Synaptic plasticity is altered in the aging brain and is a fundamental mechanism of age-related cognitive decline. We work at the boundary of Alzheimer's disease and the more modest disruption of memory often referred to as age-associated cognitive impairment, or mild cognitive impairment, that occurs in normal aging. We study the cellular, synaptic, and molecular basis of the earliest age-related alterations that lead to cognitive aging comparing humans and closely related non-human primates as well as small animal models to dissect factors contributing to cognitive resilience or decline. We also study how these events relate to the complex physiology of aging and age-related neurodegenerative diseases, such as the interactions between sleep, stress and cognitive function, the brain and body, aging and traumatic brain injury as well as aging-related comorbidities, such as cerebrovascular and cardiovascular risk factors.

Investigators in this research area include:

• Deanna Benson, PhD
• Joseph M Castellano, PhD
• John Crary, MD, PhD
• Kristen Dams-O’Connor, PhD
• Michelle Ehrlich, MD
• Fanny Elahi, MD, PhD
• Gregory A. Elder, MD
• Samuel E. Gandy, MD, PhD
• Vahram Haroutunian, PhD
• Patrick R Hof, MD
• George W. Huntley, PhD
• Cameron McAlpine, PhD
• Giulio Maria Pasinetti, MD, PhD
• Ana Pereira, MD
• Nikolaos K. Robakis, PhD
• Mary Sano, PhD
• Andrew W. Varga, MD
• Merina T. Varghese, PhD
• Zhenyu Yue, PhD

The ability to learn new facts and remember recent events is a fundamental part of everyday life experiences. Neural mechanisms of learning, memory, executive function, and decision-making are all vulnerable as we age, and these functions fail in many individuals with neuropsychiatric disorders. At Icahn School of Medicine at Mount Sinai, our research interests include: the functional neuroanatomy of neocortex and hippocampus, the neuromodulation of higher cognitive functions, pathways underlying circuit formation, and the mechanisms of cognitive impairments in aging and neurodegenerative disease. Different brain networks are crucial for different types of learning, such as memory for new facts and recent events, emotional associations, and skill learning. We focus on how the hippocampus, prefrontal cortex, amygdala, and neostriatum contribute to memory in experimental animals and humans, and how mechanisms of neuronal plasticity within these structures contribute to memory functions.

Investigators in this research area include:

• Denise Cai, PhD
• Samuel E. Gandy, MD, PhD
• Trey Hedden, PhD
• Patrick R. Hof, MD
• Jane Martin, PhD
• Erin L. Rich, MD, PhD
• Peter Rudebeck, PhD
• Stephen Salton, MD, PhD
• Ignacio Saez, PhD
• Tristan Shuman, PhD
• Brian Sweis, MD, PhD
• Herbert Wu, PhD
• Xiaoting Wu, PhD

Obesity is a risk factor for most age-related diseases, while dietary restriction appears to slow the aging process and extend maximum lifespan. Because almost all major pathologies are influenced by caloric intake, the mechanisms modulating metabolic state and homeostasis represent critical therapeutic targets. Moreover, diabetes and cardiovascular disease are considered risk factors for developing Alzheimer’s disease. Our approach uses small and large animal models of metabolic changes, in the context of aging and age-related neurodegenerative disorders, combined with tools such as photoactivatable probes to identify therapeutic targets and undertake preclinical testing.

Investigators in this research area include:

• Jessica Ables, MD, PhD
• Christoph Buettner, MD, PhD
• Graham Ellis-Davies, PhD
• Patrick R. Hof, MD
• Ki Ann Goosens, PhD
• Charles Mobbs, PhD
• Samuel E. Gandy, MD, PhD
• Hillel T. Grossman, MD
• Thomas O' Loughlin, PhD

Multiple risk genes as well as epigenetic, proteomic, and metabolomic changes have been associated with age-related neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. Our foundational discoveries stem from genetic, transcriptomic, genomic, epigenomic, proteomics, and metabolomics approaches combined with biostatistical methods and computational biology to identify gene networks contributing to disease pathogenesis. These are followed by validations using in vitro models such as primary cells, induced pluripotent stem cells, and brain organoids alongside in vivo small mammalian models, to identify affected brain regions, cell types, and disease pathways that can be targeted for therapeutic interventions.

Investigators in this research area include:

• Joel Blanchard, PhD
• Susan Bressman, MD
• Alison Goate, DPhil
• Edoardo M. Marcora, PhD
• Towfique Raj, PhD
• Panagiotis Roussos, MD, MS, PhD
• Anne Schaefer, MD
• Andrew J. Sharp, PhD
• Rachel Saunders-Pullman, MD, MPH, MS
• Jeremy M. Silverman, PhD
• Rong Wang, PhD
• Bin Zhang, PhD