U01AG079850_Genetics of neuropsychiatric symptoms in AD

Neuropsychiatric Symptoms (NPS) (e.g. aggression, psychosis, anxiety, apathy, depression, agitation, sleep disturbances, repetitive behaviors) occur in 85% of AD patients, and are associated with greatly increased suffering of patients and families. Despite this, our understanding of the etiology of NPS in AD is inadequate, with treatments for NPS often being ineffective and associated with serious adverse effects. This knowledge gap is particularly egregious in underserved racial and ethnic groups. The aim of the current project (U01AG079850) is to collate, harmonize, and analyze the AD-associated NPS data collected on ADSP/ADSP-FUS samples. We plan to (1) expand the racially and ethnically diverse datasets of the ADSP-FUS and related efforts to include harmonized NPS data, creating the largest and most diverse genomic resource on NPS in AD to date allowing researchers to assess a wide range of additional critical hypotheses through these resources; (2) utilize these harmonized data to identify and describe genetic determinants, pathways, and polygenic effects underlying specific NPS in AD; (3) explore the shared genetic architecture across AD-associated NPS and with primary psychiatric disorders; and (4) disentangle the role of ancestry in NPS genetic risk. Included in these analyses will be in particular early-onset samples already recruited and whole-genome sequenced under the READR , EFIGA and NIA-FBS initiatives which have a particularly high prevalence of NPS. We anticipate that this work will lead to a better understanding of the genetic basis of NPS in AD which is vital to infer the mechanistic pathways underlying these highly disabling symptoms and develop more effective pharmacological targets. To collate NPS data on all ADSPFUS cohorts we closely collaborate with the ADSP-Phenotype Harmonization Consortium. Creation of refined harmonized NPS phenotypes will be conducted by Dr. Ted Huey’s group at Brown University. Genomic data analyses will be conducted by Dr. Reitz’ group at Columbia University and Dr. Beecham’s group at the University of Miami.

Although neuropsychiatric symptoms (e.g. aggression, psychosis, anxiety, apathy, depression, and sleep disturbances) occur in ~85% of Alzheimer disease patients and are associated with accelerated decline, increased cost, out-of-home placement, and greatly increased suffering of patients and families, our understanding of their etiology is still inadequate, with treatments often being ineffective and even associated with serious adverse effects (including increased mortality). This knowledge gap is particularly egregious in underserved racial and ethnic groups such as Hispanics and African-Americans. We propose to expand the racially and ethnically diverse ADSP-FUS and related resources to include harmonized neuropsychiatric symptom data allowing researchers to assess a variety of additional critical hypotheses, and to utilize these harmonized data to identify ancestry-specific genetic determinants, molecular pathways, and polygenic effects underlying neuropsychiatric symptoms in Alzheimer disease.