biostudies-literatureEissman JMNCATS NIH HHSNICHD NIH HHSNIA NIH HHSU.S. Department of DefenseNHGRI NIH HHSNINDS NIH HHSNational Institutes of HealthNIH HHS1250-1267https://www.ebi.ac.uk/biostudies/studies/S-EPMC10917043biostudies-literatureUnknown20(2)<h4>Background</h4>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.<h4>Methods</h4>We conducted the largest sex-aware genetic study on late-life memory to date (N_males  = 11,942; N_females  = 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.<h4>Results</h4>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.<h4>Discussion</h4>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.<h4>Highlights</h4>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.Alzheimer's & dementia : the journal of the Alzheimer's AssociationSex-specific genetic architecture of late-life memory performance.PMC10917043K12 HD043483U19 AG024904R01 AG019085P20 AG068053R01 AG073439P30 AG066444R01 AG022018R01 AG048927R01 AG064614RF1 AG054080P30 AG072958P30 AG072959R01 AG030146P30 AG066546K23 AG045966RF1 AG058501RF1 AG053303R01 AG42210R01 AG048015U01 AG032984HHSN311201600276PU24 AG041689P30 AG072946P30 AG072947P01 AG003991U19 AG066567R01 AG036836U24 AG021886P30 AG072931P20 AG068077R01 AG044546U01 AG046152R01 AG056534P30 AG079280U01 AG068057F31 AG077791P30 AG066530P20 AG068082U01 AG046161S10 OD023680U24 AG056270R01 AG017917U01 AG058654P30 AG062677K01 AG073584P30 AG066514P30 AG066515P30 AG066518P30 AG062715P30 AG066519U01 AG058922R01 AG062634U19 AG068753U54 AG052427P30 AG062421P30 AG062422P30 AG010161UL1 TR000445P30 AG066506P30 AG066507P30 AG062429P30 AG066508P30 AG066509R01 AG036042RC2 AG036547P30 AG066511P30 AG066512U24 AG072122P20 AG068024U01 AG052410R01 AG061518R01 AG015819U01 AG061356W81XWH‐12‐2‐0012R01 AG059716U01 AG006781P30 AG072975P30 AG066462P30 AG072976P30 AG072977R21 AG059941U24 AG074855P30 AG072972P30 AG072973P30 AG066468R01 AG064877P30 AG072978RC2 AG036650R01 AG079280P30 AG072979K24 AG046373K01 AG049164U01 HG004610U01 AG016976RF1 AG057473R01 NS100980R01 AG034962RC2 AG036528P01 AG026276U01 AG024904R01 AG042210Barnes LLScollard PJefferson ALMartin ERNaj ACSchellenberg GDKukull WAHaines JLCuccaro MLPericak-Vance MAEissman JMFarrer LASaykin AJDumitrescu LMayeux RPWang LSCrane PKHohman TJKunkle BWCruchaga CArcher DBBush WSAlzheimer's Disease Neuroimaging Initiative (ADNI) | Alzheimer's Disease Genetics Consortium (ADGC) | The Alzheimer's Disease Sequencing Project (ADSP)Bennett DASchneider JAChoi SEGifford KAMukherjee STrittschuh EHMez JBThompson PMKeene CDLee MLfalseSex-specific genetic architecture of late-life memory performance.<h4>Background</h4>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.<h4>Methods</h4>We conducted the largest sex-aware genetic study on late-life memory to date (N_males  = 11,942; N_females  = 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.<h4>Results</h4>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.<h4>Discussion</h4>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.<h4>Highlights</h4>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.2024-01-01T00:00:00Z2024 Feb2026-05-29T15:16:00.56Z2026-04-08T05:13:20.066ZS-EPMC109170433798485310.1002/alz.13507