Accelerated long-term forgetting in asymptomatic APOE ε4 carriers

In The Lancet Neurology, Philip Weston and colleagues report that presymptomatic individuals carrying familial Alzheimer's disease gene mutations demonstrate accelerated long-term forgetting over an extended 1 week retention interval compared with gene-negative controls.1 These findings raise the question of whether accelerated long-term forgetting is also detectable in presymptomatic individuals at genetic risk of the much more common sporadic form of Alzheimer's disease. In white people, risk of Alzheimer's disease is 15 times higher among homozygous ε4 carriers (with two copies of the ε4 allele) and three times higher among heterozygous carriers (with one copy each of the ε3 and ε4 alleles) compared with ε4 non-carriers.2 Standard memory tests show longitudinal differentiation according to APOE genotype at around 60 years of age,3 but evidence from cross-sectional studies of pre-symptomatic individuals at this age or earlier is inconclusive.4 We recruited 60 healthy white English-fluent participants—20 homozygous for ε4, 20 heterozygous for ε3 and ε4, and 20 homozygous for ε3—between 40 and 60 years of age (appendix). Taken together, these findings suggest that APOE ε4 confers a specific impairment of long-term memory storage dependent on the number of copies of the allele rather than an impairment of memory encoding or retrieval.