Consistent with our second hypothesis, we found a novel interaction with age and HIV/Binge drinking group such that the HIV+/Binge+ group displayed a stronger negative relationship between age and three domain-specific neurocognitive outcomes compared to the HIV-/Binge- group. Importantly, the alcohol-related detriments to neurocognition appeared to be specific to binge drinking, as total 30-day alcohol consumption was not a significant independent predictor of any neurocognitive outcome in our statistical models. These findings suggest that recent, discrete episodes of heavy alcohol exposure relate to poorer brain function and highlight the need for interventions to reduce binge drinking behavior among PWH, especially older PWH, in order to promote cognitive health. The findings showing additive main effects of HIV and binge drinking are consistent with several other studies demonstrating additive, but not synergistic, effects of HIV and heavy alcohol use on neurocognitive functioning . In fact, there is only onestudy to our knowledge that has shown an interactive effect of HIV and heavy alcohol on neurocognition, specifically in the domains of motor and visuomotor speed . Our finding of HIV/Binge group differences in neurocognitive domains of processing speed, delayed recall, and working memory is also consistent with the frontostriatal and frontolimbic neural damage that has been observed in studies of adults with HIV and heavy alcohol use . As briefly discussed, there are a number of possible mechanisms underlying the relationship between heavy alcohol use and adverse neurocognitive outcomes in HIV, including those related to antiretroviral therapy ; possible pharmacokinetic interactions with alcohol . Recent research, however,rolling grow table has revealed neuroinflammatory and neuro-immunological effects as major pathways underlying the relationship between heavy alcohol use and neurobiological damage , with several of these neuroimmune pathways overlapping with effects from HIV .

Although these immunobiological underpinnings are still poorly understood in the context of comorbid HIV and heavy drinking, this represents an important line of research needed to develop potential targeted interventions for reducing the incidence and/or severity of neurocognitive impairment in this population. The current study also uniquely found that the negative relationship between age and neurocognitive functioning was steepest among the PWH who reported binge drinking in the last 30 days, particularly in the domains of learning, delayed recall, and motor skills. Our findings are consistent with what is known about the greater vulnerability to brain atrophy and neurocognitive deficits in older PWH and older adults who drink heavily . Furthermore, this result showing an age by HIV/Binge group interaction is also similar to findings from a previous study in which age was found to be a significant predictor of demographically-corrected episodic memory scores only among individuals with comorbid HIV and AUD . Speculation about accelerated aging or neurocognitive decline cannot be made from our data, as they are cross-sectional; however, this result does suggest that older adults are the most susceptible to adverse neuropsychological outcomes in the context of HIV and binge drinking. Notably, this result also held when restricting the maximum age range to 60 years old for all groups, indicating that HIV/ Binge group differences in delayed recall and motor skills emerge even in the earlier stages of older adulthood. Notably, findings from this report appear to be driven specifically by our binge drinking variable, as total 30-day alcohol consumption did not significantly predict any neurocognitive outcome above and beyond binge drinking. Although there are a dearth of studies examining the specific impact of binge drinking on neuropsychological outcomes compared to that of chronic drinking over a longer span of time, some evidence suggests that the repeated periods of high level of intoxication and withdrawal from binge drinking exacerbates the detrimental neurobiological effects of alcohol .

Future research is needed to examine chronicity of binge drinking and whether there may be a specific threshold associated with the greatest level of CNS risk. Still, given evidence that binge drinking may be at least as detrimental to the central nervous system as alcohol dependence, public safety measures that aim to reduce binge drinking behavior may have widespread benefits, especially among older PWH. While this study has strengths in novelty, use of a comprehensive neuropsychological battery, and clinical relevance, it also has several limitations. First, the HIV/Binge group-specific sample sizes were relatively small, particularly in Binge+ groups. Although this limited our ability to examine a full factorial three-way interaction between age, HIV status, and binge drinking status, we were still able to examine the novel age by HIV/Binge group interaction with adequate statistical power. Next, our assessment of binge drinking is based solely on self-report and may be subject to error by recall bias, memory difficulties, and/or social desirability bias; however, the majority of alcohol and substance use research relies on self-report of use. In addition, while binge drinking data specifically pertained to use within the last 30 days, we do not know exact amounts of time between participants’ last binge episode and their participation in the study, limiting our ability to comment on how recency relates to cognitive performance. Future research may benefit from the use of more objective measures of alcohol use in daily life to more accurately characterize alcohol use patterns . Finally, our exclusion of participants with current non-alcohol substance use disorders limits generalizability to others with binge drinking behavior and/or alcohol use disorder among whom polysubstance use is common. In summary, the current study demonstrated detrimental additive effects of HIV and binge drinking on neurocognitive functioning, and that older adults appear to be most vulnerable to these adverse effects particularly in the neurocognitive domains of learning, delayed recall, and motor skills. Our findings support the need for clinical screening for binge drinking behavior given that many adults who engage in binge drinking behavior do not meet criteria for an AUD, as well as psychoeducation and psychosocial interventions targeting the reduction of binge drinking among older PWH.

Additionally, given evidence that improvements in neurocognitive functioning may be possible after sustained sobriety following AUD recovery among HIV- populations , future work is needed to understand whether this may also be true among PWH who reduce or cease binge drinking behavior. Alcohol problems typically develop in late adolescence and early adulthood, though they can manifest at any time during adult life. Early age at first drink has been shown in many analyses to be a powerful predictor of an alcohol use disorder .Males are more likely than females to develop alcohol use disorders ,indoor plant table and this is true within families of alcohol-dependent probands as well as the general population . Recent data have shown that, in the US, African Americans are less likely to develop an AUD than European- Americans  though analysis over different age groups suggests that a different developmental course may characterize AUDs in African-Americans, with relatively later onset of disorders in comparison to EA groups . It must be borne in mind that these rates are a moving target and there is evidence for relative increases of AUD in women and AA subjects compared to EA males over recent years . There is also a known risk relationship between other psychiatric disorders and alcohol use disorders. Persons with a mood disorder have an increased lifetime risk for an alcohol use disorder, as compared with persons without mood disorders . The increased risk for a substance use disorder following onset of a mood disorder is perhaps most precisely demonstrated by Plana Ripoll et al. 2019, using a study of the Danish population that showed a cumulative risk of 20% for men and 10% for women for an SUD during the fifteen years following the onset of a mood disorder. This represents a hazard ratio of ~5 for a disorder severe enough to come to clinical attention. Adolescents with a mood disorder are at increased risk for onset of alcohol problems and vice versa . Mood disorder may be associated with the course of alcohol problems as well as onset . Scores on an internalizing scale were correlated with risk for alcohol and other drug use disorders in a prior analysis of the Collaborative Study on the Genetics of Alcoholism subjects . There is an extensive literature supporting the relationship of externalizing disorders to subsequent development of AUDs and this has formed the basis of certain typologies of AUD, including Types 1 and 2 and Types A and B . Type 2 subjects are characterized by high novelty seeking, low harm avoidance, and low reward dependence . They are more likely to be diagnosed with antisocial personality disorder and less likely to be able to abstain from alcohol. Type B subjects are more likely to have a history of childhood aggression and conduct disorder and less likely to have a sustained response to treatment in comparison to Type A subjects . More recent studies also emphasize the role of externalizing disorders, such as conduct disorder and attention deficit hyperactivity disorder in increasing the risk for alcohol problems . Cannabis and tobacco use are also associated with increased risk for concomitant alcohol problems . We studied a sample at risk for the development of alcohol use disorder on the basis of family history. Initial assessment was done on all subjects in the age range 12–21.

These subjects have been followed over time with assessments every two years for up to 10 years. The present report evaluates the relationship of comorbid externalizing and internalizing disorders to age of onset of an AUD in a group of adolescents/young adults at high risk for AUDs. We also compare the onset of two alcohol milestones in groups divided by AUD severity. We hypothesized that persons developing AUDs following the onset of externalizing and internalizing disorders would show earlier onset than those without those baseline disorders. We also hypothesized that more severe AUDs would show an earlier onset of alcohol-related developmental milestones such as age of first drink and age of first regular drinking. The present report is one of the first we are aware of that tracks the development of AUDs in the context of multiple comorbid disorders in a high risk group, and it shows that some subjects are at great risk for alcohol problems in very early adolescence. Our subjects were participants in the adolescent to young adult Prospective sample of COGA . The COGA study started in 1989 and families were recruited between 1989 and 1995. Each family was recruited through a proband with an alcohol use disorder , targeting successive admissions to treatment facilities. There was a family size requirement with the idea of prioritizing larger families. All first-degree relatives were interviewed and families were extended through affected subjects . The subjects in the present study were offspring of the proband . The response rate for recruitment was about 70% or more . More information about the COGA study may be found in Bucholz et al., 2017 and Reich et al., 1998. All offspring in the age range at the start of follow-up were included. Offspring reaching the age of 12 during the course of the study were also included. Subjects were interviewed at two-year intervals with the Semi-Structured Assessment for the Genetics of Alcoholism interview Bucholz et al., 1994. The mean age at first interview was 16.1 and the mean age at last interview 23.1 . Subjects had an average of 4.0 interviews . 50.9% were female, 64.9% were EA and 30.9% AA. Ethnicity was assigned based on genotypic data, or by self-report if genotypes were not available. Subjects were members of a case family or a comparison family . Non-drinkers were not excluded from the sample. The study was approved by The Indiana University Institutional Review Board . Written informed consent for the research was obtained from all participants in the study. All subjects in the study were invited to participate in interviews at two-year intervals. Detailed information on participation is provided in Bucholz et al., 2017. Information on all available interviews for each subject was combined in the present analysis with age of onset assigned according to the earliest description of psychopathology and a judgment of severity based on the time when the most symptoms were described. Every subject with at least one complete interview was included in the analysis.