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The biological mechanisms underlying the increased prevalence of Alzheimer’s disease (AD) in women remain undefined. While previous case/control studies have identified sex-biased molecular pathways, the sex-specific relationships between gene expression and AD endophenotypes, particularly involving sex chromosomes, are underexplored. With bulk transcriptomic data across 3 brain regions from 767 decedents, we investigated sex-specific associations between gene expression and post-mortem β-amyloid and tau, as well as antemortem longitudinal cognition. Among 23,118 significant gene associations, 10% were sex-specific, with 73% of these identified in females and primarily associated with tau tangles and longitudinal cognition (90%). Notably, four X-linked genes, MCF2 , HDAC8 , FTX , and SLC10A3 , demonstrated significant sex differences in their associations with AD endophenotypes (i.e., significant sex x gene interaction). Our results also uncovered sex-specific biological pathways, including a female-specific role of neuroinflammation and neuronal development, underscoring the importance of sex-aware analyses to advance precision medicine approaches in AD. The genetic basis of sex differences in Alzheimer’s disease (AD) is not well characterized. Here, authors report 2,320 sex-specific gene associations with 3 AD endophenotypes using bulk RNAseq data from 3 brain regions in ROS/MAP.

The biological mechanisms underlying women's increased Alzheimer's disease (AD) prevalence remain undefined. Previous case/control studies have identified sex-biased molecular pathways, but sex-specific relationships between gene expression and AD endophenotypes, particularly sex chromosomes, are underexplored. With bulk transcriptomic data across 3 brain regions from 767 decedents, we investigated sex-specific associations between gene expression and post-mortem β-amyloid and tau as well as antemortem longitudinal cognition. Of 23,118 significant gene associations, 10% were significant in one sex and not the other (sex-specific). Most sex-specific gene associations were identified in females (73%) and associated with tau tangles and longitudinal cognition (90%). Four X-linked genes, , , , and , demonstrated significant sex differences in their associations with AD endophenotypes (i.e., significant interaction). Our results also uncovered sex-specific biological pathways, including a female-specific role of neuroinflammation and neuronal development, reinforcing the potential for sex-aware analyses to enhance precision medicine approaches in AD.

Background Late‐life cognitive trajectories display heterogeneity between individuals and across cognitive domains. We aimed to identify latent classes of cognitive trajectories among three cognitive domains (memory, executive function, and language) and to investigate their association with baseline demographic and clinical characteristics. Method Harmonized data were obtained from 14 longitudinal cohorts of cognitive aging and dementia. Participants were restricted to those with at least 3 observations for each domain (memory, language and executive function). We developed three latent class linear mixed models, whereby each composite domain was modeled as both a linear and quadratic function of age. Separate models were developed with 1 through 5 classes. We assessed goodness of fit through a comparison of class proportions, AIC, BIC, and entropy. Baseline variables were compared across classes, with ANOVA for continuous and Chi‐square for categorical variables. Result We included 38,358 participants (73% non‐Hispanic white, 41% male, age=73 ± 9 years, education = 15 ± 4, mild cognitive impairment=19%, Alzheimer's disease = 14%, APOE‐ε4=31%, APOE‐ε2=13%) (Table 1). Across domains, the 4‐class model displayed the best performance (Figure 1) including non‐decliners, slow decliners, steady decliners, and rapid decliners. The memory classes deviated from the other two domains with the rapid decliners class displaying poor performance at younger ages with a less precipitous decline, whereas the rapid decline group in the other two domains declined rapidly with age. Across domains, the non‐decliners had the highest proportion of non‐Hispanic Black, cognitively unimpaired, ε2 carriers, and lowest proportion of ε4 carriers. Slow decliners were older and included more ε2 carriers. Steady decliners had the second highest proportion of AD at baseline and had the highest or second highest proportion of ε4 carriers. Rapid decliners had the highest proportion of AD at baseline, and the highest or second highest proportion of ε4 carriers. Conclusion While multiple subgroups move from cognitively normal to dementia, our latent class approach highlights subtypes that decline at different times and at different rates. Future work will seek to integrate disease time into models, clarify the stability of the observed subgroups of decliners, and characterize the neuropathological and neuroimaging features that contribute to the distinct etiologies of decline across domains.

Background Cerebrovascular disease (CVD) is a major cause of mortality in females, while two‐thirds of Alzheimer’s disease (AD) patients are female. AD and CVD share many genetic risk factors, one of them being apolipoprotein E (APOE) genotype. Sex differences in APOE and AD are well‐established; it is unclear if associations between APOE and CVD are sex‐specific. Method Autopsy data (females = 3,464; males = 3,130) from three AD cohorts included measures of arteriolosclerosis and atherosclerosis (levels for each: none [0], mild [1], moderate [2], and severe [3]) harmonized as part of the AD Sequencing Project Phenotype Harmonization Consortium. Non‐Hispanic White (NHW) individuals >60 years at age of death were included (average age at death = 85±9; 58% AD dementia). Linear analyses assessed sex‐stratified and APOE*sex interactions on CVD outcomes covarying for age at death. APOE‐ε4 and APOE‐ε2 were modeled additively and dominantly, respectively. Result Females were older on average and included more APOE‐ε2 and less APOE‐ε4 carriers when compared to males. Among males and females, APOE‐ε2 was not related to arteriolosclerosis (p = 0.90) or atherosclerosis (p = 0.30), while APOE‐ε4 related to higher arteriolosclerosis (β = 0.07 p<0.001) and atherosclerosis (β = 0.04, p = 0.03). There was a significant APOE‐ε2*sex interaction on arteriolosclerosis (p = 0.02) whereby the ε2 allele was associated with less arteriolosclerosis among females (β = ‐0.05, p = 0.27) and more arteriolosclerosis among males (β = 0.08, p = 0.13), although neither stratified effect reached statistical significance. Similarly, the ε4 allele was associated with more arteriolosclerosis among females (β = 0.11, p<0.001), but not among males (β = 0.04, p = 0.16), although the APOE‐ε4*sex interaction did not reach statistical significance (interaction‐p = 0.052). The ε4 allele was associated with more atherosclerosis among females (β = 0.07, p = 0.01), but not males (β = 0.01, p = 0.56), but again the APOE‐ε4*sex interaction did not reach statistical significance (p = 0.28). Conclusion We provide evidence that the ε4 allele is related to higher levels of arteriolosclerosis and atherosclerosis, while providing modest evidence of a sex difference in the association between the ε2 allele and arteriolosclerosis. Future work will seek to better characterize these sex‐specific effects within the context of other neurodegenerative pathologies in the aging brain, and more fully characterize sex‐specific clinical consequences of APOE and CVD.

Late-life cognitive trajectories display heterogeneity between individuals and across cognitive domains. We aimed to identify latent classes of cognitive trajectories among three cognitive domains (memory, executive function, and language) and to investigate their association with baseline demographic and clinical characteristics. Harmonized data were obtained from 14 longitudinal cohorts of cognitive aging and dementia. Participants were restricted to those with at least 3 observations for each domain (memory, language and executive function). We developed three latent class linear mixed models, whereby each composite domain was modeled as both a linear and quadratic function of age. Separate models were developed with 1 through 5 classes. We assessed goodness of fit through a comparison of class proportions, AIC, BIC, and entropy. Baseline variables were compared across classes, with ANOVA for continuous and Chi-square for categorical variables. We included 38,358 participants (73% non-Hispanic white, 41% male, age=73 ± 9 years, education = 15 ± 4, mild cognitive impairment=19%, Alzheimer's disease = 14%, APOE-ε4=31%, APOE-ε2=13%) (Table 1). Across domains, the 4-class model displayed the best performance (Figure 1) including non-decliners, slow decliners, steady decliners, and rapid decliners. The memory classes deviated from the other two domains with the rapid decliners class displaying poor performance at younger ages with a less precipitous decline, whereas the rapid decline group in the other two domains declined rapidly with age. Across domains, the non-decliners had the highest proportion of non-Hispanic Black, cognitively unimpaired, ε2 carriers, and lowest proportion of ε4 carriers. Slow decliners were older and included more ε2 carriers. Steady decliners had the second highest proportion of AD at baseline and had the highest or second highest proportion of ε4 carriers. Rapid decliners had the highest proportion of AD at baseline, and the highest or second highest proportion of ε4 carriers. While multiple subgroups move from cognitively normal to dementia, our latent class approach highlights subtypes that decline at different times and at different rates. Future work will seek to integrate disease time into models, clarify the stability of the observed subgroups of decliners, and characterize the neuropathological and neuroimaging features that contribute to the distinct etiologies of decline across domains.

Cerebrovascular disease (CVD) is a major cause of mortality in females, while two-thirds of Alzheimer's disease (AD) patients are female. AD and CVD share many genetic risk factors, one of them being apolipoprotein E (APOE) genotype. Sex differences in APOE and AD are well-established; it is unclear if associations between APOE and CVD are sex-specific. Autopsy data (females = 3,464; males = 3,130) from three AD cohorts included measures of arteriolosclerosis and atherosclerosis (levels for each: none [0], mild [1], moderate [2], and severe [3]) harmonized as part of the AD Sequencing Project Phenotype Harmonization Consortium. Non-Hispanic White (NHW) individuals >60 years at age of death were included (average age at death = 85±9; 58% AD dementia). Linear analyses assessed sex-stratified and APOE*sex interactions on CVD outcomes covarying for age at death. APOE-ε4 and APOE-ε2 were modeled additively and dominantly, respectively. Females were older on average and included more APOE-ε2 and less APOE-ε4 carriers when compared to males. Among males and females, APOE-ε2 was not related to arteriolosclerosis (p = 0.90) or atherosclerosis (p = 0.30), while APOE-ε4 related to higher arteriolosclerosis (β = 0.07 p<0.001) and atherosclerosis (β = 0.04, p = 0.03). There was a significant APOE-ε2*sex interaction on arteriolosclerosis (p = 0.02) whereby the ε2 allele was associated with less arteriolosclerosis among females (β = -0.05, p = 0.27) and more arteriolosclerosis among males (β = 0.08, p = 0.13), although neither stratified effect reached statistical significance. Similarly, the ε4 allele was associated with more arteriolosclerosis among females (β = 0.11, p<0.001), but not among males (β = 0.04, p = 0.16), although the APOE-ε4*sex interaction did not reach statistical significance (interaction-p = 0.052). The ε4 allele was associated with more atherosclerosis among females (β = 0.07, p = 0.01), but not males (β = 0.01, p = 0.56), but again the APOE-ε4*sex interaction did not reach statistical significance (p = 0.28). We provide evidence that the ε4 allele is related to higher levels of arteriolosclerosis and atherosclerosis, while providing modest evidence of a sex difference in the association between the ε2 allele and arteriolosclerosis. Future work will seek to better characterize these sex-specific effects within the context of other neurodegenerative pathologies in the aging brain, and more fully characterize sex-specific clinical consequences of APOE and CVD.