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The observation that inheritance of the apolipoprotein E (APOE) ε4 allele predisposes dramatically to Alzheimer disease (AD) was first reported in 19931 and has been replicated in hundreds of studies thereafter. It is one of the most robust genetic associations with common disease discovered in all of medicine, yet despite 20 years of research, the reason that APOE ε4 has such a profound increase of risk in AD remains uncertain. Several facts are clear: (1) the APOE ε4 genotype predisposes toward AD pathology, primarily with amyloid deposits2; (2) the predisposition is relatively specific because the effect of the APOE ε4 genotype on other neurodegenerative diseases is either minimal or absent3; (3) the APOE ε4 genotype predisposes toward an earlier age at onset of AD dementia2,4 and appears to be additive in this effect of earlier age at onset even in the presence of other AD-predisposing genes like PS1 or even Down syndrome; and (4) the APOE ε4 genotype is associated with diminished glucose metabolism in posterior brain regions in a pattern characteristic of AD even in healthy, nondemented individuals.5 The article by Dean et al6 in this issue builds on these observations that the APOE ε4 genotype is associated with an early cerebral blood flow phenotype even in middle-aged individuals at risk for AD and asks just how early in the life span an APOE ε4 effect on the brain can be observed. They carried out an observational study on infants between the ages of 2 and 25 months and astonishingly found evidence for morphological changes in brain areas that would be susceptible for AD-related neuropathological changes decades later. Specifically, among ε4 carriers, gray matter volume and myelin water fraction were lower in the precuneus, posterior and middle cingulate, and lateral temporal and medial occipitotemporal regions than in ε4 noncarriers, whereas these measures were greater in frontal regions. These observations prompted Dean et al to speculate that the APOE ε4 genotype is a more powerful genetic predeterminant of AD than previously expected. The results also raise intriguing questions about just “when” AD-related brain alterations might be considered to start.
Growdon JH, Hyman BT. APOE Genotype and Brain Development. JAMA Neurol. 2014;71(1):7-8. doi:10.1001/jamaneurol.2013.5200