Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia

Abstract

Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with Alzheimer's dementia (AD) have abnormally low rates of cerebral glucose metabolism in posterior cingulate, parietal, temporal, and prefrontal cortex. We previously found that cognitively normal, late-middle-aged carriers of the apolipoprotein E epsilon4 allele, a common susceptibility gene for late-onset Alzheimer's dementia, have abnormally low rates of glucose metabolism in the same brain regions as patients with probable AD. We now consider whether epsilon4 carriers have these regional brain abnormalities as relatively young adults. Apolipoprotein E genotypes were established in normal volunteers 20-39 years of age. Clinical ratings, neuropsychological tests, magnetic resonance imaging, and PET were performed in 12 epsilon4 heterozygotes, all with the epsilon3/epsilon4 genotype, and 15 noncarriers of the epsilon4 allele, 12 of whom were individually matched for sex, age, and educational level. An automated algorithm was used to generate an aggregate surface-projection map that compared regional PET measurements in the two groups. The young adult epsilon4 carriers and noncarriers did not differ significantly in their sex, age, educational level, clinical ratings, or neuropsychological test scores. Like previously studied patients with probable AD and late-middle-aged epsilon4 carriers, the young epsilon4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Carriers of a common Alzheimer's susceptibility gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia.

Figures

Fig. 1.

Regions of the brain with abnormally low CMRgl in young adult carriers of the APOE ε4 allele and their relation to brain regions with abnormally low CMRgl in patients with probable AD. In this analysis, a 3D surface-projection map of abnormally low CMRgl in the young adult ε4 carriers was superimposed on a map of abnormally low CMRgl in previously studied patients with the probable AD and a spatially standardized and volume-rendered MRI of the brain (P < 0.005, uncorrected for multiple comparisons) (6, 9). The purple areas are regions in which CMRgl was abnormally low only in the patients with AD, the bright blue areas are regions in which CMRgl was abnormally low in both the young adult ε4 carriers and patients with probable AD, and the muted blue areas are regions in which CMRgl was abnormally low only in the ε4 carriers. (Lines point to the locations of the ε4 carriers' most significant CMRgl reductions and correspond to the brain atlas coordinates in Table 3.) Like patients with AD, the young adult ε4 carriers had abnormally low CMRgl bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex.

Fig. 2.

Regional/pontine CMRgl in young adult APOE ε4 carriers and controls. Measurements were normalized to that in the pons, which appears to be the region least affected in patients with the probable AD (25), and extracted from the locations specified in Table 3, which were associated with the most significant differences between the ε4 carriers (ε4) and controls who do not carry the ε4 allele (NC) (P < 0.001, uncorrected for multiple comparisons).