Alcohol-Drinking Under Limited-Access Procedures During Mature Adulthood Accelerates the Onset of Cognitive Impairment in Mice

Abstract

A history of heavy drinking increases vulnerability to, and the severity of, Alzheimer’s disease (AD) and related dementias, with alcohol use disorder identified as the strongest modifiable risk factor for early-onset dementia. Heavy drinking has increased markedly in women over the past 10 years, particularly in mature adult women during the coronavirus (COVID-19) pandemic. This is concerning as women are more sensitive to many alcohol-related disease states, including AD and related dementias. Herein, we conducted two studies to determine if a 1-month period of binge drinking during mature adulthood (i.e., 5–9 months of age) impairs spatial and working memory to a greater extent in female vs. male C57BL/6J (B6J) mice. The anxiogenic and cognitive-impairing effects of binge drinking were also compared between mature adult and old B6J mice (18 months of age) in a third study. Throughout, females consumed more alcohol than males, indicating that a sex difference in binge drinking persists into old age. Despite the sex difference in intake, we detected no consistent sex difference in our measures of alcohol withdrawal-induced anxiety during a behavioral test battery. Although mature adult females exhibited more cognitive deficits than males, the precise outcome exhibiting a female-selective effect varied across studies. Old mice drank lower amounts of alcohol than mature adult mice, yet their blood ethanol concentrations (BECs) were within error of the 80 mg/dl criterion for binge drinking, indicative of an age-related slowing of alcohol metabolism. As expected, 18-month-old controls exhibited more signs of cognitive impairment than their 6-month-old counterparts, and binge drinking history impaired the Morris water maze performance of mice of both ages. In contrast, binge drinking history impaired the radial arm maze performance of 6-month-old mice only, and the extent of the impairment was comparable to the behavior exhibited by the older mice. We conclude from our studies that: (1) both biological sex and the age of drinking onset are subject factors that impact voluntary alcohol consumption by mice into old age; (2) binge drinking during later life elicits a negative affective state that is relatively sex-independent; (3) binge drinking during both mature adulthood and old age impairs spatial learning and memory; (4) binge drinking during mature adulthood accelerates deficits in working memory; and (5) mature adult females tend to exhibit more alcohol-induced cognitive impairments than males. If relevant to humans, these findings suggest that binge-like drinking by older adult men and women induces a negative affective state and cognitive decline, but that mature adult women, in particular, may be more sensitive to both the immediate and persistent cognitive-impairing effects of heavy drinking.

Alcohol Use Disorder and Dementia: A Review

“…Recent translational work highlights sex differences in the interaction of EtOH with Alzheimer’s disease-related pathology. EtOH exposure caused greater cognitive impairment in female than male “middle aged” (ages 6 to 9 months) wild-type C57BL/6J mice, 390 which was associated with an increase in hippocampal amyloid levels. 391 In mice with abnormal tau deposition (i.e., PS19 model with the T34 tau isoform), 16 weeks of intermittent access to water containing 20% EtOH increased the excitability of the locus coeruleus more in female than male mice.…”

Sex-difference in the association between social drinking, structural brain aging and cognitive function in older individuals free of cognitive impairment

“…Recent data show robust increase in the prevalence of excessive alcohol drinking among women ( 8 – 12 ). Women exhibit more sensitivity to alcohol; with sooner progression to alcohol-related diseases at less drinking levels compared to men ( 13 – 15 ). The deleterious effects of excessive alcohol drinking on cognitive functions are well documented ( 16 – 19 ) specifically in women ( 20 , 21 ).…”

Alcohol-drinking during later life by C57BL/6J mice induces sex- and age-dependent changes in hippocampal and prefrontal cortex expression of glutamate receptors and neuropathology markers

“…Heavy alcohol drinking (> 14 drinks/week) significantly increases the likelihood of developing dementia [ 1 – 4 ] and reduces the age of dementia-onset in both humans [ 5 ] and laboratory rodents [e.g., 6 – 8 ]. In fact, alcohol use disorders ( AUDs ) account for approximately 60% of early-onset dementia cases and thus are the strongest modifiable risk factor for this condition [ 9 ].…”

“…Aligning with these data, studies of wild-type, inbred, C57BL/6 ( B6 ) mice also indicate that alcohol can induce microglial activation [ 22 ] and upregulate the expression of ADRD-related genes in brain [e.g., 7,23,24]. In terms of behavior, a history of binge-drinking by adolescent B6 mice is reported to induce signs of cognitive impairment when assessed in later adulthood [ 25 ] and we recently showed that binge-drinking by B6 mice during mature adulthood (i.e., 6 months of age; [ 26 ]) accelerates cognitive decline to a level comparable to aged (18 month-old) animals [ 8 ]. Although we did not detect a sex difference in age-related cognitive decline in our recent study, in two replicate studies of B6 mice, mature adult female alcohol-drinking mice exhibited more signs of cognitive impairment than their male counterparts [ 8 ], arguing that mature adult females are more vulnerable than males to an alcohol-induced acceleration of cognitive decline.…”

“…Here, we begin to probe the potential neurobiological bases for the Age by Alcohol by Sex interaction observed in our recent behavioral study of B6 mice [ 8 ]. Based on the evidence that alcohol can induce ADRD-related gene expression in B6 mice [ 7 , 23 , 24 ], we evaluated changes in the expression of certain ADRD-related proteins within the hippocampus and prefrontal cortex ( PFC ) of alcohol-drinking animals, two regions that are critical for a number of cognitive functions and known to be affected in ADRDs.…”