Disentangling the genetic underpinnings of neuropsychiatric symptoms in Alzheimer's disease in the Alzheimer's Disease Sequencing Project: Study design and methodology

Abstract

Introduction: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). There are no effective treatments targeting these symptoms.

Methods: To facilitate identification of causative mechanistic pathways, we initiated an effort (NIH: U01AG079850) to collate, harmonize, and analyze all available NPS data (≈ 100,000 samples) of diverse ancestries with whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP).

Results: This study will generate a genomic resource for Alzheimer's disease with both harmonized whole-genome sequencing and NPS phenotype data that will be publicly available through NIAGADS. Primary analyses will (1) identify novel genetic risk factors associated with NPS in AD, (2) characterize the shared genetic architecture of NPS in AD and primary psychiatric disorders, and (3) assess the role of ancestry effects in the etiology of NPS in AD.

Discussion: Expansion of the ADSP to harmonize and refine NPS phenotypes coupled with the proposed core analyses will lay the foundation to disentangle the molecular mechanisms underlying these detrimental symptoms in AD in diverse populations.

Highlights: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD).There are no effective treatments targeting NPS in AD.The current effort aims to collate, harmonize, and analyze all NPS data from the Alzheimer's Disease Sequencing Project.Core analyses will identify underlying genetic factors and mechanistic pathways.The harmonized genomic and phenotypic data from this initiative will be available through National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site.

Keywords: Alzheimer's Disease Sequencing Project; Alzheimer's disease; genetics; neuropsychiatric symptoms.

FIGURE 1

Integration of the present effort with the ADSP/ADSP‐FUS and the ADSP‐PHC. The current effort will capitalize on existing ADSP‐PHC infrastructure including data use agreements to acquire NPS data and deliver harmonized phenotypes to NIAGADS for distribution to the research community. Additional (endo)phenotypes collated and harmonized by the ADSP‐PHC include cognitive, brain imaging, biomarker, neuropathology, and cardiovascular data. ADSP, Alzheimer's Disease Sequencing Project; ADSP‐FUS, Alzheimer's Disease Sequencing Project Follow Up Study; ADSP‐PHC, Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium; NIAGADS, National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site; NPS, neuropsychiatric symptoms

FIGURE 2

Types of data harmonized by the ADSP/ADSP‐PHC in addition to neuropsychiatric variables harmonized through the current effort. Aβ, amyloid beta; ADSP, Alzheimer's Disease Sequencing Project; ADSP‐PHC, Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium; BMI, body mass index; MRI, magnetic resonance imaging; NPI‐Q, Neuropsychiatric Inventory Questionnaire; PET, positron emission tomography; pTau, phosphorylated tau; TDP43, TAR DNA‐binding protein 43