Vulnerability to alcohol's effects in older drinkers: A proof-of-concept study

About This Grant

While data linking chronic heavy drinking to accelerated cognitive aging and early onset dementia risk are compelling, epidemiological data probing the effects of less severe patterns of drinking unaccompanied by alcohol use disorder (AUD; here, moderate drinking (MD)) produce inconsistent findings. Outcomes from the sparse body of human laboratory research lend little clarity regarding the long-term neurobiobehavioral (NBB) outcomes of alcohol consumption in MDs, who constitute the majority of older drinkers. In this innovative R21 application, we propose a framework for understanding differential risk and seek to clarify its core tenets. We assert that the heterogeneity of reported outcomes derive, in part, from varying degrees of unaccounted for individual differences in vulnerability to alcohol’s effects on cognitive aging processes. More specifically, we suggest that alcohol-related impairment/decline occurs among MDs who are differentially vulnerable to the interaction of alcohol’s neurobiological effects and cognitive aging processes. With continued drinking, this heightened sensitivity to alcohol’s neurobiological effects exacerbates cognitive aging processes, eventuating in alcohol-related cognitive impairment/decline for this subgroup of MDs, i.e., vulnerable MDs. In contrast, moderate drinking is not expected to compromise cognitive status for others, i.e., resilient MDs, even when controlling for typical intake. While the premise is appealing, the constructs are ill-defined. In the absence of empirically vetted operational definitions that avoid tautologies and lacking preliminary data, the longitudinal designs needed for rigorous evaluation are premature. Thus, we propose a proof-of-concept study designed to interrogate the framework’s key requisite conditions to the extent permitted within R21 constraints. Using a blinded w/in Ss placebo-controlled design (N= 60 (30 each sex) aged 65-80), our intent is to derive performance differences between alcohol/placebo conditions (i.e., deriving individual estimates of acute alcohol sensitivity in behavior & neurophysiology), explore variability in sensitivity and correlates thereof, and interrogate the relationship between sensitivity and performance on a neuropsychological battery. Our intent is not to predict late-onset AUD or drinking problems. Instead, we query relationships between alcohol sensitivity and cognitive vulnerability. We note that the predicted interaction may be modulated by numerous factors. Here, we explore if healthy MDs who carry risk for accelerated cognitive decline exhibit greater sensitivity. We anticipate this subgroup to exhibit stronger negative relationships between alcohol sensitivity and performance- suggesting its relevance in longitudinal study. Extant data and feasibility concerns led to our defining “at-risk” based on subjective cognitive complaints. Acute sensitivity provides a starting point but is unlikely to account for all variability. Thus, we will probe how variables such as age, substance use history, family history (AUD /dementia), and other factors impact outcomes. Critically, regardless of specific outcomes, this proof-of-concept study constitutes a significant step in establishing a framework for systematic research in this critical domain.