Moderate alcohol consumption, apolipoprotein E, and neuroprotection

Paul and colleagues 1 reported the results of a very interesting cross-sectional population-based study involving 1839 respondents aged 33 to 88 years without stroke or dementia from the Framingham Off spring Cohort. In this sample, there were no protective effects of alcohol in reducing the normal age-related differences in brain volume. Instead, higher levels of alcohol consumption were consistently associated with smaller brain volume after adjusting for covariates (age, sex, education, body mass index, and Framingham Stroke Risk Profile score). This association was modified by the participants' sex, with women showing larger total cerebral brain volume than men at every level of alcohol consumption. Paul and colleagues also found no significant correlation between alcohol consumption and white matter lesion volume. The body of evidence examined in very recent systematic reviews2,3 and a meta-analysis4 of all research published within the last 10 years suggests that low to moderate alcohol use may be associated with a reduced risk of unspecified incident dementia and Alzheimer disease, while for vascular dementia, cognitive decline, and predementia syndromes the current evidence is only suggestive of a protective effect. In the Italian Longitudinal Study on Aging, we evaluated 2963 individuals from a population-based sample and found that alcohol consumption was associated with the rate of progression of mild cognitive impairment to dementia; in fact, up to 1 drink/d of alcohol or wine may decrease the rate of progression to dementia in patients with mild cognitive im- pairment.5 Paul and colleagues acknowledged some limitations in their study, including the lack of an evaluation of re-gional brain areas and of a prospective analysis. However, genetic susceptibility seems to modify the effect of alcohol on risk of dementia and predementia syndromes, with some studies suggesting that the apolipo- protein E (APOE) ℰ4 carrier status could be a possible effect modifier for these associations but with varied re- sults.2,3 Nonetheless, the protective effects of light to moderate alcohol consumption against dementia and cognitive decline are more likely in the absence of an APOE ℰ4 allele.2,3 One possible explanation could be that people with the ℰ4 allele have less effective neural repair mechanisms; thus, they would be more susceptible to the deleterious effects of alcohol.2,3 On the other hand, regionally reduced gray matter density is detectable in cognitively intact adults (aged 19-80 years) with a single copy of the APOE ℰ4 allele.6 Furthermore, longitudinal studies have confirmed relationships between changes in hippocam- pal volume and APOE genotype in nondemented older adults.7 Finally, women with alcoholism and the APOE ℰ4 genotype were found to have significantly smaller hip- pocampal volumes than those not carrying an ℰ4 allele, whereas no differences in hippocampal volume were seen in men with alcoholism.8 In the Framingham Offspring Cohort, in unadjusted analyses participants who had low alcohol consumption had slightly larger total cerebral brain volume compared with the other groups. However, when adjusted for covariates, there was a significant negative linear association between the amount of alcohol consumed and total cerebral brain volume.1 Given the relevant role of adjustment in reverting the direction of the relationship, we suggest that the APOE genotype could influence, as a confounder, the findings of this population-based study and could be important in explaining the lack of a protective effect of moderate alcohol consumption on brain volume in adults without stroke or dementia.