Cholesterol and APOE genotype interact to influence Alzheimer disease progression
Evans RM, Hui S, Perkins A, Lahiri DK, Poirier J and Farlow MR;
Commented by , 16 Jun 2004
Aim of the study:
Establish if there is an interaction between serum cholesterol levels, APOE genotype and progression of AD as reflected by cognitive decline.
Method
Retrospective analysis of 443 patients with probable AD from a 30-week double-blind, placebo-controlled, multicentre trial of tacrine . Disease progression was estimated using the changes in scores on the AD Assessment Scale (ADAS) from baseline to final value. APOE genotyping was determined from frozen samples.
Total serum cholesterol (TC) levels (nonfasting) were determined at baseline, and dichotomized as high (> or equal to 240 mg/dL) or normal (< 240 mg/dL). APOE was categorized as epsilon 4 or no epsilon 4. A random coefficients model determined the association of TC and APOE genotype with ADAS score over time after controlling for gender, educational level, baseline ADAS score and treatment arm.
Results
Of 659 participants, 443 were suitable for this analysis: 278 were carriers of at least one copy of the epsilon 4 gene mutation. Among those, 101 had high TC serum levels. Of 165 patients with no epsilon 4 gene mutation, 37 had high TC serum levels. After adjusting for age, education, gender, baseline ADAS score and treatment group, the three-way interaction for time, TC and APOE genotype was significant (p = 0.004). In the no-epsilon 4 group, the ADAS score increase (worsened) over time in the high TC subgroup.
In the epsilon 4 group, the ADAS score change little regardless of TC level. The rate of change (worsening) of ADAS score over time in the high TC/no epsilon 4 group was significantly different from the rates of the other subgroups. There was no interaction with treatment (placebo or three doses of tacrine) group, and the placebo treated patients (N: 184) showed the same faster decline for the patients with high TC and no epsilon 4.
Discussion
The group of patients with high TC and no epsilon 4 allele had a greater decline over the 30-week period of study. This could be explained by an increased deposition of Abeta associated with higher TC, in the presence of the APOE3 allele, which binds cholesterol with greater affinity than APOE4. The authors acknowledge that these results need to be validated in large population long-term studies.
A community-based cohort study found that higher levels of TC were associated with a decreased risk of incident AD after adjustment for demographics, APOE genotype and cardiovascular risk factors (Reitz et al, Arch Neurol 2004, 61, 705-714), and that use of drugs to lower lipid levels did not change the risk of AD. Other observational and therapeutic studies are thus required to clarify if cholesterol-lowering strategies using statins and/or diet is a viable option for persons at risk for AD. It is sobering to think that even APOE3 carriers, the most common allele, may be at risk if their TC is high.