Autopsy measures of Alzheimer’s disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer’s disease risk, sex-stratified models have not been incorporated into previous GWAS analyses.

We looked for sex-specific genetic associations with Alzheimer’s disease endophenotypes from six brain bank data repositories. These cohorts (LOAD, Mayo, ACT, NACC, ROS/MAP, TGEN) contained neuropathology and genotype data for 2,701 males and 3,275 females. Neuropathology data were harmonized across cohorts and genotypes underwent standard quality control and imputation (genome build 37). Stratified GWAS assessed for associations with neuropathology within males and females separately and genome-wide significant loci in each sex were tested for sex interactions.

Timothy J. Hohman
Vanderbilt University Medical Center

Acknowledgment statement for any data distributed by NIAGADS:

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

For investigators using Sex differences in the genetic predictors of Alzheimer’s pathology – Dumitrescu, et al. 2019 data:

This research was supported in part by K01 AG049164, R21 AG05994, K12 HD043483, K24 AG046373, HHSN311201600276P, S10 OD023680, R01 AG034962, R01 HL111516, R01 NS100980, R01 AG056534, P30 AG10161, RF1 AG15819, R01 AG17917, R01 AG30146, R01 AG019085, R01 AG15819, R01 AG30146, R01 AG027161, R01 AG021155, R01 AG037639, U01 AG46152, U01 AG006781, U01 AG032984, U01 HG004610, U01 HG006375, U24 AG021886, U24 AG041689, R01 AG044546, P01 AG003991, RF1 AG053303, R01 AG035083, R01 NS085419, UL1 TR000445, KL2 TR000446, TL1 TR000447, S10 OD023680, and the Alzheimer’s Association (NIRG-11–200110), further supported in part by the Intramural Research Program, NIA, NIH and the Vanderbilt Memory & Alzheimer’s Center. Y.D. was supported by an NIMH training grant (T32MH014877). Support for P.D.J. was provided by R01 AG048015. H.Z. is a Wallenberg Academy Fellow and is further supported but the Swedish and European Research Councils and the UK Dementia Research Institute. KB holds the Torsten Söderberg professorship at the Royal Swedish Academy of Sciences.

The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Steven Ferris, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016570 (PI David Teplow, PhD), P50 AG005131 (PI Douglas Galasko, MD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P50 AG005136 (PI Thomas Grabowski, MD, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), and P50 AG005681 (PI John Morris, MD).

Dumitrescu L., et al. Sex differences in the genetic predictors of Alzheimer’s pathology. Brain. 2019 Sep. doi: 10.1093/brain/awz206. PubMed link