F5–04–02: A coding mutation in APP protects against Alzheimer's disease and age‐related cognitive decline

Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. Recent advances in whole-genome sequencing and imputation methods have proven extremely powerful for detection of rare sequence variants affecting risk of disease. Through whole-genome sequencing of 1,795 Icelanders, we identified several coding variants in the Amyloid Precursor Protein (APP). We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. To our knowledge, A673T represents the first example of a sequence variant conferring strong protection against Alzheimer's disease. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms, and suggests that that Alzheimer's disease may represent the extreme of the age-related decline in cognitive function.