NG00189 – Summary statistics for GWAS of nine individual neuropsychiatric symptoms in mild cognitive impairment and dementia

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Description

Nine individual neuropsychiatric symptom domains (agitation or aggression, anxiety, apathy or indifference, delusions, depression or dysphoria, disinhibition, hallucinations, irritability or lability, nighttime behaviors) measured using the Neuropsychiatric Symptom Inventory Questionnaire were tested for association with single-nucleotide polymorphisms (SNPs) with minor allele frequency > 5% in a sample of 12,806 participants with mild cognitive impairment or dementia.

Participants were sampled from Alzheimer’s Disease Research Centers (ADRCs) throughout the United States and were of European genetic ancestry. For each NPS domain, a participant was classified as a “case” if they experienced the symptom in the month preceding any visit, and as a “control” otherwise. Parallel logistic regressions were performed for each NPS domain while controlling for sex (male v. female), batch (categorical with 15 levels), and the first 10 genetic PCs.

Available Filesets

Name	Accession	Latest Release	Description
GWAS for 9 Neuropsychiatric Symptoms: Full Summary Statistics (application needed)	fsa000159	NG00189.v1	Full Summary Statistics
GWAS for 9 Neuropsychiatric Symptoms: P-values only (open access)	fsa000160	NG00189.v1	P-values only

View the File Manifest for a full list of files released in this dataset.

Consent Level	Number of Subjects
DS-ADRD-IRB-PUB-NPU	NA

Acknowledgment statement for any data distributed by NIAGADS:

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

Use the study-specific acknowledgement statements below (as applicable):

For investigators using any data from this dataset:

Please cite/reference the use of NIAGADS data by including the accession NG00189.

For investigators using GWAS links APOE to neuropsychiatric symptoms in mild cognitive impairment and dementia – Vattathil, et al. 2025 (sa000076) data:

The authors are grateful to the ADRC, ADNI, and BioVU participants who made this research

possible. This work was supported in full or in part by the following grants to the authors: R01

AG075827, R01 AG072120, IK4BX005219, I01BX005686; R01 AG079170; T32 HG008341;

1R01MH118233. The contents do not represent the views of the U.S. Department of Veterans

Affairs or the United States Government. The Alzheimer's Disease Genetics Consortium supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01AG032984 and RC2AG036528. The NACC database is funded by NIA/NIH Grant U24 AG072122. VUMC BioVU is supported by numerous sources including the NIH funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Data collection and sharing for this project were funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2- 0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Total number of approved DARs: 2

Investigator:
Kamboh, M. Ilyas
Institution:
University of Pittsburgh
Project Title:
Genetics of Alzheimer's Disease and Endophenotypes
Date of Approval:
March 31, 2026
Request status:
Approved
Research use statements:
Show statements
Technical Research Use Statement:
Objectives: We are requesting access to the NIAGADS datasets to augment our ongoing studies on the genetics of Alzheimer’s disease (AD) and AD-related endophenotypes being carried out by Kamboh and his group since 1995. We are doing GWAS using array genotypes, whole-exome sequencing and whole-genome sequencing on datasets derived from University of Pittsburgh ADRC and ancillary population-based longitudinal studies on dementia and biomarkers. Different available phenotypes include AD and non-AD dementia, age-at-set, disease progression and survival, neuroimaging, cognitive decline, plasma biomarkers for the core ATN and non-ATN pathologies. We also plan to expand on gene-gene interaction and sex-stratified analyses which require the actual genotype data. The NIAGADS datasets will be used for replication and meta-analysis, and for gene-gene interaction and sex-stratified analyses. Study Design: A case-control design will incorporate a diverse cohort of individuals with AD and age-matched controls. For quantitative traits (neuroimaging and plasma biomarkers, cognitive performance measures, indicators of disease progression), linear regression analyses will be performed to identify genetic loci. To ensure the findings are robust and inclusive, participants from diverse demographic backgrounds will be included, enabling the exploration of potential genetic variations across populations. Analysis Plan: We will conduct GWAS and targeted analyses on candidate genes on different AD and AD-related phenotypes. Primary phenotypic variables include AD disease status, age-at-onset, last age for controls, APOE genotype, cognitive decline trajectories, sex, and race. Analyses will evaluate the influence of specific genetic variants on disease risk, cognitive performance, and biomarker levels, considering both individual and interactive effects of the APOE genotype. Results will be adjusted for potential confounders, such as demographic factors, to ensure valid associations. Detail analytical methods are described in our published papers for case-control (PMID: 32651314;35694926), quantitative traits (PMID: 30361487;37666928), and cognitive decline (PMID: 37089073; 30954325).
Non-Technical Research Use Statement:
Our research group at the University of Pittsburgh (Pitt), has been working on the genetics of Alzheimer’s disease (AD) and AD-related endophenotypes for almost three decades, on data derived largely from the University of Pittsburgh Alzheimer’s Disease Research Center and ancillary dementia studies. We are requesting access to the NIAGADS genotype and phenotype datasets to augment our sample size to increase power to detect novel genetic associations with AD and related endophenotypes.
Investigator:
Kim, Jong Hun
Institution:
KOREA UNIVERSITY RESEARCH AND BUSINESS FOUNDATION
Project Title:
Discovery of APOE-Interacting Genes Through Trans-Ancestry and Sex-Stratified Analysis to Elucidate Alzheimer's Disease Risk Mechanisms and Stratify ARIA Risk Using Proxy Outcomes
Date of Approval:
July 20, 2026
Request status:
Approved
Research use statements:
Show statements
Technical Research Use Statement:
Objectives: This project identifies ancestry- and sex-specific APOE ε4 modifier genes—variants that amplify or attenuate APOE ε4’s effect on AD risk and ARIA susceptibility from anti-amyloid immunotherapy. Aim 1: Trans-ancestry sex-stratified GWIS to construct an APOE-Wide Epistasis Map. Aim 2: Mechanistic validation via eQTL/pQTL colocalization and epistasis network. Aim 3: Explainable AI (XAI) integrating modifier SNPs, multi-omics subtypes, and ARIA proxy outcomes to stratify pre-treatment ARIA risk. Study Design: Multi-cohort secondary analysis using NIAGADS-controlled ADSP data exclusively. Individual-level data from all 15 ADC cohorts (NG00022–NG00151) and multi-ancestry ADSP WGS (NG00067, NG00166) span European, African American, Hispanic/Latino, and South/East Asian ancestries. Functional datasets (eQTL/pQTL: NG00102, NG00118, NG00120, NG00130) support Aim 2; imaging and neuropathology datasets (NG00103, NG00147, NG00175) enable Aim 3 ARIA proxy development. No prospective recruitment. Multi-dataset rationale: GWIS requires 4–8× more samples than standard GWAS (Gauderman 2002); no single cohort is independently powered—all 15 ADC cohorts must be pooled. Trans-ancestry GWIS requires ancestry-matched datasets (NG00100/African, NG00106/South Asian, NG00141/Hispanic) because population-specific LD cannot be imputed from summary statistics. Functional datasets (eQTL, pQTL, methylation) are non-redundant—each covers a distinct regulatory layer for Aim 2. All datasets are AD-specific; non-AD neurodegeneration data are excluded. Analysis Plan: Phenotypes: AD case/control (primary); APOE ε4 × SNP interaction; lobar microbleed count (ARIA-H proxy); SVD score (WMH, lacunar infarcts, perivascular spaces); longitudinal cognitive decline. Covariates: age, sex, top 20 ancestry PCs, stratum. Methods: logistic GWIS; trans-ancestry meta-analysis (METAL/MR-MEGA); sex-stratified/X-chromosome analyses; eQTL/pQTL colocalization (COLOC2/SMR); XGBoost XAI with 5-fold CV and SHAP.
Non-Technical Research Use Statement:
Alzheimer’s disease affects tens of millions worldwide. Lecanemab, approved in 2024, slows Alzheimer’s progression by removing amyloid plaques—but causes dangerous brain side effects (ARIA: Amyloid-Related Imaging Abnormalities) especially in APOE ε4 carriers, who also most need treatment. Currently, doctors cannot predict which APOE ε4 carriers will benefit versus be harmed.Our research identifies modifier genes controlling how dangerous APOE ε4 is. We leverage the ADSP’s diverse dataset spanning 15+ cohorts across European, African American, Hispanic/Latino, and Asian ancestries—a scale statistically necessary because detecting gene–gene interactions requires 4–8× more samples than standard genetic studies. Population-specific patterns allow high-confidence modifier identification. MRI-based brain bleeds and vascular markers serve as validated ARIA surrogates available at scale.The result is an explainable AI tool that predicts—before treatment begins—which APOE ε4 patients face high ARIA risk and which will benefit from lecanemab, enabling precision Alzheimer’s therapy.

NG00189 – Summary statistics for GWAS of nine individual neuropsychiatric symptoms in mild cognitive impairment and dementia – Vattathil, et al. 2025

Overview

Description

Available Filesets

Related Studies

Consent Levels

Acknowledgement

Acknowledgment statement for any data distributed by NIAGADS:

For investigators using any data from this dataset:

For investigators using GWAS links APOE to neuropsychiatric symptoms in mild cognitive impairment and dementia – Vattathil, et al. 2025 (sa000076) data:

Publications

Approved Users

Total number of subjects: 0

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