Could targeting variants of this gene help fight Alzheimer’s disease?

Aging
Scientists have identified gene variants that appear able to alter the risk of Alzheimer’s disease by changing levels of a protein that is present in cerebrospinal fluid.
dna structure
A new study focuses on the variants of a single gene and their role in promoting Alzheimer’s.

In a recent Science Translational Medicine paper, the international team describes how variants in the MS4A4A gene influence the risk of both early and late onset Alzheimer’s disease.

The gene variants alter levels of a protein called TREM2, which helps the brain to clear away excess amyloid and tau.

Toxic buildup of excess amyloid and tau proteins in the brain are hallmarks of Alzheimer’s disease.

Alzheimer’s is a disease that impairs communications in the brain as it damages nerve cells, or neurons, and the connections between them. As the disease progresses, more and more neurons stop working and die.

“The findings point to a new therapeutic strategy,” says co-senior study author of the latest study Carlos Cruchaga, Ph.D., a professor of psychiatry and director of the NeuroGenomics and Informatics Group at Washington University School of Medicine in St. Louis, MO.

Changes in the brain in Alzheimer’s disease

Alzheimer’s disease begins in parts of the brain that involve memory. Typically, the disease then spreads to areas responsible for reasoning, social behavior, and language. Eventually, few parts of the brain remain intact.

In this way, Alzheimer’s disease gradually undermines a person’s ability to remember, think, hold a conversation, and live an independent life.

Many changes to molecular and cell processes occur in the brain as Alzheimer’s disease progresses. Scientists have observed some of their results in postmortem samples of brain tissue.

A distinguishing feature of Alzheimer’s disease is the buildup of beta-amyloid protein that forms toxic plaques between neurons and stops them from working properly.

Another hallmark is the accumulation of a protein called tau. This protein collects inside neurons and forms neurofibrillary tangles that are also toxic. The tau tangles disrupt the ability of neurons to communicate with each other.

There is growing evidence that complex interactions between accumulations of tau and beta-amyloid, together with other factors, could be the cause rather than the byproduct of Alzheimer’s disease.

TREM2 and microglia

One of the other factors involved in Alzheimer’s disease is the role of microglia. Scientists believe that the failure of these immune cells to clear away waste, such as beta-amyloid plaques, contributes to Alzheimer’s disease.

Researchers have been focusing on TREM2 because it directs microglia to clear away beta-amyloid plaques and helps to reduce inflammation in the brain.

People who have a variant of TREM2 that does not function correctly show signs of plaque buildup between their brain cells.

In the new study, the researchers took a closer look at TREM2 and the genetic factors that influence its role in Alzheimer’s disease.

They measured cerebrospinal fluid levels of TREM2 in 813 older people. The participants were mostly between 55 and 90 years of age and included individuals with Alzheimer’s disease, others with different levels of mild cognitive impairment, and some with no symptoms of cognitive impairment.

The team also undertook a genome-wide association study (GWAS) of the participants’ DNA to “identify genetic modifiers” of cerebrospinal fluid TREM2.

MS4A4A variants affect Alzheimer’s risk

“It turns out,” says co-senior study author and investigator Celeste M. Karch, Ph.D., an assistant professor in the Department of Psychiatry at Washington University School of Medicine, “that about 30% of the population in the study had variations in the MS4A4A gene that appear to affect their risk for developing Alzheimer’s disease.”

“Some variants protected people from Alzheimer’s or made them more resilient while others increased their risk,” she adds.

Further investigation revealed that some MS4A4A variants with a link to a higher risk of Alzheimer’s disease had an association with lower levels of TREM2. In contrast, other variants that had links to higher levels of TREM2 appeared to protect against the disease.

The team confirmed the findings in DNA samples from a separate group of 580 older people.

If we can do something to raise levels of the TREM2 protein in the cerebrospinal fluid, we may be able to protect against Alzheimer’s disease or slow its development.”

Prof. Carlos Cruchaga

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