Knowledge advances of a variant that protects against early hereditary Alzheimer’s

He Alzheimer’s It can be hereditary and appear early, as in the case of a Colombian family, although some carry genetic variants that give them some protection. Continued study of one of them revealed that having just one copy is enough to delay the onset of the disease by five years.

A Colombian family has been known for years to be a carrier of the so-called Paisa mutation in the PSEN1 gene, which is rare, but which predisposes one to suffer from early-onset autosomal dominant Alzheimer’s (it is enough to receive the gene from one of the parents).

The family is made up of about 6,000 blood relatives – living and dead – of which 1,200 are carriers of the mutation. Those affected usually develop mild cognitive impairment around age 44, dementia at age 49, and die from complications at age 60.

The follow-up of this group led to the identification of two people, already deceased, who, in addition to the mutation, each of them had a different genetic variant that delayed the onset of Alzheimer’s.

A new study led by Mass General Brigham, a network of hospitals based in Boston (USA) and published by The New England Journal of Medicine, has delved into one of these variants, ‘APOE3 Christchurch’ (APOE3Ch), and adds new indications that the research could point to a new therapeutic target.

APOE3Ch was identified in 2019 as potentially protective against Alzheimer’s in the case of a woman who had two copies of that rare variant. She did not develop cognitive impairment until she was 70 years old, that is, three decades later than expected.

Researchers have now identified 27 relatives who, instead of two copies of the variant, are carriers of only one, and in whom the onset of Alzheimer’s was delayed by five years compared to those who do not have it.

A single variant, ‘some degree’ of protection

The study concludes that having a single copy of the APOE3Ch variant is enough to confer ‘a certain degree of protection’, although less pronounced than when carrying two copies.

This finding has “important implications for drug development, as they suggest the potential effects of targeting this genetic pathway”Mass General Brigham highlighted in a statement.

“Our original study told us that protection was possible and that was important information, but if a person needs two copies of a rare genetic variant, it all comes down to luck”said Joseph F. Arboleda-Velasquez, co-lead author of the work.

The researcher stressed that the new study is ‘significant’ because it increases confidence that “This target is not only protective, but can be pharmacovigilated. “We believe that therapies inspired by protected humans are much more likely to work and be safer.”

The scans of the people examined showed lower levels of tau protein, which forms tangles characteristic of the disease, in addition to preserved metabolic activity in areas typically involved in Alzheimer’s.

The team also analyzed autopsy samples from four deceased individuals that showed less pathology in blood vessels, a characteristic that appears important for the protective effects of APOE3Ch.

40 years of follow-up

The family carrying the Paisa mutation was located by researcher Francisco Lopera, director of the Antioquia Neuroscience Group in Medellín (Colombia), co-author of the studies and who has followed its members for the last 40 years.

The same research team identified another resilience genetic variant called Reelin-COLBOS in 2023, in a man who remained without cognitive impairment until age 67, progressed to moderate dementia at age 72, and died at age 74.

The authors note that the new study was limited to a relatively small number of people carrying the Paisa mutation and the APOE3Ch variant in a single extended family, so other studies should include larger and more ethnically diverse samples of the disease.

In this way, more light could be shed on the protective effect of the APOE3Ch variant and help determine whether the family’s findings in Colombia could be translated into relevant discoveries for the treatment of sporadic forms of Alzheimer’s disease.

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