TY - JOUR
T1 - Preclinical evidence of Alzheimer's disease in persons homozygous for the ε4 allele for apolipoprotein E
AU - Reiman, Eric M.
AU - Caselli, Richard J.
AU - Yun, Lang S.
AU - Chen, Kewei
AU - Bandy, Daniel
AU - Minoshima, Satoshi
AU - Thibodeau, Stephen N.
AU - Osborne, David
PY - 1996/3/21
Y1 - 1996/3/21
N2 - 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 ε4 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 ε4 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 ε4 homozygotes and 22 controls without the ε4 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 ε4 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 ε4 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 ε4 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.
AB - 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 ε4 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 ε4 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 ε4 homozygotes and 22 controls without the ε4 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 ε4 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 ε4 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 ε4 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.
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U2 - 10.1056/NEJM199603213341202
DO - 10.1056/NEJM199603213341202
M3 - Article
C2 - 8592548
AN - SCOPUS:0029970342
SN - 0028-4793
VL - 334
SP - 752
EP - 758
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 12
ER -