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Evidence for sexual antagonism and antagonistic pleiotropy in the maintenance of late onset Alzheimer’s disease alleles
Trade-offs form a key constraint in many aspects of organismal evolution, though they may help maintain genetic diversity. Late-onset Alzheimer’s disease (LOAD) shows features in common with the male-female health survival paradox: females suffer from higher prevalence and risk, as well as faster rates of cognitive decline while males suffer higher mortality. Though antagonistic pleiotropy could explain the tendency of LOAD to appear late in life, the sexually dimorphic profile suggests a role for intralocus sexual conflict. Using published data on sex-specific genetic associations with LOAD risk, we found evidence for a number of sexually antagonistic loci, where alleles with net negative effects that reduce male risk but increase female risk are more common than alleles with reversed effects. Multiple lines of evidence also suggest there is an inverse relationship between cancer and LOAD risk. The combined effect of sexual antagonism and antagonistic pleiotropy could explain the persistence of alleles that increase LOAD risk in post-reproductive females, if they also reduce cancer risk in males. This framework could be applied to other female-biased late-life conditions, and our results may be useful in informing polygenic risk scores or therapies where genotype-by-sex effects may result in undesired outcomes for one particular sex. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement EHM was supported by the Swedish Research Council (grant numbers: 2019-03567 and 2025-03964). JAH was supported by a Wellcome Trust grant awarded to Matthew Neale (#225852/Z/22/Z) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The source data were openly available before the study was initiated. The source data were obtained from the following study: Prokopenko, D., Hecker, J., Kirchner, R., Chapman, B.A., Hoffman, O., Mullin, K., et al. 2020. Identification of Novel Alzheimer's Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data. Sci. Rep. 10: 5029. Nature Publishing Group. <https://www.nature.com/articles/s41598-020-61883-6> I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at: <https://doi.org/10.5281/zenodo.18681253>
