PRECLINICAL EVIDENCE OF ALZHEIMERS-DISEASE IN PERSONS HOMOZYGOUS FOR THE EPSILON-4 ALLELE FOR APOLIPOPROTEIN-E

Background. Variants of the apolipoprotein pared regional rates of glu cose metabolism in the two groups. E allele appear to account for most cases of late-onset Alzheimer's disease, and persons with two copies of the epsilon 4 allele appear to have an especially high risk of deme ntia. Positron-emission tomography (PET) has identified specific regio ns of the brain In which the rate of glucose metabolism declines progr essively in patients with probable Alzheimer's disease, We used PET to investigate whether these same regions of the brain are affected in s ubjects homozygous for the epsilon 4 allele before the onset of cognit ive impairment. Methods. Apolipoprotein E genotypes were established i n 235 volunteers 50 to 65 years of age who reported a family history o f probable Alzheimer's disease, Neurologic and psychiatric evaluations , a battery of neuropsychological tests, magnetic resonance imaging, a nd PET were performed in 11 E4 homozygotes and 22 controls without the epsilon 4 allele who were matched for sex, age, and level of educatio n. An automated method was used to generate an aggregate surface-proje ction map that compared regional rates of glucose metabolism in the tw o groups. Results. The epsilon 4 homozygotes were cognitively normal, They had significantly reduced rates of glucose metabolism In the same posterior cingulate, parietal, temporal, and prefrontal regions as in previously studied patients with probable Alzheimer's disease, They a lso had reduced rates of glucose metabolism in additional prefrontal r egions, which may be preferentially affected during normal aging. Conc lusions. In late middle age, cognitively normal subjects who are homoz ygous for the epsilon 4 allele for apolipoprotein E have reduced gluco se metabolism in the same regions of the brain as in patients with pro bable Alzheimer's disease, These findings provide preclinical evidence that the presence of the epsilon 4 allele is a risk factor for Alzhei mer's disease, PET may offer a relatively rapid way of testing future treatments to prevent Alzheimer's disease. (C) 1996, Massachusetts Med ical Society.