Rare Genetic Mutation Linked to Higher Alzheimer’s Risk, MIT Study Reveals

Researchers at the Massachusetts Institute of Technology’s Picower Institute for Learning and Memory have unveiled a significant correlation between the rare genetic mutation TREM2 R47H/+ and elevated susceptibility to Alzheimer’s disease. Published in the online peer-reviewed neurobiology journal Glia, the study delves into the impact of this mutation on microglia, pivotal immune cells within the brain responsible for maintaining optimal brain health.

Examination of microglia bearing the TREM2 mutation exposed notable defects linked to Alzheimer’s pathology. These mutated cells showcased inflammation, a diminished response to neuronal injury, and a compromised ability to clear detrimental debris, particularly the amyloid beta protein. When scientists introduced the mutant microglia into mice, they observed reduced synapses, culminating in impaired memory and compromised brain function.

Various foundations and organizations supported this study, including the Cure Alzheimer’s Fund, The Robert A. and Renee E.Belfer Family Foundation, and the National Institutes of Health. The research team is led by Li-Huei Tsai and Jay Penney.

Complex Dynamics of TREM2 Mutation

Contrary to previous notions solely implicating a functional impairment of the protein, this latest research paints a nuanced picture. The mutant microglia demonstrated reduced debris clearance and injury response and exhibited heightened activity in other facets, including excessive inflammation and synapse pruning.

Researchers utilized human microglia cell cultures derived from a healthy 75-year-old woman to comprehensively investigate the mutation’s effects. Employing CRISPR gene editing, they introduced the TREM2 mutation, facilitating a direct comparison between mutated microglia and their genetically identical, healthy counterparts. The mutated microglia showcased elevated gene expression related to inflammation and immune response, coupled with an augmented inflammatory reaction to simulated infection.

Observations further revealed the mutant microglia’s compromised debris clearance and reduced responsiveness to neuronal injury compared to their healthy counterparts. In mice, the introduction of mutant microglia significantly reduced synaptic proteins in the hippocampus, a brain region pivotal for memory.

This study’s findings illuminate the intricate molecular mechanisms governing microglial dysfunction in Alzheimer’s disease. The insights garnered could pave the way for targeted therapeutic interventions. Understanding how the TREM2 R47H/+ mutation contributes to the disease enables drug developers to explore novel strategies to mitigate the heightened risk associated with this mutation.

Medical Costs Challenge an Aging Population

The National Institute on Aging predicts in fiscal year 2024, the overall funding needed for Alzheimer’s and related dementia research will total $3.87 billion.

The Robert A. and Renee E. Belfer Family Foundation has been a key supporter of MIT’s research initiatives, contributing to various scientific endeavors, including Alzheimer’s research. The foundation’s philanthropic commitment aligns with MIT’s mission to advance knowledge and address pressing global challenges. Specifically, their support in neurodegeneration research underscores a shared dedication to advancing breakthroughs in medical science.

In 2012, the Belfer Family Foundation created the Neurodegeneration Consortium, which brings together the drug discovery power of The MD Anderson Cancer Center Therapeutics Discovery Division, leading neuroscientists at MIT, Mount Sinai School of Medicine, and researchers at several other institutions. According to Robert Belfer, president of the Belfer Family Foundation, its purpose is “to better understand the molecular and genetic basis of neurodegenerative diseases, particularly Alzheimer’s disease.”

At that time, Belfer stated, “Neurodegenerative diseases, including Alzheimer’s, are, like cancer, diseases of aging. An aging population challenges us with runaway medical costs. To enhance the quality of life in later years and reduce costs, we need a national effort. Recent advances in medical technology pave the way for this progress. My hope is that this project, which brings together three of the world’s leading medical research centers, will be a meaningful and much-needed step in advancing this urgent national problem.”