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Early-Onset Alzheimer's Mutation Possibly Mitigated by APOE Variant

By LabMedica International staff writers
Posted on 19 Nov 2019
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Image: Rare gene variant APOE3ch may hold clues to preventing Alzheimer’s disease (Photo courtesy of Alice Bough).
Image: Rare gene variant APOE3ch may hold clues to preventing Alzheimer’s disease (Photo courtesy of Alice Bough).
Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and, eventually, the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s.

The apolipoprotein E (APOE) is the main gene associated with the risk of late-onset Alzheimer's disease, and while the APOE3/3 genotype is thought of as neutral to disease risk, APOE2 is associated with a lower risk of disease or later onset and APOE4 is associated with a higher risk of disease or earlier onset.

Neurologists at the Harvard Medical School (Boston, MA, USA) and their international colleagues discovered a woman carrying a mutation associated with early-onset Alzheimer's disease did not develop the condition until decades after expected, likely due to the protective effect of other variants she had. Typically, mutations in the presenilin 1 (PSEN1) gene cause an autosomal dominant form of Alzheimer's disease, which then develops early in life, prior to the age of 65. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements.

The investigators studied a kindred of thousands of Colombian individuals, many of whom carry the Alzheimer's-causing PSEN1 E280A variant. Most members of the kindred with that alteration experience mild cognitive decline by a median 44 years of age and dementia by a median 49 years of age. But one woman did not develop mild cognitive decline until her 70s, decades after other members of this kindred.

After confirming that this woman did indeed have the PSEN1 E280A variant and that it was expressed in blood cells, the team studied the rest of her exome to find the she also carried two copies of the APOE3 R136S or 'Christchurch' (APOE3ch) mutation. They confirmed that variant through Sanger sequencing, and further combed through her whole genome for other potential modifying genes, though their analysis indicated APOE3ch was the most likely genetic modifier. They additionally noted that 6% of the kindred appeared to harbor one copy of APOE3ch.

In in vitro studies, the team examined Aβ aggregation in the presence of recombinant APOE3 protein, APOE3ch protein, and no APOE protein of any type. Through this, they found that the APOE3ch protein was less able to trigger Aβ aggregation than APOE3 protein. The APOE3ch alteration falls within a region of the APOE3 protein that has a role in binding lipoprotein receptors and heparan sulfate proteoglycans (HSPGS), and in functional analyses they found APOE3ch has an altered ability to bind heparin.

The authors concluded that APOE3ch affects tau pathology and neurodegeneration, even in the face of high Aβ plaque levels, through its altered binding affinity to HSPGs or other APOE receptors. That, they added, indicates that other molecules that bind this region could potentially mimic this effect. Eric M. Reiman, MD, a Professor of Neuroscience at the Banner Alzheimer's Institute (Phoenix, AZ, USA), and co-senior author of the study said, “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.” The study was published on November 4, 2019 in the journal Nature Medicine.

Related Links:
Harvard Medical School
Banner Alzheimer's Institute


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