Psychiatry Center for Dementia Research

Scientists in NYU Langone’s Department of Psychiatry conduct basic and translational research in dementia, Alzheimer’s disease, and related conditions through the Center for Dementia Research (CDR) at the Nathan S. Kline Institute for Psychiatric Research. Our research team, led by Ralph A. Nixon, MD, PhD, studies disease etiology, as well as prevention and treatment strategies.

Synapse Dysfunction in Alzheimer’s Disease

Scientists in the Nixon laboratory focus on synapse dysfunction, considered to be a crucial component in the development of dementia. We are defining the two-way communications between the nucleus of the neuronal cell body and the synapses that maintain synapse structure and regulate neurotransmission.

Our previous work established accelerated endocytosis and aberrant endosomal signaling as neuronal abnormalities in Alzheimer’s disease that are closely linked to Alzheimer’s disease–related genes. We discovered that amyloid precursor protein, apolipoprotein E4 (ApoE4), and presenilins progressively corrupt lysosome function, which causes amyloid and tau accumulation and neuron death. Using a novel genetic mouse model, we are defining the specific steps leading from abnormal endosomal signaling to synaptic dysfunction, early cholinergic neurodegeneration, and memory decline and how genetic and environmental factors impair lysosomes.

We are also exploring the interrelationships between protein subnetworks and each neurofilament protein in central nervous system synapses, including links to regulation of endocytosis at synapses in genetic mouse and cell models. We have identified therapeutic targets in the endosomal–lysosomal pathway and are validating these in preclinical and clinical trials.

Proteomic and genomic analyses have identified specific protein subnetworks in synapses, including one that is highly enriched in proteins related to the genetic basis for cognitive disorders, including Alzheimer’s disease, frontotemporal dementias, and neurodevelopmental disorders. We are further investigating molecular interrelationships between this synaptic protein subnetwork, endocytosis regulation, and cognition in disease models.

Altered Excitability and the Etiology of Diverse Psychiatric Conditions

Research led by Helen E. Scharfman, PhD, in the Scharfman Lab, focuses on altered excitability and the etiology of diverse neurological and psychiatric conditions. Our scientists mainly use animal models, assessing rodents with seizures or with a mutation leading to Alzheimer’s disease brain pathology and cognitive impairments. Our goals are to use drugs to normalize this excitability in rodents and determine which agents improve symptoms. Our intent is to develop new therapeutic approaches for humans.

We are defining the fundamental circuitry of complex brain areas like the hilus of the dentate gyrus; as such, one of our projects addresses the normal role of neurons born in the dentate gyrus during adulthood. Adult-born neurons may keep the neural activity of the dentate gyrus low, which could be crucial to dentate gyrus cognitive functions. We are also studying the mossy cells of the dentate gyrus, in addition to hippocampal area CA2 and whether it is more powerful than its size would predict.

Our translational research assesses the use of selective suppression or enhancement of adult-born neurons to treat epilepsy and whether inhibiting mossy cells or CA2 can influence epilepsy in animal models. Our lab also investigates early abnormal electrical activity as a biomarker in an Alzheimer’s disease mouse model and therapeutic approaches to suppressing this activity.

Molecular, Cellular, and System Levels of Alzheimer’s Disease

Dun-Sheng Yang MD, PhD, studies Alzheimer’s disease pathogenesis in the human brain and in mice at the molecular, cellular, and system levels. He also explores novel targets within the autophagic–lysosomal system as therapies.

The Yang Lab is characterizing the autophagic–lysosomal pathway in relation to Alzheimer’s disease–associated degradation impairments in proteins and lipids and the pathophysiological consequences in. The lab also uses Alzheimer’s disease models to validate innovative therapeutic approaches based on remediating the prominent dysfunction of the autophagic–lysosomal system.

Changes in Vesicular Trafficking in Alzheimer’s Disease Neurons

The Levy Lab, led by Efrat Levy, PhD, studies pathogenic processes leading to Alzheimer’s disease and related neurodegenerative disease. Our researchers study mechanisms underlying the generation and secretion of extracellular vesicles and their neuroprotective properties or potential neurotoxicity in the brains of patients and mice with Alzheimer’s disease.

Based on prior research, our scientists are enhancing the release of extracellular vesicles to prevent neuron loss caused by cellular accumulation of toxic material. Extracellular vesicles can also carry content long distances through extracellular space, delivering protective molecules into recipient cells and providing a novel therapeutic approach to treating Alzheimer’s disease.

Our lab has identified a range of neuronal abnormalities in the brain of APOE carriers, including impaired release of neuroprotective vesicles (exosomes) within the extracellular space. We are identifying new therapeutic targets based on the differences in brain changes between APOE4 allele carriers and APOE2 allele carriers; the APOE2 allele appears to be protective. Our research also involves the delivery via extracellular vesicles of proteins and peptides that prevent disease development.

Mechanisms of Alzheimer’s Disease and Related Cognitive Symptoms

The Ohno Laboratory, led by Masuo Ohno, PhD, studies the mechanisms of Alzheimer’s disease, specifically β-secretase 1 (BACE1), which initiates the production of harmful β-amyloid (Aβ) peptides, the major constituent of amyloid plaques. Our researchers also aim to develop disease-modifying therapy to prevent or treat memory deficits.

By applying gene knockout and small-molecule inhibitors to mouse models, we are finding that successful therapeutic BACE1 inhibition for cognitive benefit needs to start during early or asymptomatic disease stages. We are also investigating BACE1-elevating mechanisms, which can represent novel therapeutic targets. Our goal is to increase BACE1-inhibition efficacy in ameliorating memory deficits, while avoiding unwanted effects.

Neuronal Cell Types’ Vulnerability to Brain Disease

The Ginsberg laboratory, led by Stephen D. Ginsberg, PhD, aims to understand mechanisms underlying selective vulnerability associated with Alzheimer’s disease. Our researchers extensively characterize individual populations of neurons from Alzheimer’s disease and Down syndrome models and postmortem brains using high-throughput gene assays. Individuals with Down syndrome develop neuropathological changes seen in early Alzheimer’s disease.

We are currently profiling selectively vulnerable neurons and comparing them with relatively spared neurons during Alzheimer’s disease onset and progression. We are also analyzing selective vulnerability in the hippocampus. Animal studies suggest that specific gene pathways associated with neuron survival and intracellular trafficking are important for normal neuron function, partially explaining why some neurons are vulnerable and others resilient. Parallel studies in the postmortem brain indicate that individual genes and their encoded proteins in these critical pathways are disrupted in Alzheimer’s disease, especially within vulnerable neurons early in the disease.

Our translational research is directed towards reversing the dysregulation of genetic pathways in vulnerable neurons. One project employs a chronic dietary restriction approach in adult Alzheimer’s disease mice. Another uses an early-development dietary supplementation in Down syndrome mice to positively affect vulnerable hippocampal neurons. We then evaluate treatment benefits using the single-population profiling procedure.

Molecular Mechanisms of Neurodegeneration in Amyotrophic Lateral Sclerosis and Alzheimer’s Disease

Mala V. Rao, PhD, and colleagues in the Rao Lab, address molecular mechanisms of amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease. Our researchers study proteolytic degradation mechanisms in neurons and disease pathogenesis.

We also investigate influences of proteolysis on axonal transport and structure, synaptic functions, and motor and cognitive behaviors in relation to disease onset, progression, and survival. This helps us define the contribution of altered proteostasis to pathogenesis and identify therapeutic targets for neurological disease.

Our basic research explores how neurons communicate with each other at synapses through neurofilament (NF) proteins. We’re examining the role of NF-H and α-internexin in regulating synaptic functions, and we hope to identify the synaptic mechanisms that modulate NF function.

Our translational research focuses on calpastatin, the only natural inhibitor of calpains, as a therapy for various neurological diseases. Calpains activate during calpastatin depletion in neurons under various neurological conditions. Our mouse models demonstrate that calpastatin replenishment may alleviate disease symptoms in Alzheimer’s disease, tauopathy, Huntington’s disease, Parkinson’s disease, and ALS and improve survival in tauopathy and ALS. We hope to identify the role of glial cells in disease progression and survival with calpain inhibition.

Current Grants

Our research is supported by a variety of National Institutes of Health grants.

National Institute on Aging

Cell and Molecular Pathobiology of Alzheimer’s Disease; 5P01AG017617-17

Dynamics of the Neuronal Cytoskeleton in Aging Brain; R01AG005604

Endosome Dysfunction in Alzheimer's Disease: Mechanisms and Role in Pathogenesis; 1R01AG062376-01

In Vivo Evaluation and Therapeutic Modulation of Neuronal Autophagy Flux in HD Mouse Models

Hyperexcitability in Alzheimer’s Disease; 5R01AG055328-02

Postdoctoral Research Training in Neurodegenerative Disorders and the Aging Brain; 5T32AG052909-02

Preventing Early Events in a Beta-Driven Pathology In Vivo; 5R01AG056732-02

Neuronal Protective Apolipoprotein E2–Mediated Endocytic and Exocytic Pathways; 1RF1AG057517-01

National Institute of Neurological Disorders and Stroke

Diverse Roles of Adult Dentate Gyrus Neurogenesis; 5R01NS081203-05

The Role of CA2 in Epilepsy and Social Comorbidity; 1R01NS106983-01

Dynamics of pH Regulation in the Brain; 5R01NS032123-22

Accelerated Depletion of Hippocampal Neural Stem Cells in Neurological Disease; 5R01NS086965-05

National Institute of Mental Health

Hilar Mossy Cells and Dentate Gyrus Function; 5R01MH109305-03

Research Training

We provide a range of training opportunities in basic and translational neuroscience, psychiatric research, and cross-disciplinary collaborative research. We have an exceptional track record of preparing trainees for independent faculty and leadership positions in academia, industry, and scientific foundations. Graduate students, postdoctoral fellows, and recent college graduates with diverse interests are welcome in many of our labs.

Research Faculty

Our research faculty are leaders in the field of dementia research.

Stephen D. Ginsberg, PhD
Efrat Levy, PhD
Masuo Ohno, PhD
Ralph A. Nixon, MD, PhD
Mala V. Rao, PhD
Helen E. Scharfman, PhD
Dun-Sheng Yang MD, PhD

Contact Us

For more information about the Department of Psychiatry’s work through the Center for Dementia Research, please contact Ralph A. Nixon, MD, PhD, at