Carriers of the PSEN1E280A mutation overproduce amyloid-β (Aβ) and develop autosomal dominant Alzheimer disease (ADAD) in their forties. However, this study reports that one woman with PSEN1E280A did not show cognitive impairment until her seventies, despite a high burden of Aβ pathology. The woman had two copies of a rare APOE3 allele with a R136S mutation that reduces APOE3’s affinity for heparan sulfate proteoglycans, which have been suggested to promote neuronal uptake of tau. Thus, APOE3R136S might delay ADAD by limiting tau pathology.
Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019)
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Bray, N. A protective mutation. Nat Rev Neurosci 21, 3 (2020). https://doi.org/10.1038/s41583-019-0246-x