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Basic Science and Pathogenesis.

Pamela Del Rosario1, Alyssa N De Vito2, Colin Stein3

  • 1Columbia University Irving Medical Center, New York, NY, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
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Summary
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Neuropsychiatric symptoms in Alzheimer's Disease (AD) are common and impact quality of life. This study analyzes genetic data from diverse populations to identify causes and develop better treatments for these debilitating symptoms.

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Area of Science:

  • Neurogenetics
  • Alzheimer's Disease Research
  • Psychiatric Symptomology

Background:

  • Neuropsychiatric Symptoms (NPS) are highly prevalent in Alzheimer's Disease (AD) patients.
  • NPS are linked to accelerated cognitive decline and reduced quality of life for patients and caregivers.
  • Current pharmaceutical interventions for NPS in AD are ineffective, necessitating research into underlying mechanisms.

Purpose of the Study:

  • To identify genetic loci and mechanistic pathways contributing to NPS in AD.
  • To facilitate the development of improved therapeutic strategies for NPS in AD.
  • To analyze data from diverse ancestral populations to ensure broad applicability.

Main Methods:

  • Harmonization of NPS data from over 70 Alzheimer's Disease Sequencing Project (ADSP) cohorts (>80,000 samples).
  • Inclusion of whole-genome sequencing data from the ADSP-FUS.
  • Definition and calculation of symptom clusters: Early psychosis/agitation (EPA), late psychosis/agitation (LPA), and affective symptoms (AS), accounting for covariates.

Main Results:

  • Harmonization of neuropsychiatric data from 13 ADSP cohorts (over 30,000 individuals) completed, with ongoing harmonization of additional diverse cohorts.
  • Analysis of whole-genome sequencing data is underway.
  • Primary analyses will identify novel genetic risk factors, characterize shared genetic architecture with psychiatric disorders, and assess ancestry effects.

Conclusions:

  • Expansion of the ADSP-FUS with harmonized NPS phenotypes is crucial.
  • Proposed analyses will provide a foundation for understanding molecular mechanisms of NPS in diverse AD populations.
  • This research aims to disentangle the complex etiology of detrimental NPS in AD.