Unlocking Cognitive Resilience in Aging

Advances in molecular biology, stem cell biology, and bioinformatics are transforming the ability to study cognitive resilience and its relationship to Alzheimer’s disease and neurodegenerative disorders.

“Resilience is a growing focus in research on Alzheimer’s disease and age-related neuropathologies,” says Anil R. Wadhwani, MD, PhD, an assistant professor of neurology at NYU Langone Health. “Resilience means function, despite the presence of disease.”

Dr. Wadhwani studies how genome–epigenome interactions influence cognitive resilience, with the goal of identifying ways to preserve function as people age.

Identifying Resilience Factors

A key step, Dr. Wadhwani explains, is to identify the biological mechanisms that bolster cognitive resilience as people age. Over the past two decades, researchers have used neuroimaging, cognitive testing, and longitudinal studies to identify some of these factors, which include lifestyle modifications, sleep quality, social engagement, and educational attainment.

“While numerous factors have been identified, the precise molecular mechanisms underpinning these relationships remain unclear,” says Dr. Wadhwani.

One aim, he explains, is to develop biomarkers that improve prediction of cognitive decline. Blood biomarkers already help identify Alzheimer’s pathology and estimate the risk of future decline, Dr. Wadhwani says, but predicting an individual’s long-term cognitive trajectory remains a challenge.

“Our goal is to stratify risk before cognitive impairment begins, improving prognostic accuracy and helping patients plan for the future,” he says.

The Genome–Epigenome Interaction

The epigenome helps regulate how cells use genetic information without changing the underlying DNA sequence. Dr. Wadhwani and colleagues at the University of Pennsylvania have investigated how epigenetic differences relate to Alzheimer’s pathology and cognitive resilience.

In a December 2025 study, they investigated the link between differential DNA methylation and Alzheimer’s disease pathology. They used machine learning to construct several epigenetic signatures that predicted an individual’s disease severity. Surprisingly, one of these signatures may help to risk stratify patients with similar neuropathological burden into biologically distinct groups associated with varying levels of cognitive resilience.

While this work is still ongoing, these findings could have important clinical implications, he says, and long-term, could offer insights into disease biology, biomarkers, and potential therapeutic targets in Alzheimer’s disease.

“Epigenetic signatures could help categorize patients across a spectrum of aging trajectories, from healthy to accelerated.”

“The epigenome is highly related to cognition in Alzheimer’s disease,” explains Dr. Wadhwani. “Epigenetic signatures could help categorize patients across a spectrum of aging trajectories, from healthy to accelerated.”

“Currently, neurologists excel at identifying Alzheimer’s pathology after its onset, yet the question remains, how do we help individuals before that point?”

Partnership for Discovery

In the Translational Aging Neurogenetics Laboratory (TANGL), Dr. Wadhwani and his team will use human stem cell-derived neurons to model tau pathology, a hallmark of Alzheimer’s disease. As part of the Center for Human Genetics and Genomics, they will also test how genetic and epigenetic changes affect neuronal vulnerability and function. With no approved Alzheimer’s therapies currently targeting tau, the research aims to uncover mechanisms that could inform future treatments.

To extend these findings beyond the laboratory, the team will collaborate with colleagues at NYU Langone’s Alzheimer’s Disease Research Center and Optimal Aging Institute to investigate whether mechanisms identified in cell models help explain differences in biomarkers and cognitive outcomes in people.

Together, the partnership seeks to connect the biology of aging with measurable changes in cognition and identify opportunities to preserve cognitive resilience. “Molecular biology may explain how resilience can become impaired,” Dr. Wadhwani says, “but we also want to find out what we can do to promote resilience in everyday life.”

Over the next decade, he envisions a new paradigm for neurodegenerative disorders that emphasizes prevention in midlife and earlier interventions to slow disease progression.

“Finding ways to intervene earlier and preserve cognitive function could help people remain independent for longer as they age,” Dr. Wadhwani concludes.