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Early-Onset Alzheimer's Mutation May Be Mitigated by APOE Variant

NEW YORK – 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 PSEN1 gene cause an autosomal dominant form of Alzheimer's disease, which then develops early in life, prior to the age of 65.

By studying individuals from a large pedigree in which the autosomal dominant Alzheimer's disease-causing PSEN1 E280A variant was rampant, researchers led by Yakeel Quiroz-Gaviria from Harvard Medical School homed in on one woman who didn't develop signs of dementia until her 70s.

A further analysis of her genome found that she also carried two copies of the APOE3 R136S mutation that appeared to buffer the effect of the PSEN1 mutation, a finding that could have implications for disease treatment.

"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," Quiroz said in a statement. The case report was published Monday in Nature Medicine.

Quiroz and her colleagues 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 researchers 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 percent of the kindred appeared to harbor one copy of APOE3ch.

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.

Through neuroimaging, the researchers found that this woman had a high amyloid-β plaque burden — a hallmark of Alzheimer's disease — but her tau burden — another sign of the disease — and neurodegeneration was limited, even for her age.

In in vitro studies, the researchers 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, and in functional analyses they found APOE3ch has an altered ability to bind heparin.

This suggests, the researchers said, 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.

"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," co-senior author Eric Reiman, from the Banner Alzheimer's Institute, said in a statement.