Melbourne School of Psychological Sciences - Research Publications

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Longitudinal GWAS Identifies Novel Genetic Variants and Complex Traits Associated with Resilience to Alzheimer’s Disease

Phillips, J ; Dumitrescu, L ; Archer, DB ; Smith, AN ; Mukherjee, S ; Lee, ML ; Choi, S ; Scollard, P ; Trittschuh, EH ; Mez, JB ; Mahoney, ER ; Bush, WS ; Engelman, CD ; Lu, Q ; Fardo, DW ; Widaman, KF ; Buckley, RF ; Mormino, EC ; Harrison, TM ; Sanders, E ; Clark, LR ; Gifford, KA ; Vardarajan, BN ; Cuccaro, ML ; Pericak‐Vance, MA ; Farrer, LA ; Wang, L ; Schellenberg, GD ; Haines, JL ; Jefferson, AL ; Johnson, SC ; Kukull, WA ; Albert, MS ; Keene, CD ; Saykin, AJ ; Larson, EB ; Sperling, RA ; Mayeux, R ; Goate, A ; Neuner, S ; Renton, AE ; Marcora, E ; Fulton‐Howard, B ; Patel, T ; Bennett, DA ; Schneider, JA ; Crane, PK ; Hohman, TJ (Wiley, 2022-12)

Background We completed a large genetic analysis of resilience to cognitive decline in Alzheimer’s Disease (AD) and discovered novel variants, genes, and complex traits associated with better‐than or worse‐than‐expected cognitive performance given an individual’s age, sex, and APOE genotype. Method Leveraging 15,933 non‐Hispanic white participants across four longitudinal cohort studies of aging and AD (Figure 1), our group determined the effects of genetic variants on resilience metrics using mixed‐effects regressions. Models adjusted for age, sex, APOE ε4 allele count, presence of the APOE ε2 allele and all covariate interactions with interval (years from baseline). The outcomes of interest were residual cognitive resilience, quantified from residuals in three cognitive domains (memory, executive function, and language), and combined resilience, summarized as the covariance of educational attainment with residual cognitive resilience. Post‐GWAS analyses included gene tests using MAGMA and estimates of genetic correlation with 65 complex traits using GNOVA. Result We observed genome‐wide significant associations at multiple established AD loci, including BIN1 and CR1 (Figure 2). We observed a novel association with combined resilience on chromosome 13 (top SNP: rs11838654, MAF = 0.06, P = 4.7×10−8; Figure 3) and a novel signal on chromosome 1 approaching significance (top SNP: rs2817183, MAF = 0.41, P = 5.1×10−8). Interestingly, rs11838654 is an eQTL for four genes in hippocampus (WBP4, COG6, MRPS31, and NHLRC3I; Braineac database). We also observed an association with residual cognitive resilience on chromosome 5 that approached genome‐wide significance (top SNP: rs4482935, MAF = 0.25, P = 5.5×10−8; Figure 2). Gene‐level tests identified associations of CD2AP (P.fdr = 0.027) and ZNF146 (P.fdr = 0.049) with residual cognitive resilience and combined resilience, respectively. Additionally, we identified negative genetic correlations of combined resilience with ischemic stroke and coronary artery disease (all P.fdr<2.5×10−2; Figure 4). Conclusion Compared to models of resilience that regress out the effects of AD neuropathology on cognition, the present models benefit from larger sample size at the cost of molecular precision. Although the genetic architecture of resilience from these less precise models more closely resembles that of clinical AD, we uncovered novel genetic drivers of resilience through this approach. Such findings will require future replication but suggest a trajectory‐based definition of resilience holds substantial promise for discovery.
Sex‐specific genetic predictors of memory, executive function, and language performance

Eissman, JM ; Smith, AN ; Mukherjee, S ; Lee, ML ; Choi, S ; Scollard, P ; Trittschuh, EH ; Mez, JB ; Bush, WS ; Engelman, CD ; Lu, Q ; Fardo, DW ; Widaman, KF ; Buckley, RF ; Mormino, EC ; Kunkle, BW ; Naj, AC ; Clark, LR ; Gifford, KA ; Cuccaro, ML ; Cruchaga, C ; Pericak‐Vance, MA ; Farrer, LA ; Wang, L ; Schellenberg, GD ; Haines, JL ; Jefferson, AL ; Johnson, SC ; Kukull, WA ; Albert, MS ; Keene, CD ; Saykin, AJ ; Larson, EB ; Sperling, RA ; Mayeux, R ; Thompson, PM ; Martin, ER ; Bennett, DA ; Barnes, LL ; Schneider, JA ; Crane, PK ; Hohman, TJ ; Dumitrescu, L (Wiley, 2022-12)

Background Alzheimer’s disease (AD) is more prevalent in women than men, and robust evidence shows sex differences in the biological response to the AD neuropathological cascade. However, there is a lack of large‐scale genetic studies on sex‐specific genetic predictors of AD‐related cognitive outcomes. Thus, we sought to elucidate the sex‐specific genetic etiology of memory, executive function, and language performance. Method This study included six cohorts of cognitive aging (Nmales=7,267, Nfemales=9,518). We applied psychometric approaches to build harmonized memory, executive function, and language composite scores. Next, for all domains, we calculated slopes from the cognitive scores (two or more timepoints) with linear mixed effects models. Then we performed sex‐stratified and sex‐interaction GWAS on these phenotypes, covarying for baseline age and the first three genetic principal components. We meta‐analyzed across cohorts with a fixed‐effects model. Sensitivity analyses for all models restricted the sample to cognitively unimpaired individuals. Result In addition to well‐established associations with cognition at the APOE locus, we identified three genetic loci that showed sex‐specific effects with cognition. A chromosome 16 locus (rs114106271), a splicing‐quantitative trait locus for RP11‐152O14.4 and LINC02180 in the testis (GTEx), associated with baseline memory performance in men (β=0.13, P=2.40×10‐8; PInteraction=8.96×10‐6; Figures 1‐2) but not in women (β=‐0.01, P=0.76). A chromosome 14 locus (rs34074573), an expression‐quantitative trait locus (GTEx) for HOMEZ (a homeobox gene), and for BCL2L2 (a previously reported AD risk gene), associated with longitudinal memory performance in men (β=‐0.01, P=4.15×10‐8; PInteraction=5.83×10‐7; Figures 3‐4) but not in women (β=0.001, P=0.09). Finally, a chromosome 6 locus (rs9382966) associated with longitudinal language performance in men with near genome‐wide significance (β=‐0.004, P=6.29×10‐8; PInteraction=2.01×10‐4) but not in women (β=‐0.0003, P=0.61). Conclusion Our results highlight some key sex differences in the genetic architecture of cognitive outcomes. Findings further suggest that some sex‐specific genetic predictors have domain‐specific associations, providing an exciting opportunity to better understand the molecular basis of memory, executive function, and language through genomic analysis. Although our findings need to be replicated, our GWAS analyses highlight the contribution of sex‐specific genetic predictors beyond the APOE locus in conferring risk for late‐life cognitive decline.
Contribution of modifiable dementia risk factors to cognitive performance and subjective cognition in middle‐aged adults

Bransby, L ; Rosenich, E ; Buckley, RF ; Yassi, N ; Maruff, P ; Pase, MP ; Lim, YY (Wiley, 2022-12)

Background Characterization of the contribution of modifiable risk factors (MRF) to dementia generally consider MRFs individually, despite strong evidence that MRFs co‐occur. In a large group of middle‐aged adults, the prevalence and co‐occurrence of MRFs for dementia was determined, spanning five broad domains (mood, lifestyle behaviours (e.g., physical inactivity), cardiovascular health, cognitive/social engagement, and sleep). We then investigated relationships between MRFs, both individually and combined, to cognitive performance and subjective cognition. Method Middle‐aged adults (n = 1610), most (70%) with a family history of dementia, enrolled in the Healthy Brain Project, completed an extensive set of questionnaires about their physical and psychological health and lifestyle. Participants also completed the Cogstate Brief Battery (CBB), and the Cognitive Function Instrument (CFI), a measure of subjective cognition. Participants were classified according to the number of domains (mood, lifestyle behaviours, cardiovascular health, cognitive/social engagement, and sleep, ranging from 0‐5) in which they reported at least one MRF. Age, sex, education and ethnicity were adjusted for in analyses. Result Most participants (65%) reported at least one MRF in two or more domains (Fig 1A). Compared to participants reporting no MRFs, participants who reported at least one MRF in 3‐5 domains showed worse memory performance and reported greater subjective cognitive concerns, with magnitudes of differences moderate to large (d = 0.30‐0.93; Fig 1B). Participants who reported at least one MRF in five domains also showed worse attention than those reporting no MRFs (d = 0.58). When individual MRFs were considered simultaneously, MRFs in the mood (e.g., anxiety symptomatology) and cognitive/social engagement domains (e.g., leisure activities) were associated with worse attention and memory performance. Individual MRFs reflecting mood and sleep symptomatology were associated with greater subjective cognitive concerns. Conclusion In middle‐aged community dwelling adults, multidomain MRFs for dementia are highly prevalent and co‐occur, and are associated with poorer cognitive outcomes. This suggests that the presence of multiple MRFs as early as midlife may have negative neurological outcomes, however, this will need to be explored in future neuroimaging studies. These findings indicate that multidomain lifestyle prevention trials in middle‐aged adults may be useful to delay or prevent future cognitive impairment or dementia.
Optimizing early detection of beta‐amyloid accumulation with PET using spatial extent

Farrell, ME ; Thibault, EG ; Becker, A ; Price, JC ; Schultz, AP ; Properzi, MJ ; Buckley, RF ; Jacobs, HIL ; Hanseeuw, B ; Sperling, RA ; Johnson, KA (Wiley, 2022-12)

Background As clinical trials shift towards prevention, there has been increasing interest in improving early detection of beta‐amyloid (Aβ), below standard global PET positivity thresholds. While many studies have demonstrated that some regions appear more vulnerable to the earliest deposits, those regions have varied widely across studies. We sought to develop more flexible metrics for identifying subthreshold individuals at risk for progression to global Aβ positivity by evaluating a wide range of early regional targets and expanding our measurement beyond tracer retention (DVR/SUVR) to include spatial extent. Method 269 clinically‐normal older adults were included from the Harvard Aging Brain Study, focusing on 150 initially globally PIB‐ adults with longitudinal PET. Region‐specific positivity thresholds were computed using iterative longitudinal two‐level linear mixed effect models that identified the cutoff beyond which local accumulation significantly increases over time. Next, we identified all regions significantly predictive of future global accumulation in initially PIB‐ adults and generated 3 aggregate masks at liberal (p<.05), moderate (p<.001) and conservative a‐levels (Bonferroni p<.0007). DVR and spatial extent (number of elevated ROIs) were computed in each mask. Receiver operator characteristic (ROC) curve analysis determined sensitivity/specificity of each metric to predict future global positivity. External validation was performed using globally florbetapir‐negative (FBP‐) healthy controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=211). Result Regional variations in measurement reliability were detected (Fig1) and accounted for by employing accumulation‐based regional positivity thresholds. A broad set of ROIs were identified as potential early targets based on prediction of global accumulation, encompassing bilateral cingulate, medial frontal/parietal cortices and left‐lateralized lateral frontal/parietal/temporal cortices (Fig2). ROC analyses demonstrated that spatial extent outperformed DVR in predicting progression to global PIB+ within 3 years (Fig3), with 82% sensitivity and 97% and 98.5% specificity, respectively, for the two larger aggregate masks. External validation in ADNI (Fig4) again demonstrated the superior performance of spatial extent (SE=100%, SP=91.6%) in predicting progression to global positivity within 3 years. Conclusion Our findings demonstrate that due to a high level of heterogeneity in early Aβ deposition, measures of spatial extent across a broad set of neocortical regions are more sensitive to detect early Aβ than traditional DVR/SUVR.
Sex differences in the protective effects of APOE ε2 on longitudinal cognitive decline

Wood, M ; Xiong, LY ; Buckley, RF ; Swardfager, W ; Masellis, M ; Black, SE ; Rabin, JS (Wiley, 2022-12)

Background The APOE ε2 allele confers protection against cognitive decline and Alzheimer’s disease. There is some suggestion that APOE ε2 may have sex‐specific effects on cognition. We investigated sex differences in associations between APOE ε2 and longitudinal cognitive trajectories in a large sample of older adults. Method We used data from the National Alzheimer’s Coordinating Centre (NACC) database. We included participants who were ≥ 50 years old, White, free from dementia at baseline, and completed at least one follow‐up cognitive assessment. We categorized participants as APOE ε2 carriers (combining heterozygous and homozygous ε2 carriers) or APOE ε3 homozygote carriers. APOE ε4 carriers (including ε2/ε4 carriers) were excluded. Cognition was assessed approximately annually. We computed composite scores for memory, language, attention, and executive function. We examined the interaction between APOE allele (ε2 vs ε3), sex, and time on longitudinal cognition in linear mixed models, adjusting for baseline age, baseline MMSE, education, number of follow‐up visits, NACC test version, and their interactions with time. Result We included 6,733 participants classified as cognitively normal at baseline (mean age=72.9±9.12 years, mean education=16.0±2.87 years, 62.5% female), and 1,932 participants classified as mild cognitive impairment (MCI) at baseline (mean age=75.2±8.91 years, mean education=15.6±3.28 years, 44% female). Among participants with normal cognition, we observed significant interactions between sex, genotype, and time on longitudinal memory (β=0.022, p=0.039) and language (β=0.015, p=0.038), but not attention (β=0.01, p=0.09) or executive function (β=0.006, p=0.30). In sex stratified analyses, relative to male APOE ε3 carriers, male APOE ε2 carriers showed slower rates of decline in domains of memory and language. This effect was not observed in females. No significant interactions between sex, genotype, and time were observed in participants with MCI (memory: β=‐0.04, p=0.1; language: β=‐0.02, p=0.4; attention: β=‐0.01, p=0.5; executive function: β=‐0.02, p=0.3). Conclusion Among cognitively normal adults, APOE ε2 carriage protects males but not females against longitudinal memory and language decline. The sex‐specific effect of APOE ε2 may contribute to the lower incidence of Alzheimer’s disease in males compared to females. Future research is needed to elucidate the mechanisms behind the observed sex disparities in cognitive decline.
Modifiable dementia risk factors associated with higher CSF tau and poorer cognition in middle‐aged adults

Bransby, L ; Rosenich, E ; Buckley, RF ; Maruff, P ; Yassi, N ; Lim, YY (Wiley, 2022-12)

Background Modifiable factors in domains such as mood, lifestyle behaviours, cardiovascular health, cognitive/social engagement, and sleep are associated with increased risk for dementia. These modifiable risk factors could promote Alzheimer’s disease (AD) related biological processes, such as beta‐amyloid (Aβ) or tau accumulation, but these associations remain poorly understood. This study aimed to determine associations between modifiable dementia risk factors with Aβ, tau, and cognition in cognitively unimpaired middle‐aged adults. Method Middle‐aged adults (n = 82) (age range 40‐70) enrolled in a biomarker sub‐study of the Healthy Brain Project completed self‐report questionnaires about their physical and psychological health and lifestyle. Cerebrospinal fluid (CSF) levels of Aβ42, total tau (t‐tau), and phosphorylated tau (p‐tau) (Roche Elecsys) were obtained. A comprehensive neuropsychological battery was administered to measure cognition, and composite scores were derived for memory, executive function, and the Preclinical Alzheimer’s Cognitive Composite (PACC). Participants were classified according to reporting normal modifiable risk (NMR) (risk in ≤1 domains; n = 34) or high modifiable risk (HMR) (risk in ≥2 domains; n = 48) across five domains (mood, lifestyle behaviours, cardiovascular health, cognitive and social engagement, and sleep). Result Compared to those with NMR, those with HMR had increased t‐tau (d = 0.54, p = .021) and p‐tau (d = 0.47, p = .044) levels but did not differ on Aβ42 (d = 0.23, p = .319) after adjusting for age and sex. With age, sex, and education adjusted for, HMR participants showed worse performance on PACC (d = 0.69, p = .003), executive function (d = 0.55, p = .016), and episodic memory (d = 0.40, p = 0.076) compared to NMR participants. Differences in cognitive performance remained when levels of Aβ42, t‐tau and p‐tau levels were controlled in the models [PACC (d = 0.59, p = .011), memory (d = 0.64, p = .005) and executive function (d = 0.45, p = .049)]. Conclusion Modifiable dementia risk factors across multiple domains are related to higher total and phosphorylated tau levels and with subtle cognitive deficits, but not with Aβ, in middle‐aged adults. Together with the observation that differences in cognition across modifiable risk groups remained when Aβ and tau levels were controlled statistically, this suggests that modifiable dementia risk factors may increase risk through neurodegenerative processes non‐specific to AD, such as increased cerebrovascular burden, although this needs to be confirmed in future neuroimaging studies.
Sex differences in the genetic architecture underlying resilience in AD

Eissman, JM ; Dumitrescu, L ; Mahoney, ER ; Mukherjee, S ; Lee, ML ; Bush, WS ; Engelman, CD ; Lu, Q ; Fardo, DW ; Trittschuh, EH ; Mez, J ; Kaczorowski, CC ; Saucedo, HH ; Widaman, KF ; Buckley, RF ; Properzi, MJ ; Mormino, EC ; Yang, H ; Harrison, TM ; Hedden, T ; Nho, K ; Andrews, SJ ; Tommet, D ; Hadad, N ; Sanders, RE ; Ruderfer, DM ; Gifford, KA ; Zhong, X ; Raghavan, NS ; Vardarajan, BN ; Initiative, ADN ; Consortium, ADG ; Team, AS ; Pericak‐Vance, MA ; Farrer, LA ; Wang, L ; Cruchaga, C ; Schellenberg, GD ; Cox, NJ ; Haines, JL ; Keene, CD ; Saykin, AJ ; Larson, EB ; Sperling, RA ; Mayeux, R ; Cuccaro, ML ; Bennett, DA ; Schneider, JA ; Crane, PK ; Jefferson, AL ; Hohman, TJ (Wiley, 2021-12-01)

Background Approximately 30% of older adults are cognitively normal at death despite presence of Alzheimer’s disease (AD) neuropathology at autopsy. Studying these “resilient” individuals may lead to the discovery of novel therapeutic targets. In addition, growing evidence suggests sex differences in downstream neurodegenerative consequences of AD neuropathology, with recent studies highlighting notable sex-specific genetic drivers of AD pathogenesis. We sought to extend this work by elucidating sex-specific genetic factors underlying resilience to AD. Method We used our published genetic resilience pipeline to assess sex-specific genetic predictors (Dumitrescu et al., 2020). Briefly, we used modern psychometric approaches to harmonize cognitive measures across four cohorts of cognitive aging (N=5054), in-vivo amyloid PET across two studies, and leveraged autopsy measures of amyloidosis (CERAD staging) across two studies. A continuous measure of resilience was quantified using a latent variable framework whereby higher scores reflected better-than-predicted cognitive performance given amyloidosis level and lower scores reflected worse-than-predicted performance. We then performed sex-stratified GWASs and sex-interaction GWASs, covarying for age and the first three principal components and meta-analyzed across cohorts. Finally, we performed sex-stratified genetic correlation analyses (GNOVA) between our meta-analysis results and summary statistics from 63 complex traits. Result Among individuals with normal cognition, we identified a female-specific locus on chromosome 10 (rs827389, [p(females)=7.4E-09, p(males)=0.64, p(interaction)=8.3E-05, MAF=0.46]). This variant is a modest eQTL for KIN (p=0.003), a gene encoding a DNA/RNA binding protein (http://www.braineac.org). In our genetic correlation analyses, we observed male-specific correlations between resilience and two heart rate-related traits, whereby higher resilience was associated with lower genetic risk for poor heart health. We also observed opposing genetic correlations between resilience and multiple sclerosis such that females with higher resilience scores had lower susceptibility for multiple sclerosis (p.FDR=0.009), whereas males with higher resilience had higher susceptibility (p.FDR=0.001). Conclusion Our results highlight sex-specific genes and pathways that may drive resilience in a biological sex-dependent manner, although independent replication is needed. The best target to enhance resilience to AD neuropathology may depend on sex and genetic context of an individual. Future work should continue to evaluate sex differences in the genetic architecture of the AD neuropathological cascade.
Sex‐specific genetic predictors of memory performance

Smith, AN ; Dumitrescu, L ; Mukherjee, S ; Lee, ML ; Choi, S ; Trittschuh, EH ; Mez, J ; Mahoney, ER ; Bush, WS ; Engelman, CD ; Lu, Q ; Fardo, DW ; Widaman, KF ; Buckley, RF ; Mormino, EC ; Harrison, TM ; Sanders, RE ; Clark, LR ; Gifford, KA ; Vardarajan, BN ; Initiative, ADN ; Consortium, ADG ; Team, AS ; Project, TADS ; Cuccaro, ML ; Pericak‐Vance, MA ; Farrer, LA ; Wang, L ; Schellenberg, GD ; Haines, JL ; Jefferson, AL ; Johnson, SC ; Kukull, WA ; Albert, MS ; Keene, CD ; Saykin, AJ ; Larson, EB ; Sperling, RA ; Mayeux, R ; Bennett, DA ; Schneider, JA ; Crane, PK ; Hohman, TJ (Wiley, 2021-12-01)

Background There are notable sex differences in the clinical manifestation of Alzheimer’s disease (AD), including differences in baseline and longitudinal changes in memory performance. However, sex-stratified models have not been routinely incorporated into genetic studies of cognitive performance or decline. We sought to identify sex-specific genetic predictors of memory performance in aging adults. Method We obtained harmonized memory scores from 11,601 females and 8,885 males from 7 cohorts of cognitive aging. We calculated scores using latent variable modeling techniques anchored on overlapping neuropsychological test items across datasets to perform both sex-stratified and sex-interaction genome-wide association studies in each cohort using mixed-effects regression models to assess genetic associations with baseline memory score and rate of memory decline. Covariates included age at baseline and population principal components. We then combined results in a fixed-effect meta-analysis. Results As expected, we observed robust associations at the APOE locus in males and females in both baseline and longitudinal models. Additionally, we identified a sex-specific locus for longitudinal memory performance (interaction-p=2.54e-6) on chromosome 7 within LINC-PINT that was genome-wide significant in males (index SNP= rs66754621; p=1.62e-8; MAF=0.20), but not females (p=0.65). This variant is in an enhancer region within several brain regions, as well as within a promoter-anchored chromatin interaction loop and a methylation eQTL in the prefrontal cortex. No female-specific loci were identified. Interestingly, we did observe nominal associations in baseline memory at some known AD loci, including male-specific effects at MS4A6A, FERMT2, and KAT8 (interaction ps=0.0026, 0.027, and 0.0058, respectively) and opposing effects between males and females at INPP5D (interaction p=0.0021). Conclusion These results highlight a novel male-specific locus of memory performance on chromosome 7 near the LINC-PINT gene. LINC-PINT is upregulated in the substantia nigra in Parkinson’s disease and is downregulated in multiple brain regions over the course of normal aging, making it a fascinating male-specific candidate gene. Replicate and functional analyses of the region are ongoing to verify our finding and elucidate the biological mechanism. Our results add to the growing body of literature suggesting that there are sex-specific genetic contributors to cognitive decline.
Association between APOE‐ε4 allele and CSF amyloid in memory performance differ by sex

Brugulat‐Serrat, A ; Tsoy, E ; Milà‐Alomà, M ; Sánchez‐Benavides, G ; Buckley, RF ; Gispert, JD ; Molinuevo, J ; Possin, KL ; Kramer, JH (Wiley, 2021-12)

Background There is growing evidence of sex differences in the association between Alzheimer’s disease (AD) biomarkers and cognition. However, few studies have examined the effect of sex on the associations between established AD risk factors and cognitive performance in clinically normal older adults. This study aimed to elucidate potential sex differences in the relationship between APOE‐ε4 status, AD biomarkers, and cognitive performance in a large multinational cohort of clinically normal older adults. Method Participants were 952 cognitively unimpaired older adults from the multicenter European Prevention of Alzheimer’s Disease (EPAD) study (age range 50‐88 years, mean age 65.0(7.0), mean education 14.6(3.6) years, 58% females). All participants underwent a lumbar puncture and CSF Aβ42, p‐tau and t‐tau biomarkers (Roche Elecsys®) were measured, APOE genotyping, and a battery of digital cognitive tests (UCSF TabCAT; Favorites (associative memory), Dot Counting (executive function), and Flanker (processing speed)). APOE genotype was dichotomized (ε4 carrier vs. ε4 non‐carrier). We performed multiple linear regression models to examine the effect of sex, CSF biomarkers, APOE‐ε4, and their interactions on cognitive performance covarying for age, education, and testing language. Result There were no differences in age (p=.07), frequency of APOE‐ε4 carriers (33.1%, p=.55) or CSF biomarkers (all p>0.1) between males and females. Females had lower educational attainment (p=.01). Females outperformed males on an associative memory task (p=.002), whereas males performed better on tasks of working memory (p=.01) and inhibitory control (p=.01). A sex*Aβ*APOE‐ε4 status interaction (p=.01) revealed APOE‐ε4 carriership and abnormal levels of CSF Aβ were associated with poorer associative memory performance only in males (Fig 1). Conclusion Sex seems to moderate the association between CSF Aβ and APOE‐ε4 allele and memory performance in cognitively unimpaired older adults. Our results suggest a cross‐sectional association of APOE‐ε4 and CSF Aβ with cognitive performance in males that complement previous literature on the relationship between APOE‐ε4 and longitudinal cognitive decline in females. Taken together, these findings highlight the importance of understanding the complexity of sex differences in individuals at higher risk of AD.
Menopause moderates sex differences in tau PET signal: Findings from the Framingham Study

Buckley, RF ; O’Donnell, A ; McGrath, ER ; Jacobs, HIL ; Satizabal, CL ; Ghosh, S ; Rubinstein, ZB ; Murabito, JM ; Sperling, RA ; Beiser, AS ; Seshadri, S (Wiley, 2021-12)

Background Cognitively‐normal (CN) older women exhibit elevated tau‐PET signal in medial temporal and neocortical regions compared with men. The effect of menopause on tau deposition remains unclear. We explored menopausal status as a moderator of sex differences in tau deposition in middle‐aged adults. Method 273 CN (Age=55yrs(±8), Female(n)=134, Post‐menopausal(n)=70) from the Framingham Study 3rd generation cohort underwent 18F‐Flortaucipir (FTP)‐PET and/or 11C‐Pittsburgh Compound‐B (PiB)‐PET scans. We examined FTP‐PET signal in four a priori regions that demonstrate large sex differences in CN older adults (entorhinal, rostral middle frontal, inferior parietal and lateral occipital). FTP‐PET and global PiB‐PET signal were referenced to cerebellar grey. Linear regression examined sex differences in each ROI, adjusting for age and PET camera. Separate models examined menopausal status (post‐menopause/pre‐menopause females), menopausal age (≤|>50 years), and interactions with APOEε4. Sensitivity analyses included age‐matched males (‘pseudo‐premenopausal’/‘pseudo‐menopausal’) against the menopause groups to account for confounds with chronological age. Result Middle‐aged females exhibited higher FTP‐PET signal in the inferior parietal, rostral middle frontal and lateral occipital regions than males by ∼0.04SUVr (p<0.009; Fig. 1). No sex or menopause differences were evident in PiB‐PET. Post‐menopausal females exhibited higher FTP‐PET signal in the lateral occipital lobe than pre‐menopausal (p=0.05; Fig. 2). Menopause age≤50 years corresponded with higher lateral occipital and rostral middle frontal FTP‐PET signal than >50years (p<0.05; Fig. 2). Post‐menopausal females maintained higher signal in lateral occipital, inferior parietal and rostral middle frontal regions compared with even age‐matched ‘pseudo‐menopausal’ males (Table 1). Finally, a significant menopause*APOEε4 interaction suggested that the menopause effect was only evident in APOEε4 non‐carriers, localized to the parietal lobe (p∼0.03; Fig. 3). Conclusion Sex differences in tauopathy are apparent in CN individuals approximately 20 years earlier than previously demonstrated. Our findings suggest that sex differences are exacerbated by menopause, particularly when the age‐at‐menopause is below 50 years. Chronological age did not appear to confound the results, as age‐matched males exhibited significantly lower tau signal. Finally, the effect of APOEε4 carriership may ameliorate menopause effects; only pre‐menopausal APOEε4 non‐carriers appeared to exhibit protective effects of circulating estradiol relative to post‐menopausal non‐carriers. Future work will need to identify direct hormonal contributions, the impact of surgery and hormone‐therapy.

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