOE epsilon4 negative Alzheimer's disease with early onset. Psychol Med. 2009;39(11):1907\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMendez MF. Early-onset Alzheimer Disease and Its Variants. Continuum (Minneap Minn). 2019;25(1):34\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eImokawa T, Yokoyama K, Takahashi K, Oyama J, Tsuchiya J, Sanjo N, et al. Brain perfusion SPECT in dementia: what radiologists should know. Japanese J Radiol. 2024;42(11):1215\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Multiple sclerosis, Alzheimer’s disease, Progress independently of relapse activity, Cognitive impairment, Neurodegeneration, Biomarkers","lastPublishedDoi":"10.21203/rs.3.rs-8570961/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8570961/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCognitive impairment (CI) is a common and disabling feature of multiple sclerosis (MS) and is increasingly recognized as part of progression independent of relapse activity (PIRA). However, distinguishing MS-related cognitive PIRA from comorbid neurodegenerative disorders remains challenging, particularly in younger patients, in whom diagnostic overshadowing may delay appropriate diagnosis and management. Herein, we report a case of a patient with MS who developed rapid, memory-predominant CI.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eA 46-year-old man with long-standing MS developed rapidly progressive, memory-predominant CI that mimicked cognitive PIRA. Despite the absence of clinical relapses and limited magnetic resonance imaging (MRI) activity, cognitive decline progressed and was disproportionate to physical disability. Neuropsychological assessment revealed an early amnestic-dominant profile rather than the processing speed-predominant pattern observed in MS-related CI. Despite escalation from interferon-β1a to high-efficacy anti-CD20 therapy (ofatumumab), cognitive deterioration persisted, arguing against ongoing inflammatory disease activity as the primary cause. Longitudinal MRI showed progressive corpus callosum and parietal lobe atrophy without new white matter lesions. Single-photon emission computed tomography showed hypoperfusion in the bilateral parietal lobes, precuneus, and posterior cingulate gyrus. Cerebrospinal fluid analysis showed reduced amyloid-β1\u0026ndash;42/1\u0026ndash;40 with elevated phosphorylated tau levels, consistent with Alzheimer\u0026rsquo;s disease (AD) pathology. Based on the clinical course, neuropsychological profile, neuroimaging findings, and biomarker evidence, comorbid early-onset AD was identified as the predominant cause of cognitive decline.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis case highlights a critical diagnostic pitfall in MS: rapidly progressive memory-dominant CI may represent a cognitive PIRA mimic rather than MS-related progression. Therefore, clinicians should consider comorbid AD when cognitive decline is amnestic, disproportionate to physical disability, and unresponsive to high-efficacy disease-modifying therapies.\u003c/p\u003e","manuscriptTitle":"Early-Onset Alzheimer’s Disease Mimicking Cognitive Progression Independent of Relapse Activity in Multiple Sclerosis: A Case Report and Diagnostic Strategy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-20 10:41:27","doi":"10.21203/rs.3.rs-8570961/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-01T11:06:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-20T08:51:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-18T09:28:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"13247043151805373471007558375198463116","date":"2026-01-23T08:01:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"174747028945748225643293096210979464446","date":"2026-01-22T10:04:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-16T07:35:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-16T07:31:42+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-14T04:51:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-13T23:05:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2026-01-13T23:01:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"552a6df4-8af6-4235-9ec7-efd64eca03c9","owner":[],"postedDate":"January 20th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T14:53:37+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-20 10:41:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8570961","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8570961","identity":"rs-8570961","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}