Apolipoprotein E Genetic Variation and Alzheimer’s Disease

Abstract

In order to quantify the effects of apolipoprotein (apo) E on early- and late-onset, sporadic and familial Alzheimer’s disease (AD) more precisely we performed a meta-analysis of 42 case-control series published before July 1996. We excluded studies of late-onset AD with fewer than 50 cases and 50 controls. The estimated odds ratio of AD over the age of 65 years associated with the apo ε4 allele, relative to apo ε3, was 3.18 (95% CI 2.93–3.45, p < 0.00001). Apo ε4 was associated with a significantly higher relative risk of early-onset disease (<65 years) unselected for family history (OR 4.86, 95% CI 3.61–6.54, p < 0.0001), but its impact on early-onset familial disease was weaker (OR 1.48, 95% CI 1.02–2.16). The estimated odds ratio associated with the ε4/ε4 genotype, relative to the ε3/ε3 genotype, was 11.57 (95% CI 8.67–15.44) for all cases over 65 and 61.44 (95% CI 13.47–280.3) for early-onset disease unselected for family history. Apo ε2 was associated with a significantly reduced odds ratio for AD above the age of 65 (OR 0.68, 95% CI 0.58–0.80, p < 0.00001), but not in familial early-onset AD, where apo ε2 may be associated with an increased risk (OR 1.70, 95% CI 1.02–2.84). We estimate that 60% (95% CI 48–68%) of AD cases over the age of 65 years and 92% of cases below the age of 65 would be attributable to apo E and that apo E probably accounts for less than 50% of the familial aggregation of the disease.

Differential qualitative responses to rivastigmine in APOE ɛ4 carriers and noncarriers

“…The patients were representative of those typically included in clinical trials, but they were probably younger than the dementia population in general, increasing the likelihood of including APOE e4 carriers, since the allele accelerates disease onset and greater percentages of early-onset AD cases are reported to carry APOE e4. 7 Our data are therefore not conclusive, but do suggest possible differences, and further investigations would be interesting.…”

“…However, the latter two studies showing less decline in APOE e4 carriers after disease onset may be more reliable than the former two studies showing similar or greater decline, since the earlier studies did not control for age or severity. Therefore, we would suggest that although APOE e4 hastens the onset of dementia, 3,4,7,8 patients with the allele may progress at a slower rate once the disease process has begun.…”

“…5,6 Approximately 60% of late-onset and as many as 92% of early-onset AD cases are reported to carry APOE E4. 7 The specific mechanisms and interactions governing APOE isoform-specific effects in AD are not fully understood, although apolipoprotein E4 has been shown to intensify a number of the disturbances that are characteristic of AD. 3,4,8 Of particular clinical interest, considering that the only successful pharmacological treatment of cognitive impairment of AD to date has been the cholinesterase inhibitors, may be the reported interaction between APOE e4 genotype and cholinesterase genotype.…”

Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease

“…First, positive or negative findings from a prevention study in 4 carriers may not be generalizable to 4 noncarriers, who account for nearly half of persons with Alzheimer's dementia (29). [Still, new discoveries (30,31) could increase the spectrum of cognitively normal persons at risk for Alzheimer's disease who are eligible for such prevention studies.]…”

Brain Cholesterol: Long Secret Life Behind a Barrier

“…In a recent meta-analysis, 78 it was calculated that the odds ratio for late-onset Alzheimer disease associated with the carriers of the ⑀4/⑀4 compared with ⑀3/⑀3 was 11.6. Moreover, the authors estimated that Ϸ60% of late-onset Alzheimer disease was attributable to presence of the ⑀4 isotype.…”