In late middle age, cognitively normal subjects who are homozygous for the epsilon 4 allele for apolipoprotein E have reduced glucose metabolism in the same regions of the brain as in patients with probable Alzheimer's disease. These findings provide preclinical evidence that the presence of the epsilon 4 allele is a risk factor for Alzheimer's disease. PET may offer a relatively rapid way of testing future treatments to prevent Alzheimer's disease.

No 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 4 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 4 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 4 heterozygotes, all with the 3͞ 4 genotype, and 15 noncarriers of the 4 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 4 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-middleaged 4 carriers, the young 4 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.apolipoprotein E ͉ positron emission tomography ͉ glucose metabolism ͉ brain mapping ͉ surrogate markers A lzheimer's dementia (AD) afflicts Ϸ10% of those over the age of 65 and almost half of those over the age of 85 (1). To develop and test effective primary prevention therapies, it would be helpful to characterize brain changes associated with the susceptibility to AD as early as possible before the onset of cognitive impairment (2).Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with AD have abnormally low cerebral metabolic rates for glucose (CMRgl) in posterior cingulate, parietal, temporal, and prefrontal cortex and a progressive decline in these rates over time (3-8). We (2, 9, 10) and others (11, 12) have been using PET to detect and track these functional brain abnormalities before the onset of dementia in carriers of the apolipoprotein E (APOE) 4 allele, a common Alzheimer's susceptibility gene associated with up to half of cases of late-onset AD (13-15). Previously, we found that cognitively normal 50-to 65-year-old 4 carriers have abnormally low CMRgl in each of the same regions as patients with probable AD and abnormal rates of regional CMRgl decline over time (2, 9, 10). We now consider whether 4 carriers have these regional brain abnormalities as relatively young adults, several decades before the possible onset of dementia. Our a...