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Carrying just one copy of a genetic variant has conferred some protection against dementia for a family at high risk of inheriting early Alzheimer’s disease, according to research that could flag new therapeutic targets for dementia.

The findings come from a South-American family of more than a thousand people who are genetically predisposed to develop Alzheimer’s disease in their 40s.

The study in the New England Journal of Medicine showed that possessing the  apolipoprotein APOE3 “Christchurch variant” (APOE3Ch) delayed cognitive impairment by approximately five years.

The results follow on from an earlier study in which a female family member with two copies of this rare variant only developed mild cognitive impairment in her 70s, almost three decades after it would be expected.

“Our original study told us that protection was possible, and that was an important insight. But if a person needs two copies of a rare genetic variant, it just comes down to luck,” said co-senior author Joseph Arboleda-Velasquez, PhD, from Mass General Brigham.

“Our new study is significant because it increases our confidence that this target is not only protective, but druggable. We think that therapeutics inspired by protected humans are much more likely to work and to be safer.”

The family from the Antioquia region of Columbia carries the E280A mutation in the PSEN1 gene, which encodes the protein presenilin 1.

This causes autosomal dominant Alzheimer’s disease, with nearly 100% of carriers destined to develop the neurodegenerative condition.

Most carriers in the 1077-member family have mild cognitive impairment by their mid-40s and dementia before they reach 50.

The onset of dementia is influenced by the APOE genotype and is approximately 5 years earlier among APOE4 carriers and approximately 5 years later for APOE2 carriers.

Previously, exome sequencing in the unaffected woman in her 70 years who had the PSEN1 mutation identified that she was homozygous for the rare, but previously identified, APOE3Ch variant (R136S).

To further investigate whether this variant was protective in the presence of presenilin variants that brought on Alzheimer’s disease, the researchers identified 27 other family members heterozygous for the APOE3Ch variant.

The median age for the onset of cognitive impairment among these individuals was 52 versus 47 years for a matched group of carriers of the PSEN1 variant but without the protective APOE3Ch variant.

Among two family members with the protective APOE3 variant who underwent brain imaging, metabolic activity was relatively preserved in areas typically involved in Alzheimer’s disease.

Autopsies on four of the people with the protective variant surprisingly suggested that they had more amyloid deposition but less tangle deposition than corresponding family members without the protective APOE3Ch mutation.

In an accompanying editorial, John Hardy, PhD, from University College London said that understanding the mechanism behind protection from the APOE3Ch variant could point to therapeutic targets.

He noted it was intriguing that both homozygosity in the APOE3Ch variant and APOE2 homozygosity were also associated with type III hyperlipoproteinemia

“The effects of the protective APOE3Ch variant and the many other rare variants that are associated with increased and decreased risks of both Alzheimer’s disease and blood lipid disorders perhaps offer starting points for cell biologic and transgenic work designed to dissect these mechanisms,” stated Hardy.

He added: “Clearly, the time is ripe for a focused and detailed study of the pathogenic involvement of APOE in Alzheimer’s disease.”

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