The relationship between apolipoprotein E4 and lipid metabolism is impaired in Alzheimer's disease

Abstract

Background: Human apolipoprotein (Apo) E4 (ApoE4) is an important determinant of lipid metabolism and cell-to-cell cholesterol transport. It is also a major genetic risk factor for both vascular disease and familial and sporadic late-onset Alzheimer's disease (AD). Since vascular pathology could dramatically reduce neuronal reserve capacity, a biological chain of events between ApoE4, hypercholesterolemia and AD has been postulated. The aim of the present study is to explore the relationship between lipid metabolism and ApoE isoforms in a large series of elderly subjects in relation to the presence or absence of AD.

Methods: Of 332 referrals to a neurology clinic specializing in memory disorders, 146 were given a diagnosis of AD (age, mean +/- SD 76 +/- 13.1 years, 64.4% women) according to DSM-IIIR criteria. One hundred and seventy-six subjects were included as controls (age 80 +/- 5.6 years, 58% women). The ApoE phenotype was determined by the isoelectrofocalization method, cholesterol, triglycerides, phospholipids, ApoA and ApoB were determined by routine chemistry.

Findings: A significant association was observed between the E4 allele and AD (chi2 = 13, p < 0.001) only below age 80. In the control group, cholesterol levels were found to be significantly higher in men but not in women with an E4 allele (6.35 +/- 1.3 mmol/l) as opposed to those without (5.8 +/- 1.2 mmol/l). ApoB levels were also found to be higher in the presence of ApoE4, with no gender effect. Within the AD group no significant relationship was found between ApoE4 and cholesterol levels (mean 6.05 +/- 0.9 mmol/l in E4-AD subjects versus 5.8 +/- 1.21 mmol/l in non-E4-AD subjects). Similar observations were made in relation to triglycerides and phospholipids.

Interpretation: Our results demonstrate the disappearance of the ApoE4-raising effect on serum cholesterol, triglyceride and phospholipid levels in AD suggesting a more complex relationship between AD and lipid metabolism than has previously been supposed. This lipid abnormality may further contribute to the progression of AD.