PRECLINICAL EVIDENCE OF ALZHEIMER’S DISEASE IN PERSONS HOMOZYGOUS FOR THE

Background. Variants of the apolipoprotein E allele appear to account for most cases of late-onset Alzheimer’s disease, and persons with two copies of the e 4 allele appear to have an especially high risk of dementia. Positron-emission tomography (PET) has identified specific regions of the brain in which the rate of glucose metabolism declines progressively in patients with probable Alzheimer’s disease. We used PET to investigate whether these same regions of the brain are affected in subjects homozygous for the e 4 allele before the onset of cognitive impairment. Methods. Apolipoprotein E genotypes were established in 235 volunteers 50 to 65 years of age who reported a family history of probable Alzheimer’s disease. Neurologic and psychiatric evaluations, a battery of neuropsychological tests, magnetic resonance imaging, and PET were performed in 11 e 4 homozygotes and 22 controls without the e 4 allele who were matched for sex, age, and level of education. An automated method was used to generate an aggregate surface-projection map that compared regional rates of glucose metabolism in the two groups. Results. The e 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 also had reduced rates of glucose metabolism in additional prefrontal regions, which may be preferentially affected during normal aging. Conclusions. In late middle age, cognitively normal subjects who are homozygous for the e 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 e 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. (N Engl J Med 1996;334:752-8.)  1996, Massachusetts Medical Society. From the Positron Emission Tomography Center, Good Samaritan Regional Medical Center, Phoenix, Ariz. (E.M.R., L.S.Y., K.C., D.B.); the Departments of Psychiatry (E.M.R.) and Radiology (K.C.), University of Arizona, Tucson; the Departments of Neurology (R.J.C.) and Psychology (D.O.), Mayo Clinic, Scottsdale, Ariz.; the Department of Computer Science, Arizona State University, Tempe (L.S.Y.); the Division of Nuclear Medicine, University of Michigan, Ann Arbor (S.M.); and the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn. (S.N.T.). Address reprint requests to Dr. Reiman at the Positron Emission Tomography Center, Good Samaritan Regional Medical Center, 1111 E. McDowell Rd., Phoenix, AZ 85006. Supported by grants from the Samaritan Foundation (to Dr. Reiman), the Mayo Clinic Foundation (to Dr. Caselli), the Robert S. Flinn Foundation (to Dr. Reiman), the Department of Energy (DE-FG02-87-ER60561), and the National Institutes of Health (RO1-NS-24896), and by the family of Joe Weinstein. Presented in part at the Annual Meeting of the American Academy of Neurology, Seattle, May 12, 1995. V ARIANTS of the apolipoprotein E gene appear to account for the majority of cases of late-onset Alzheimer’s disease (i.e., those involving the onset of dementia after the age of 60). 1-7 The gene, located on chromosome 19, has three major alleles: e 2, e 3, and e 4. 8 The e 2 allele appears to be protective, decreasing the risk of Alzheimer’s disease and delaying the onset of dementia. 4 In contrast, the e 4 allele appears to be harmful, increasing the risk of Alzheimer’s disease and hastening the onset of dementia. 2,5 If, as case–control studies suggest, persons with two copies of the e 4 allele (the e 4/ e 4 genotype) have an especially high risk of Alzheimer’s disease, the study of presymptomatic subjects who are homozygous for the e 4 allele could provide additional support for this genetic risk factor, produce new information about the pathophysiology of the disorder, and identify biologic markers that may be very useful in monitoring future disease-prevention therapies. Positron-emission tomography (PET) is a brain-imaging technique that can be used to study the physiologic processes that herald the onset of dementia. When used to measure cerebral glucose metabolism, PET reveals characteristic abnormalities in patients with probable and definite Alzheimer’s disease, including abnormally low parietal, temporal, and posterior cingulate levels; abnormally low prefrontal and whole-brain levels in more severely affected patients; and a progressive decline in these levels over time. 9-14 Case series suggest that abnormalities in glucose metabolism can be detected by PET before substantial impairment occurs in persons at risk for Alzheimer’s disease 14-16 and certain other neurodegenerative disorders. 17,18 In a recent study, subjects with the apolipoprotein E e 3/ e 4 genotype, age-associated memory impairment, and a family history of Alzheimer’s disease had abnormally low and asymmetric rates of glucose metabolism in a preselected parietal region before the onset of dementia. 15 We used PET to investigate regions of the brain that are affected before the onset of cognitive decline in persons homozygous for the apolipoprotein E e 4 allele. We sought to test the hypothesis that such persons have abnormally low rates of glucose metabolism in the same brain regions as previously studied patients with probable Alzheimer’s disease, explore the possibility that they also have abnormally low rates in other regions of the brain, and begin to fashion a way to test possible preventive therapies for Alzheimer’s disease.