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Genetic Evidence Supporting a Causal Role of Depression in Alzheimer’s Disease

Published:December 16, 2021DOI:https://doi.org/10.1016/j.biopsych.2021.11.025

      Abstract

      Background

      Depression has been associated with a higher risk of Alzheimer’s disease (AD) in several prospective studies; however, mechanisms underlying this association remain unclear.

      Methods

      We examined genetic correlation between depression and AD using linkage disequilibrium score regression. We then tested for evidence of causality between depression and AD using Mendelian randomization and genome-wide association study results. Subsequently, cis and trans quantitative trait locus analyses for the depression genome-wide association study signals were performed to resolve the genetic signals to specific DNA methylation sites, brain transcripts, and proteins. These transcripts and proteins were then examined for associations with AD and its endophenotypes. Finally, the associations between depression polygenic risk score and AD endophenotypes were examined.

      Results

      We detected a significant genetic correlation between depression and AD, suggesting that they have a shared genetic basis. Furthermore, we found that depression had a causal role in AD through Mendelian randomization but did not find evidence for a causal role of AD on depression. Moreover, we identified 75 brain transcripts and 28 brain proteins regulated by the depression genome-wide association study signals through quantitative trait locus analyses. Of these, 46 transcripts and seven proteins were associated with rates of cognitive decline over time, AD pathologies, and AD diagnosis in two separate cohorts, thus implicating them in AD. In addition, we found that a higher depression polygenic risk score was associated with a faster decline of episodic memory over time.

      Conclusions

      Depression appears to have a causal role in AD, and this causal relationship is likely driven, in part, by the 53 brain transcripts and proteins identified in this study.

      Keywords

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      Linked Article

      • Human Genetics Clarifies the Relationship Between Depression and Alzheimer’s Disease
        Biological PsychiatryVol. 92Issue 1
        • Preview
          Depression and Alzheimer’s disease (AD) dementia are prevalent brain disorders that lead to an immense patient, caregiver, and societal suffering. Observational studies strongly support the association between depression and the risk of AD dementia (1,2). Still, confounders and reverse causation can impact observational studies (3), and the causal relationship between depression and AD dementia remains unclear. In the current issue of Biological Psychiatry, Harerimana et al. (4) leverage genetic associations to address these limitations and to clarify the causal relationship between depression and AD dementia.
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