Impact of Alcohol Abuse on Susceptibility to Rare Neurodegenerative Diseases

Abstract

Despite the prevalence and well-recognized adverse effects of prenatal alcohol exposure and alcohol use disorder in the causation of numerous diseases, their potential roles in the etiology of neurodegenerative diseases remain poorly characterized. This is especially true of the rare neurodegenerative diseases, for which small population sizes make it difficult to conduct broad studies of specific etiological factors. Nonetheless, alcohol has potent and long-lasting effects on neurodegenerative substrates, at both the cellular and systems levels. This review highlights the general effects of alcohol in the brain that contribute to neurodegeneration across diseases, and then focuses on specific diseases in which alcohol exposure is likely to play a major role. These specific diseases include dementias (alcohol-induced, frontotemporal, and Korsakoff syndrome), ataxias (cerebellar and frontal), and Niemann-Pick disease (primarily a Type B variant and Type C). We conclude that there is ample evidence to support a role of alcohol abuse in the etiology of these diseases, but more work is needed to identify the primary mechanisms of alcohol's effects.

Keywords: Epigenetics; addiction; aging; alcoholism; ataxia; dementia; inflammation; stress.

FIGURE 1

Although alcohol has effects on a number of ubiquitous cellular processes, such as, autophagy, inflammation, and stress, the localization of alcohol-induced neurodegeneration is likely to be specific to areas where alcohol produces its greatest effects. These areas include the prefrontal cortex, the site of working memory and executive function processes; basal ganglia, the dopaminergic site of motor initiation and habitual behavior; the mammillary bodies, the hypothalamic nuclei that integrate with the emotion and memory centers of the limbic system; the hippocampus, the site of declarative memory consolidation; and the cerebellum, the site of motor coordination and balance.

FIGURE 2

Although there are dozens of rare neurodegenerative disorders, we have chosen to focus on those in which the etiology suggests an increased susceptibility to the effects of alcohol abuse, as well as those in which at least some research has been done to suggest a direct effect of alcohol on neurodegeneration.

FIGURE 3

Most of the work examining the role of alcohol exposure on dementia has been in the field of Korsakoff syndrome; despite the rarity of this disease, alcohol is almost exclusively the culprit in the cases that have been identified. Alcohol-induced dementia is even less common, although alcohol-related dementias (those in which alcohol is one of multiple etiological factors) occur across all dementia subtypes. In addition, frontotemporal dementia occurs due to neurodegeneration in areas that are most heavily impacted by alcohol exposure; although little work has been done to examine the role of alcohol in the etiology of frontotemporal dementia, this topic deserves further study.

FIGURE 4

Alcohol acts through diverse signaling pathways, including oxidative stress, to increase neuroinflammation and reduce both autophagic and cytophagic clearance of toxic protein species that contribute to neurodegeneration. At the same time, alcohol alters the expression and activity of epigenetic proteins (e.g., methyltransferases/demethylases and DNA acetylases/deacetylases. Finally, alcohol drives an unhealthy stress response through the hypothalamic-pituitary-adrenal (HPA) axis, leading to long-term increases in circulating cortisol.