APOE 2 and presymptomatic stage Alzheimer disease: How much is not enough?

Although its mechanism of action is still debated, the effect of APOE genotype on risk and age at onset of Alzheimer disease (AD)1 has been replicated many times. Because APOE e4 increases AD risk, e4 carriers have provided an unparalleled opportunity to study the metabolic, structural, pathologic, and cognitive changes that precede the symptomatic expression of mild cognitive impairment (MCI) and dementia and have led to the identification and characterization of presymptomatic stage AD.2 By contrast, APOE e2 confers a reduced risk of AD, but is the least prevalent of the 3 common APOE alleles. Although e2's protective effect has been considered for therapeutic purposes of primary prevention, surprisingly few studies have examined the e2 effect on brain and cognitive aging. In this issue of Neurology ®, Chiang and colleagues3 report findings from the Alzheimer's Disease Neuroimaging Initiative, showing that e2 carriers have a lower rate of annual hippocampal atrophy than individuals with the e3/3 genotype. The e2 carriers also had a higher CSF β-amyloid and lower phosphotau (p-tau), a CSF biomarker profile that suggests less AD pathology. The authors conclude that, consistent with its previously demonstrated protective effect, the e2 allele confers less AD-related brain pathology over time compared to the …