Genetic evidence supporting a causal role of depression on Alzheimer’s disease

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Genetic evidence supporting a causal role of depression on Alzheimer’s disease

• Nadia V. Harerimana
• Yue Liu
• Ekaterina S. Gerasimov
• 
  
• Nicholas T. Seyfried
• Thomas S. Wingo
• Aliza P. Wingo
• Show all authors

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

Abstract

Background

Depression is associated with higher risk for 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 LDSC regression. We then tested for evidence of causality between depression and AD using Mendelian randomization and genome-wide association study (GWAS) results. Subsequently, cis and trans quantitative trait locus (QTL) analyses for the depression-GWAS 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. Lastly, associations between depression polygenic risk score (PRS) 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 has 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 GWAS signals through QTL analyses. Among these, 46 transcripts and 7 proteins were associated with rates of cognitive decline over time, AD pathologies, and AD diagnosis in two separate cohorts, implicating them in AD. Additionally, we found that higher depression PRS was associated with 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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