APOEGenotype and Brain Development

Abstract

Theobservationthat inheritanceoftheapolipoproteinE(APOE) e4allelepredisposesdramaticallytoAlzheimerdisease(AD)was first reported in 19931 and has been replicated in hundreds of studies thereafter. It is oneof themost robust genetic associationswith common disease discovered in all ofmedicine, yet despite 20years of research, the reason thatAPOE e4has such aprofoundincreaseofrisk inADremainsuncertain.Several facts are clear: (1) theAPOE e4genotypepredisposes towardADpathology, primarily with amyloid deposits2; (2) the predisposition is relatively specific becausetheeffectof theAPOE e4genotypeonotherneurodegenerativediseases iseitherminimal or absent3; (3) theAPOE e4 genotype predisposes toward an earlier age at onset ofADdementia2,4 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) theAPOEe4genotype is associatedwithdiminishedglucosemetabolisminposteriorbrain regions inapattern characteristicofADeveninhealthy,nondementedindividuals.5 The article byDeanet al6 in this issuebuilds on these observations that theAPOE e4genotype is associatedwith anearly cerebral blood flowphenotype even inmiddle-aged individuals at risk for AD and asks just how early in the life span anAPOE e4effect on thebrain canbeobserved. They carriedout anobservationalstudyoninfantsbetweentheagesof2and25months and astonishingly found evidence formorphological changes in brain areas thatwould be susceptible forAD-relatedneuropathological changesdecades later. Specifically, amonge4carriers, graymattervolumeandmyelinwater fractionwere lower in the precuneus, posterior andmiddle cingulate, and lateral temporal andmedial occipitotemporal regions than in e4noncarriers,whereasthesemeasuresweregreater infrontal regions. These observations promptedDean et al to speculate that the APOE e4genotype is amorepowerful genetic predeterminant ofAD thanpreviously expected. The results also raise intriguing questions about just “when” AD-related brain alterations might be considered to start. Before accepting these speculations, several issues must be examined. The measures are extremely technically difficult, and while there is no reason to think that the APOE e4 groupwouldbe systematicallymeasureddifferently from the control group, inexact measures might lead to nonrandomly distributed noise. The analysis depends on selecting regions of interest thatwere determinedbyprior experience inAD, so a certain circularity in the logic is inevitable. Also, by the nature of the study, multiple possible measurements are compared, and most results do not hold up to multiple comparison testing,making thismore of ahypothesis-generatingdata set than a confirmed set of observations. The population examinedwasnot selected, but thepercentageof e4 carrierswas substantiallyhigher thanonewouldhaveexpected in thegeneral population, raising a concern about someunderlying bias variable in selection for the study. However, if onedoes accept themeasures as valid and sets aside the other considerations noted earlier, the study suggests the intriguing possibility that APOE e4 impacts underlyingbrain structureatveryearly stagesofdevelopment inaway thatpredisposes toward laterneurodegeneration.7This is apotentially important conceptandshouldgenerate furtherexploration intomolecularmechanismsthat linkAPOEandneurodevelopment.Forexample,onepossibilitymight involve thevery low-density lipoproteinreceptorandAPOEreceptor2.Theseare 2 neuronal receptors that can both bind APOE and also act as receptors for reelin, a molecule important in neural development.6 Although only fairly subtle anatomical alterationshavebeendescribedinmousemodelsthatexpressthevarious APOE alleles, one might speculate that different isoforms ofAPOE,whichisanalternative ligandforthesereceptors,might impact theirnormal functionduringan infant’sdevelopment.8 As to the potential link to AD, the eventual significance of an APOE e4 effect on neurodevelopment and the risk of AD is still unclear. If neurodevelopmental differences occur with inheritance of APOE e4, is this linked in a causative way to degenerative changes that manifest many decades later in AD or simply an additional subtle difference in the neurobiology of the APOEmolecule? While in general neurodevelopmental abnormalities are not associated with later AD (with the exception of Down syndrome where trisomy 21 leads to an extra copy of the amyloid precursor protein and elevated β-amyloid levels), recent data emphasize effects of the β-amyloid peptide on neural plasticity during brain development.9,10 Together, these observations raise intriguing questions about the kind of substrate in the developing nervous system that might predispose to AD neuropathological changes and neurodegeneration much later in life. Further evaluation of this provocative hypothesis awaits confirmatory examination of additional patient populations.