From The Cover: Correlations between apolipoprotein E 4 gene dose and brain-imaging measurements of regional hypometabolism

E. M. Reiman, K. Chen, G. E. Alexander, R. J. Caselli, D. Bandy, D. Osborne, A. M. Saunders, J. Hardy
2005 Proceedings of the National Academy of Sciences of the United States of America  
Patients with Alzheimer's disease (AD) have abnormally low positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) in regions of the precuneus and the posterior cingulate, parietotemporal, and frontal cortex. Apolipoprotein E (APOE) 4 gene dose (i.e., the number of 4 alleles in a person's APOE genotype) is associated with a higher risk of AD and a younger age at dementia onset. We previously found that cognitively normal late-middle-aged APOE 4
more » ... have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia. In a PET study of 160 cognitively normal subjects 47-68 years of age, including 36 4 homozygotes, 46 heterozygotes, and 78 4 noncarriers who were individually matched for their gender, age, and educational level, we now find that 4 gene dose is correlated with lower CMRgl in each of these brain regions. This study raises the possibility of using PET as a quantitative presymptomatic endophenotype to help evaluate the individual and aggregate effects of putative genetic and nongenetic modifiers of AD risk. Alzheimer's disease ͉ genetics ͉ positron emission tomography ͉ endophenotype T o evaluate putative genetic and nongenetic modifiers of the risk for a psychiatric or neurological disorder, it would be helpful to identify an "endophenotype," a measurable feature that is more closely related to disease susceptibility than the clinical syndrome itself (1). A useful endophenotype should be associated with the disorder, associated with heritable or nonheritable risk factors in clinically unaffected persons, and correlated with relative risk. Fluorodeoxyglucose positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) provide a promising quantitative neuroimaging endophenotype of Alzheimer's disease (AD) risk. AD is associated with abnormally low CMRgl in the precuneus and the posterior cingulate, parietotemporal, and frontal cortex (2, 3). In patients with Alzheimer's dementia, the CMRgl reductions are progressive (2) and correlated with dementia severity (3) and predict subsequent clinical decline and the histopathological diagnosis of AD (4). In patients with mild cognitive impairment, the CMRgl reductions predict subsequent conversion to probable AD (5-7). In comparisons between nondemented carriers and noncarriers of the apolipoprotein E (APOE) 4 allele, a susceptibility gene for late-onset AD (8, 9) , which is found in almost one-fourth of the population (10), we (11-13) and others (14, 15) found that the 4 carriers have significantly lower CMRgl in each of the same brain regions as clinically affected patients. Extending our original findings to almost four times as many cognitively normal late-middle-aged persons with two, one, and no copies of the 4 allele, we now demonstrate that APOE 4 gene dose (i.e., the number of 4 alleles in a person's APOE genotype), a heritable factor known to be associated with a progressively higher risk of AD (8, 9) and a progressively younger age at dementia onset (8) , is correlated with lower CMRgl in the brain regions preferentially affected by AD. Based on these findings, we suggest how PET could be used before the possible onset of symptoms as a quantitative endophenotype to help assess the individual and aggregate effects of putative genetic and nongenetic modifiers of the risk for AD. Methods Subjects. Newspaper advertisements were used to recruit cognitively normal volunteers 47-68 years of age who reported a first-degree family history of probable AD, understood they would not receive any information about their APOE genotype, provided their informed consent, and were studied under guidelines approved by the human subjects committees at Banner Good Samaritan Medical Center and the Mayo Clinic. Venous blood samples were drawn and APOE genotypes characterized with analysis involving restriction fragment length polymorphisms (16). Clinical ratings, neuropsychological tests, volumetric MRI, and fluorodeoxyglucose PET were performed as described (7) in APOE 4 homozygotes, heterozygotes, and noncarriers who denied an impairment in memory or other cognitive skills, had scores of at least 28 on the Folstein MiniMental State Examination and Ͻ10 on the Hamilton Depression Rating Scale, did not satisfy criteria for a current psychiatric disorder using a structured psychiatric interview, did not use centrally acting medications for at least 2 weeks before their PET session, and had a normal neurological examination. The APOE 4 heterozygotes (all with the 3͞4 genotype) and 4 noncarriers were individually matched to each 4 homozygote for their gender, age (within 3 years), and educational level (within 2 years). The 160 subjects included 36 APOE 4 homozygotes, 46 4 heterozygotes, and 78 4 noncarriers (60 with the 3͞3 genotype and 18 with the 2͞3 genotype). [Eleven 114 homozygotes, 11 4 heterozygotes, and 22 4 noncarriers were included in our previous reports (11, 12) .] This paper was submitted directly (Track II) to the PNAS office. Abbreviations: PET, positron emission tomography; APOE, apolipoprotein E; AD, Alzheimer's disease; CMRgl, cerebral metabolic rate for glucose.
doi:10.1073/pnas.0500579102 pmid:15932949 pmcid:PMC1149416 fatcat:uh7tl5qaz5hy5nbsk4jqczfjlq