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Basic Science and Pathogenesis.

Moonil Kang1, Ting Fang Alvin Ang2,3,4, Sherral A Devine2,4

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This study identified novel genetic loci pleiotropic for blood pressure and cognition, suggesting shared mechanisms linking hypertension and Alzheimer's disease risk. These findings offer insights into potential therapeutic targets for both conditions.

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Area of Science:

  • Genetics
  • Neuroscience
  • Cardiovascular Science

Background:

  • Genome-wide association studies (GWAS) have identified numerous loci for blood pressure (BP) and Alzheimer's disease (AD).
  • Blood pressure is a known risk factor for Alzheimer's disease.
  • Investigating pleiotropy between BP and cognitive performance may reveal mechanistic links between BP and AD.

Purpose of the Study:

  • To identify pleiotropic loci influencing both blood pressure and cognitive performance.
  • To explore the shared genetic underpinnings of hypertension and cognitive function.
  • To investigate potential mechanistic links between blood pressure regulation and Alzheimer's disease pathogenesis.

Main Methods:

  • Pleiotropy GWAS was performed using generalized linear mixed models on longitudinal data from over 25,000 participants.
  • PLACO was used to estimate SNP effects, SNP×age interactions, and their joint effect on pleiotropy.
  • Mendelian randomization evaluated the direct or BP-mediated effects of pleiotropic SNPs on cognition, and gene expression analysis assessed their contribution to cognitive resilience.

Main Results:

  • GWAS identified genome-wide significant (GWS) pleiotropy for BP and cognitive domains (executive function, language, memory) at APOE and 11 novel loci.
  • Specific SNPs in genes like JPH2, GATA3, RTN4, ADAMTS3, ULK2, PAX2, LOC105371656, SUFU, LINC02946, SORBS2, and LOC100128993 showed GWS pleiotropic associations.
  • Five GWS pleiotropic loci directly influence cognition, and genes at six loci were differentially expressed in AD cases with varying clinical symptoms.

Conclusions:

  • The findings provide novel insights into the shared genetic mechanisms underlying blood pressure regulation and Alzheimer's disease.
  • Identifying pleiotropic loci can help elucidate the complex relationship between hypertension and cognitive decline.
  • Harmonizing BP and cognitive measures across cohorts will enhance future discoveries of pleiotropic associations.