Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes.

We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. This study leveraged data from seven studies of cognitive aging (Knight ADRC, ADNI1, ADNI2, BIOCARD, Mayo, Sweden, UPENN, UW) with 1,527 males and 1,509 females. CSF Ab42 and t-tau biomarker data were harmonized across cohorts and genotypes underwent standard quality control and imputation (genome build 37). A SNP*sex interaction GWAS evaluated differences in variant associations with pathology by sex and stratified GWAS assessed for associations with neuropathology within males and females separately.

Carlos Cruchaga
Washington University School of Medicine

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-specific genetic predictors of Alzheimer's disease biomarkers – Deming, et al. 2018 data:

This research was supported in part by K01 AG049164, 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, 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. YD is supported by an NIMH training grant (T32MH014877). Support for PDJ was provided by R01 AG048015. SK received support from NIA R03 AG050856, Alzheimer’s Association, Michael J Fox Foundation, and ARUK Biomarkers Across Neurodegenerative Diseases (BAND). MR received support from the German Federal Ministry of Education and Research (BMBF) National Genome Research Network (NGFN) Grant No. 01GS08125 and through the Helmholtz Alliance for Mental Health in an Aging Society (HELMA) Grant No. Ha-15. HZ 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).

Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible; 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-AG041689–01).

Deming Y., et al. Sex-specific genetic predictors of Alzheimer’s disease biomarkers Acta Neuropathol. 2018 Dec. doi: 10.1007/s00401-018-1881-4. PubMed link