Is it possible not to develop Alzheimer’s disease even if you are genetically predisposed? In 2023 a team of scientists described in the journal Nature Medicine the case of a Colombian patient who, due to a genetic variant called Presenillin 1, he was expected to develop Alzheimer’s by age 40. Instead this Colombian man, mechanic, father of two children, continued to work until he retired shortly after turning 60. Only at 67 did the first signs of moderate cognitive decline appear and the mechanic died in 2019 at the age of 74. To protect him in genetic lottery it was a second mutationa genetic variant of Reln gene.
In 2019, some American researchers from Boston described in Nature Medicine the case of another patient capable of protecting herself from the same fate. This woman’s memory began to decline only at the age of 70. It was another nicknamed genetic mutation that protected her Christchurch APOE3 (from the name of the New Zealand city where it was discovered): although his brain was clogged with amyloid plaques was relatively free from tau protein. The woman, mother of four children and with just one year of education behind her, had a good cognitive condition: the protection she benefited from could not derive from a high level of education, but instead depended on a biological factor. The patient’s genetic analyzes revealed an extremely rare mutation: two copies of the APOE3 variant both with one mutation known as Christchurch . The double mutation protected her, despite her family’s inconvenient heritage.
The Colombian extended family with early Alzheimer’s
Now an international team has continued to study this extended Colombian family of 6,000 people born between Medellín and some remote Andean villages with a hereditary form of early-onset Alzheimer’s disease. Around 1,200 people carry the variant Presenillin 1, therefore destined to develop Alzheimer’s disease; most of them experience mild cognitive deterioration around the age of 40, dementia around the age of 50 and die due to the complications brought by dementia around the age of 60.
The disease delayed for 5 years
With a new chapter of work, scientists have discovered that even a single copy of the protective APOE3 genetic variant Christchurch helps delay the disease. The research team reported that others 27 members of this large family, carriers of a single copy of this variant showed a delayed onset of the disease: five years later than expected (compared to 30 for those who possess the double copy of the variant). The new findings were published in the New England Journal of Medicine. The research group evaluated 1,077 descendants of the Colombian family, identifying 27 people who carried both the mutation Presenillin 1which causes autosomal dominant Alzheimer’s disease, leading to death by age 60 from complications of dementia, both a copy of the APOE3 variant Christchurch. On average, these family members began showing signs of cognitive impairment at age 52, compared to a matched group of family members who did not have the variant, who began showing signs of cognitive impairment at age 47 years old.
New therapeutic targets
The results are particularly important because they bring new evidence to push research to work on a new therapeutic target. «As a physician, I am very encouraged by our findings, as they suggest the potential to delay cognitive decline and dementia in older individuals. Now we must leverage this new knowledge to develop effective treatments for dementia prevention,” said co-first author Yakeel T. Quiroz, clinical neuropsychologist and neuroimaging researcher and director of the Familial Dementia Neuroimaging Lab in the Departments of Psychiatry and Neurology at Massachusetts General Hospital. “As a neuroscientist,” he added, “I am excited about our findings because they highlight the complex relationship between APOE and a mutation deterministic for Alzheimer’s disease, potentially paving the way for innovative therapeutic approaches for neurodegenerative disease».
