# Elucidating the Molecular Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Disease

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $1,295,549

## Abstract

Abstract
Alzheimer's disease (AD) is the most common cause of dementia, and the most common neurodegenerative
disease worldwide, affecting 1 in 8 individuals over 65 years old in the US. Within AD, approximately 40-60%
individuals are affected by psychotic symptoms (AD+P), which are associated with more rapid cognitive
decline, greater disability, mortality and caregiver burden, resulting in a disproportionately large disease
burden. Recent studies indicate a genetic basis for AD+P risk, but the molecular basis of AD+P remains largely
uncharacterized, hindering the search for appropriate treatments and novel therapeutics. In this proposal, we
seek to systematically dissect the mechanistic basis of AD+P by systematic generation, integration, and
experimental dissection of transcriptional and epigenomic phenotypes across two brain regions and four cell
types. (1) We profile single-cell RNA-seq and cell-type specific H3K27ac ChIP-seq across 192 post-mortem
brain samples, each in two regions across AD patients with psychosis, AD patients with no psychosis,
schizophrenia patients with no AD, and control individuals. (2) We integrate the resulting datasets with genetic
information and GWAS data to predict driver genes, regions, variants, and pathways underlying AD+P using
state-of-the-art machine learning methods for causality, mediation analysis, and genetic Bayesian fine-
mapping. (3) We use our computational predictions to guide a systematic dissection of the molecular
underpinnings of AD+P using a modular and programmable CRISPR-Cas9 methodology in iPSC lines to
modulate regulatory elements, genes and alleles, and measure the resulting molecular and cellular phenotypes
in cell-autonomous and non-autonomous phenotypes. If successful, this ambitious proposal has the potential
to provide the first mechanistic insights on the development of psychotic symptoms in AD+P and/or P-AD,
reveal functional risk variants and target genes for therapeutic intervention that will likely influence clinical
management in order to alleviate the personal and societal burden associated with these disorders.

## Key facts

- **NIH application ID:** 9950945
- **Project number:** 5R01AG062335-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Manolis Kellis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,295,549
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9950945

## Citation

> US National Institutes of Health, RePORTER application 9950945, Elucidating the Molecular Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Disease (5R01AG062335-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9950945. Licensed CC0.

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