APOE-ε4 is the strongest genetic risk factor for Alzheimer’s disease (AD), and is associated with an increase in the levels of amyloid deposition and an early age of onset. Recent data demonstrate that AD pathological changes occur decades before clinical symptoms, raising questions about the precise onset of the disease. Now a convergence of approaches in mice and humans has demonstrated that APOE-ε4 affects normal brain function even very early in life in the absence of gross AD pathological changes. Normal mice expressing APOE4 have task-specific spatial learning deficits, as well as reduced NMDAR-dependent signaling and structural changes to presynaptic and postsynaptic compartments in neurons, particularly in hippocampal regions. Young humans possessing APOE-ε4 are more adept than APOE-ε4 negative individuals at some behavioral tasks, and functional magnetic resonance imaging has shown that inheritance of APOE-ε4 has specific effects on medial temporal brain activities. These findings suggest that inheritance of APOE-ε4 causes life long changes to the brain that may be related to the late risk of AD. Several possible mechanisms of how APOE-ε4 could affect brain neurochemistry, structure, and function are reviewed.

Apolipoprotein E (apoE) is associated with lipoproteins in the cerebrospinal fluid (CSF). APOE4 increases and APOE2 decreases the risk for Alzheimer disease (AD) compared to the risk associated with APOE3 Because apoE4 is less efficient at cholesterol efflux than apoE2 or apoE3 in vitro, we hypothesized that APOE genotype may affect apoE particle size in vivo and that these size differences may be related to AD risk. We used nondenaturing gel electrophoresis to test for differences in the size of apoE complexes in human CSF samples of various APOE genotypes and created profiles of each sample to compare the patterns of apoE distribution. For middle-aged adults with no dementia, APOE 2.3 individuals had significantly larger apoE complexes than APOE 3.3 subjects, who had significantly larger apoE complexes than APOE 3.4 and APOE 4.4 individuals. Similarly, in an independent cohort of older adults, CSF apoE complexes of APOE4-positive individuals were smaller than those of the APOE4-negative individuals. Compared to individuals with no dementia, those with the mildest stages of dementia had similar sized CSF apoE complexes. These results identify a novel phenotypic difference in the size of CSF apoE complexes in middle age that correlate with the risk of AD later in life.

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