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Genes and Alzheimer’s Resilience

Posted by Nancy Humphrey on Friday, March 19, 2021 in Related Content, Spring 2021 .

There are several examples in medicine where people are resilient to a disease — when they are exposed to the disease but don’t show any symptoms.

There are people, for example, who carry a rare genetic mutation that prevents HIV from infiltrating cells.

These individuals also exist in the world of Alzheimer’s disease — those who live to an old age without any apparent signs of dementia, but at autopsy, when their brains are examined under a microscope, they meet the neuropathological criteria for Alzheimer’s disease. These are people who would be expected by any measure to have memory loss and cognitive symptoms of dementia, but never do.

And the Alzheimer’s research community can learn a lot from them.

VUMC’s Timothy Hohman, PhD, is a scientist in the Vanderbilt Memory and Alzheimer’s Center, whose research focuses on understanding how certain individuals can accumulate Alzheimer’s disease neuropathology without showing clinical symptoms of the disease.

Studies have shown that about 30% of people age 60 and older who are cognitively normal have the plaques and tangles in their brains that are the hallmarks of Alzheimer’s disease. Hohman leverages advanced neuroimaging and fluid biomarkers to identify plaques and tangles in the brains of living patients, and then identifies those resilient individuals that can stave off disease.

Hohman’s team also works to identify genetic markers for such resilience to better understand its molecular basis. His work integrates an individual’s age, sex, genetic and neuropathological features into a precision medicine model to characterize if an individual patient is resilient against disease or is susceptible to future dementia. Ultimately, the hope is to move genetic markers of resilience toward therapeutics and intervention.

“One of the biggest challenges in not just Alzheimer’s disease but in the field of genomics is the development of platforms to move from a genetic predictor to a therapeutic intervention. To do this, we have to work across disciplines to rapidly move through the process of validation. That can mean testing a mechanism from our genomic studies in a mouse model or moving the other direction to confirm that what you’re seeing in a mouse is also true in humans. That crosswalk from model systems to human genomics has been either slow or nonexistent,” Hohman said. “This new center will allow us to build robust interdisciplinary collaborations that facilitate rapid translation and move us toward new, impactful interventions for Alzheimer’s disease.”