Scientists have built the most extensive molecular map yet of Alzheimer’s disease and several related brain disorders, analyzing more than 6.3 million individual brain-cell nuclei from nearly 1,500 donors.

 

The NIH-funded research, led by the PsychAD Consortium at Mount Sinai, provides an unprecedented look at how brain cells and molecular pathways change across Alzheimer’s disease, Parkinson’s disease, Lewy body disease, vascular dementia, schizophrenia and bipolar disorder.

 

“This is the most comprehensive, population-scale, molecular mapping of Alzheimer’s and related neurodegenerative and neuropsychiatric disorders to date,” said Dr. Richard Hodes, director of NIH’s National Institute on Aging (NIA), which supported the research. 

 

“These insights provide a foundation that will help identify precision targets for managing, treating, and reducing the neuropsychiatric symptoms of Alzheimer’s and related dementias, while also adding to our knowledge of the molecular processes happening in different conditions.”

 

The researchers created a single-cell atlas of the human dorsolateral prefrontal cortex, a region involved in memory and other complex cognitive functions. The atlas draws on brain tissue from 1,494 donors, including people with Alzheimer’s and other neurological and psychiatric disorders, as well as neurotypical controls.

 

The scale of the analysis allowed researchers to identify both molecular changes shared across disorders and changes specific to individual diseases. They also traced cellular patterns associated with Alzheimer’s progression and neuropsychiatric symptoms.

 

Those symptoms—including depression, agitation, aggression, psychosis, insomnia and irritability—are common in Alzheimer’s and related dementias. They can severely affect patients and caregivers, while also accelerating disease progression and proving difficult to treat.

 

The NIH established the PsychAD program to uncover the molecular mechanisms behind these symptoms and help develop more effective ways to prevent and treat them. The program also examines connections between psychiatric disorders earlier in life and the later development of dementia.

 

“these highly complex brain disorders impose an enormous public health burden, yet we still have a limited understanding of the molecular mechanisms that drive symptoms, progression, and resilience,” said Panos Roussos, professor in the Department of Genetics and Genomics Sciences and the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai, and senior author of the studies. 

 

“By mapping shared and distinct cellular programs across Alzheimer’s disease, related dementias, and psychiatric disorders, PsychAD creates a framework for moving beyond traditional diagnostic boundaries toward precision approaches for target discovery, biomarker development, and therapeutic prioritization.”

 

The research goes beyond a single brain atlas. The studies also produced:

 

A single-nucleus transcriptome-wide association study covering human brain disorders.

 

A single-cell atlas tracking the human prefrontal cortex across the lifespan, offering a reference for distinguishing normal aging from disease-related changes.

 

An atlas of cell-type-specific gene regulation that links genetic risk variants to particular brain cell types and molecular pathways.

 

An artificial intelligence framework designed to identify cell states associated with Alzheimer’s pathology, cognitive decline, resilience and neuropsychiatric symptoms.

 

New personalized-medicine tools and methods for conducting large-scale brain research.

 

The researchers have made the data and methods publicly available, allowing scientists worldwide to use the findings in research on brain aging, neurodegeneration and psychiatric disorders.

 

The researchers say the new maps could ultimately help identify biomarkers, molecular targets and treatment strategies tailored to specific biological features of disease—moving Alzheimer’s and related disorders toward more precise approaches to diagnosis and therapy.