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