| Title: |
Sex-Specific Genetic Drivers of Memory, Executive Functioning, and Language Performance in Older Adults |
| Authors: |
Eissman, Jaclyn M.; Regelson, Alexandra N.; Walters, Skylar; Archer, Derek B.; Durant, Alaina; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse; Kang, Moonil; Bush, William S.; Kunkle, Brian W.; Naj, Adam C.; Gifford, Katherine A.; Bilgel, Murat; Kuzma, Amanda B.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); Alzheimer’s Disease Sequencing Project (ADSP); Cuccaro, Michael L.; Cruchaga, Carlos; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Schellenberg, Gerard D.; Vardarajan, Badri N.; Mayeux, Richard; Haines, Jonathan L.; Jefferson, Angela L.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Thompson, Paul M.; Martin, Eden R.; Albert, Marilyn S.; Johnson, Sterling C.; Engelman, Corinne D.; Ferrucci, Luigi; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Resnick, Susan M.; Sperling, Reisa A.; Crane, Paul K.; Hohman, Timothy J.; Dumitrescu, Logan |
| Contributors: |
Radiology and Imaging Sciences, School of Medicine |
| Source: |
PMC |
| Publisher Information: |
medRxiv |
| Publication Year: |
2025 |
| Collection: |
Indiana University - Purdue University Indianapolis: IUPUI Scholar Works |
| Subject Terms: |
Sex-specific genetic loci; Memory performance; Alzheimer's disease (AD) endophenotype |
| Description: |
We previously identified sex-specific genetic loci associated with memory performance, a strong Alzheimer's disease (AD) endophenotype. Here, we expand on this work by conducting sex-specific, cross-ancestral, genome-wide meta-analyses of three cognitive domains (memory, executive functioning, and language) in 33,918 older adults (57% female; 41% cognitively impaired; mean age=73 years) from 10 aging and AD cohorts. All three domains were comparably heritable across sexes. Genome-wide meta-analyses identified three novel loci: a female-specific language decline-associated locus, VRK2 (rs13387871), which is a published candidate for neuropsychiatric traits involving language ability; a male-specific memory decline-associated locus among cognitive impaired, DCHS2 (rs12501200), which is a published candidate gene for AD age-at-onset; and a sex-interaction with baseline executive functioning, AGA (rs1380012), among cognitive impaired. We additionally provide evidence for shared genetic architecture between lifetime estrogen exposure and AD-related cognitive decline. Overall, we identified sex-specific variants, genes, and pathways relating to three cognitive domains among older adults. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://hdl.handle.net/1805/49429 |
| Availability: |
https://hdl.handle.net/1805/49429 |
| Rights: |
Attribution-NonCommercial-NoDerivatives 4.0 International ; https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.4EDF7539 |
| Database: |
BASE |