Unique case of disease resistance reveals possible Alzheimer’s treatment

New Delhi, 06^th November 2019. Defying the odds, an individual at high risk for early-onset Alzheimer’s disease remained dementia-free for many years beyond what was anticipated.

A study
funded in part by the National Institute on Aging (NIA), part of the National
Institutes of Health, led researchers to suggest that a gene variant may be the
key, perhaps providing a new direction toward developing a treatment.

National
Institute on Aging (NIA leads the U.S. federal government effort to conduct and
support research on aging and the health and well-being of older people.

The research
focused on the case of a woman who carried a gene mutation known to cause
early-onset Alzheimer’s. However, she did not develop signs of the disease
until her 70s, nearly three decades after her expected age of onset.

The
researchers suspect that she may have been protected because in addition to the
gene mutation causing early-onset Alzheimer’s in her family, she also had two
copies of the APOE3 Christchurch (APOE3ch) gene variant. Findings of this case
study as published in Nature Medicine suggest that two copies of the APOE3ch
variant, named after Christchurch, New Zealand where it was first identified,
may protect against Alzheimer’s.

“Sometimes
close analysis of a single case can lead to discovery that could have broad
implications for the field,” said NIA Director Richard J. Hodes, M.D. “We are
encouraged that as part of our wide array of studies, this research in the
unique genetic makeup of an exceptional individual can reveal helpful
information.”

Early-onset
Alzheimer’s disease : A Rare disease

Early-onset
Alzheimer’s disease
is rare, representing less than 10% of all people who have Alzheimer’s. It
typically occurs between a person’s 30s to mid-60s. Risk for both early- and
late-onset Alzheimer’s disease is affected by genetic factors.

For the
study, researchers led by investigators at Massachusetts General
Hospital, Boston, in collaboration with the University of Antioquia,
Medellin, Colombia, Schepens Eye Research Institute of Massachusetts Eye and
Ear, Boston, and Banner Alzheimer’s Institute, Phoenix, looked at genetic data
from a Colombian family with more than 6,000 living members. Family members who
carry a rare gene mutation called Presenilin 1 (PSEN1) E280A, have a
99.9% risk of developing early-onset Alzheimer’s disease.

The
researchers confirmed that the woman in this case carried the PSEN1 E280A
mutation, which caused early-onset Alzheimer’s in her other family members.
However, she also had two copies of the APOE3ch gene variant, while no other
affected family member carried two copies of this variant. Affected family members
develop Alzheimer’s in their 40s, but she remained disease free until her 70s.
Imaging tests showed that the woman had only minor neurodegeneration. She did
have large amounts of amyloid protein deposits, a hallmark of Alzheimer’s
disease, in her brain. But the amount of tau tangles, another hallmark of the
disease, and the one more correlated with how thinking and memory are affected,
was relatively low.

Experiments
as part of the study showed that the APOE3ch variant may reduce the ability of
APOE to bind to certain sugars called heparan sulphate proteoglycans (HSPG).
APOE binding to HSPG has been implicated as one mechanism that may contribute
to the amyloid and tau protein deposits that destroy the brain. The research
suggests that a drug or gene therapy that could reduce APOE and HSPG binding
has the potential to be a new way to treat or prevent Alzheimer’s disease.

The research team was led by Yakeel T. Quiroz, Ph.D., a clinical neuropsychologist and neuroimaging researcher at Massachusetts General Hospital, and a 2014 NIH Director’s Early Independence Award recipient. Quiroz partnered with Joseph F. Arboleda-Velasquez, M.D., Ph.D., at Shepens, Francisco Lopera, M.D., at the University of Antioquia, and Eric M. Reiman, M.D., at Banner Alzheimer’s Institute. The individual is from the same family participating in the ongoing Autosomal Dominant Alzheimer’s Disease (ADAD) trial, which is designed to find out if the anti-amyloid treatment crenezumab can prevent the disease.

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