Using positron emission tomography (PET), Reiman et al. (1996) found that 11 cognitively normal subjects aged 50 to 65 years who were homozygous for the APOE4 allele had reduced glucose metabolism in the same regions of the brain ... Using positron emission tomography (PET), Reiman et al. (1996) found that 11 cognitively normal subjects aged 50 to 65 years who were homozygous for the APOE4 allele had reduced glucose metabolism in the same regions of the brain as patients with probable Alzheimer disease. The affected areas included temporal, parietal, posterior cingulate, and prefrontal regions. These findings provided preclinical evidence that the presence of the APOE4 allele is a risk factor for Alzheimer disease. Reiman et al. (1996) suggested that PET may offer a relatively rapid way of testing treatments to prevent Alzheimer disease in the future. Reiman et al. (2001) found that 10 cognitively normal apoE4 heterozygotes aged 50 to 63 years also had abnormally low measurements of the cerebral metabolic rate for glucose in the same regions as AD patients. Over a period of 2 years, the E4 heterozygotes had declines in several regions, including temporal, posterior cingulate, prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus. These declines were significantly greater than those of 15 non-E4 carriers. Using PET scans, Reiman et al. (2004) found that 12 young adult volunteers, ranging in age from 20 to 39 years, who were heterozygous for the apoE4 allele had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Reiman et al. (2004) concluded that carriers of the E4 allele have brain abnormalities in young adulthood, several decades before the possible onset of dementia. Rippon et al. (2006) examined potential modifying risk factors for familial AD in a Latino population comprising 778 AD patients from 350 families. The population was primarily from the Dominican Republic and Puerto Rico and had been previously studied by Romas et al. (2002). The APOE E4 allele was associated with a nearly 2-fold increased risk of AD, a history of stroke (601367) was associated with a 4-fold increase, and a statistical interaction between APOE E4 and stroke was observed. Women with the E4 allele who were on estrogen replacement therapy did not have an increased risk of AD, but in women with a history of stroke, estrogen therapy was a deleterious effect modifier. Among risk factors, diabetes mellitus, myocardial infarction, head injury, hypertension, and smoking were not associated with AD. Among 100 patients with AD, van der Flier et al. (2006) found an association between presence of the E4 allele and the typical amnestic phenotype, characterized by initial presentation of forgetfulness and difficulties with memory. Those with the memory phenotype were 3 times more likely to carry an E4 allele compared to AD patients who displayed a nonmemory phenotype, with initial complaints including problems with calculation, agnosia, and apraxia. The memory phenotype was almost exclusively observed in homozygous E4 carriers. Borroni et al. (2007) also reported an association between the memory phenotype of AD and presence of the E4 allele. Among 319 late-onset AD patients, 77.6% of E4 allele carriers presented with the memory phenotype compared to 64.6% of noncarriers. Wolk et al. (2010) compared the phenotypes of 67 AD patients carrying at least 1 APOE E4 allele to 24 AD patients without an E4 allele. Both groups of patients had a cerebrospinal fluid profile consistent with AD. E4 carriers had significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. E4 carriers also had greater atrophy of the medial temporal lobe and smaller hippocampal volumes on neuroimaging, whereas noncarriers had greater frontoparietal atrophy. The findings suggested that APOE genotype may influence selective regional brain pathology, which in turns reflects phenotypic variation in the specific cognitive symptoms of AD.
Corder et al. (1993) found that the risk for late-onset AD increased from 20 to 90% and mean age of onset decreased from 84 to 68 years with increasing number of APOE*E4 alleles (107741.0016) in 42 families with ... Corder et al. (1993) found that the risk for late-onset AD increased from 20 to 90% and mean age of onset decreased from 84 to 68 years with increasing number of APOE*E4 alleles (107741.0016) in 42 families with late-onset AD. Onset was early in 4 other families tested; 2 had chromosome 21 APP (104760) mutations and 2 showed linkage to chromosome 14, thus representing AD1 (104300) and AD3 (607822), respectively. The frequency of APOE*E4 was not elevated in these families or in 12 other early-onset families. Homozygosity for APOE*E4 was virtually sufficient alone to cause AD by age 80. Bray et al. (2004) applied highly quantitative measures of allele discrimination to cortical RNA from individuals heterozygous for the APOE E2, E3, and E4 alleles. A small, but significant, increase in the expression of E4 allele was observed relative to that of the E3 and E2 alleles (P less than 0.0001). Similar differences were observed in brain tissue from confirmed late-onset Alzheimer disease subjects, and between cortical regions BA10 (frontopolar) and BA20 (inferior temporal). Stratification of E4/E3 allelic expression ratios according to heterozygosity for the -219G-T promoter polymorphism (107741.0030) revealed significantly lower relative expression of haplotypes containing the -219T allele (P = 0.02). Bray et al. (2004) concluded that, in human brain, most of the cis-acting variance in APOE expression may be accounted for by the E4 haplotype, but there are additional small cis-acting influences associated with the promoter genotype.
Romas et al. (2002) found that both early-onset and late-onset familial AD occurs in Caribbean Hispanics. In contrast to sporadic AD, late-onset familial AD among Caribbean Hispanics was strongly associated with APOE4.