Rare gene variant APOE3ch may hold clues to preventing Alzheimer’s disease

Written by Alice Bough (Future Science Group)

A group led by researchers from Harvard Medical School (MA, USA) and the University of Antioquia (Medellín, Colombia) have studied a unique case in which a woman genetically predisposed to early-onset Alzheimer’s disease exhibited symptoms 30 years later than expected. They propose that this is due to the presence of another gene mutation known as APOE3ch, which may offer protection against Alzheimer’s disease.

The paper, published in Nature Medicine, suggests that further research into this protective mutation could open new avenues for the treatment and prevention of the neurodegenerative condition.

The woman is a member of a Columbian family, of which there are over 6000 living members, who carry a rare genetic mutation of PSEN1 E280A. Individuals with this mutation have a 99.9% chance of developing early-onset autosomal dominant Alzheimer’s disease. These family members generally display clinical symptoms in their 40s.

However, the woman only started to exhibit symptoms in her 70s. The researchers determined that in addition to the PSEN1 E280A mutation, she carried two copies of the APOE3 Christchurch (APOE3ch) mutation. It was also identified that no other family members carried two copies of this gene variant.

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While imaging tests displayed large deposits of amyloid protein, there was a relatively low amount of tau tangles present in the woman’s brain. Further experiments suggested that the APOE3ch variant may prevent apolipoprotein from binding to heparan sulphate proteoglycans, a binding event that has been linked to deposition of amyloid and tau protein accumulation and therefore neurodegeneration.

The researchers hope that further investigation into the role of apolipoprotein E in the pathogenesis of Alzheimer’s disease may aid the development of new treatments.

“Sometimes close analysis of a single case can lead to discovery that could have broad implications for the field,” commented Richard Hodes, Director of the National Institute on Aging (MD, USA). “We are encouraged that as part of our wide array of studies, this research in the unique genetic makeup of an exceptional individual can reveal helpful information.”

Sources: Arboleda-Velasquez JF, Lopera F, O’Hare M et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med.  doi:10.1038/s41591-019-0611-3 (2019); www.nih.gov/news-events/news-releases/unique-case-disease-resistance-reveals-possible-alzheimers-treatment