A mutation could protect from familiar Alzheimer’s cognitive decline

mutation protects Alzheimer's
Source: Wallpaper Flare

A reported case study in a Colombian woman 1, member of a family carriers of a mutation in the presinilin 1 gene which leads to early onset Alzheimer’s, has shown that a certain mutation in the gene APOE3 can protect from the cognitive decline associated with Alzheimer’s disease.

This woman was already aged 70 but not showing any of the cognitive decline that many other members of her family were already showing by 40 years of age. That was surprising for the researchers, specially because her brain was filled with amyloid plaques, a typical sign of Alzheimer’s.

Even though most cases of Alzheimer’s start later and have no singular genetic hallmark, in the case of early, familiar Alzheimer’s are linked to certain mutations like the one found in this Colombian family in the presinilin 1 gene. This gene codes for a protein involved in cutting the amyloid precursor into small pieces to be disposed off. However, when mutated these pieces are too big for degradation and end up accumulating in the amyloid plaques typical of Alzheimer’s.

Even though the effects of the mutation seem to have a strong influence on the disease progression, it is not yet clear whether the plaques are protective or responsible for the cognitive symptoms. Genetic tests of the “resistant” woman showed that, aside from her familial mutation in the presinilin 1 gene, responsible for the extreme amyloid build-up in the brain, she also had the so-called Christchurch mutation in both copies of her APOE gene. Also, that this mutation seemed to be related to her immunity to cognitive decline, and since the APOE gene is a strong genetic factor increasing the risk of dementia, this relationship makes sense.

This mutation in the APOE gene prevents the protein from binding to heparan sulfate proteoglycans, or HSPGs, which have been shown to promote not only amyloid plaque formation but also to produce another toxic protein: tau. It seems that by breaking these interactions, the disease progression gets impaired. Obviously, this finding paves the way for drug development which take advantage of the effects of this mutation.


  1. Arboleda-Velasquez et al (2020) Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report Nature Medicine doi: 10.1038/s41591-019-0611-3

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