The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (apoE-4), is associated with lowered cerebral glucose metabolism in brain regions showing AD neuropathological damage. To determine metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates using positron emission tomography (PET) in middle-aged and older persons with normal memory performance. We collected PET, magnetic resonance imaging (MRI), neuropsychological, and apoE data on 54 non-demented subjects (27 with apoE-4, 27 without apoE-4) at baseline, and 20 of them (10 with apoE-4, 10 without apoE-4) two years later (mean, SD for follow-up was 27.9, 1.7 months). The MRI scans were co-registered to PET scans, and statistical parametric mapping was performed. Baseline PET measures indicated significantly lower metabolism in non-demented subjects with a single copy of the apoE-4 allele compared to those without apoE-4 in the inferior parietal, lateral temporal, and posterior cingulate regions. PET scans performed after two years showed the greatest magnitude (5%) and extent of metabolic decline in the inferior parietal and lateral temporal cortices in subjects at genetic risk for AD. After correction for multiple comparisons, these metabolic changes remained significant for the apoE-4 group, wherein every subject had observable metabolic decline in these regions. These results indicate that combining cerebral metabolic rate and genetic risk measures provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments. Moreover, this strategy could allow testing of relatively small sample sizes when assessing treatments aimed at preventing cognitive decline and delaying dementia onset.
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