Middle- and old-aged individuals: Moderate lifetime alcohol intake was associated with lower cerebral beta amyloid deposition compared to a lifetime history of not drinking

Association of moderate alcohol intake with in vivo amyloid-beta deposition in human brain: A cross-sectional study. Jee Wook Kim et al. PLOS, February 25, 2020. https://doi.org/10.1371/journal.pmed.1003022

Abstract
Background: An emerging body of literature has indicated that moderate alcohol intake may be protective against Alzheimer disease (AD) dementia. However, little information is available regarding whether moderate alcohol intake is related to reductions in amyloid-beta (Aβ) deposition, or is protective via amyloid-independent mechanisms in the living human brain. Here we examined the associations of moderate alcohol intake with in vivo AD pathologies, including cerebral Aβ deposition, neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMHs) in the living human brain.

Methods and findings: The present study was part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study that started in 2014. As of November 2016, 414 community-dwelling individuals with neither dementia nor alcohol-related disorders (280 cognitively normal [CN] individuals and 134 individuals with mild cognitive impairment [MCI]) between 56 and 90 years of age (mean age 70.9 years ± standard deviation 7.8; male, n [%] = 180 [43.5]) were recruited from 4 sites (i.e., 2 university hospitals and 2 public centers for dementia prevention and management) around Seoul, South Korea. All the participants underwent comprehensive clinical assessments comprising lifetime and current histories of alcohol intake and multimodal brain imaging, including [11C] Pittsburgh compound B positron emission tomography (PET), [18F] fluorodeoxyglucose (FDG) PET, and magnetic resonance imaging (MRI) scans. Lifetime and current alcohol intake were categorized as follows: no drinking, <1 standard drink (SD)/week, 1–13 SDs/week, and 14+ SDs/week. A moderate lifetime alcohol intake (1–13 SDs/week) was significantly associated with a lower Aβ positivity rate compared to the no drinking group, even after controlling for potential confounders (odds ratio 0.341, 95% confidence interval 0.163–0.714, p = 0.004). In contrast, current alcohol intake was not associated with amyloid deposition. Additionally, alcohol intake was not related to neurodegeneration of AD-signature regions or cerebral WMH volume. The present study had some limitations in that it had a cross-sectional design and depended on retrospective recall for alcohol drinking history.

Conclusions: In this study, we observed in middle- and old-aged individuals with neither dementia nor alcohol-related disorders that moderate lifetime alcohol intake was associated with lower cerebral Aβ deposition compared to a lifetime history of not drinking. Moderate lifetime alcohol intake may have a beneficial influence on AD by reducing pathological amyloid deposition rather than amyloid-independent neurodegeneration or cerebrovascular injury.

Discussion

In this study, we observed that lifetime alcohol intake of 1–13 SDs/week (moderate drinking) was associated with lower cerebral Aβ deposition compared to the no drinking group in these middle- and old-aged individuals with neither dementia nor alcohol-related disorders.
The present finding of an association between moderate alcohol intake and lower Aβ deposition is in line with results from previous studies using animal or cultured cell models, which indicated that moderate alcohol intake exerts a protective effect via attenuating Aβ accumulation [17,20]. Many clinical and epidemiological studies have reported an inverse association between moderate alcohol intake and the risk of AD dementia [3,9–13], and the present findings regarding the association between moderate alcohol intake and decreased cerebral Aβ positivity may explain this inverse association.
While moderate lifetime alcohol intake had a significant association with Aβ deposition, moderate current intake did not. This difference indicates that the protective effects of moderate alcohol intake against Aβ pathology involve the chronic effects associated with long-term exposure rather than an acute effect. The significant finding for lifetime intake only also suggests that the protective association for moderate alcohol intake is not due to the inclusion of forced abstainers, i.e., those who stopped using alcohol owing to other health concerns related to problem drinking, among the reference group (i.e., non-drinkers). Forced abstainers were classified as drinkers for lifetime alcohol intake status, whereas they were classified as non-drinkers for current alcohol intake status.
Unlike for Aβ deposition, there were no associations between moderate alcohol intake and neurodegeneration or WMHs. Similarly, previous human MRI studies did not observe an association between moderate alcohol intake and cerebral gray matter volume [29] or total brain volume [30]. However, several preclinical and human studies reported that moderate alcohol intake has protective effects against vascular changes and atrophy in the brain. Studies using cultured cell or animal models showed that moderate alcohol intake is protective against ischemic brain injury [24,27], and human MRI studies have suggested that moderate alcohol intake is protective against damage to cerebral gray [23] and white [21,22] matter. These discrepancies may be related to methodological differences between studies. However, as suggested in a systematic review of the chronic effects of moderate alcohol intake on the structural and functional properties of the brain [53], the present findings based on both structural MRI (cortical thickness and WMHs) and FDG PET (cerebral glucose metabolism) measures support that moderate alcohol intake did not exert its protective effects directly through neurodegenerative or vascular mechanisms.
Although excessive alcohol intake has been related with an increased risk of cognitive decline [1–4], and U- or J-shaped association has been implied together with the decreased risk of cognitive impairment with moderate alcohol intake [3,5–16], we did not find any association between higher alcohol intake and increased AD pathologies. Alcohol-related brain damage (ARBD) [54] was suggested as an umbrella term for conditions including Wernicke–Korsakoff syndrome, alcohol-related dementia, and other forms of persistent alcohol-related cognitive impairment. ARBD encompasses a range of clinical presentations that manifest as impairments in memory, executive functioning, and judgement, which are related to frontal brain function. Several brain imaging studies also reported damage of the frontal lobe in individuals with alcoholism [55], while AD-CT and AD-CM measures mainly include temporo-parietal degeneration. Therefore, we additionally analyzed the association between alcohol intake and frontal lobe state (i.e., glucose metabolism, cortical thickness, and WMH volume of the frontal region) in order to find out if there was any ARBD-like damage with alcohol intake. As shown in S9 Table, however, we did not find any significant results from those analyses. These null findings may be because individuals with alcohol-related disorders were excluded and, as a result, heavy drinkers (14+ SDs/week) in the present study consisted of individuals without alcoholism or other severe alcohol problems.
The investigation of the influence of age on the association between moderate alcohol intake and Aβ positivity revealed that the protective effect of moderate alcohol intake on Aβ positivity was more prominent in older individuals (≥75 years) than younger ones. This finding may be due in part to age-associated increases in the Aβ positivity rate in individuals without dementia [56]. In the present study, the Aβ positivity rate was 24.5% (n = 62) in the younger age group and 37.3% (n = 57) in the older group. The relatively small proportion of Aβ+ individuals in the younger group might decrease the likelihood of detecting a significant difference. It is also possible, as mentioned above, that these age-related differences are related to the chronic effects associated with long-term alcohol exposure. In contrast, sex, APOE4, and clinical diagnosis did not have any moderating effect on the association between moderate alcohol intake and Aβ positivity.
The present study had a couple of strengths. To the best of our knowledge, this study is the first to show the association of moderate alcohol intake with Aβ accumulation in the living human brain. The study included a relatively large number of participants who were well-characterized through comprehensive clinical assessments including systematic interview for detailed alcohol drinking history and multimodal brain imaging for in vivo AD pathologies and WMHs. In addition, various potential confounders were systematically evaluated and controlled in the statistical models in order to reveal the association between alcohol intake and brain pathologies as clearly as possible. Even after controlling for all potential confounders, the findings did not change. The results were also confirmed by sensitivity analyses conducted after excluding binge or former drinkers.
Nevertheless, the present study also had several limitations that should be considered. First, because this was a cross-sectional study, causal relationships cannot be inferred from the findings. Second, in terms of lifetime alcohol intake, underestimation of drinking or retrospective recall bias may have affected the results in older individuals. However, it is unlikely that underestimation of alcohol intake was significant because harmful drinkers and individuals with a history of alcohol use disorder were excluded from the analyses, and moderate drinkers have no reason to underestimate their alcohol intake. Moreover, to reduce recall bias, information was obtained from reliable informants as well as the study participants. Additionally, a review of self-report bias in the assessment of alcohol intake suggested that this recall bias is not greater in older individuals than in the general population [57]. Third, about one-third of the study participants were diagnosed with MCI, which may also raise some concern about the accuracy of self-report for alcohol intake. However, although individuals with MCI have some problems with their recent memory, their remote memory is very well preserved [58]: It is not likely that individuals with MCI reported their history for alcohol intake more erroneously, because the self-report for lifetime alcohol intake mainly depends on remote memory rather than recent memory. In addition, even when we controlled for clinical diagnosis (CN versus MCI) as an additional covariate in Model 3 (Tables 2, 3, and S2–S7), the results were still very similar. Fourth, there are quite different alcohol intake patterns regarding the frequency and regularity of intake, and the amount of alcohol consumed in a single session, within the moderate drinking category. Although we obtained similar findings after excluding binge drinkers in sensitivity analyses, a more detailed understanding of the influence of drinking patterns is needed. Finally, although we did not find any significant association between alcohol intake and neurodegeneration or WMHs, the lack of association may reflect a lack of statistical power given the sample size.
Although further long-term follow-up investigations in larger populations with heterogeneous alcohol intake patterns are still needed, the association of moderate alcohol intake with reduced risk of pathological Aβ deposition (about one-third of the risk for no drinking) observed in the present study may suggest that moderate lifetime alcohol intake may be beneficial in preventing AD dementia or related cognitive decline.
In conclusion, the present findings from middle- and old-aged individuals with neither dementia nor alcohol-related disorders suggest that moderate lifetime alcohol intake may have some beneficial influence on AD by reducing pathological amyloid deposition rather than amyloid-independent neurodegeneration or cerebrovascular injury.