A Rare Genetic Mutation May Protect Against Alzheimer’s

Alzheimer's Research

November 11, 2019

Researchers have discovered a rare genetic mutation that appears to be protective against Alzheimer’s disease. The finding provides new insights into the underlying causes of Alzheimer’s and could lead to innovative therapies for a disease that currently has no effective long-term treatments.

The rare gene mutation was found in a woman from Colombia from a large, extended family at high risk for early-onset Alzheimer’s disease. People in that family typically develop memory loss and other symptoms of Alzheimer’s disease starting in their 40s. Many die by their 60s.

Like others in the family, the woman carried another mutation in a gene that codes for a protein known as presenilin 1, which predisposes family members carrying this specific mutation to early-onset Alzheimer’s. Presenilin 1 plays a critical role in the buildup of beta-amyloid, the toxic protein that clumps together to form the telltale brain plaques of Alzheimer’s. And indeed, brain scans revealed that the woman ‘s brain was riddled with amyloid plaques.

But the woman was in her 70s, she is carrying the bad PS1 mutation, and had not yet developed serious memory problems. She had few signs of nerve cell degeneration. Something was protecting her brain from succumbing to the ravages of Alzheimer’s.

The protective factor appeared to be another rare mutation known as Christchurch, named for the city in New Zealand where it was originally discovered. The woman carried two copies of the Christchurch mutation on an APOE gene, which is involved in the body’s regulation of fats and cholesterol. (APOE comes in various forms; the Christchurch mutation was found on the APOE3, the most common form.)

Researchers speculate that having two Christchurch mutations protected the woman against the buildup of a protein called tau, the second most important telltale hallmark of Alzheimer’s disease. Tau typically forms tangles in the brains of those with Alzheimer’s, choking off brain cells and causing them to degenerate. But this woman had little tau buildup. The Christchurch mutation may reduce the ability of APOE to bind to certain components in the cell called heparan sulfate proteoglycans, or HSPGs, that are necessary to produce tau. The findings were published in the journal Nature Medicine.

Better understanding of why this woman did not develop symptoms of Alzheimer’s disease for more than 30 years later than would be expected, despite the heavy buildup of plaques in her brain, could open up new avenues to treat or prevent the disease. For example, one can imagine designing small drug-like molecule to mimic the Christchurch mutation and block APOE3 from interacting with HSPGs. The Fisher Center has a strong interest in APOE genes from a therapeutic perspective and continues to pursue research in this area.

The findings also raise new questions about the underlying causes of Alzheimer’s. This woman had extremely high levels of amyloid plaques in her brains, yet she showed few signs of memory problems or nerve cell degeneration. Many experimental drugs have targeted beta-amyloid in an attempt to prevent Alzheimer’s onset, with little success.

“This single case opens a new door for treatments of Alzheimer’s disease, based more on the resistance to Alzheimer’s pathology rather than on the cause of the disease,” said study author Yakeel T. Quiroz, a clinical neuropsychologist and neuroimaging researcher at Massachusetts General Hospital. “In other words, not necessarily focusing on reduction of pathology, as it has been done traditionally in the field, but instead promoting resistance even in the face of significant brain pathology.”

“This study underscores the importance of APOE in the development, treatment and prevention of Alzheimer’s, not to mention the profound impact that even one research volunteer can have in the fight against this terrible disease,” said Dr. Eric M. Reiman, executive director of Banner Alzheimer’s Institute and co-senior author of the study. “We hope that our findings galvanize and inform the discovery of APOE-related drug and gene therapies, such that we can put them to the test in treatment and prevention studies as soon as possible.”

By ALZinfo.org, The Alzheimer’s Information Site. Reviewed by Marc Flajolet, Ph.D., Fisher Center for Alzheimer’s Research Foundation at The Rockefeller University.

Source: Joseph F. Arboleda-VelasquezFrancisco Lopera, et al, Yakeel T. Quiroz:  “Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report.” Nature Medicine, Nov. 4, 2019


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