Impact of APOE Genotype on Neurocognition Following Conformal Whole Brain Radiotherapy for Brain Metastases: A Post hoc Analysis of Phase II Randomized Trial

Impact of APOE Genotype on Neurocognition Following Conformal Whole Brain Radiotherapy for Brain Metastases: A Post hoc Analysis of Phase II Randomized Trial | 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 Impact of APOE Genotype on Neurocognition Following Conformal Whole Brain Radiotherapy for Brain Metastases: A Post hoc Analysis of Phase II Randomized Trial Ming-Che Kuo, Wen-Chi Yang, Ya-Fang Chen, Chi-Cheng Yang, Ming-Jang Chiu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6431871/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The genetic risk of radiotherapy-induced cognitive decline (RICD) in patients undergoing whole-brain radiotherapy (WBRT) has not been clearly established. Apolipoprotein E (APOE) polymorphisms, known to influence cognitive aging and Alzheimer’s disease risk, may also modulate neurocognitive outcomes after cranial irradiation. This post-hoc analysis investigates the association between APOE genotype and RICD in patients with brain metastases (BM) treated with conformal or hippocampal-avoidant (HA) WBRT. Methods Patients with BM were randomly assigned to receive conformal or hippocampal avoidant (HA) WBRT. Patients had at least four-month follow-up and APOE genotype information were eligible for this post-hoc analysis. The association between APOE genotype and RICD measured by the Hopkins Verbal Learning Test–Revised (HVLT-R) was analyzed by the general linear model. Results Among 70 randomized patients, APOE genotyping was available for 60% of patients (ε3/ε3, n = 24; ε2/ε3, n = 11; ε4/ε3, n = 7). No differences in baseline characteristics and cognition were observed among patients with different APOE genotypes. At six-month, patients carrying the APOE ε2 allele had the best preservation in HVLT-R total recall (mean difference, ε2: +3.18 versus ε4: −3.20, p = 0.007) and delayed recall (mean difference, ε2 carrier: +0.46 versus ε4 carrier: −2.40, p = 0.049) whereas those with the ε4 allele had the worst. Only patients with the APOE ε3 homozygous alleles showed an improvement in late memory score preservation six months following HA-WBRT (mean difference, HA: +3.67 versus conformal: −3.18, p = 0.037) and beyond. Conclusions APOE genotype is associated with the RICD risk and the effect of benefit in the preservation of late verbal memory following HA-WBRT for patients with BM. Further prospective investigations are warranted to validate our proposed hypothesis. Trial Registration This trial is registered at ClinicalTrials.gov (NCT02393131). Apolipoprotein E Genotype Whole brain radiotherapy Cognition Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Brain metastasis (BM) is common in cancer patients. Up to 30 percent of cancer patients develop BM in their disease course and have poor survival outcomes [ 1 ]. Whole brain radiotherapy (WBRT) has been considered as the standard of care for patients with multiple BM [ 2 ]. Despite its effectiveness, patients who received standard WBRT frequently undergo a decline in neurocognitive function 4 to 6 months after treatment, which can be irreversible and rapidly progressive at 12 months or later [ 3 – 5 ]. After WBRT, multiple domains including executive function, processing speed, learning, memory, and attention are affected due to the involvement of both the hippocampus and pre-frontal cortex [ 6 ], as opposed to the memory decline exclusively seen in early Alzheimer’s disease. The pathogenesis of radiotherapy-induced cognitive decline (RICD) is multifactorial and involves a decrease in neurogenesis, alterations in NMDA receptor subunit composition, disrupted Arc expression in hippocampal neurons, oxidative stress/neuroinflammation, gliosis, demyelination, vascular injury, and genetic risk factors [ 7 , 8 ]. However, WBRT remains the mainstay treatment for multiple BM and thus ameliorating the side effects of RICD has remained an active area of research in recent decades. Recent advances in multi-modality therapies (including pharmacological therapies and radio-surgical techniques) have led to improvements in survival for patients with BM [ 9 ]. Previous studies have also shown that two medications prescribed for Alzheimer’s disease, memantine and donepezil, can reduce WBRT-induced neurocognitive decline [ 10 , 11 ]. Hippocampal avoidant WBRT (HA-WBRT) was also shown to be protective against neurocognition decline in randomized clinical trials [ 12 , 13 ]. In our previous single-blinded phase II randomized trial, the protective effect of hippocampal avoidance was only found for verbal function and memory after WBRT for multiple BM [ 13 ]. This finding suggests that hippocampal injury participates in the impaired verbal learning following RICD. However, the risks to other neurocognitive domains such as processing speed and executive function as consequences of RICD remain largely unknown. Apolipoprotein E (APOE) polymorphisms are well known to affect the risk of Alzheimer’s disease [ 14 ] wherein the APOE ε4 allele confers an increased risk and ε2 confers a decreased risk of Alzheimer’s disease [ 15 ]. Genetic variations, including those in the APOE gene, have also been reported to influence the risk of cognitive impairment for patients with primary brain tumors [ 16 – 18 ]. Nevertheless, there is limited research addressing the impact of the APOE genotype on the risks of WBRT-related RICD [ 19 ]. This study is a post hoc analysis based on our previous data to investigate the association of APOE genotype with neurocognitive outcomes in BM patients who received WBRT with or without hippocampal avoidance. Methods Study design and participants This study was approved by the institutional research ethics committee and informed consent was obtained from each patient in written form. This randomized trial is registered in ClinicalTrials.gov with the identifier NCT02393131. Eligible patients included those with histologically-proven non-hematological malignancy and radiographic evidence of BM outside a 5 mm margin around either hippocampus via gadolinium contrast-enhanced MRI obtained within the 30 days prior to registration. The detailed enrollment criteria are described in our previous study [ 13 ]. Patients who met all eligibility criteria were randomly assigned to receive either hippocampal avoidance WBRT or conformal WBRT. Treatment The WBRT treatment was 3 Gy per fraction once per workday for continuous workdays (Monday to Friday) for 10 days, for a total dose of 30 Gy. Contouring was carried out in accordance with the Radiation Therapy Oncology Group (RTOG) atlas with the assistance of experienced neuro-radiologists [ 20 ]. Dosimetry criteria for radiotherapy planning have been previously described [ 13 ]. Treatment was delivered with daily image guidance. Patients were not allowed to take neurological drugs for Alzheimer’s disease (memantine, donepezil, etc.) during the study period. Clinical assessment All patients were evaluated at entry, during, and after treatment as previously reported [ 13 ]. Neurocognitive function tests were assessed at baseline as well as following WBRT at one, two, four, and six months, followed by every three months up to 24 months unless intracranial progression or death occurred. The neuropsychological test battery included the Hopkins Verbal Learning Test–Revised (HVLT-R) and Trail Making Test (TMT) was performed by blinded independent health professionals and data were recorded as raw scores and time without normalization in accordance to the protocol of our previous work [ 13 ]. The memory score (MS) of HVLT-R is defined as the sum of the HVLT-R recognition index (RI) and total recall (TR) [ 21 ]. The Traditional Chinese versions of all tests and questionnaires were used and approved by a board-certified neurologist and psychologist. The gadolinium contrast-enhanced MRI was used to assess baseline intracranial volume, hippocampal volume, and the ratio of hippocampus to total intracranial volume. APOE genotyping APOE genotyping data was obtained by a genome-wide analysis performed at the National Center for Genome Medicine of Academia Sinica using the Axiom‐Taiwan Biobank Array Plate (TWB chip; Affymetrix Inc, Santa Clara, CA, USA). The TWB chip, which consists of 653,291 SNPs, was specifically customized for the Taiwanese population. Statistical analysis Descriptive data were reported and compared between groups. For continuous variables, an independent one-way analysis of variance (ANOVA) was used whereas Chi-square or Fisher’s exact tests were performed to compare categorical variables. General linear models including one-way ANOVA, unpaired t-tests, and mixed effect models were used to assess the effect of factors associated with the changes in neurocognitive function after WBRT. Factorial ANOVA based on type II sums of squares was used to assess the independent factors associated with neurocognitive outcomes. Survival outcomes were estimated using the Kaplan–Meier method and the genotypic differences between groups were assessed using the log–rank test. A two-sided p-value of less than 0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism version 8.4 (GraphPad Software Inc., San Diego, CA, USA) and IBM SPSS version 25 (SPSS Inc., Chicago, IL, USA). Results Patient characteristics From March 2015 to December 2018, 70 eligible patients were enrolled and randomized, of which 65 completed the trial protocol for clinical analysis. Among them, 49 patients had a four-month or longer follow-up time for neurocognitive outcome assessment and of these, 42 had available APOE genotyping data and were ultimately included in this post hoc analysis. The CONSORT diagram is shown in Fig. 1 . Patient characteristics between different APOE genotype groups are summarized in Table 1 . The most frequent APOE genotype was ε3/ε3 alleles ( n = 24, 57%), followed by ε2/ε3 alleles ( n = 11, 26%), and lastly ε4/ε3 alleles ( n = 7, 17%). No ε2 or ε4 homozygotes were identified. The median age was 59.9 years old. The study cohort was predominantly female and nearly all patients had primary lung cancer except one patient in the ε3/ε3 group, who had primary breast cancer. There were no significant differences in terms of age, sex, Karnofsky performance status, education level, or graded prognostic assessment score between patients with different APOE genotypes. The proportion of patients that received hippocampal avoidance WBRT was similar between groups ( p = 0.858). In addition, there was no difference in baseline absolute intracranial volume, absolute hippocampal volume, and relative hippocampal percentage between patients with different APOE genotypes (Table 1 ). Table 1 Patient characteristics APOE ε2/ε3 APOE ε3/ε3 APOE ε4/ε3 Feature N = 11 n (%) N = 24 n (%) N = 7 n (%) p value Age (median, range), years old 59.9 (43–66) 58.9 (44–71) 60.4 (48–65) 0.843 Sex 0.686 Male 4 (36) 11 (46) 4 (57) Female 7 (64) 13 (54) 3 (43) KPS (median, range) 90 (70–90) 90 (70–90) 80 (70–90) 0.129 GPA (median, range) 1.0 (0.5–3) 1.5 (0.5–2.5) 1.5 (0.5–2.5) 0.656 Pre-treatment neurological symptoms 0.781 None 9 (82) 17 (71) 5 (71) Minor 2 (18) 7 (29) 2 (29) Primary cancer 0.681 Lung 11 (100) 23 (96) 7 (100) Breast 0 (0) 1 (4) 0 (0) Highly educated a 11 (100) 20 (83) 7 (100) 0.191 Hippocampal-avoidance WBRT 5 (46) 11 (46) 4 (57) 0.858 Baseline intracranial volume (mean, range), cm 3 1358 (1059–1528) 1363 (1090–1592) 1418 (1185–1539) 0.631 Baseline hippocampus volume (mean, range), cm 3 6.93 (5.89–8.37) 6.76 (5.34–8.51) 6.89 (6.07–8.32) 0.818 Baseline hippocampus percentage (mean, range), % 0.51 (0.56–0.61) 0.5 (0.42–0.58) 0.49 (0.42–0.59) 0.495 APOE genotype and neurocognitive outcomes after WBRT At baseline, there were no differences among patient APOE genotypes in terms of neurocognitive functions including HVLT-R TR, DR, RI, MS, or TMT-B (Table 2 ). At four months after WBRT, there were still no differences in HVLT-R TR, DR, RI, MS, or TMT-B from baseline among patients with different APOE genotypes ( Table 2 ). Among the patients who survived six months after WBRT without intracranial progression, APOE genotypes were associated with risks of neurocognitive decline as measured by HVLT-R TR ( p = 0.007), DR ( p = 0.049), and MS ( p = 0.015) but not HVLT-R RI ( p = 0.357) or TMT-B ( p = 0.450) (Table 2 ). By pairwise multiple comparisons, patients carrying the APOE ε2 protective allele had a superior preservation of HVLT-R TR scores (+ 3.18, 95% confidence interval [CI]: +0.78 to + 5.58) after WBRT compared to those with the homozygous ε3 neutral alleles (− 0.59, 95% CI: −2.97 to + 1.80, p = 0.02) and those carrying the ε4 high-risk allele (− 3.20, 95% CI: −7.26 to + 0.86, p = 0.003; Fig. 2 A). In contrast, patients carrying the ε4/ε3 alleles had an inferior preservation of HVLT-R DR scores (− 2.40, 95% CI: −5.12 to + 0.32) after WBRT compared to patients with the ε3/ε3 alleles (0.00, 95% CI: −0.96 to + 0.96, p = 0.045) and those carrying the ε2/ε3 alleles (+ 0.46, 95% CI: −0.80 to + 1.71, p = 0.015). Overall, the preservative effect was strongest in the APOE ε2 carriers followed by the ε3 homozygotes, and weakest in the ε4 carriers. Of note, six months following hippocampal avoidance WBRT, the study cohort showed an improved preservation of HVLT-R RI (+ 0.50 versus − 1.37, p = 0.027) and memory scores (+ 2.43 versus − 2.32, p = 0.027), but not HVLT-R TR (+ 1.93 versus − 0.95, p = 0.091) or HVLT-R DR (+ 0.50 versus − 0.74, p = 0.087; Fig. 2 B), as previously reported [ 13 ]. Table 2 Neurocognitive function at baseline and changes from baseline at four and six months in patients with different APOE genotypes APOE ε2/ε3 APOE ε3/ε3 APOE ε4/ε3 p value Baseline neurocognitive function N = 11 N = 24 N = 7 HVLT-R total recall 18.73 (15.42–20.03) 18.54 (16.21–20.88) 21.43 (16.63–26.23) 0.570 HVLT-R delayed recall 7.00 (4.65–9.35) 5.58 (4.38–6.79) 7.71 (5.53–9.90) 0.145 HVLT-R recognition index 11.09 (10.33–11.85) 9.75 (8.71–10.79) 10.57 (9.40–11.75) 0.214 HVLT-R memory score 29.82 (26.25–33.38) 28.29 (25.15–31.43) 32.00 (26.58–37.52) 0.564 TMT-B (s) 60.64 (50.19–71.08) 76.96 (58.42–95.49) 77.00 (52.64–101.4) 0.338 Changes from baseline to four months after WBRT N = 11 N = 24 N = 7 HVLT-R total recall + 2.73 (-1.11 – +6.56) + 1.04 (-1.53 – +3.61) + 2.29 (-4.05 – +8.62) 0.558 HVLT-R delayed recall + 0.46 (-1.36 – +2.27) + 0.33 (-0.72 – +1.39) -1.00 (-3.39 – +1.39) 0.439 HVLT-R recognition index -1.00 (-2.70–0.70) -1.04 (-2.35 – +0.26) -0.71 (-2.20 – +0.77) 0.844 HVLT-R memory score + 1.73 (-2.69 – +6.14) + 0.00 (-3.35 – +3.35) + 1.57 (-5.01 – +8.15) 0.880 TMT-B (s) -0.9 (-13.7 – +11.9) + 14.5 (-7.7 – +36.7) + 13.7 (-38.9 – +66.2) 0.866 Changes from baseline to six months after WBRT N = 11 N = 17 N = 5 HVLT-R total recall + 3.18 (+ 0.78 – +5.58) -0.59 (-2.97 – +1.80) -3.20 (-7.26 – +0.86) 0.007 HVLT-R delayed recall + 0.46 (-0.80 – +1.71) + 0.00 (-0.96 – +0.96) -2.40 (-5.12 – +0.32) 0.049 HVLT-R recognition index -0.36 (-1.28 – +0.56) -0.18 (-1.54 – +1.19) -2.40 (-6.58 – +1.77) 0.357 HVLT-R memory score + 2.82 (-0.30 – +5.94) -0.77 (-3.91 – +2.38) -5.60 (-12.3 – +1.06) 0.015 TMT-B (s) -6.2 (-25.7 – +13.3) + 4.5 (-17.1 – +26.1) + 7.4 (-96.8 – +111.6) 0.450 APOE genotype and hippocampal avoidant WBRT The impact of APOE genotype on outcomes following WBRT with and without hippocampal avoidance was investigated. Patient characteristics between the hippocampal avoidant WBRT arm and the conformal WBRT arm relative to the APOE genotypes are summarized in Supplementary Table S1 . Verbal learning and memory were preserved by avoiding the hippocampus during WBRT in patients with the neutral APOE ε3 alleles (Fig. 3 A) but not in patients with the ε2 or ε4 allele (Fig. 3 B). For the APOE ε3 homozygotes with BM, patients who received hippocampal avoidant WBRT had a significantly better preservation in memory score compared to those receiving conformal WBRT without hippocampal avoidance at six (+ 3.67 versus − 3.18, p = 0.037), nine (+ 3.40 versus − 3.38, p = 0.037), and 12 (+ 9.20 versus + 0.71, p = 0.045) months after treatment. Independent factors associated with neurocognitive outcomes Age (≥ median versus < median), radiotherapy technique (hippocampal avoidant versus conformal), and APOE genotype (ε2/ε3 versus ε3/ε3 versus ε3/ε4) were used for factorial ANOVA to evaluate the independent factors associated with memory preservation assessed by HVLT-R at six months after WBRT. APOE genotype was independently associated with HVLT-R TR ( p = 0.042) and HVLT-R DR ( p = 0.032) but not HVLT-R RI ( p = 0.264). Hippocampal avoidance during WBRT was independently associated with HVLT-R RI ( p = 0.022) but not HVLT-R TR ( p = 0.051) or HVLT-R DR ( p = 0.060). Age was independently associated with HVLT-R RI ( p = 0.020) and HVLT-R DR ( p = 0.026) but not HVLT-R TR ( p = 0.148). APOE genotype and survival outcomes With a median follow-up of 42 months (range: 4.4 to 54.8 months), the median overall survival and freedom from intracranial progression was 26.4 months and 17.9 months, respectively. The median overall survival for patients with the APOE ε2/ε3, ε3/ε3, and ε4/ε3 alleles was 26.8, 27.5, and 9.1 months (log–rank, p = 0.348, Fig. 4 A), respectively. The median intracranial progression-free interval was 15.4, 19.7, and 9 months (log–rank, p = 0.794, Fig. 4 B), respectively. APOE genotype had no significant impact on intracranial control. Patients carrying APOE ε4 allele had a numerical worse overall survival compared to those with APOE ε2 allele (pairwise log–rank, p = 0.099). Discussion APOE genotype is well known to play a crucial role in the pathogenesis of Alzheimer’s disease [ 22 , 23 ]. However, the impact of APOE genotype on an individual’s neurocognitive prognosis after brain irradiation previously remained undetermined. This post hoc analysis of a phase II blinded randomized trial demonstrates the modulatory effect of APOE genotypes on the risk of RICD following WBRT with and without hippocampal avoidance. Importantly, a protective effect of the APOE ε2 allele as well as a deleterious effect of the ε4 allele on memory function were identified six months after WBRT. This association has only been previously reported in a conference abstract of the randomized blinded controlled trial (RTOG-0614) [ 19 ]. To the best of our knowledge, the present study contains the first fully published clinical evidence to support the hypothesis that APOE genotypes may modulate RICD for BM in a prospective trial, particularly in a Han-Chinese population. Although the mechanisms of RICD remain poorly understood [ 7 , 8 ], radiation-induced vascular damage, neuroinflammation, deficits in neuron lineages and glial progenitors, and impairments in hippocampal neurogenesis have all been hypothesized to be responsible for radiation-induced brain injury. Two-thirds of post-RT brain tumor survivors meet the National Institute on Aging and the Alzheimer's Association criteria for mild cognitive impairment [ 24 ]. Although RICD is common and multifactorial [ 24 ], there is considerable heterogeneity in neurocognitive outcomes across individuals, suggesting that genetic risk factors may modulate patient vulnerability to treatment-induced neurotoxicity [ 25 ]. Several genetic variations have been reported to be associated with cognitive functions for patients diagnosed with primary brain tumors [ 16 – 18 ]. The majority of these patients also received cranial irradiation. Correa et al. reported that patients who carried the APOE ε4 allele had significantly impaired verbal learning at least six months after completion of chemotherapy or RT [ 16 ]. The authors also reported that certain polymorphisms in catechol-O-methyl transferase, brain-derived neurotrophic factor, and dystrobrevin-binding protein 1 were significantly associated with lower scores in verbal memory [ 18 ]. On the other hand, Liu et al. reported the single nucleotide polymorphism in RAD51L1, which is involved in DNA repair, as a potential modulator of verbal memory prior to surgery [ 17 ]. Of note, none of these studies conducted longitudinal studies to evaluate the impact of genetic variations on cognitive function changes before and after treatment. In contrast to primary brain tumors, little is known about the generic risks associated with RICD for patients with BM. Wefel et al. first performed an analysis of RTOG 0614 to evaluate APOE carrier status as a risk of neurocognitive function impairment before and after WBRT with or without memantine for BM [ 19 ]. The proportion of APOE ε4 allele carriers was 29.5% in the study population. There was no difference in performance on neurocognitive function tests at baseline among patients with different APOE genotypes, which is compatible with our findings. Furthermore, patients carrying the APOE ε4 allele exhibited worse memory outcomes after WBRT assessed by HVLT-R TR and HVLT-R RI. In the present study, patients harboring the APOE ε4 allele also showed significantly worse verbal memory function as measured by HVLT-R TR and HVLT-R DR but not by HVLT-R RI six months after WBRT. Taken together, these data suggest that APOE genotypes may play a role in the decline of memory function after WBRT for BM. Although the exact role of APOE alleles in neurocognitive decline following WBRT remains unclear, research within the last decade has shed light on the role of APOE genotypes in the pathogenesis of dementia. One potential mechanism is that the APOE ε4 allele promotes disruption of the blood brain barrier (BBB) [ 22 ], particularly in the hippocampus [ 26 ]. Interestingly, both primary and metastatic tumors as well as ionizing radiation have been shown to alter BBB integrity [ 27 ]. Therefore, one possible explanation is that BBB disruption by BM and WBRT might be aggravated in ε4 carriers, resulting in greater cognitive decline. In addition to BBB dysfunction, the APOE ε4 variant was found to be associated with disruption of vascular regulation and increased brain microbleeds [ 28 , 29 ], both of which may be further exacerbated by cranial irradiation [ 30 , 31 ], contributing to long-term neurocognitive impairment. Different APOE genotypes have also been implicated in the accumulation and clearance of β-amyloid in the brain with a similar protective effect seen in ε2 allele carriers and a negative effect in ε4 allele carriers [ 23 ]. Likewise, cranial irradiation is also a risk factor for β-amyloid deposition [ 32 ]. Despite these indirect data supporting the hypothesis of an association between APOE variants and RICD, sufficient evidence from animal studies remains elusive to fully validate this hypothesis [ 33 – 35 ]. Another important finding of the present study is the potential interaction between APOE genotype and the maintenance of neurocognitive functions following hippocampal avoidant WBRT. The benefit of hippocampal avoidant WBRT was predominantly observed in the APOE ε3 homozygotes rather than the patients carrying the ε2 or ε4 allele. Preclinical animal studies have demonstrated that the APOE genotypes distinctly affect the susceptibility of hippocampus-dependent cognitive performance to 56 Fe irradiation [ 34 , 35 ]. Haley et al. reported that radiation impaired spatial memory retention in ε2 and ε4 mice but enhanced it in ε3 mice [ 34 ]. In contrast, Yeiser et al. demonstrated that ε3 mice were more vulnerable than ε2 or ε4 mice to impairments in spatial memory retention [ 35 ]. Interestingly, both studies imply that APOE ε3 modulates RICD differently than the ε2 or ε4 variants. The present study has some limitations. There is a lack of domains other than verbal learning and memory though HVLT-R has already been widely used in cognitive studies in cancer patients [ 6 ]. Since the survival time is limited for patients with multiple BM, the sample size is relatively small, as it was constrained by the design of a post hoc analysis of a randomized controlled trial for unbalanced unrecognized confounding factors. It is likely underpowered to elucidate our novel findings, which should be further corroborated in larger prospective trials. In addition, there is a lack of imaging or biomarker evidence to adequately support the hypothesis. Hence, our planned exploratory analysis should be interpreted as a hypothesis-generating research rather than a confirmatory study. Despite these limitations, patient compliance for longitudinal neurocognitive function tests after WBRT was relatively high compared to similar trials [ 10 , 12 ]. The blinding of testers and patients also greatly mitigated any psychotherapeutic effects in test results. Furthermore, the relatively homogenous patient population, mostly diagnosed with primary lung cancer diagnosis, reduced potential biases. Conclusions Patients carrying the APOE ε2 protective allele showed better preserved late memory function, while those carrying the ε4 high-risk allele fared worse, although executive function was unaffected. The APOE neutral ε3/ε3 homozygotes benefited most from hippocampal avoidant WBRT for the maintenance of neurocognitive function for multiple BM. The protective effect of hippocampal avoidant WBRT is thus limited for APOE ε2 and ε4 carriers. Taking APOE genotype into consideration may assist in developing individualized precision radiotherapy strategies for patients with multiple BM. Abbreviations Abbreviation Full Term ANOVA Analysis of Variance APOE Apolipoprotein E BBB Blood–Brain Barrier BM Brain Metastases CI Confidence Interval DR Delayed Recall HA-WBRT Hippocampal Avoidant Whole-Brain Radiotherapy HVLT-R Hopkins Verbal Learning Test–Revised KPS Karnofsky Performance Status MRI Magnetic Resonance Imaging MS Memory Score NMDA N-Methyl-D-Aspartate RICD Radiotherapy-Induced Cognitive Decline RI Recognition Index RT Radiotherapy RTOG Radiation Therapy Oncology Group SNP Single Nucleotide Polymorphism SPSS Statistical Package for the Social Sciences TMT Trail Making Test TMT-B Trail Making Test Part B TR Total Recall TWB chip Taiwan Biobank Array Plate WBRT Whole-Brain Radiotherapy Declarations Acknowledgments This work was partially supported by the National Taiwan University Hospital, Taipei, Taiwan (NTUH 110-N4937 to Wen-Chi Yang) and the Ministry of Science and Technology, Executive Yuan, Taipei, Taiwan (MOST 110-2314-B-002-289-MY3 to Feng-Ming Hsu). We appreciate the assistance from Professor Pan-Chyr Yang, M.D., Ph.D. at Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan in resource for single nucleotide polymorphism genotyping. We acknowledge the service and support provided by the Eighth Core Lab at the Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. We would like to thank Uni-edit for editing and proofreading this manuscript. Author contributions (I) Conception and design: MCK, WCY, CCY, FMH; (II) Administrative support: MJC, TFC, JCHC, SHK, FMH; (III) Provision of study materials or patients: WCY, FMH,; (IV) Collection and assembly of data: WCY, FMH; (V) Data analysis and interpretation: MCK, WCY, YFC, FMH; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Funding Information: This work was partially supported by the National Taiwan University Hospital, Taipei, Taiwan (NTUH 110-N4937 to Wen-Chi Yang) and the Ministry of Science and Technology, Executive Yuan, Taipei, Taiwan (MOST 110-2314-B-002-289-MY3 to Feng-Ming Hsu). Conflict of Interest Statement All authors declare no conflicts of interest. Data Availability Statement Data is available on request Clinical Trial Registration The randomized trial is registered in ClinicalTrials.gov with the identifier NCT02393131. Ethics Approval and Patient Consent statement This study was approved by the Institutional Review Board (IRB) of National Taiwan University, Taiwan (IRB number: 201901084MINA). All patients provided written informed consent prior to participation. References Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. 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Liu Y, Zhou R, Sulman EP, Scheurer ME, Boehling N, Armstrong GN, et al. Genetic Modulation of Neurocognitive Function in Glioma Patients. Clin Cancer Res. 2015;21:3340–6. Correa DD, Satagopan J, Cheung K, Arora AK, Kryza-Lacombe M, Xu Y, et al. COMT, BDNF, and DTNBP1 polymorphisms and cognitive functions in patients with brain tumors. Neuro Oncol. 2016;18:1425–33. Wefel JS, Deshmukh S, Brown PD, Grosshans DR, Sulman EP, Cerhan JH, et al. Impact of apolipoprotein E (APOE) genotype on neurocognitive function (NCF) in patients with brain metastasis (BM): an analysis of NRG Oncology’s RTOG 0614. J Clin Oncol. 2018;36:2065. Gondi V, Tolakanahalli R, Mehta MP, Tewatia D, Rowley H, Kuo JS, et al. Hippocampal-sparing whole-brain radiotherapy: a how-to technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2010;78:1244–52. Hogervorst E, Combrinck M, Lapuerta P, Rue J, Swales K, Budge M. The Hopkins Verbal Learning Test and screening for dementia. Dement Geriatr Cogn Disord. 2002;13:13–20. Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020;581:71–6. Insel PS, Hansson O, Mattsson-Carlgren N. Association Between Apolipoprotein E ε2 vs ε4, Age, and β-Amyloid in Adults Without Cognitive Impairment. JAMA Neurol. 2021;78:229–35. Cramer CK, McKee N, Case LD, Chan MD, Cummings TL, Lesser GJ, et al. Mild cognitive impairment in long-term brain tumor survivors following brain irradiation. J Neurooncol. 2019;141:235–44. Wefel JS, Noll KR, Scheurer ME. Neurocognitive functioning and genetic variation in patients with primary brain tumours. Lancet Oncol. 2016;17:e97–108. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85:296–302. Arvanitis CD, Ferraro GB, Jain RK. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer. 2020;20:26–41. Koizumi K, Hattori Y, Ahn SJ, Buendia I, Ciacciarelli A, Uekawa K, et al. Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function. Nat Commun. 2018;9:3816. Knol MJ, Lu D, Traylor M, Adams HHH, Romero JRJ, Smith AV, et al. Association of common genetic variants with brain microbleeds: A genome-wide association study. Neurology. 2020;95:e3331–3343. Hahn CA, Zhou SM, Raynor R, Tisch A, Light K, Shafman T, et al. Dose-dependent effects of radiation therapy on cerebral blood flow, metabolism, and neurocognitive dysfunction. Int J Radiat Oncol Biol Phys. 2009;73:1082–7. Morrison MA, Hess CP, Clarke JL, Butowski N, Chang SM, Molinaro AM, et al. Risk factors of radiotherapy-induced cerebral microbleeds and serial analysis of their size compared with white matter changes: A 7T MRI study in 113 adult patients with brain tumors. J Magn Reson Imaging. 2019;50:868–77. Sugihara S, Ogawa A, Nakazato Y, Yamaguchi H. Cerebral beta amyloid deposition in patients with malignant neoplasms: its prevalence with aging and effects of radiation therapy on vascular amyloid. Acta Neuropathol. 1995;90:135–41. Villasana L, Acevedo S, Poage C, Raber J. Sex- and APOE isoform-dependent effects of radiation on cognitive function. Radiat Res. 2006;166:883–91. Haley GE, Villasana L, Dayger C, Davis MJ, Raber J. Apolipoprotein e genotype-dependent paradoxical short-term effects of (56)fe irradiation on the brain. Int J Radiat Oncol Biol Phys. 2012;84:793–9. Yeiser LA, Villasana LE, Raber J. ApoE isoform modulates effects of cranial ⁵⁶Fe irradiation on spatial learning and memory in the water maze. Behav Brain Res. 2013;237:207–14. Squire LR, Genzel L, Wixted JT, Morris RG. Memory consolidation. Cold Spring Harb Perspect Biol. 2015;7:a021766. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTableS1.docx Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6431871","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":457305259,"identity":"1861ef68-d370-483e-b74d-e309271df191","order_by":0,"name":"Ming-Che Kuo","email":"","orcid":"","institution":"National Taiwan University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Ming-Che","middleName":"","lastName":"Kuo","suffix":""},{"id":457305260,"identity":"1d2451b8-71eb-46db-b66f-e055d54e4131","order_by":1,"name":"Wen-Chi Yang","email":"","orcid":"","institution":"National Taiwan University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Wen-Chi","middleName":"","lastName":"Yang","suffix":""},{"id":457305261,"identity":"66965bac-9a34-4773-be96-8516d60d4719","order_by":2,"name":"Ya-Fang Chen","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ya-Fang","middleName":"","lastName":"Chen","suffix":""},{"id":457305262,"identity":"4f52d28a-f04b-4055-9ccb-045d9ad0add5","order_by":3,"name":"Chi-Cheng Yang","email":"","orcid":"","institution":"National Chengchi University","correspondingAuthor":false,"prefix":"","firstName":"Chi-Cheng","middleName":"","lastName":"Yang","suffix":""},{"id":457305263,"identity":"2164203a-4dd1-411b-9aec-f5786e770443","order_by":4,"name":"Ming-Jang Chiu","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ming-Jang","middleName":"","lastName":"Chiu","suffix":""},{"id":457305264,"identity":"7321f7b5-fdf5-4eb5-94fe-081887418739","order_by":5,"name":"Ta-Fu Chen","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ta-Fu","middleName":"","lastName":"Chen","suffix":""},{"id":457305265,"identity":"20051dac-7d9a-4482-90d1-83a1c78eacb0","order_by":6,"name":"Jason Chia-Hsien Cheng","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jason","middleName":"Chia-Hsien","lastName":"Cheng","suffix":""},{"id":457305266,"identity":"3b92332f-4e68-482b-b489-ff31d8dd398f","order_by":7,"name":"Sung-Hsin Kuo","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sung-Hsin","middleName":"","lastName":"Kuo","suffix":""},{"id":457305267,"identity":"8d43d698-3330-42bc-8856-4011fbf7ef50","order_by":8,"name":"Feng-Ming Hsu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/0lEQVRIiWNgGAWjYBACAyD+AGKwMTAwPgDSCcRoYZwB1cJsANQA1YJHJ1wLSJcEUVrM+c8YNnzcURvNJ91+rbrwx+E8Bv7FxyQYfxzGqcVyRo5h48wzx3PbZM6U3Z6RcLiYQeJZGtA63FoMbvCYP+ZtO5bbJpGTdpsn4XBig8QZY6CnbuPWcv6MYfNfqJZi4rQcyDFsZmyrAWpJP8YM1sLfY/gAr5YbaYWNvW0HQLYwS/OkpSe2SbAlPkhI+4/HYYc3Nvxsq8udPyP94WceG+vEfv7DBw58sEnDqQUKQOHDYwBmskkkEJMGGOqAmP0BhM1/gLD6UTAKRsEoGFEAAFq0XHMaL/WTAAAAAElFTkSuQmCC","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Feng-Ming","middleName":"","lastName":"Hsu","suffix":""}],"badges":[],"createdAt":"2025-04-12 03:23:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6431871/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6431871/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83019984,"identity":"f9a1f758-abf7-4d5b-954c-1ad1d2eb1cfe","added_by":"auto","created_at":"2025-05-19 07:13:32","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":396844,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT diagram of the post hoc study cohort.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6431871/v1/2d27032160559dee3c353346.jpg"},{"id":83019057,"identity":"4af239c2-d121-420d-a765-b278d795f56c","added_by":"auto","created_at":"2025-05-19 07:05:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":872268,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plots of raw score changes in Hopkins verbal learning test–revised (HVLT-R) total recall, delayed recall, recognition index, and memory score at six months after WBRT grouped by \u003cstrong\u003e(A)\u003c/strong\u003e APOE genotype (ε2/ε3, ε3/ε3, ε4/ε3), and \u003cstrong\u003e(B)\u003c/strong\u003e whole brain radiotherapy techniques (hippocampal avoidance [HA], conformal [C]). Line indicates mean with 95% confidence intervals.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6431871/v1/5ab001b6d21ad764eda663dd.png"},{"id":83019059,"identity":"98022880-fcef-4517-81bb-c779c4f9d900","added_by":"auto","created_at":"2025-05-19 07:05:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1370036,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in Hopkins verbal learning test–revised (HVLT-R) memory score and the sum of total recall and recognition index from baseline between the hippocampal avoidant WBRT arm and the conformal WBRT arm in patients with the \u003cstrong\u003e(A)\u003c/strong\u003e APOE ε3/ ε3 genotype or \u003cstrong\u003e(B)\u003c/strong\u003e APOE ε2/ε3 or ε4/ε3 genotypes. Data are plotted as means and 95% confidence intervals.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6431871/v1/fd28b2fec05ec8030470776b.png"},{"id":83019067,"identity":"0fc4b430-d4e8-4eed-8d0b-1afd8d5aa637","added_by":"auto","created_at":"2025-05-19 07:05:32","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":9757418,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves of \u003cstrong\u003e(A)\u003c/strong\u003e overall survival and \u003cstrong\u003e(B)\u003c/strong\u003e intracranial progression-free interval for analyzable patients with different Apolipoprotein E (APOE) genotypes (ε2/ε3 versus ε3/ε3 versus ε4/ε3). P values are shown by pairwise comparisons between APOE genotypes using the log-rank test.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6431871/v1/7c3987331498b2c2b8228c40.png"},{"id":100788381,"identity":"a4b0cfa8-650c-43ac-9c0a-399598deb67e","added_by":"auto","created_at":"2026-01-21 12:06:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":13911722,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6431871/v1/3f5b9083-5331-4a08-8982-581282eb105e.pdf"},{"id":83019073,"identity":"a550dc7d-3b2c-46f6-86aa-d45349408d28","added_by":"auto","created_at":"2025-05-19 07:05:32","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":2742453,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6431871/v1/dec6a2589064f38571de7e69.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of APOE Genotype on Neurocognition Following Conformal Whole Brain Radiotherapy for Brain Metastases: A Post hoc Analysis of Phase II Randomized Trial","fulltext":[{"header":"Background","content":"\u003cp\u003eBrain metastasis (BM) is common in cancer patients. Up to 30 percent of cancer patients develop BM in their disease course and have poor survival outcomes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Whole brain radiotherapy (WBRT) has been considered as the standard of care for patients with multiple BM [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Despite its effectiveness, patients who received standard WBRT frequently undergo a decline in neurocognitive function 4 to 6 months after treatment, which can be irreversible and rapidly progressive at 12 months or later [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. After WBRT, multiple domains including executive function, processing speed, learning, memory, and attention are affected due to the involvement of both the hippocampus and pre-frontal cortex [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], as opposed to the memory decline exclusively seen in early Alzheimer\u0026rsquo;s disease.\u003c/p\u003e \u003cp\u003eThe pathogenesis of radiotherapy-induced cognitive decline (RICD) is multifactorial and involves a decrease in neurogenesis, alterations in NMDA receptor subunit composition, disrupted Arc expression in hippocampal neurons, oxidative stress/neuroinflammation, gliosis, demyelination, vascular injury, and genetic risk factors [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, WBRT remains the mainstay treatment for multiple BM and thus ameliorating the side effects of RICD has remained an active area of research in recent decades. Recent advances in multi-modality therapies (including pharmacological therapies and radio-surgical techniques) have led to improvements in survival for patients with BM [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Previous studies have also shown that two medications prescribed for Alzheimer\u0026rsquo;s disease, memantine and donepezil, can reduce WBRT-induced neurocognitive decline [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHippocampal avoidant WBRT (HA-WBRT) was also shown to be protective against neurocognition decline in randomized clinical trials [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In our previous single-blinded phase II randomized trial, the protective effect of hippocampal avoidance was only found for verbal function and memory after WBRT for multiple BM [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This finding suggests that hippocampal injury participates in the impaired verbal learning following RICD. However, the risks to other neurocognitive domains such as processing speed and executive function as consequences of RICD remain largely unknown.\u003c/p\u003e \u003cp\u003eApolipoprotein E (APOE) polymorphisms are well known to affect the risk of Alzheimer\u0026rsquo;s disease [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] wherein the APOE ε4 allele confers an increased risk and ε2 confers a decreased risk of Alzheimer\u0026rsquo;s disease [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Genetic variations, including those in the APOE gene, have also been reported to influence the risk of cognitive impairment for patients with primary brain tumors [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Nevertheless, there is limited research addressing the impact of the APOE genotype on the risks of WBRT-related RICD [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This study is a \u003cem\u003epost hoc\u003c/em\u003e analysis based on our previous data to investigate the association of APOE genotype with neurocognitive outcomes in BM patients who received WBRT with or without hippocampal avoidance.\u003c/p\u003e "},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003e This study was approved by the institutional research ethics committee and informed consent was obtained from each patient in written form. This randomized trial is registered in ClinicalTrials.gov with the identifier NCT02393131. Eligible patients included those with histologically-proven non-hematological malignancy and radiographic evidence of BM outside a 5 mm margin around either hippocampus via gadolinium contrast-enhanced MRI obtained within the 30 days prior to registration. The detailed enrollment criteria are described in our previous study [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Patients who met all eligibility criteria were randomly assigned to receive either hippocampal avoidance WBRT or conformal WBRT.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eThe WBRT treatment was 3 Gy per fraction once per workday for continuous workdays (Monday to Friday) for 10 days, for a total dose of 30 Gy. Contouring was carried out in accordance with the Radiation Therapy Oncology Group (RTOG) atlas with the assistance of experienced neuro-radiologists [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Dosimetry criteria for radiotherapy planning have been previously described [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Treatment was delivered with daily image guidance. Patients were not allowed to take neurological drugs for Alzheimer\u0026rsquo;s disease (memantine, donepezil, etc.) during the study period.\u003c/p\u003e\n\u003ch3\u003eClinical assessment\u003c/h3\u003e\n\u003cp\u003eAll patients were evaluated at entry, during, and after treatment as previously reported [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Neurocognitive function tests were assessed at baseline as well as following WBRT at one, two, four, and six months, followed by every three months up to 24 months unless intracranial progression or death occurred. The neuropsychological test battery included the Hopkins Verbal Learning Test\u0026ndash;Revised (HVLT-R) and Trail Making Test (TMT) was performed by blinded independent health professionals and data were recorded as raw scores and time without normalization in accordance to the protocol of our previous work [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The memory score (MS) of HVLT-R is defined as the sum of the HVLT-R recognition index (RI) and total recall (TR) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The Traditional Chinese versions of all tests and questionnaires were used and approved by a board-certified neurologist and psychologist. The gadolinium contrast-enhanced MRI was used to assess baseline intracranial volume, hippocampal volume, and the ratio of hippocampus to total intracranial volume.\u003c/p\u003e\n\u003ch3\u003eAPOE genotyping\u003c/h3\u003e\n\u003cp\u003e APOE genotyping data was obtained by a genome-wide analysis performed at the National Center for Genome Medicine of Academia Sinica using the Axiom‐Taiwan Biobank Array Plate (TWB chip; Affymetrix Inc, Santa Clara, CA, USA). The TWB chip, which consists of 653,291 SNPs, was specifically customized for the Taiwanese population.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive data were reported and compared between groups. For continuous variables, an independent one-way analysis of variance (ANOVA) was used whereas Chi-square or Fisher\u0026rsquo;s exact tests were performed to compare categorical variables. General linear models including one-way ANOVA, unpaired t-tests, and mixed effect models were used to assess the effect of factors associated with the changes in neurocognitive function after WBRT. Factorial ANOVA based on type II sums of squares was used to assess the independent factors associated with neurocognitive outcomes. Survival outcomes were estimated using the Kaplan\u0026ndash;Meier method and the genotypic differences between groups were assessed using the log\u0026ndash;rank test. A two-sided p-value of less than 0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism version 8.4 (GraphPad Software Inc., San Diego, CA, USA) and IBM SPSS version 25 (SPSS Inc., Chicago, IL, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eFrom March 2015 to December 2018, 70 eligible patients were enrolled and randomized, of which 65 completed the trial protocol for clinical analysis. Among them, 49 patients had a four-month or longer follow-up time for neurocognitive outcome assessment and of these, 42 had available APOE genotyping data and were ultimately included in this post hoc analysis. The CONSORT diagram is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Patient characteristics between different APOE genotype groups are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The most frequent APOE genotype was ε3/ε3 alleles (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;24, 57%), followed by ε2/ε3 alleles (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11, 26%), and lastly ε4/ε3 alleles (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7, 17%). No ε2 or ε4 homozygotes were identified. The median age was 59.9 years old. The study cohort was predominantly female and nearly all patients had primary lung cancer except one patient in the ε3/ε3 group, who had primary breast cancer. There were no significant differences in terms of age, sex, Karnofsky performance status, education level, or graded prognostic assessment score between patients with different APOE genotypes. The proportion of patients that received hippocampal avoidance WBRT was similar between groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.858). In addition, there was no difference in baseline absolute intracranial volume, absolute hippocampal volume, and relative hippocampal percentage between patients with different APOE genotypes (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAPOE ε2/ε3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAPOE ε3/ε3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAPOE ε4/ε3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFeature\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11 \u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e (median, range), years old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59.9 (43\u0026ndash;66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58.9 (44\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.4 (48\u0026ndash;65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.843\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.686\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKPS\u003c/b\u003e (median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90 (70\u0026ndash;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90 (70\u0026ndash;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80 (70\u0026ndash;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.129\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGPA\u003c/b\u003e (median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.0 (0.5\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5 (0.5\u0026ndash;2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.5 (0.5\u0026ndash;2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.656\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePre-treatment \u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eneurological symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.781\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrimary cancer\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.681\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHighly educated\u003c/b\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.191\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHippocampal-avoidance WBRT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.858\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline intracranial volume\u003c/b\u003e (mean, range), cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1358 (1059\u0026ndash;1528)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1363 (1090\u0026ndash;1592)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1418 (1185\u0026ndash;1539)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.631\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline hippocampus volume\u003c/b\u003e (mean, range), cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.93 (5.89\u0026ndash;8.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.76 (5.34\u0026ndash;8.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.89 (6.07\u0026ndash;8.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.818\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline hippocampus percentage\u003c/b\u003e (mean, range), %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.51 (0.56\u0026ndash;0.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5 (0.42\u0026ndash;0.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.49 (0.42\u0026ndash;0.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.495\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAPOE genotype and neurocognitive outcomes after WBRT\u003c/h2\u003e \u003cp\u003eAt baseline, there were no differences among patient APOE genotypes in terms of neurocognitive functions including HVLT-R TR, DR, RI, MS, or TMT-B (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). At four months after WBRT, there were still no differences in HVLT-R TR, DR, RI, MS, or TMT-B from baseline among patients with different APOE genotypes \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among the patients who survived six months after WBRT without intracranial progression, APOE genotypes were associated with risks of neurocognitive decline as measured by HVLT-R TR (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), DR (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049), and MS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015) but not HVLT-R RI (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.357) or TMT-B (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.450) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). By pairwise multiple comparisons, patients carrying the APOE ε2 protective allele had a superior preservation of HVLT-R TR scores (+\u0026thinsp;3.18, 95% confidence interval [CI]: +0.78 to +\u0026thinsp;5.58) after WBRT compared to those with the homozygous ε3 neutral alleles (\u0026minus;\u0026thinsp;0.59, 95% CI: \u0026minus;2.97 to +\u0026thinsp;1.80, p\u0026thinsp;=\u0026thinsp;0.02) and those carrying the ε4 high-risk allele (\u0026minus;\u0026thinsp;3.20, 95% CI: \u0026minus;7.26 to +\u0026thinsp;0.86, p\u0026thinsp;=\u0026thinsp;0.003; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). In contrast, patients carrying the ε4/ε3 alleles had an inferior preservation of HVLT-R DR scores (\u0026minus;\u0026thinsp;2.40, 95% CI: \u0026minus;5.12 to +\u0026thinsp;0.32) after WBRT compared to patients with the ε3/ε3 alleles (0.00, 95% CI: \u0026minus;0.96 to +\u0026thinsp;0.96, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045) and those carrying the ε2/ε3 alleles (+\u0026thinsp;0.46, 95% CI: \u0026minus;0.80 to +\u0026thinsp;1.71, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015). Overall, the preservative effect was strongest in the APOE ε2 carriers followed by the ε3 homozygotes, and weakest in the ε4 carriers. Of note, six months following hippocampal avoidance WBRT, the study cohort showed an improved preservation of HVLT-R RI (+\u0026thinsp;0.50 versus \u0026minus;\u0026thinsp;1.37, p\u0026thinsp;=\u0026thinsp;0.027) and memory scores (+\u0026thinsp;2.43 versus \u0026minus;\u0026thinsp;2.32, p\u0026thinsp;=\u0026thinsp;0.027), but not HVLT-R TR (+\u0026thinsp;1.93 versus \u0026minus;\u0026thinsp;0.95, p\u0026thinsp;=\u0026thinsp;0.091) or HVLT-R DR (+\u0026thinsp;0.50 versus \u0026minus;\u0026thinsp;0.74, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.087; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), as previously reported [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eNeurocognitive function at baseline and changes from baseline at four and six months in patients with different APOE genotypes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAPOE ε2/ε3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAPOE ε3/ε3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAPOE ε4/ε3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eBaseline neurocognitive function\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R \u003c/p\u003e \u003cp\u003etotal recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.73 (15.42\u0026ndash;20.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.54 (16.21\u0026ndash;20.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.43 (16.63\u0026ndash;26.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.570\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R\u003c/p\u003e \u003cp\u003edelayed recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.00 (4.65\u0026ndash;9.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.58 (4.38\u0026ndash;6.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.71 (5.53\u0026ndash;9.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.145\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R\u003c/p\u003e \u003cp\u003erecognition index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.09 (10.33\u0026ndash;11.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.75 (8.71\u0026ndash;10.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.57 (9.40\u0026ndash;11.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.214\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R\u003c/p\u003e \u003cp\u003ememory score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.82 (26.25\u0026ndash;33.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.29 (25.15\u0026ndash;31.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.00 (26.58\u0026ndash;37.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.564\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTMT-B (s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.64 (50.19\u0026ndash;71.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76.96 (58.42\u0026ndash;95.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77.00 (52.64\u0026ndash;101.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.338\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChanges from baseline to four months after WBRT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R \u003c/p\u003e \u003cp\u003etotal recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;2.73 (-1.11 \u0026ndash; +6.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;1.04 (-1.53 \u0026ndash; +3.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;2.29 (-4.05 \u0026ndash; +8.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.558\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R\u003c/p\u003e \u003cp\u003edelayed recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;0.46 (-1.36 \u0026ndash; +2.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;0.33 (-0.72 \u0026ndash; +1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-1.00 (-3.39 \u0026ndash; +1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.439\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R\u003c/p\u003e \u003cp\u003erecognition index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-1.00 (-2.70\u0026ndash;0.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.04 (-2.35 \u0026ndash; +0.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.71 (-2.20 \u0026ndash; +0.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.844\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R\u003c/p\u003e \u003cp\u003ememory score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;1.73 (-2.69 \u0026ndash; +6.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;0.00 (-3.35 \u0026ndash; +3.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;1.57 (-5.01 \u0026ndash; +8.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.880\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTMT-B (s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.9 (-13.7 \u0026ndash; +11.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;14.5 (-7.7 \u0026ndash; +36.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;13.7 (-38.9 \u0026ndash; +66.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.866\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChanges from baseline to six months after WBRT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R total recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;3.18 (+\u0026thinsp;0.78 \u0026ndash; +5.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.59 (-2.97 \u0026ndash; +1.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-3.20 (-7.26 \u0026ndash; +0.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R delayed recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;0.46 (-0.80 \u0026ndash; +1.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;0.00 (-0.96 \u0026ndash; +0.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-2.40 (-5.12 \u0026ndash; +0.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R recognition index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.36 (-1.28 \u0026ndash; +0.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.18 (-1.54 \u0026ndash; +1.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-2.40 (-6.58 \u0026ndash; +1.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.357\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHVLT-R memory score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;2.82 (-0.30 \u0026ndash; +5.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.77 (-3.91 \u0026ndash; +2.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-5.60 (-12.3 \u0026ndash; +1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTMT-B (s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-6.2 (-25.7 \u0026ndash; +13.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;4.5 (-17.1 \u0026ndash; +26.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;7.4 (-96.8 \u0026ndash; +111.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.450\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eAPOE genotype and hippocampal avoidant WBRT\u003c/h2\u003e \u003cp\u003eThe impact of APOE genotype on outcomes following WBRT with and without hippocampal avoidance was investigated. Patient characteristics between the hippocampal avoidant WBRT arm and the conformal WBRT arm relative to the APOE genotypes are summarized in \u003cb\u003eSupplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e. Verbal learning and memory were preserved by avoiding the hippocampus during WBRT in patients with the neutral APOE ε3 alleles (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA) but not in patients with the ε2 or ε4 allele (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). For the APOE ε3 homozygotes with BM, patients who received hippocampal avoidant WBRT had a significantly better preservation in memory score compared to those receiving conformal WBRT without hippocampal avoidance at six (+\u0026thinsp;3.67 versus \u0026minus;\u0026thinsp;3.18, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037), nine (+\u0026thinsp;3.40 versus \u0026minus;\u0026thinsp;3.38, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037), and 12 (+\u0026thinsp;9.20 versus +\u0026thinsp;0.71, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045) months after treatment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eIndependent factors associated with neurocognitive outcomes\u003c/h2\u003e \u003cp\u003eAge (\u0026ge;\u0026thinsp;median versus \u0026lt;\u0026thinsp;median), radiotherapy technique (hippocampal avoidant versus conformal), and APOE genotype (ε2/ε3 versus ε3/ε3 versus ε3/ε4) were used for factorial ANOVA to evaluate the independent factors associated with memory preservation assessed by HVLT-R at six months after WBRT. APOE genotype was independently associated with HVLT-R TR (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042) and HVLT-R DR (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032) but not HVLT-R RI (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.264). Hippocampal avoidance during WBRT was independently associated with HVLT-R RI (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022) but not HVLT-R TR (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.051) or HVLT-R DR (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.060). Age was independently associated with HVLT-R RI (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020) and HVLT-R DR (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026) but not HVLT-R TR (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.148).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAPOE genotype and survival outcomes\u003c/h2\u003e \u003cp\u003eWith a median follow-up of 42 months (range: 4.4 to 54.8 months), the median overall survival and freedom from intracranial progression was 26.4 months and 17.9 months, respectively. The median overall survival for patients with the APOE ε2/ε3, ε3/ε3, and ε4/ε3 alleles was 26.8, 27.5, and 9.1 months (log\u0026ndash;rank, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.348, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA), respectively. The median intracranial progression-free interval was 15.4, 19.7, and 9 months (log\u0026ndash;rank, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.794, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB), respectively. APOE genotype had no significant impact on intracranial control. Patients carrying APOE ε4 allele had a numerical worse overall survival compared to those with APOE ε2 allele (pairwise log\u0026ndash;rank, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.099).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAPOE genotype is well known to play a crucial role in the pathogenesis of Alzheimer\u0026rsquo;s disease [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, the impact of APOE genotype on an individual\u0026rsquo;s neurocognitive prognosis after brain irradiation previously remained undetermined. This post hoc analysis of a phase II blinded randomized trial demonstrates the modulatory effect of APOE genotypes on the risk of RICD following WBRT with and without hippocampal avoidance. Importantly, a protective effect of the APOE ε2 allele as well as a deleterious effect of the ε4 allele on memory function were identified six months after WBRT. This association has only been previously reported in a conference abstract of the randomized blinded controlled trial (RTOG-0614) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. To the best of our knowledge, the present study contains the first fully published clinical evidence to support the hypothesis that APOE genotypes may modulate RICD for BM in a prospective trial, particularly in a Han-Chinese population.\u003c/p\u003e \u003cp\u003eAlthough the mechanisms of RICD remain poorly understood [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], radiation-induced vascular damage, neuroinflammation, deficits in neuron lineages and glial progenitors, and impairments in hippocampal neurogenesis have all been hypothesized to be responsible for radiation-induced brain injury. Two-thirds of post-RT brain tumor survivors meet the National Institute on Aging and the Alzheimer's Association criteria for mild cognitive impairment [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Although RICD is common and multifactorial [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], there is considerable heterogeneity in neurocognitive outcomes across individuals, suggesting that genetic risk factors may modulate patient vulnerability to treatment-induced neurotoxicity [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral genetic variations have been reported to be associated with cognitive functions for patients diagnosed with primary brain tumors [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The majority of these patients also received cranial irradiation. Correa et al. reported that patients who carried the APOE ε4 allele had significantly impaired verbal learning at least six months after completion of chemotherapy or RT [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The authors also reported that certain polymorphisms in catechol-O-methyl transferase, brain-derived neurotrophic factor, and dystrobrevin-binding protein 1 were significantly associated with lower scores in verbal memory [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. On the other hand, Liu et al. reported the single nucleotide polymorphism in RAD51L1, which is involved in DNA repair, as a potential modulator of verbal memory prior to surgery [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Of note, none of these studies conducted longitudinal studies to evaluate the impact of genetic variations on cognitive function changes before and after treatment.\u003c/p\u003e \u003cp\u003eIn contrast to primary brain tumors, little is known about the generic risks associated with RICD for patients with BM. Wefel et al. first performed an analysis of RTOG 0614 to evaluate APOE carrier status as a risk of neurocognitive function impairment before and after WBRT with or without memantine for BM [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The proportion of APOE ε4 allele carriers was 29.5% in the study population. There was no difference in performance on neurocognitive function tests at baseline among patients with different APOE genotypes, which is compatible with our findings. Furthermore, patients carrying the APOE ε4 allele exhibited worse memory outcomes after WBRT assessed by HVLT-R TR and HVLT-R RI. In the present study, patients harboring the APOE ε4 allele also showed significantly worse verbal memory function as measured by HVLT-R TR and HVLT-R DR but not by HVLT-R RI six months after WBRT. Taken together, these data suggest that APOE genotypes may play a role in the decline of memory function after WBRT for BM.\u003c/p\u003e \u003cp\u003eAlthough the exact role of APOE alleles in neurocognitive decline following WBRT remains unclear, research within the last decade has shed light on the role of APOE genotypes in the pathogenesis of dementia. One potential mechanism is that the APOE ε4 allele promotes disruption of the blood brain barrier (BBB) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], particularly in the hippocampus [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Interestingly, both primary and metastatic tumors as well as ionizing radiation have been shown to alter BBB integrity [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Therefore, one possible explanation is that BBB disruption by BM and WBRT might be aggravated in ε4 carriers, resulting in greater cognitive decline. In addition to BBB dysfunction, the APOE ε4 variant was found to be associated with disruption of vascular regulation and increased brain microbleeds [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], both of which may be further exacerbated by cranial irradiation [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], contributing to long-term neurocognitive impairment. Different APOE genotypes have also been implicated in the accumulation and clearance of β-amyloid in the brain with a similar protective effect seen in ε2 allele carriers and a negative effect in ε4 allele carriers [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Likewise, cranial irradiation is also a risk factor for β-amyloid deposition [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Despite these indirect data supporting the hypothesis of an association between APOE variants and RICD, sufficient evidence from animal studies remains elusive to fully validate this hypothesis [\u003cspan additionalcitationids=\"CR34\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother important finding of the present study is the potential interaction between APOE genotype and the maintenance of neurocognitive functions following hippocampal avoidant WBRT. The benefit of hippocampal avoidant WBRT was predominantly observed in the APOE ε3 homozygotes rather than the patients carrying the ε2 or ε4 allele. Preclinical animal studies have demonstrated that the APOE genotypes distinctly affect the susceptibility of hippocampus-dependent cognitive performance to \u003csup\u003e56\u003c/sup\u003eFe irradiation [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Haley et al. reported that radiation impaired spatial memory retention in ε2 and ε4 mice but enhanced it in ε3 mice [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In contrast, Yeiser et al. demonstrated that ε3 mice were more vulnerable than ε2 or ε4 mice to impairments in spatial memory retention [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Interestingly, both studies imply that APOE ε3 modulates RICD differently than the ε2 or ε4 variants.\u003c/p\u003e \u003cp\u003eThe present study has some limitations. There is a lack of domains other than verbal learning and memory though HVLT-R has already been widely used in cognitive studies in cancer patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Since the survival time is limited for patients with multiple BM, the sample size is relatively small, as it was constrained by the design of a post hoc analysis of a randomized controlled trial for unbalanced unrecognized confounding factors. It is likely underpowered to elucidate our novel findings, which should be further corroborated in larger prospective trials. In addition, there is a lack of imaging or biomarker evidence to adequately support the hypothesis. Hence, our planned exploratory analysis should be interpreted as a hypothesis-generating research rather than a confirmatory study. Despite these limitations, patient compliance for longitudinal neurocognitive function tests after WBRT was relatively high compared to similar trials [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The blinding of testers and patients also greatly mitigated any psychotherapeutic effects in test results. Furthermore, the relatively homogenous patient population, mostly diagnosed with primary lung cancer diagnosis, reduced potential biases.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003ePatients carrying the APOE ε2 protective allele showed better preserved late memory function, while those carrying the ε4 high-risk allele fared worse, although executive function was unaffected. The APOE neutral ε3/ε3 homozygotes benefited most from hippocampal avoidant WBRT for the maintenance of neurocognitive function for multiple BM. The protective effect of hippocampal avoidant WBRT is thus limited for APOE ε2 and ε4 carriers. Taking APOE genotype into consideration may assist in developing individualized precision radiotherapy strategies for patients with multiple BM.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"595\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbbreviation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFull Term\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eANOVA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAnalysis of Variance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAPOE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eApolipoprotein E\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBBB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBlood–Brain Barrier\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBrain Metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eConfidence Interval\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDelayed Recall\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHA-WBRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHippocampal Avoidant Whole-Brain Radiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHVLT-R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHopkins Verbal Learning Test–Revised\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eKPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eKarnofsky Performance Status\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMagnetic Resonance Imaging\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMemory Score\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNMDA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eN-Methyl-D-Aspartate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRICD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRadiotherapy-Induced Cognitive Decline\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRecognition Index\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRadiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRTOG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRadiation Therapy Oncology Group\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSNP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSingle Nucleotide Polymorphism\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSPSS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eStatistical Package for the Social Sciences\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTrail Making Test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMT-B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTrail Making Test Part B\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal Recall\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTWB chip\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTaiwan Biobank Array Plate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eWBRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eWhole-Brain Radiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was partially supported by the National Taiwan University Hospital, Taipei, Taiwan (NTUH 110-N4937 to Wen-Chi Yang) and the Ministry of Science and Technology, Executive Yuan, Taipei, Taiwan (MOST 110-2314-B-002-289-MY3 to Feng-Ming Hsu). We appreciate the assistance from Professor Pan-Chyr Yang, M.D., Ph.D. at Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan in resource for single nucleotide polymorphism genotyping. We acknowledge the service and support provided by the Eighth Core Lab at the Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. We would like to thank Uni-edit for editing and proofreading this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(I) Conception and design: MCK, WCY, CCY, FMH; (II) Administrative support: MJC, TFC, JCHC, SHK, FMH; (III) Provision of study materials or patients: WCY, FMH,; (IV) Collection and assembly of data: WCY, FMH; (V) Data analysis and interpretation: MCK, WCY, YFC, FMH; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Information:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was partially supported by the National Taiwan University Hospital, Taipei, Taiwan (NTUH 110-N4937 to Wen-Chi Yang) and the Ministry of Science and Technology, Executive Yuan, Taipei, Taiwan (MOST 110-2314-B-002-289-MY3 to Feng-Ming Hsu).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is available on request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe randomized trial is registered in ClinicalTrials.gov with the identifier NCT02393131.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Patient Consent statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board (IRB) of National Taiwan University, Taiwan (IRB number: 201901084MINA). All patients provided written informed consent prior to participation.\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBarnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004;22:2865\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhuntia D, Brown P, Li J, Mehta MP. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol. 2006;24:1295\u0026ndash;304.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology. 1989;39:789\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaad S, Wang TJ. 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Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function. Nat Commun. 2018;9:3816.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnol MJ, Lu D, Traylor M, Adams HHH, Romero JRJ, Smith AV, et al. Association of common genetic variants with brain microbleeds: A genome-wide association study. Neurology. 2020;95:e3331\u0026ndash;3343.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHahn CA, Zhou SM, Raynor R, Tisch A, Light K, Shafman T, et al. Dose-dependent effects of radiation therapy on cerebral blood flow, metabolism, and neurocognitive dysfunction. Int J Radiat Oncol Biol Phys. 2009;73:1082\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorrison MA, Hess CP, Clarke JL, Butowski N, Chang SM, Molinaro AM, et al. 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Int J Radiat Oncol Biol Phys. 2012;84:793\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYeiser LA, Villasana LE, Raber J. ApoE isoform modulates effects of cranial ⁵⁶Fe irradiation on spatial learning and memory in the water maze. Behav Brain Res. 2013;237:207\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSquire LR, Genzel L, Wixted JT, Morris RG. Memory consolidation. Cold Spring Harb Perspect Biol. 2015;7:a021766.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Apolipoprotein E, Genotype, Whole brain radiotherapy, Cognition","lastPublishedDoi":"10.21203/rs.3.rs-6431871/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6431871/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\u003eThe genetic risk of radiotherapy-induced \u0026nbsp;cognitive decline (RICD) in patients undergoing whole-brain radiotherapy \u0026nbsp;(WBRT) has not been clearly established. Apolipoprotein E (APOE) \u0026nbsp;polymorphisms, known to influence cognitive aging and Alzheimer’s disease risk, \u0026nbsp;may also modulate neurocognitive outcomes after cranial irradiation. This \u0026nbsp;post-hoc analysis investigates the association between APOE genotype and RICD \u0026nbsp;in patients with brain metastases (BM) treated with conformal or \u0026nbsp;hippocampal-avoidant (HA) WBRT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with BM were randomly assigned to \u0026nbsp;receive conformal or hippocampal avoidant (HA) WBRT. Patients had at least \u0026nbsp;four-month follow-up and APOE genotype information were eligible for this \u0026nbsp;post-hoc analysis. The association between APOE genotype and RICD measured by \u0026nbsp;the Hopkins Verbal Learning Test–Revised (HVLT-R) was analyzed by the general \u0026nbsp;linear model.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 70 randomized patients, APOE genotyping \u0026nbsp;was available for 60% of patients (ε3/ε3, n = 24; ε2/ε3, n = 11; ε4/ε3, n = \u0026nbsp;7). No differences in baseline characteristics and cognition were observed \u0026nbsp;among patients with different APOE genotypes. At six-month, patients carrying \u0026nbsp;the APOE ε2 allele had the best preservation in HVLT-R total recall (mean \u0026nbsp;difference, ε2: +3.18 versus ε4: −3.20, p = 0.007) and delayed recall (mean \u0026nbsp;difference, ε2 carrier: +0.46 versus ε4 carrier: −2.40, p = 0.049) whereas \u0026nbsp;those with the ε4 allele had the worst. Only patients with the APOE ε3 \u0026nbsp;homozygous alleles showed an improvement in late memory score preservation six \u0026nbsp;months following HA-WBRT (mean difference, HA: +3.67 versus conformal: −3.18, \u0026nbsp;p = 0.037) and beyond.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAPOE genotype is associated with the RICD risk \u0026nbsp;and the effect of benefit in the preservation of late verbal memory following \u0026nbsp;HA-WBRT for patients with BM. Further prospective investigations are warranted \u0026nbsp;to validate our proposed hypothesis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis trial is registered at ClinicalTrials.gov \u0026nbsp;(NCT02393131).\u003c/p\u003e","manuscriptTitle":"Impact of APOE Genotype on Neurocognition Following Conformal Whole Brain Radiotherapy for Brain Metastases: A Post hoc Analysis of Phase II Randomized Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-19 07:05:27","doi":"10.21203/rs.3.rs-6431871/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f4f4c537-016a-43fd-9b18-5186c03c665a","owner":[],"postedDate":"May 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-21T12:01:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-19 07:05:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6431871","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6431871","identity":"rs-6431871","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}