Indiana University School of Medicine researchers discover gene mutation associated with increased Alzheimer’s risk

The discovery can help pharmaceutical companies develop more targeted therapies.
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Hannah Minn

· 3 min read

Researchers at the Indiana University (IU) School of Medicine found a gene mutation that may be a key to unlocking the underlying causes of Alzheimer’s disease—and could help lead to targeted therapeutic treatments.

The research, published on September 1, analyzed gene variants connected to the microglia, or the brain’s immune cells, that help defend against infections, toxins, and other damage. The researchers found that immune cells with a specific mutation (M28L) led to a higher accumulation of amyloid plaques in the brain, which, according to the National Institute on Aging, can disrupt cell functions.

“The microglial response affects neurons which then affects the capacity to learn and form new memories,” Gary Landreth, a coauthor on the study and professor of Alzheimer’s research at the IU School of Medicine, said in a statement.

The researchers found that mice with the M28L variant of the phospholipase C gamma 2 (PLCG2) gene, which is related to the microglia, had “exacerbated plaque deposition” in their brains compared to mice with the P522R variant, or the protective variant associated with a reduced risk of Alzheimer’s. The M28L brains had 1.31x the number of MRI abnormalities in the cortex than the P522R variant brains, the study found.

The findings suggest that the M28L gene variant may be a possible risk-elevating variant for Alzheimer’s disease, and that these variants “can differentially orchestrate microglial responses in [Alzheimer’s] pathogenesis that can be therapeutically targeted,” according to the study.

About 6.7 million US patients aged 65 and older live with Alzheimer’s disease, one of the most common forms of dementia, according to the nonprofit Alzheimer’s Association. The Centers for Disease Control and Prevention (CDC) estimates that figure will rise to 14 million by 2030.

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The disease—the sixth-leading cause of death among adults in the US—can cause memory loss, impaired judgment, and difficulty completing familiar tasks, according to the CDC.

IU School of Medicine researchers aren’t the only ones looking at how the brain’s microglia relate to Alzheimer’s disease.

In a study published last month, researchers at the Oregon Health and Science University (OHSU) School of Medicine found that a type of cell death called ferroptosis can destroy microglia cells.

These degenerating microglia appear to be “a mechanism in advancing cognitive decline in Alzheimer’s disease and vascular dementia” and could prompt pharmaceutical companies to look at treatments that reduce microglial decay, according to Stephen Back, the study’s senior author and pediatrics professor at the OHSU School of Medicine.

“That’s where the field will go next,” Back said in a statement. “A discovery like ours will stimulate a lot of excitement in the pharmaceutical industry to develop therapeutically important compounds.”

Many of the available Alzheimer’s drugs only treat the disease’s symptoms, and new treatments are “slow to emerge,” per the Mayo Clinic.

Earlier this summer, the FDA granted full approval to the Alzheimer’s drug Leqembi, the first Alzheimer’s medication to receive full approval in 20 years, Healthcare Brew previously reported. The medication can’t reverse the course of the disease, but it may help slow early-stage cognitive decline.

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