Browsing by Author "Trittschuh, Emily H."
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Item A genome-wide search for pleiotropy in more than 100,000 harmonized longitudinal cognitive domain scores(BMC, 2023-06-22) Kang, Moonil; Ang, Ting Fang Alvin; Devine, Sherral A.; Sherva, Richard; Mukherjee, Shubhabrata; Trittschuh, Emily H.; Gibbons, Laura E.; Scollard, Phoebe; Lee, Michael; Choi, Seo-Eun; Klinedinst, Brandon; Nakano, Connie; Dumitrescu, Logan C.; Durant, Alaina; Hohman, Timothy J.; Cuccaro, Michael L.; Saykin, Andrew J.; Kukull, Walter A.; Bennett, David A.; Wang, Li-San; Mayeux, Richard P.; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Crane, Paul K.; Au, Rhoda; Lunetta, Kathryn L.; Mez, Jesse B.; Farrer, Lindsay A.; Radiology and Imaging Sciences, School of MedicineBackground: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. Methods: We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Results: Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10-9). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10-8) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10-8). GRN (rs5848, P = 4.21 × 10-8) and PURG (rs117523305, P = 1.73 × 10-8) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10-8) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10-9) and PTPRD (rs145989094, P = 8.34 × 10-9) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10-8) and PTPRD (rs145989094, P = 3.85 × 10-8) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Conclusion: Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias.Item Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults(American Medical Association, 2023) Walters, Skylar; Contreras, Alex G.; Eissman, Jaclyn M.; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse B.; Bush, William S.; Kunkle, Brian W.; Naj, Adam C.; Peterson, Amalia; Gifford, Katherine A.; Cuccaro, Michael L.; Cruchaga, Carlos; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Haines, Jonathan L.; Jefferson, Angela L.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Thompson, Paul M.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Crane, Paul K.; Hohman, Timothy J.; Dumitrescu, Logan; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Genetics Consortium; Alzheimer’s Disease Sequencing Project; Radiology and Imaging Sciences, School of MedicineImportance: Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele. Objective: To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition. Design, setting, and participants: This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022. Main outcomes and measures: Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons. Results: Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = -0.071, SE = 0.014; P = 9.6 × 10-7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = -0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals. Conclusions and relevance: In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.Item Differential patterns of gray matter volumes and associated gene expression profiles in cognitively-defined Alzheimer's disease subgroups(Elsevier, 2021) Groot, Colin; Grothe, Michel J.; Mukherjee, Shubhabrata; Jelistratova, Irina; Jansen, Iris; van Loenhoud, Anna Catharina; Risacher, Shannon L.; Saykin, Andrew J.; Mac Donald, Christine L.; Mez, Jesse; Trittschuh, Emily H.; Gryglewski, Gregor; Lanzenberger, Rupert; Pijnenburg, Yolande A.L.; Barkhof, Frederik; Scheltens, Philip; van der Flier, Wiesje M.; Crane, Paul K.; Ossenkoppele, Rik; Radiology and Imaging Sciences, School of MedicineThe clinical presentation of Alzheimer's disease (AD) varies widely across individuals but the neurobiological mechanisms underlying this heterogeneity are largely unknown. Here, we compared regional gray matter (GM) volumes and associated gene expression profiles between cognitively-defined subgroups of amyloid-β positive individuals clinically diagnosed with AD dementia (age: 66 ± 7, 47% male, MMSE: 21 ± 5). All participants underwent neuropsychological assessment with tests covering memory, executive-functioning, language and visuospatial-functioning domains. Subgroup classification was achieved using a psychometric framework that assesses which cognitive domain shows substantial relative impairment compared to the intra-individual average across domains, which yielded the following subgroups in our sample; AD-Memory (n = 41), AD-Executive (n = 117), AD-Language (n = 33), AD-Visuospatial (n = 171). We performed voxel-wise contrasts of GM volumes derived from 3Tesla structural MRI between subgroups and controls (n = 127, age 58 ± 9, 42% male, MMSE 29 ± 1), and observed that differences in regional GM volumes compared to controls closely matched the respective cognitive profiles. Specifically, we detected lower medial temporal lobe GM volumes in AD-Memory, lower fronto-parietal GM volumes in AD-Executive, asymmetric GM volumes in the temporal lobe (left < right) in AD-Language, and lower GM volumes in posterior areas in AD-Visuospatial. In order to examine possible biological drivers of these differences in regional GM volumes, we correlated subgroup-specific regional GM volumes to brain-wide gene expression profiles based on a stereotactic characterization of the transcriptional architecture of the human brain as provided by the Allen human brain atlas. Gene-set enrichment analyses revealed that variations in regional expression of genes involved in processes like mitochondrial respiration and metabolism of proteins were associated with patterns of regional GM volume across multiple subgroups. Other gene expression vs GM volume-associations were only detected in particular subgroups, e.g., genes involved in the cell cycle for AD-Memory, specific sets of genes related to protein metabolism in AD-Language, and genes associated with modification of gene expression in AD-Visuospatial. We conclude that cognitively-defined AD subgroups show neurobiological differences, and distinct biological pathways may be involved in the emergence of these differences.Item Differential trajectories of hypometabolism across cognitively-defined Alzheimer’s disease subgroups(Elsevier, 2021) Groot, Colin; Risacher, Shannon L.; Chen, J.Q. Alida; Dicks, Ellen; Saykin, Andrew J.; MacDonald, Christine L.; Mez, Jesse; Trittschuh, Emily H.; Mukherjee, Shubhabrata; Barkhof, Frederik; Scheltens, Philip; van der Flier, Wiesje M.; Ossenkoppele, Rik; Crane, Paul K.; Radiology and Imaging Sciences, School of MedicineDisentangling biologically distinct subgroups of Alzheimer's disease (AD) may facilitate a deeper understanding of the neurobiology underlying clinical heterogeneity. We employed longitudinal [18F]FDG-PET standardized uptake value ratios (SUVRs) to map hypometabolism across cognitively-defined AD subgroups. Participants were 384 amyloid-positive individuals with an AD dementia diagnosis from ADNI who had a total of 1028 FDG-scans (mean time between first and last scan: 1.6 ± 1.8 years). These participants were categorized into subgroups on the basis of substantial impairment at time of dementia diagnosis in a specific cognitive domain relative to the average across domains. This approach resulted in groups of AD-Memory (n = 135), AD-Executive (n = 8), AD-Language (n = 22), AD-Visuospatial (n = 44), AD-Multiple Domains (n = 15) and AD-No Domains (for whom no domain showed substantial relative impairment; n = 160). Voxelwise contrasts against controls revealed that all AD-subgroups showed progressive hypometabolism compared to controls across temporoparietal regions at time of AD diagnosis. Voxelwise and regions-of-interest (ROI)-based linear mixed model analyses revealed there were also subgroup-specific hypometabolism patterns and trajectories. The AD-Memory group had more pronounced hypometabolism compared to all other groups in the medial temporal lobe and posterior cingulate, and faster decline in metabolism in the medial temporal lobe compared to AD-Visuospatial. The AD-Language group had pronounced lateral temporal hypometabolism compared to all other groups, and the pattern of metabolism was also more asymmetrical (left < right) than all other groups. The AD-Visuospatial group had faster decline in metabolism in parietal regions compared to all other groups, as well as faster decline in the precuneus compared to AD-Memory and AD-No Domains. Taken together, in addition to a common pattern, cognitively-defined subgroups of people with AD dementia show subgroup-specific hypometabolism patterns, as well as differences in trajectories of metabolism over time. These findings provide support to the notion that cognitively-defined subgroups are biologically distinct.Item Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease(Wiley, 2024) Archer, Derek B.; Eissman, Jaclyn M.; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse B.; Bush, William S.; Kunkle, Brian W.; Naj, Adam C.; Gifford, Katherine A.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Alzheimer's Disease Genetics Consortium (ADGC); Alzheimer's Disease Sequencing Project (ADSP); Cuccaro, Michael L.; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Schellenberg, Gerard D.; Mayeux, Richard P.; Haines, Jonathan L.; Jefferson, Angela L.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Thompson, Paul M.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Crane, Paul K.; Dumitrescu, Logan; Hohman, Timothy J.; Radiology and Imaging Sciences, School of MedicineIntroduction: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline. Methods: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts. Results: We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits. Discussion: We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline. Highlights: Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits.Item Longitudinal cognitive performance of Alzheimer's disease neuropathological subtypes(Alzheimer’s Association, 2021-09-27) Uretsky, Madeline; Gibbons, Laura E.; Mukherjee, Shubhabrata; Trittschuh, Emily H.; Fardo, David W.; Boyle, Patricia A.; Keene, C. Dirk; Saykin, Andrew J.; Crane, Paul K.; Schneider, Julie A.; Mez, Jesse; Radiology and Imaging Sciences, School of MedicineIntroduction: Alzheimer's disease (AD) neuropathological subtypes (limbic predominant [lpAD], hippocampal sparing [HpSpAD], and typical [tAD]), defined by relative neurofibrillary tangle (NFT) burden in limbic and cortical regions, have not been studied in prospectively characterized epidemiological cohorts with robust cognitive assessments. Methods: Two hundred ninety-two participants with neuropathologically confirmed AD from the Religious Orders Study and Memory and Aging Project were categorized by neuropathological subtype based on previously specified diagnostic criteria using quantitative regional NFT counts. Rates of cognitive decline were compared across subtypes using linear mixed-effects models that included subtype, time, and a subtype-time interaction as predictors and four cognitive domain factor scores (memory, executive function, language, visuospatial) and a global score as outcomes. To assess if memory was relatively preserved in HpSpAD, non-memory factor scores were included as covariates in the mixed-effects model with memory as the outcome. Results: There were 57 (20%) with lpAD, 22 (8%) with HpSpAD and 213 (73%) with tAD. LpAD died significantly later than the participants with tAD (2.4 years, P = .01) and with HpSpAD (3.8 years, P = .03). Compared to tAD, HpSpAD, but not lpAD, performed significantly worse in all cognitive domains at the time of initial impairment and declined significantly faster in memory, language, and globally. HpSpAD did not have relatively preserved memory performance at any time point. Conclusion: The relative frequencies of AD neuropathological subtypes in an epidemiological sample were consistent with a previous report in a convenience sample. People with HpSpAD decline rapidly, but may not have a memory-sparing clinical syndrome. Cohort-specific differences in regional tau burden and comorbid neuropathology may explain the lack of clinicopathological correlation.Item Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease(Oxford University Press, 2022) Eissman, Jaclyn M.; Dumitrescu, Logan; Mahoney, Emily R.; Smith, Alexandra N.; Mukherjee, Shubhabrata; Lee, Michael L.; Scollard, Phoebe; Choi, Seo Eun; Bush, William S.; Engelman, Corinne D.; Lu, Qiongshi; Fardo, David W.; Trittschuh, Emily H.; Mez, Jesse; Kaczorowski, Catherine C.; Hernandez Saucedo, Hector; Widaman, Keith F.; Buckley, Rachel F.; Properzi, Michael J.; Mormino, Elizabeth C.; Yang, Hyun Sik; Harrison, Theresa M.; Hedden, Trey; Nho, Kwangsik; Andrews, Shea J.; Tommet, Douglas; Hadad, Niran; Sanders, R. Elizabeth; Ruderfer, Douglas M.; Gifford, Katherine A.; Zhong, Xiaoyuan; Raghavan, Neha S.; Vardarajan, Badri N.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); A4 Study Team; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li San; Cruchaga, Carlos; Schellenberg, Gerard D.; Cox, Nancy J.; Haines, Jonathan L.; Keene, C. Dirk; Saykin, Andrew J.; Larson, Eric B.; Sperling, Reisa A.; Mayeux, Richard; Cuccaro, Michael L.; Bennett, David A.; Schneider, Julie A.; Crane, Paul K.; Jefferson, Angela L.; Hohman, Timothy J.; Radiology and Imaging Sciences, School of MedicineApproximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context.Item Sex-specific genetic architecture of late-life memory performance(Wiley, 2024) Eissman, Jaclyn M.; Archer, Derek B.; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse B.; Bush, William S.; Kunkle, Brian W.; Naj, Adam C.; Gifford, Katherine A.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Alzheimer's Disease Genetics Consortium (ADGC); The Alzheimer's Disease Sequencing Project (ADSP); Cuccaro, Michael L.; Cruchaga, Carlos; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Schellenberg, Gerard D.; Mayeux, Richard P.; Haines, Jonathan L.; Jefferson, Angela L.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Thompson, Paul M.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Crane, Paul K.; Hohman, Timothy J.; Dumitrescu, Logan; Radiology and Imaging Sciences, School of MedicineBackground: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. Methods: We conducted the largest sex-aware genetic study on late-life memory to date (Nmales = 11,942; Nfemales = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants. Results: We identified three sex-specific loci (rs67099044-CBLN2, rs719070-SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633-EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits. Discussion: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory. Highlights: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits.Item Sex-specific genetic predictors of memory, executive function, and language performance(Wiley, 2022) Eissman, Jaclyn M.; Smith, Alexandra N.; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse B.; Bush, William S.; Engelman, Corinne D.; Lu, Qiongshi; Fardo, David W.; Widaman, Keith F.; Buckley, Rachel F.; Mormino, Elizabeth C.; Kunkle, Brian W.; Naj, Adam C.; Clark, Lindsay R.; Gifford, Katherine A.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); A4 Study Team; The Alzheimer’s Disease Sequencing Project (ADSP); Cuccaro, Michael L.; Cruchaga, Carlos; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Schellenberg, Gerard D.; Haines, Jonathan L.; Jefferson, Angela L.; Johnson, Sterling C.; Kukull, Walter A.; Albert, Marilyn S.; Keene, C. Dirk; Saykin, Andrew J.; Larson, Eric B.; Sperling, Reisa A.; Mayeux, Richard; Thompson, Paul M.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Crane, Paul K.; Hohman, Timothy J.; Dumitrescu, Logan; Radiology and Imaging Sciences, School of MedicineBackground: 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.