Alzheimer’s Onset Delayed by Rare Mutation

Having only one copy of the APOE3 Christchurch variant was enough to confer some protection against PSEN1 autosomal dominant Alzheimer’s disease, retrospective data showed.

Among carriers of PSEN1 E280A who also had one copy of the APOE3 Christchurch variant, the median age at cognitive impairment onset was 52 (95% CI 51-58), compared with age 47 (95% CI 47-49) in a matched group without the Christchurch variant, reported Yakeel Quiroz, PhD, of Massachusetts General Hospital in Boston, and co-authors in the New England Journal of Medicine.

The median age at dementia onset among Christchurch carriers was 54 (95% CI 49-57), compared with age 50 (95% CI 48-51) in noncarriers.

Carriers of PSEN1 E280A are destined to develop autosomal dominant Alzheimer’s disease and belong to a large kindred from the Colombian state of Antioquia. The family consists of about 6,000 blood relatives; about 1,200 of them carry the PSEN1 E280A variant. The average age of Alzheimer’s onset in these PSEN1 carriers is 45.

In 2019, Quiroz and colleagues identified a PSEN1 E280A mutation carrier who had two copies of the APOE3 Christchurch variant and remained cognitively unimpaired for nearly 30 years after her expected age of clinical onset. In 2023, the researchers found another variant in the Colombian kindred that appeared to delay cognitive symptoms.

The current study reported on 27 other family members who carried only one copy of the Christchurch variant.

The data may have implications for Alzheimer’s drug development, Quiroz observed. “As a clinician, I am highly encouraged by our findings, as they suggest the potential for delaying cognitive decline and dementia in older individuals,” she said in a statement.

“As a neuroscientist, I’m thrilled by our findings because they underscore the complex relationship between APOE and a deterministic mutation for Alzheimer’s disease, potentially paving the way for innovative treatment approaches for Alzheimer’s disease, including targeting APOE-related pathways.”

“Genetic variation at the APOE locus is, by far, the most important determinant of risk of Alzheimer’s disease discovered so far,” noted John Hardy, MD, PhD, of University College London, in an accompanying editorial. “Despite this, we have relatively little understanding of its pathogenic role beyond the fact that genetic variation is closely associated with amyloid deposition.”

The most prevalent protective allele is APOE2, which is seen in about 10% of the general population, Hardy said. Sporadic Alzheimer’s disease is delayed by about 10 years in APOE2 homozygotes and by about 5 years in APOE2 heterozygotes.

Both APOE3 Christchurch homozygosity and APOE2 homozygosity are associated with type III hyperlipoproteinemia, Hardy pointed out. “This observation suggests that both protective APOE variants have disrupted interactions with APOE receptors in a similar manner, which, in itself, may offer a mechanistic clue for both conditions,” he wrote.

Quiroz and co-authors assessed data from 27 people with one copy of the APOE3 Christchurch variant among 1,077 PSEN1 E280A carriers in the Antioquia kindred. Two of the 27 participants had brain imaging, and autopsy was performed in four participants.

In the two participants who had brain imaging, PET scans showed relatively preserved metabolic activity in areas typically involved in Alzheimer’s disease. Autopsy material showed fewer vascular amyloid pathologic features in those with the Christchurch variant, greater amyloid plaque burden, and a relatively limited tau burden compared with other PSEN1 E280A variant carriers.

“The PET imaging findings in two participants heterozygous for the APOE3 Christchurch variant, which showed limited tau pathological findings and relatively preserved glucose metabolism, suggest that the delayed clinical onset that is associated with the APOE3 Christchurch variant may involve mechanisms that limit tau pathologic conditions and neurodegeneration, even in the presence of a high burden of amyloid-beta plaque,” Quiroz and co-authors wrote.

Study limitations include the relatively small number of persons who have both the APOE3 Christchurch and PSEN1 E280A variants, which increases uncertainty around differences in point estimates for mild cognitive impairment and dementia onset ages. Insights about the Christchurch variant in this Colombian cohort may not translate to sporadic Alzheimer’s disease or to other groups of people.

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