Fan CC, Banks SJ, Thompson WK, Chen CH, McEvoy LK, Tan CH, Kukull W, Bennett DA, Farrer LA, Mayeux R, Schellenberg GD, Andreassen OA, Desikan R, Dale AM. Sex-dependent autosomal effects on clinical progression of Alzheimer's disease. Brain. 2020 Jul 1;143(7):2272-2280. PubMed.

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  1. For anyone interested, along the lines of this excellent new study, we also recently published a paper using family-based association to identify novel AD genetic risk factors that are sex-specific, in this case actually conferring opposite risk effects in men and women.

    The top hit was ZBTB7C, which encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases, implicated in AD neuropathology.

    References:

    Prokopenko D, Hecker J, Kirchner R, Chapman BA, Hoffman O, Mullin K, Hide W, Bertram L, Laird N, DeMeo DL, Lange C, Tanzi RE. Identification of Novel Alzheimer's Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data. Sci Rep. 2020 Mar 19;10(1):5029. PubMed.

    View all comments by Rudy Tanzi

  2. C.C. Fan et al. developed and examined a sex-stratified polygenic score for prediction of AD age of onset and other AD phenotypes, including AD pathological hallmarks. Their study expands recently published GWAS papers, exploring genes that were associated with AD phenotypes either in men or in women, not in both.

    Fan’s paper has two main findings. First, polygenic hazard score, developed through conduction of Cox hazard function, predicted AD phenotypes better than polygenic risk score, developed by conduction of logistic regression. Second, sex-matched polygenic scores, which are developed and applied in the same sex, outperformed sex-mismatched polygenic scores, which are developed in one sex and applied in another sex, in prediction of AD.

    Currently, polygenic scores are gaining widespread attention and use in the field of medicine as most common human diseases have genetic susceptibility originating from cumulative effects of thousands of SNPs, each having a very small effect on the disease of interest. In the field of AD, several groups have developed an AD polygenic score. Fan’s paper suggests that AD polygenic risk scores should be developed separately in men and women, the same path that other investigators followed previously, including those who developed the Framingham Cardiovascular risk scores for prediction of vascular events.

    View all comments by Shahram Oveisgharan

  3. The findings of this paper are interesting and add some further food for thought in the search for an explanation as to why we observe differences between men and women in the onset and progression of AD. It is interesting to note that there was no difference in the prediction accuracy of the polygenic risk score (PRS, a measure of general risk for AD diagnosis at any time within a person's lifetime, or at death) but the more “temporal” polygenic hazard score (PHS) showed sex-specific prediction accuracy. These findings, in combination with the AD endophenotype studies, demonstrate why it is so important that researchers move toward the biologically based ATN research framework proposed by Cliff Jack and colleagues (Jack et al., 2018). Further research is necessary to determine why there is this growing evidence for sex differences in AD risk and progression. In terms of purely strict genetic inheritance, the sex chromosomes are the only difference between biological males and females, which means that what we are seeing in these sex-specific genetic associations are reflections of biological, environmental, social, and/or even cohort differences between men and women.

    As a side note, I like that they use the E2 and E4 dosages for their APOE genotype correction instead of the simple E4-carrier status that many groups use, as this takes into account the nonlinear relative risk of the APOE genotype.

    References:

    Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R, Contributors. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018 Apr;14(4):535-562. PubMed.

    View all comments by Yuetiva Robles

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  1. Women and Men Differ in Their Genetic Risk for Alzheimer’s Progression