In this stroke-free community-based cohort we found that current drinkers had less cognitive decline on a telephone cognitive assessment than never drinkers, adjusting for sociodemographic and vascular risk factors. In addition, there was no interaction by APOE-4 status on the beneficial effect of alcohol intake on cognitive function. This study has several strengths including the prospective design, allowing for measurement of cognitive decline. Also, our multi-ethnic urban population includes Hispanics and blacks at greater risk of dementia than their white counterparts.[40
Our findings are in agreement with other recent prospective studies showing that alcohol intake may decrease the risk of cognitive decline.[1
] One prospective study found no effect but they used the Mini Mental State Exam, which lacks sensitivity.[14
] Some studies have found a graded association between reported alcohol intake and cognition,[29
] although U-shaped relationships have also been found.[32
] Other prospective studies have found a benefit for those who consumed less than one drink a day or an equal benefit among all categories of intake.[1
] We found a dose-response effect against cognitive decline for those that reported current drinking. There was no difference in cognitive decline between past drinkers and never drinkers, but this is a heterogeneous group that includes a wide range of both past alcohol intake and time since becoming abstinent. Therefore, we felt it was important to keep them separate. Participants that reported drinking more than two drinks daily showed incrementally less cognitive decline than never drinkers. Given that the heavier drinking group was small (N=31), and the potential harm of excessive alcohol intake considerable, larger studies are needed to clarify the effects of this level of alcohol intake on cognition. In this study 70% of those in the highest category drank less than or equal to 4 drinks daily (N=22 of 31). Thus, most were not heavy drinkers.
We did not find a difference at baseline or over time in TICS-m scores between APOE-4 carriers and non-carriers. Results of other studies have been mixed, with two studies showing a benefit of alcohol intake in APOE-4 non-carriers in relation to cognitive decline and dementia, respectively.[5
] In the NHLBI twin study, only drinkers that were APOE-4 carriers appeared to benefit. Interestingly, the Nurses' Health Study also used the TICS-m, as well as other tests, and likewise found APOE-4 status had no effect. One possible explanation of our findings is that the smaller sample size combined with the relatively short mean follow-up (2.2 years) may have limited our ability to detect differences between the groups in this smaller sample. The mechanism by which alcohol might mediate the effect of APOE-4 on cognition is not clear. However, APOE4 is known to be less effective at membrane repair and as an antioxidant than other isoforms.[34
] Given that APOE-4 binds beta amyloid and is involved in its deposition in the plaques of AD, alcohol may decrease oxidation and deposition of beta-amyloid in the brains of those at risk.[35
] Separately, evidence from animal studies suggests alcohol may increase brain acetylcholine.[36
] Since this neurotransmitter is depleted in AD, alcohol could improve cognition in those affected even in the early stages.
Many if not most cases of dementia may be due to Alzheimer disease with
vascular disease. In such cases, alcohol may have a benefit through its effects on the vascular system. We find it of note that adjusting for vascular risk factors had little effect on the change in TICS-m scores. Thus, alcohol may act on the vascular system independently of other risk factors. Moderate alcohol consumption appears to be protective against stroke and subclinical cerebrovascular disease, which may explain part of any beneficial effect of moderate alcohol consumption on cognition.[8
] In a cross-sectional study we did not find carotid plaque to be a mediator of this relationship.[37
] But, in the Cardiovascular Health Study moderate alcohol consumption was associated with less subclinical brain disease.[9
] Thus, microangiopathy may be more relevant and additional studies are needed to clarify the importance of small vessel disease in this relationship. One potential mechanism is through raising HDL-C levels.[38
] In this study, HDL-C levels did not differ significantly by alcohol category and were not associated with cognitive performance in multivariate analysis. Moderate alcohol consumption also has inhibitory effects on platelet aggregation, degranulation, and formation of thromboxane A-2.[39
] We did not systematically gather information on non-steroidal anti-inflammatory drug use, although we did ask about aspirin use. Excluding aspirin users in a post-hoc analysis had no effect on our results (data not shown).
This study has several limitations. In this and other studies involving self-reported alcohol use and cognition, current drinkers may be healthier than nondrinkers. This may be because the latter have stopped drinking due to health problems or because they lack social or other attributes possessed by the drinkers. Such bias is minimized by examining changes in scores. Also, factors in our cohort known to be associated with lower socio-economic status such as having Medicaid, no insurance, or being Hispanic or black compared to white were more common among nondrinkers, which would tend to minimize our findings. Another potential source of bias is differential drop out from the repeated TICS-m assessments that is dependent on alcohol intake. However, we found that drop-outs did not differ by TICS-m score or the interaction between TICS-m and alcohol intake. Another limitation is our reliance on cognitive assessment done over the telephone. While the TICS-m may not be as valid as in-person neuropsychological testing, scores on the TICS-m correlate well with in-person testing in a somewhat healthier sample of 323 NOMAS participants that have received both. In addition, the TICS-m has been found to be sensitive in detecting mild cognitive impairment in other studies.[41
In this longitudinal study of cognitive performance, we found that current drinkers suffered less decline on a cognitive test compared to never drinkers. This effect was not modified by APOE-4 allele status. A larger sample of heavier drinkers is needed to clarify the dose of alcohol that may protect against cognitive decline without causing damage. Future studies in a larger sample from this cohort may clarify this and race-ethnic differences in drinking patterns and cognitive performance. In addition, brain imaging studies will help determine the relative importance of subclinical vascular disease in the causal pathway between alcohol consumption and cognition.