Genetic and neuroanatomical basis of neuropsychiatric symptoms in Alzheimer's disease in populations of diverse ancestry

PROJECT SUMMARY This application is in response to PAR-21-212, Alzheimer’s Disease Sequencing Project Follow-Up Study 2.0 (ADSP FUS 2.0): The Diverse Population Initiative. 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 accelerated decline, out-of-home placement, increased costs, and 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 (including increased mortality). This knowledge gap is particularly egregious in underserved racial and ethnic groups such as Hispanics and African-Americans, which historically have had limited genetic and phenotypic studies of AD, although AD is up to twice as prevalent in these ethnic groups compared to non-Hispanic Whites. To begin addressing this lack of diversity in AD genomics studies, the NIH/NIA has begun a number of diverse genomics initiatives, among these the Alzheimer Disease Sequencing Project (ADSP) and its Follow-Up-Study (ADSP-FUS) which have assembled and whole-genome sequenced ~60,000 individuals of diverse ancestral background (Hispanic, African American, Asian, non-Hispanic White) and are now in the process of harmonizing cognitive, brain imaging, neuropathological and biomarker data on these individuals. There is, however, no plan to collect, harmonize, or analyze the important AD-associated NPS data that has been collected for these samples. This is a critical oversight, as a better understanding of the genetic basis of NPS in AD, informed by ancestral background, is vital to infer the mechanistic pathways underlying these highly disabling symptoms and develop more effective pharmacological targets. To begin addressing this gap, we propose 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 (n=61,343) 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.