Binge drinking may be linked to both the onset and severity of Alzheimer’s disease, but scientists have only now embarked on a path to decipher each molecular step involved in how excessive alcohol consumption leads to the most common form of dementia.
The research, underway at the Feinstein Institutes for Medical Research in New York, builds on a deceptively simple premise: Excessive alcohol consumption is toxic to the brain.
Binge drinking likely plays an insidious role in the alteration of a normal brain protein into a biological rogue that is highly prevalent in Alzheimer’s disease.
The protein is identified by a simplistic monosyllabic name – tau.
In its normal conformation, tau is found in neurons modulating the stability of axonal microtubules.
But in its abnormal conformation, tau has long been considered one of the leading hallmarks of Alzheimer’s, and makes up the tangles in the notorious “plaques and tangles” pathology.
The plaques are deposits of the protein beta amyloid. The Feinstein Institutes research involving binge drinking and Alzheimer’s dementia is riveted, however, on tau.
A potential breakthrough in the investigation would be a definitive explanation of how tau transforms from a normal protein into a neuron-annihilating cause of Alzheimer’s under the influence of excessive alcohol.
The New York researchers think they’re on the right path to make that discovery.
Already, the scientists are delving into how tau can become phosphorylated, which means its structural conformation changes and its role in the brain becomes chemically altered under the influence of binge drinking.
“Studies have shown that frequent and heavy alcohol drinking is linked to earlier onset and increased severity of Alzheimer’s disease,” Dr. Max Brenner, assistant professor at the Feinstein Institutes told Medical Xpress.
“It has been reported that alcohol consumption correlates with Alzheimer’s-like cortical atrophy in individuals at high risk of developing the disease as well as younger age of onset.
“In addition, chronic alcohol exposure caused neural tau phosphorylation in the hippocampus and memory-impairment in Alzheimer’s-predisposed mice,” Brenner said.
The goal of the research is to shed light on specific proteins that apparently play key roles in the proliferation of tau. Brenner and colleagues want to understand the activities of cold-inducible RNA-binding protein (CIRP) and its associated form, extracellular cold-inducible RNA-binding protein (eCIRP).
“CIRP is normally present in the cell nucleus where it helps to regulate which proteins each cell produces,” Brenner explained.
“When cells detect potentially harmful conditions, such as alcohol exposure, they release molecules like eCIRP to alert other cells nearby to start preparing their defenses to overcome the stress conditions.
The cells being alerted recognize eCIRP outside the cell when it binds to specific protein receptors in the cell membrane.
The cascade of eCIRP proteins is triggered when alcohol diffuses throughout the brain, and while alcohol is a major influence, the eCIRP cascade can occur under other deleterious conditions.
“A number of potentially harmful conditions trigger the release of eCIRP, including low oxygen, low temperature and radiation exposure,” Brenner said.
Alzheimer’s disease is the sixth-leading cause of death in the United States, and is the most common form of neurodegenerative dementia.
It afflicts 5.8 million people nationwide. Globally, the disease is inexorably on the rise. An estimated 50 million people are believed to be living with Alzheimer’s and other forms of dementia.
According to the United Nations, the number of affected people could reach 152 million worldwide by 2050 unless therapeutics are discovered to stop the escalating number of cases.
Brenner and colleagues theorize that blocking eCIRP might prove to be a viable treatment for alcohol-related Alzheimer’s disease.
Binge drinking, meanwhile, is a major societal and public health concern. In the United States, the Centers for Disease Control and Prevention has found an array of collateral problems associated with the habit: car crashes, falls, burns, and alcohol poisoning. T
he agency also has traced domestic violence, homicide and intimate partner violence, sexual assault, sexually transmitted diseases and suicides to binge drinking. It is estimated that roughly half of all alcohol-related deaths in the U.S. are directly related to binge drinking.
Brenner and colleagues say these drinkers can have a blood alcohol concentration ranging anywhere from 0.08% to amounts that are substantially higher.
Despite the tantalizing clues of their preliminary research, the Feinstein team is uncertain about precise sequence of mechanisms involved in how excessive alcohol consumption leads to Alzheimer’s. However, they’re keenly aware that eCIRP is a critical mediator of memory impairment induced by exposure to binge-drinking levels of alcohol.
The National Institutes of Health has found the research by Brenner and his team so intriguing that it has awarded the Long Island-based Feinstein Institutes a $419,000 grant to further investigate the role of alcohol in the development of Alzheimer’s disease.
Brenner said there are also early suggestions that beta amyloid, the cause of Alzheimer’s plaques, may also be linked to binge drinking.
“Early-stage studies suggest that alcohol aggravates beta amyloid deposition by increasing the levels of amyloid precursor protein (APP), which increases the enzyme that changes the precursor into beta amyloid and decreases the cellular disposal of beta amyloid.
We have decided to focus our research on the effects of alcohol on tau, however, because tau deposition correlates better with the cognitive decline in Alzheimer’s disease than beta amyloid,” Brenner said.
Alcohol Effects on the Central Nervous System
Acute Effects of Alcohol
Alcohol usually refers to the molecule ethanol. As amphiphile, it is rapidly absorbed from the stomach and duodenum after oral consumption and passes the blood-brain barrier.
The distribution and elimination show strong variability due to fed- or fasting state, drinking patterns, age, and genetics.16
In the central nervous system, ethanol modulates the function of multiple receptors: voltage-gated calcium channels and glutamate receptors are inhibited by alcohols, whereas some others, such as g-amino butyric acid type A (GABA-A) receptors, glycine receptors, n-acetylcholine- and 5-HT3-receptors, are potentiated.17,18
Prior hypotheses on the effect of alcohol on cell membrane function in the central nervous system are viewed as less relevant to its acute effects.17
The effects appear to be dose-related, since at low dosages alcohol affects monoaminergic transmission and produces disinhibition and euphoria, while at high dosages anxiolytic and sedative effects are more prominent, mediated through increasing GABA activity and inhibiting excitatory amino acids.18
Molecular Mechanisms of Central Nervous System Toxicity
In humans, chronic alcohol exposure leads to in vivo up- (glutamate) and down-regulation (D2,19 GABAA) of neuroreceptors availability related to alcohol withdrawal and craving (for a summary see Heinz et al20). Genetic constitution interacts with monoaminergic dysfunction in alcohol withdrawal.21
Adaptive up-regulation of NMDA-receptors and consecutively enhanced calcium influx is supposed to contribute to cell apoptosis (“excitotoxicity”) and link the acute and chronic effects of alcohol consumption.22,23
The alcohol metabolite acetaldehyde was shown to be directly neurotoxic.24 Other probable causes of cell death are inflammatory processes via release of pro-inflammatory cytokines and microglia activation after high dose alcohol consumption25
Alcohol activates oxidases in the central nervous system, which leads to formation of free radicals and cell membrane damage.23 Homocysteine is elevated after consumption of higher doses of alcohol and might contribute to alcohol-related brain damage.26
While these three mechanisms may underlie the more unspecific neurotoxic effects of alcohol, thiamine deficiency caused by malnutrition and decreased intestinal absorption in alcohol-dependent individuals shows distinct neuroanatomical patterns and symptomatology, which Karl Wernicke and Sergei Korsakoff already described accurately in the nineteenth century.27,28
While Wernicke specified an acute neurological syndrome (stand and gait ataxia, confusion, and ophthalmoplegia), the overlapping Korsakoff’s syndrome refers to more chronic alterations and symptoms, mainly perseveration and anterograde amnesia.
Marchiafava-Bignami-Syndrome refers to thiamine deficiency-associated degeneration of the corpus callosum presenting with a wide array of symptoms including altered mental state, loss of consciousness and epileptic seizures (see Table 1 for details)29
Table 1
Thiamine Deficiency Associated Neurological Syndrome
| Syndrome, Publication | Symptomatology | Pathology |
|---|---|---|
| Wernicke Encephalopathy – Carl Wernicke, Germany, 188128 | Acute onset of ophthalmoplegia, ataxia, and mental confusion14 | Hemorrhagic lesions in the mamillary bodies (confusion), hypothalamic nucleus, the periaqueductal region, pons, superior vermis of cerebellum88 |
| Korsakoff´s Syndrome – Sergej Korsakoff, Moscow, 188727 | Severe memory loss, anterograde amnesia, confabulation, desorientation8 | Lesions in the diencephalon-hippocampal circuit: midline thalamus, anterior thalamic nuclei88 |
| Marchiafava-Bignami-Syndrome – Ettore Marchiafava, Amico Bignami, Rome 191389 | Altered mental state, impaired walking, loss of consciousness, dysarthria, pyramidal signs, impaired memory, seizures29 | Necrosis and atrophy in the corpus callosum29 |
Neurotoxicity of acetaldehyde, excitotoxicity and via NDMA-activation, neuroinflammation, and formation of free radicals as neuroanatomically less specific mechanism of neurotoxicity and thiamine deficiency with specific neuroanatomical susceptibility (corpora mammillaria, dorsal thalamic nucleus, hippocampus, periaqueductal region, corpus callosum) supposedly amplify each other, explaining the variety of neuropsychiatric symptoms in patients with high levels of alcohol consumption (for details on the correlation of etiology of neurotoxicity with neuroanatomy see Zahr et al30).
The entity of alcohol-related dementia is still controversially discussed, since there is no consensus whether it represents an entity distinct from Korsakoff syndrome and neuropsychological findings are unspecific,31 encompassing cortical and subcortical patterns.12
Neuropathology and Neuro-Imaging Studies
Autopsy studies show mild cerebral atrophy and lower mean brain weight in cases of uncomplicated alcoholism, when the individual was not affected by Wernicke-Korsakoff encephalopathy.32
The loss in brain volume is mainly attributed to white matter loss,30 diffusion tensor magnetic resonance imaging (MRI) show fiber tract degeneration.33
Histopathological studies revealed cerebellar atrophy,34 corpus callosum thinning35 and pyramidal cell loss in superior frontal and frontal association cortex,35 as well as neuronal dendritic shrinkage, presumably reversible in abstinence.32
MRI studies have generally confirmed postmortem studies by demonstrating that these patients have regional cortical volume deficits,36–38 conceptualized as accelerated aging.38
MRI cohort studies show a correlation between cerebral volume decrease and number of drinks consumed.39,40
Potentially Positive Effects of Alcohol on the Central Nervous System
A variety of positive effects on alcohol on the central nervous system have been suggested, mainly by reducing cardiovascular risk factors. Robust evidence exists for elevated high-density lipoprotein cholesterol blood levels,41 even exceeding the effect of drugs prescribed for dyslipidemia.42
The coagulation cascade is modulated by alcohol intake through down-regulation of fibrinogen, a substrate of blood clot formation.43 In vitro experiments show an inhibition of platelet aggregation.44,45
High alcohol consumption leads to higher blood pressure, while low to moderate consumption (equal or less than two drinks per day) has no effect.44,46 The definition of one standard drink and consecutively, the definition of low-risk consumption varies in-between countries.47
In the references cited, the US-American definition is used: one drink equals 14 g of pure alcohol. Nevertheless, any alleged positive aspects of drinking on cardiovascular risk factors must be weighed against seriously harmful effects, including changes in circulation, inflammatory response, oxidative stress, as well as anatomical damage to the cardiovascular system, especially the heart itself.48
Effects of Alcohol on Alzheimer’s Pathology
Regarding effects of alcohol on Alzheimer’s disease (AD)-related pathophysiology, only scarce and contradictory evidence exists: in rats, alcohol application leads to higher acetylcholine release in the hippocampus in low concentrations, while higher concentrations inhibit acetylcholine release.49
The hippocampus is affected early in Alzheimer’s disease by formation of neurofibrillary tangles and neurodegeneration, leading to the typical early symptom of disability to memorize new information.7
Findings from transgenic mouse models and cell culture models of AD are contradictory. One study on transgenic AD-mice and hippocampal cell cultures established a possible mechanism of lower Aß-toxicity through alcohol administration by reducing Aß-induced synaptic failure,50 another study argued that Aß-aggregation is reduced in cell cultures treated with alcohol.51
However, findings from experiments conducted in a different transgenic mouse model fed with alcohol showed higher expression of APP and ß-secretase with consecutively elevated amyloid deposition and neurotoxicity.52
Alcohol is supposed to enhance neuroinflammation and thereby enhancing neurotoxicity of the ß-amyloid cascade.53
In vitro studies suggest that alcohol might impede phagocytosis of ß-amyloid by microglia and thereby promote Alzheimer’s disease.54
In summary, while a number of studies have reported experimental findings to explain risk reduction through alcohol consumption for vascular dementia, data regarding the impact of alcohol on Alzheimer´s pathophysiology is more contradictory.
Conclusion
High-level alcohol consumption (>14 drink units/week) is certainly linked to an increase in dementia risk, post-mortem reduction in brain volume and MRI signs of brain damage via possibly multiple pathways.
Concerning low-level consumption of alcohol no recommendation to begin drinking moderate doses of alcohol in higher age to reduce dementia risk can be deducted, because
(1) results of studies are heterogeneous
(2) the detrimental effects on other organ systems and risk of addiction;
(3) the possible confounders in the studies presented and
(4) because of the varying individual metabolism (gender, body weight, acetaldehyde dehydrogenase type16) and susceptibility. On the other hand, there is no rationale either, to recommend cutting down on alcohol consumption to reduce dementia risk if consumption is moderate (disregarding other risks of alcohol consumption).
A prospective, randomized, controlled trial could distinguish between direct, alcohol-related effects, statistical confounders, and lifestyle effects,87 while more insight on the pathogenesis of Alzheimer’s disease in general and more specifically the influence of alcohol on the different biochemical pathways could provide a cogent model of alcohol effects on dementia pathogenesis and progression.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957093/
More information: Archna Sharma et al. Potential Role of Extracellular CIRP in Alcohol-Induced Alzheimer’s Disease, Molecular Neurobiology (2020). DOI: 10.1007/s12035-020-02075-1
