Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer's disease

Abstract

The discovery that the apolipoprotein E (apoE) ε4 allele is genetically linked to both sporadic and familial late-onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain of AD subjects. The presence of the ε4 allele has been associated with lower levels of apoE in both serum and brain tissues of normal and AD subjects. In an attempt to reverse the apoE deficit in AD, we identified and characterized several apoE inducer agents using a low-throughput in vitro screening assay. The most promising of these compounds is called probucol. Administration of probucol, an old cholesterol-lowering drug, in a pilot trial in mild-to-moderate sporadic AD led to a significant increase in cerebrospinal fluid (CSF) apoE levels and a decrease in CSF in both phosphorylated tau 181 and beta-amyloid 1-42 concentrations without significant modifications of lipid hydroperoxide levels.

Keywords: Alzheimer's disease; Apolipoprotein E; Cholesterol; Genetics; Lipids; Probucol; Statins.

Fig. 1

(A) Life expectancy over the centuries in the Western world. (B) Projected prevalence of Alzheimer’s disease in the next 40 years in the United States. Adapted from US Alzheimer Association (2010).

Fig. 2

Schematic representation of the physiological compartmentalization of the most important proteins associated with the top 6 genetic risk factors identified by genome-wide association study these past 5 years.

Fig. 3

Apolipoprotein E (ApoE) levels in different regions according to apoE genotype or diagnosis. (A) Human hippocampal and frontal cortex apoE levels as a function of disease status and APOE genotype (adapted from Beffert et al., 1999). Data represent average ± standard error of the mean. Statistical analysis: p < 0.05 for both APOE genotype and pathology effect (analysis of variance [ANOVA]) in the hippocampus; not significant, p = 0.12 for APOE genotype (ANOVA) in the frontal cortex. (B) Plasma apoE levels as a function of APOE genotype in mild-to-moderate Alzheimer’s disease (AD) cases (p < 0.001, adapted from Poirier, 2005). (C) Baseline plasma apoE levels as a function of disease progression and diagnosis (p < 0.001, adapted from Soares et al., 2012). The diagnosis was established at the follow-up, which was no later than 48 months after the first visit. ApoE levels are lower in patients with AD and mild cognitive impairment (MCI) compared with healthy age-matched controls. Data represent means and 95% confidence intervals. MCInp, MCI patients who were not diagnosed with dementia at the follow-up; MCIp, patients with MCI who were diagnosed with dementia at the follow-up; and HCS, healthy control subjects.

Fig. 4

Pilot study of probucol in mild-to-moderate Alzheimer’s disease (AD). (A) Cerebrospinal fluid (CSF) apoE protein variation between 1 month and baseline correlated with cumulative dose of probucol (number of 250 mg pills consumed). (B) Contrasting changes on Alzheimer’s disease Assessment Scale–Cognitive (ADAS-Cog) (6 months vs. baseline) as a function of cumulative probucol dose. (C) ADAS-Cog change as a function of CSF apoE variation (1 month vs. baseline). (D) Reduction of phosphorylated tau 181 concentration (standardized Innogenetic AlzBio3 X-MAP luminex bioassay) as a function of CSF apoE levels.