Browsing by Author "The Alzheimer's Disease Sequencing Project (ADSP)"

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    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 Medicine
    Background: 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.
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    The effect of Alzheimer's disease genetic factors on limbic white matter microstructure
    (Wiley, 2025) Lorenz, Anna; Sathe, Aditi; Zaras, Dimitrios; Yang, Yisu; Durant, Alaina; Kim, Michael E.; Gao, Chenyu; Newlin, Nancy R.; Ramadass, Karthik; Kanakaraj, Praitayini; Khairi, Nazirah Mohd; Li, Zhiyuan; Yao, Tianyuan; Huo, Yuankai; Dumitrescu, Logan; Shashikumar, Niranjana; Pechman, Kimberly R.; Jackson, Trevor Bryan; Workmeister, Abigail W.; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Arfanakis, Konstantinos; Erus, Guray; Davatzikos, Christos; Habes, Mohamad; Wang, Di; Tosun, Duygu; Toga, Arthur W.; Thompson, Paul M.; Mormino, Elizabeth C.; Zhang, Panpan; Schilling, Kurt; Alzheimer's Disease Neuroimaging Initiative (ADNI)The BIOCARD Study Team; The Alzheimer's Disease Sequencing Project (ADSP); Albert, Marilyn; Kukull, Walter; Biber, Sarah A.; Landman, Bennett A.; Johnson, Sterling C.; Bendlin, Barbara; Schneider, Julie; Barnes, Lisa L.; Bennett, David A.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Hohman, Timothy J.; Archer, Derek B.; Radiology and Imaging Sciences, School of Medicine
    Introduction: White matter (WM) microstructure is essential for brain function but deteriorates with age and in neurodegenerative conditions such as Alzheimer's disease (AD). Diffusion MRI, enhanced by advanced bi-tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences. Methods: To evaluate how AD genetic risk factors affect limbic WM microstructure - crucial for memory and early impacted in disease - we conducted linear regression analyses in a cohort of 2,614 non-Hispanic White aging adults (aged 50.12 to 100.85 years). The study evaluated 36 AD risk variants across 26 genes, the association between AD polygenic scores (PGSs) and WM metrics, and interactions with cognitive status. Results: AD PGSs, variants in TMEM106B, PTK2B, WNT3, and apolipoprotein E (APOE), and interactions involving MS4A6A were significantly linked to WM microstructure. Discussion: These findings implicate AD-related genetic factors related to neurodevelopment (WNT3), lipid metabolism (APOE), and inflammation (TMEM106B, PTK2B, MS4A6A) that contribute to alternations in WM microstructure in older adults. Highlights: AD risk variants in TMEM106B, PTK2B, WNT3, and APOE genes showed distinct associations with limbic FW-corrected WM microstructure metrics. Interaction effects were observed between MS4A6A variants and cognitive status. PGS for AD was associated with higher FW content in the limbic system.