Stanford University

The Role of an AD Protective- and Longevity-Associated Variant of PLCG2 in Brain Aging

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. AD is the most common form of dementia, affecting an estimated 50 million people worldwide, and this number is expected to increase significantly due to the lack of effective treatments and the aging population.

Age is the greatest known risk factor for AD, but AD is not an inevitable consequence of biological aging. Slowing age-related changes in the brain could increase cognitive reserve and reduce the risk of dementia. Many theories have been proposed to explain the aging process. Studies point to several ways, including exercise and a healthy diet, that people can take control of their health and perhaps slow the rate of brain aging. Others suggest that the effects of aging are a consequence of environmental factors and genetics. Surprisingly, such a belief may ring true. Recent genetic findings have identified a mutation that can extend life and protect against brain aging. This P522R mutation in phospholipase C-gamma-2 (PLCG2), has been found to be enriched in the centenarians who retain good cognitive and functional abilities. These findings open an intriguing possibility with the hope of prolonging life and living free of dementia. The primary objective of this proposal is to unravel the mystery of this PLCG2 P522R mutation, how to keep the brain young and away from pathologies.

The success of this proposal will provide potential targets and strategies to reverse brain aging, with the goal of improving cognitive function.