APOE3 mutation protects from familial Alzheimer’s disease
The anonymous woman inherited familial Alzheimer’s disease – caused by presenilin variant (PSEN1 E280). Normally she would develop severe disease in her 50s, but two decades later she is still enjoying normal life:
Her brain was functioning really well. Compared to people who are 45 or 50, she’s actually better.Yakeel Quiroz, senior author of the study (source)
Protective mutation was found in both copies of APOE3 gene – 136th arginine in the protein was changed to serine, so called “Christchurch” mutation. As a result, APOE had impaired binding to lipoprotein receptors and this probably prevented accumulation of tau proteins.
The finding – although limited to one case – can open new therapeutic possibilities, including eventual gene therapy introducing the mutation. The first step on this way will involve cell lines and animal models:
Because the APOE-R136S mutation is extremely rare in humans, generating mouse models and human induced pluripotent stem cell lines with the mutation in an APOE4, APOE3 or APOE2 background by gene editing would be reasonable next steps to capitalize on this exciting finding.K. Zalocusky, M. Nelson, Y. Huang (source)
Publication: Arboleda-Velasquez, J.F., Lopera, F., O’Hare, M. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med (2019) doi:10.1038/s41591-019-0611-3