Alcohol Use Disorder and Dementia: A Review

PURPOSE By 2040, 21.6% of Americans will be over age 65, and the population of those older than age 85 is estimated to reach 14.4 million. Although not causative, older age is a risk factor for dementia: every 5 years beyond age 65, the risk doubles; approximately one-third of those older than age 85 are diagnosed with dementia. As current alcohol consumption among older adults is significantly higher compared to previous generations, a pressing question is whether drinking alcohol increases the risk for Alzheimer’s disease or other forms of dementia. SEARCH METHODS Databases explored included PubMed, Web of Science, and ScienceDirect. To accomplish this narrative review on the effects of alcohol consumption on dementia risk, the literature covered included clinical diagnoses, epidemiology, neuropsychology, postmortem pathology, neuroimaging and other biomarkers, and translational studies. Searches conducted between January 12 and August 1, 2023, included the following terms and combinations: “aging,” “alcoholism,” “alcohol use disorder (AUD),” “brain,” “CNS,” “dementia,” “Wernicke,” “Korsakoff,” “Alzheimer,” “vascular,” “frontotemporal,” “Lewy body,” “clinical,” “diagnosis,” “epidemiology,” “pathology,” “autopsy,” “postmortem,” “histology,” “cognitive,” “motor,” “neuropsychological,” “magnetic resonance,” “imaging,” “PET,” “ligand,” “degeneration,” “atrophy,” “translational,” “rodent,” “rat,” “mouse,” “model,” “amyloid,” “neurofibrillary tangles,” “α-synuclein,” or “presenilin.” When relevant, “species” (i.e., “humans” or “other animals”) was selected as an additional filter. Review articles were avoided when possible. SEARCH RESULTS The two terms “alcoholism” and “aging” retrieved about 1,350 papers; adding phrases—for example, “postmortem” or “magnetic resonance”—limited the number to fewer than 100 papers. Using the traditional term, “alcoholism” with “dementia” resulted in 876 citations, but using the currently accepted term “alcohol use disorder (AUD)” with “dementia” produced only 87 papers. Similarly, whereas the terms “Alzheimer’s” and “alcoholism” yielded 318 results, “Alzheimer’s” and “alcohol use disorder (AUD)” returned only 40 citations. As pertinent postmortem pathology papers were published in the 1950s and recent animal models of Alzheimer’s disease were created in the early 2000s, articles referenced span the years 1957 to 2024. In total, more than 5,000 articles were considered; about 400 are herein referenced. DISCUSSION AND CONCLUSIONS Chronic alcohol misuse accelerates brain aging and contributes to cognitive impairments, including those in the mnemonic domain. The consensus among studies from multiple disciplines, however, is that alcohol misuse can increase the risk for dementia, but not necessarily Alzheimer’s disease. Key issues to consider include the reversibility of brain damage following abstinence from chronic alcohol misuse compared to the degenerative and progressive course of Alzheimer’s disease, and the characteristic presence of protein inclusions in the brains of people with Alzheimer’s disease, which are absent in the brains of those with AUD.

In 2020, an estimated 17% of the U.S. population was older than age 65; this proportion is projected to rise to about 23% by 2060. 1,2This prompts an urgent need for identifying potential and modifiable risk factors contributing to health decline. 3,4After tobacco, alcohol is the most misused substance in the United States and abroad. 5Even prior to the coronavirus disease 2019 (COVID- 19) pandemic, which contributed to increased drinking rates, alcohol consumption was notably accelerating in several demographic categories, including in men and women older than age 65. [6][7][8] Consuming alcohol in harmful patterns-such as binge drinking (five or more drinks in men, or four or more drinks in women, in about 2 hours; where a drink is equivalent to 12 oz beer, 5 oz wine, or 1.5 oz distilled spirits)-occurs in more than 25% of older Americans; 5,9 annual growth trends in alcohol misuse are reported to be 2.4% in older men and 1.6% in older women. 10lthough not causative, older age is a risk factor for dementia: Every 5 years beyond age 65, the risk doubles; 11 and approximately one-third of people over age 85 are diagnosed with dementia. 12,13Emerging data support alcohol misuse as a risk factor for dementia. 14This review considers the literature to determine whether chronic alcohol misuse increases the risks for (1) alcohol-related dementias, including Wernicke-Korsakoff syndrome (WKS); (2) Alzheimer's disease; or (3) other forms of dementia (i.e., vascular, frontotemporal, or Lewy body dementia).

Search Methods and Results
Table 1 presents details regarding the literature searches conducted in preparation for this review.For each section in this article, search terms initially included a combination encompassing alcohol use (e.g., alcohol consumption, alcoholism, binge alcohol, alcohol abuse, alcohol use disorder) and cognitive impairment (e.g., dementia, WKS, Alzheimer's disease), which were then narrowed to the relevant topic (e.g., clinical diagnoses, epidemiology, neuropsychology).Several search terms describing alcohol use were used as the more traditional term "alcoholism" resulted in far more citation results than the currently accepted term, "alcohol use disorder (AUD)."For example, the combination of the traditional term "alcoholism" with "dementia" resulted in 876 citations, but using the currently accepted term "alcohol use disorder (AUD)" with "dementia" produced only 87 papers.Similarly, whereas the terms "Alzheimer's" and "alcoholism" yielded 318 results, "Alzheimer's" and "alcohol use disorder (AUD)" returned only 40 citations.The searches also considered subtypes of dementia in addition to Alzheimer's disease, such as alcohol-related WKS and vascular, frontotemporal, and Lewy body dementias.Searches regarding animal models (i.e., rat, mouse) were narrowed by pathological terms or relevant mechanisms (e.g., amyloid, neurofibrillary tangles, presenilin).
The two terms "alcoholism" and "aging" retrieved about 1,350 papers; adding phrases (for example, "postmortem" or "magnetic resonance") limited the number to fewer than 100 papers.As pertinent postmortem pathology papers were published in the 1950s and recent animal models of Alzheimer's disease were created in the early 2000s, articles referenced span the years 1957 to 2024.In total, more than 5,000 articles were considered; approximately 400 are referenced herein (i.e., only articles directly related to search terms were included).

Clinical diagnoses
Diagnoses of psychiatric illnesses typically rely on use of one of two manuals: the International Classification of Disease (ICD) first published in 1984 by the World Health Organization (WHO; 11th edition [ICD-11] implemented in 2022); or the Diagnostic and Statistical Manual of Mental Disorders (DSM) first printed in 1952 by the American Psychiatric Association (fifth edition [DSM-5] released in 2013).ICD codes are commonly used by primary care physicians, whereas DSM codes are more often used by psychiatrists and psychologists.Complicating consistent diagnoses is the evolution over time of concepts underlying clinical diagnoses of alcohol misuse or dementias.Thus, publications have considered diagnosis rates by comparing criteria in ICD to DSM, [15][16][17] ICD versions, 18,19 DSM-IV to DSM-5 AUD, [20][21][22][23][24] ICD AUD, 25 ICD neurocognitive disorders, 26 DSM neurocognitive disorders; 27 bias in AUD 28,29 and dementia [30][31][32] diagnoses has also been reviewed.
The diagnosis of an alcohol problem is best made by review of medical histories and interviews with patients.4][35] Consequently, ICD diagnoses of AUD in primary care settings typically depend on the presence of health-related conditions, including alcohol-related mental health diagnoses, alcohol-related physical health diagnoses, or evidence for medication prescribed to treat alcohol-related problems. 36UD diagnosed using DSM-5 requires the patient to meet two of 11 criteria; however, specialists-including psychiatrists, psychologists, social workers, and licensed counselors-use DSM criteria for diagnosis with questionable consistency. 24Despite extensive public health efforts by the National Institute on Alcohol Abuse and Alcoholism, the Centers for Disease Control and Prevention, and the U.S. Preventive Services Task Force, current estimates are that fewer than 50% of people who visit primary care providers for alcohol-related issues are asked about the problem.Alcohol screening with validated questionnairesi.e., the 10-question Alcohol Use Disorders Identification Test
remaining dementias are typically categorized as Lewy body, frontotemporal, or alcohol-related. 68][71] In addition to alcohol-related dementia, thiamine deficiency (i.e., Wernicke's encephalopathy) can occur in settings of high alcohol consumption and in malnutrition due to other causes (e.g., parenteral feeding, bariatric surgery, severe pregnancyrelated vomiting). 72,73The acute nutritional deficiency is reversible if adequately treated but can otherwise advance to WKS characterized by severe, persistent, cognitive impairment predominantly affecting memory. 74In contrast to Alzheimer's disease, alcohol-related dementia and WKS are more commonly diagnosed in men than women [75][76][77] and are less likely to be identified as such for several reasons, including underreporting of the extent of alcohol consumption, diagnosis perception bias, and a lack of standardized measures of thiamine. 78,79pidemiological studies support alcohol misuse and AUD as a risk factor for all types of dementia (i.e., collapsed across subtypes).For example, a study in France using ICD-10 codes to define AUD (codes F10.1-F10.9,Z50.2, F10.20-F10.23) and dementia (codes F00-F03, F05.1, F1x.73, G30, G31, I67.3, R54) found that AUD was a major risk factor for all types, but especially early-onset dementia (before age 65). 77A Danish cohort comparing people with ICD-10-diagnosed alcohol dependence (code F10.2) and dementia (codes F00-F03, G30) with controls matched on sex, date of birth, and municipality reported twice the hazard ratio for dementia among men and women with alcohol dependence. 80A U.S. study of more than 4,000 women veterans over age 55 that used ICD-9 codes to define AUD (codes 305.00, 305.01, 303.00, 303.01, 303.02, 303.90, 303.91, 303.92) and dementia (i.e., a comprehensive ICD-9 code list provided by the Veterans Health Administration) 81 determined that dementia developed in 1.1% of women without AUD and in 3.7% of women with AUD. 60 The United Kingdom Whitehall II study-using alcohol consumption patterns derived from questionnaires and ICD-10-defined dementia (codes F00-F03, F05.1, G30, G31)-demonstrated that, compared with people who drank moderately (i.e., 1 to 14 alcohol units/week), those who drank heavily (i.e., more than 14 alcohol units/week) had increased risk for developing ICD-10 dementia. 82Similarly, an analysis of seven cohorts from the United Kingdom, France, Sweden, and Finland, using self-reported alcohol consumption metrics and ICD-10 dementia (codes F00-F03, G30, G31, I20-I25, I61, I63-I66, I67.2, I67.3, I67.4,I67.8, I69.3), found that relative to people who drank moderately (i.e., 1 to 14 drinks/week), those who drank heavily (i.e., more than 14 drinks/week) had a 1.2-fold greater risk of developing dementia; and noted associations between high alcohol consumption and early onset dementia. 83ith respect to the effects of alcohol misuse and AUD on subtypes of dementia, findings are equivocal.A U.S.-based study using data from commercially insured and Medicare Advantage beneficiaries suggested that AUD (ICD-9 codes 291*, 303*, 305.0*, 357.5, 425.5, 535.3, 571.0, 571.1, 571.2, 571.3;ICD-10 codes F10*, G31.2, G62.1, G72.1, I42.6, K29.2, K70*, K85.2, K86.0, Q86.0) specifically increased the risk for Alzheimer's disease (ICD-9 code 331.0;ICD-10 codes F00*, G30*). 84A study using "driving under the influence" as a proxy for alcohol addiction reported that it was associated with an earlier "Alzheimer's disease" diagnosis; however, the ICD-9 codes used in this study (i.e., 290.0-290.3,290.8-290.9,331.0) were not specific for Alzheimer's dementia. 85A study using criteriabased diagnoses of dementia and chart-confirmed alcohol misuse (defined as "alcohol consumption that negatively impacts work or social life or leads to legal ramifications") demonstrated that alcohol misuse was a frequent presenting symptom of frontotemporal but not Alzheimer's dementia. 86Other studies yielded inconclusive results regarding the relationship between alcohol consumption and frontotemporal dementia. 87,88oderate to heavy alcohol consumption (i.e., ≥ 7 drinks/week for women, ≥ 14 drinks/week for men) increased the risk for all types of stroke (i.e., ischemic and hemorrhagic stroke) and may thus be a risk factor for vascular dementia, [89][90][91] but results are inconsistent. 92,93n summary, alcohol misuse and AUD increase risk for all types of dementia.Assuming that 20% of AUD goes unrecognized and 20% of dementias are incorrectly classified as Alzheimer's disease, one might speculate that a significant proportion of dementia misclassification includes alcohol-related dementia.[96]

Neuropsychological profiles
1][102] Additionally, people with uncomplicated AUD show impairments in episodic memory (i.e., the ability to learn, store, and retrieve information about unique personal experiences including time and place), 103 visuospatial processing (i.e., the ability to perceive, analyze, and manipulate visual patterns and images, such as copying complex figures or orienting three-dimensional objects), 104,105 social cognition (i.e., the ability to interpret social information and behave appropriately), 106,107 and gait and balance. 108eatures of WKS are persistent inability to remember new information (i.e., anterograde amnesia) and occasional confabulation. 74,109][112][113] Meta-analyses suggest that immediate and delayed memory tests (e.g., word-list recall) have high diagnostic accuracy in differentiating people with Alzheimer's disease from individuals without the disease but poorly discriminate those with and without MCI. 114,115Among available tools, the Montreal Cognitive Assessment (score ≤ 24), the Mini-Mental State Examination (MMSE, score ≤ 26), and the Dementia Rating Scale (score ≤ 124) appear to be efficient at discriminating MCI from aging without cognitive impairment. 116,117efined neuropsychological data can help distinguish dementia subtypes.9][120] In people with AUD or Alzheimer's disease, the degree of impairment in verbal fluency, working memory, and frontal functions can be similar; memory problems, however, are more pronounced in Alzheimer's disease relative to AUD. 121 Similarly, although individuals with alcoholrelated dementia or vascular dementia can show executive control deficits, they have less severe memory impairments than observed in those with Alzheimer's disease. 122Further, patients with alcohol-related dementia demonstrate stabilization of functional impairment with abstinence, whereas those with Alzheimer's disease or vascular dementia show a progressive decline in cognitive functions. 123Indeed, in a longitudinal study, people with alcohol-related dementia with monitored abstinence showed improved performance on executive functioning tests, whereas people with Alzheimer's disease performed worse on memory tests over the same time spans. 124The amount of alcohol consumed was unrelated to cognitive performance in patients with DSM-III-defined "primary degenerative dementia." 125In a more recent study of people diagnosed with MCI (ICD-10 code F067) and evaluated by structured interview for alcohol use-i.e., low (less than 1 drink/week), moderate (1 to 14 drinks/week for men and 1 to 9 drinks/week for women), or heavy (more than 14 drinks/week for men and more than 9 drinks/week for women)-levels of alcohol consumed had no effect on MMSE scores; however, MMSE scores are notoriously insensitive to AUD-related cognitive decline. 126,127n summary, neuropsychological profiles differ between people with healthy aging, AUD, WKS, Alzheimer's disease, and other subtypes of dementias.AUD adds a burden to aging in the executive domain.Although AUD, WKS, and Alzheimer's disease all affect memory processes, the effects of Alzheimer's disease on mnemonic functions are greater than those observed in AUD and WKS.

Postmortem neuropathology
0][141][142] These effects of aging in the healthy brain differ from those seen with pathological aging due to neurological conditions such as Alzheimer's disease. 143,1446][147] The cause, effect, and reciprocity of A-beta and tau accumulation with neurodegeneration and symptoms of dementia are the subject of ongoing debates. 49,57,59,148Nevertheless, substantiation of an Alzheimer's diagnosis continues to require postmortem identification of these characteristic protein inclusions in regions including the entorhinal cortex and hippocampus, where they contribute to severe neuronal loss and salient impairment in memory consolidation of newly experienced events. 149,150][153] Other proteinopathies also present with neuropathological inclusions.6][157] In vascular dementia, gross examination of the brain may reveal overt lesions, microinfarcts, or damage to blood vessels, and microscopic evaluation may detect accumulation of lipids or blood clots. 158,159ther postmortem signs of vascular disease include white matter atrophy and calcification of arteries. 43,160,161 coordinated cross-sectional analysis of six communitybased autopsy cohorts in the United States and the United Kingdom highlighted the complexity of the brain pathologies that underlie dementia.The analysis assessed 12 dementia-related pathologies in brains of those age 80 and older, including vascular pathologies (arteriolosclerosis, atherosclerosis, microinfarcts, lacunes, and cerebral amyloid angiopathy); Alzheimer's disease-related pathologies (Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's Disease [CERAD] diffuse plaque score, CERAD neuritic plaque score, and hippocampal sclerosis); Lewy body dementia pathology; and TDP-43 pathology.Of the overall sample, which generally included more women than men, 40% had vascular-related pathology, 70% had Alzheimer's disease-related pathology, and 68% of the cohort had pathology co-occurrence. 162Smaller studies similarly reported a high frequency of coincident neuropathology. 163,164KS does not have clear neuropathological markers.1][242][243][244] Individuals with AUD who relapse show continuing volume decline compared with those who achieve abstinence, 225,241,245,246 but even reduced drinking without achieving or maintaining complete abstinence can improve brain structure and function. 247Similarly, a controlled longitudinal study that assessed individuals with AUD soon after withdrawal and then again after 2 weeks of sobriety suggested resolution of volume deficits specifically in hippocampal subfield CA2+3 248 (also see Zahr et al., 2019 232 ; Lee et al., 2016 249 ).This reversibility of volume deficits with abstinence is in stark contrast to the irrevocable progression of Alzheimer's disease. 250,2513][254] Quantitative MRI documents a graded pattern of accruing volume deficits in hippocampus, thalamus, mammillary bodies, cerebellum, and pons as disease severity progresses from AUD to WKS. 230,255,256 Mammillary body shrinkage has been suggested as being able to differentiate WKS from Alzheimer's disease, 257,258 as have diffusion tensor imaging medulla, and anterior-superior vermis of the cerebellum. 165,166 series of neuropathological analyses compared the effects of alcohol per se to distinct neurological conditions associated with chronic alcohol consumption, including WKS, hepatocerebral degeneration, Marchiafava Bignami disease, and central pontine myelinolysis.][169][170] Instead, quantitative histological analyses of individuals with uncomplicated AUD often use the term "alcohol-related brain damage" to refer to the plastic CNS changes associated with chronic alcohol use as discrete from neurodegenerative disease. 171,172][185][186][187][188] Alzheimer's disease-related protein markers (i.e., A-beta, tau) are not affected by alcohol consumption.For example, A-beta plaques were not increased in the brains of people who drank heavily (more than 6 drinks per day for at least 10 years). 189,190urther, men who drank moderately (not more than 4 drinks/ day or 14 drinks/week) showed less neurofibrillary tangle pathology compared with men who drank never or heavily. 191In a study of individuals with thiamine deficiency who who drank alcohol chronically, neurofibrillary pathology was found in the nucleus basalis (which is affected in WKS) but not in any other brain region. 192Further, heavy alcohol consumption (i.e., daily, socially disabling alcohol use, and continued drinking despite indisputable health-related or social damage) showed no statistically significant influence on the extent of alpha-synuclein pathology or incidence of total infarcts; 193 however, very heavy alcohol consumption (more than 32 drinks/week) may increase hemorrhagic stroke. 194n summary, evidence from postmortem histological analyses indicates that healthy CNS aging and AUD are not associated with significant neuronal loss, whereas Alzheimer's disease and WKS show regionally specific neurodegeneration.Based on postmortem evaluations, uncomplicated AUD does not contribute to archetypal Alzheimer's disease pathology characterized by the presence of protein inclusions.

Neuroimaging biomarkers
An advantage of in vivo neuroimaging over postmortem study is the ability to track individuals longitudinally, which permits evaluation of causative factors in CNS volume changes and the consequences of behavioral modifications (e.g., cessation of alcohol drinking).Cross-sectional and longitudinal magnetic resonance imaging (MRI) studies in adults have provided characterize Alzheimer's disease are not elevated in people with AUD.Two PET studies using the Pittsburgh Compound-B ([ 11 C]PiB) ligand found no significant differences in global A-beta loads between people with AUD and healthy control study participants 291,292 (also see Mendes et al., 2018 293 ).Another report found that compared with no drinking, moderate drinking (1 to 13 drinks/week) was associated with lower [ 11 C]PiBdetermined A-beta deposition. 294In contrast, people with AUD had larger WMH volumes than did healthy controls, suggesting an increased cerebrovascular risk in AUD. 207,2926][297][298] AUD can amplify the severity and extent of age-related volume decline, especially in frontal regions, but abstinence is associated with significant volume recovery. 246,299In vivo diagnosis of Alzheimer's disease necessitates PET imaging, but available evidence does not support AUD as contributing to Alzheimer's disease PET markers.In vivo MRI of individuals with Alzheimer's disease can demonstrate greater than age-corrected hippocampal atrophy, but deviations from age-related changes can be challenging to quantify.Instead, emerging data suggest that hippocampal subfield analyses (e.g., effects on CA1 in Alzheimer's disease and on CA2+3 in AUD) may help with future differential diagnoses.

CSF and blood biomarkers
4][305] Low CSF levels of A-beta-42 also can predict MCI and conversion from MCI to Alzheimer's disease. 306,307][313] Combinations and ratios (e.g., A-beta-42/A-beta-40) of CSF A-beta-42, total tau, and p-tau and their variants are under investigation to improve success of differential diagnoses. 314,315otal tau is significantly elevated in people with acute Wernicke's encephalopathy, but the overall pattern of CSF changes (involving A-beta, total tau, and p-tau) can clearly distinguish acute and chronic WKS from Alzheimer's disease. 316SF tau and A-beta markers are present in only 11% of AUD patients with cognitive deficits; 317 conversely, alcohol misuse is rarely observed in those with Alzheimer's disease (DTI) metrics indicating abnormalities in anterior thalamus to hippocampus white matter tracts. 259eviations of hippocampal volume from normal agerelated decline have been identified as a sensitive indicator of Alzheimer's disease pathology. 22,234,260,261][266][267] Longitudinal studies suggest that the pattern of gray matter atrophy in people with MCI who are later diagnosed with Alzheimer's disease mimics the pattern of atrophy observed in Alzheimer's disease but is less extreme.9][270] Similarly, detrimental changes in regional (e.g., fornix, uncinate, cingulum) diffusivity in MCI quantified using DTI are less pronounced than those observed in people with Alzheimer's disease. 114,271,272 research framework for diagnosing Alzheimer's disease, released by the National Institute on Aging in 2018, integrated neuroimaging biomarkers A, T, and N.In this framework, A represents A-beta plaques determined by cortical amyloid PET ligand binding (or CSF A-beta-42 levels); T represents fibrillar tau protein, determined by cortical tau PET ligand binding (or CSF phosphorylated tau [p-tau] levels); and N represents neuronal injury or neurodegeneration determined with fluorodeoxyglucose PET hypometabolism or MRI volume (typically hippocampal) atrophy.[273][274][275] These three markers are used to distinguish among eight dementia profiles: normal, healthy individuals (A-T-N-); people with a condition along the Alzheimer's disease continuum (A+T-N-; A+T-N+; A+T+N-; A+T+N+); and people with non-Alzheimer's changes (A-T+N-; A-T+N+; A-T-N+).57,276 Vascular dementias (which include at least six subtypes) are identified on MRI by presence of infarcts, small cavities (lacunes), and WMH.[277][278][279][280] WMH are considered a neuroimaging feature of cerebral small vessel disease that can increase the risk for stroke and vascular dementia.281,282 As they are ubiquitous and heterogeneous, however, a better characterization of the extent, distribution, and cognitive correlates of WMH is necessary.[283][284][285] In support of a high co-occurrence of Alzheimer's disease and vascular dementias, a literature review found a strong relationship between presence of amyloid and WMH burden 286 (also see Eloyan et al., 2023 287 ).
Although separate structural neuroimaging studies in people with AUD, WKS, or Alzheimer's disease report gray matter volume loss in common regions, including hippocampus, 258,288,289 a direct comparison among these patient groups demonstrates that hippocampal volume loss in people with AUD relative to Alzheimer's disease is less severe. 2908][349] Indeed, among regions demonstrating reduced volume following EtOH exposure (e.g., retrosplenial and cingulate cortices, dorsal hippocampi, central and ventroposterior thalami, corpus callosum), most show significant recovery with abstinence. 350,351Volumes of the colliculi and periaqueductal gray, however, show persistent volume deficits with abstinence. 350,351Although the colliculi may be relevant to human AUD, they have rarely been investigated in humans, possibly because of the challenges in visualizing and quantifying colliculi by MRI. 352elatively few papers have explored the effects of EtOH on the aged rodent brain.Following a single i.p.EtOH dose, older (18 months) compared with younger (postnatal days 70 to 72) Sprague Dawley rats showed greater EtOH-induced ataxia (accelerating rotarod, aerial righting reflex) and cognitive impairment (i.e., longer latency to locate submerged platform on the Morris water maze). 353However, against expectations, a longitudinal in vivo study of F344 rats exposed to intragastric EtOH for 4 days 354 showed greater transient tissue volume compromise in young rats (age 4 months) compared to older rats (age 17 months). 331By contrast, EtOH administration alters markers of astrocytes and microglia more significantly in older than younger animals.For example, chronic moderate EtOH exposure (daily 2 g/kg, i.p. doses for 45 days) increased glial fibrillary acidic protein (GFAP, an astrocyte protein expression marker) to a greater extent in older (age 19 months) than younger (age 3 months) Wistar rats. 355Similarly, a microglial mRNA marker that increased in response to EtOH resolved with abstinence in young but not older C57BL/6J mice 356 (also see Marsland et al., 2022 357 ).

Rodent models of Alzheimer's disease
Several genetically modified (i.e., transgenic) mouse models of Alzheimer's disease are now available.The first models used various constructs to overexpress amyloid precursor protein (APP), which is processed in the body by enzymes (i.e., betaand gamma-secretases) to generate soluble amyloid peptide (A-beta) fragments. 358][361] However, these animals did not have neurofibrillary tangles or show neuronal loss.Second-generation mutant mice included overexpression of presenilin (PS), a constituent of the gammasecretase complex that cleaves APP. 362PS1 overexpression alone did not induce A-beta pathology; 363 however, the combined expression of APP and PS1 increased pathogenic A-beta production and deposition, behavioral deficits, and neuronal biomarkers. 318Thus, CSF tau and A-beta markers may be useful in differentiating alcohol-related cognitive disorders from Alzheimer's disease. 319lthough neuroimaging and CSF markers approved by the U.S. Food and Drug Administration can aid in detection and diagnosis of Alzheimer's disease, the clinical implementation of these testing modalities is limited because of their availability, cost, and perceived invasiveness. 320Blood-based markers are also in development for earlier, faster, and more accessible diagnoses. 321[324][325]

Summary of human studies
The consensus among studies from multiple disciplines is that AUD can increase the risk for dementia, but not necessarily the risk of Alzheimer's disease.A review of clinical and epidemiological data suggests that criteria and nomenclature of dementia subtypes need improvement.Neuropsychological and biological markers that can differentiate dementia subtypes are in progress but currently limited.Whether alcohol misuse contributes to an added burden on pre-existing Alzheimer's disease remains an open and ongoing research question, which may be approached in animal models.Indeed, basic science strategies that can control alcohol exposure may help clarify controversies, including whether alcohol in the context of genetically induced Alzheimer's disease pathology changes the extent, distribution, or signaling pathways of relevant biomarkers.

Rodent models of AUD
In contrast to the human brain, the rat brain increases in weight and length with advancing age and demonstrates continued growth in older (e.g., age 763 days) relative to younger (e.g., age 109 days) rodents. 326,3279][330] MRI studies further show an aging-related pattern in rats contrary to that observed in humans: Total CSF, gray matter, and white matter volumes continue to increase with older age. 228,331These fundamental differences in CNS aging between rodents and humans are critical to model in studies that consider the combined effects of ethanol (EtOH) exposure and Alzheimer's disease-related pathology.
Several susceptible brain regions have been demonstrated in rodents exposed to high EtOH levels via intragastric, 332 intraperitoneal (i.p.), 333,334 or vapor 335,336 protocols.8][339][340][341][342] By memory task), and a higher frequency of A-beta deposition and plaques in hippocampus. 386Also in APP/PS transgenic mice, binge EtOH treatment during adolescence (via four i.p. injections per week of 2.5 g/kg EtOH during postnatal days 20 to 60) increased A-beta RNA and protein expression in the hippocampus at ages 6 and 12 months. 387In 3xTg-AD mice-the only transgenic model able to produce both A-beta and tau markers-EtOH exposed (via 4-month, free access to water or 25% EtOH), compared with saccharin-exposed (control) 3xTg-AD mice, showed impaired spatial memory on the Morris water maze and upregulated A-beta-42/40, total tau, and p-tau 1 month after EtOH exposure. 388Another study showed that EtOH exposure (6 weeks of 4 days/week vaporized EtOH) to 3xTg-AD mice hastened cognitive impairment and increased levels of a different protein marker, alpha-synuclein (relevant to Lewy body dementias). 389ecent 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. 391In 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. 392Finally, 3xTg-AD adolescent and adult mice exposed to EtOH showed EtOH-related increases in total and hyperphosphorylated tau in female mice but not in male mice, which were hypothesized to be related to impaired lysosome function. 393,394These recent papers demonstrating EtOH effects in only female transgenic mice 393,394 acknowledged previous findings that total tau and p-tau were increased in both sexes of 3xTg-AD mice, 388 but did not comment on the underlying reasons for such discrepancies.Indeed, the relevance of sex-related findings in transgenic rodents to the human condition await a better understanding of the pathological mechanisms underpinning Alzheimer's disease.

Conclusions
Limitations of the current narrative review are that it failed to address all nuances of the potential relationship between alcohol misuse and dementia risk.For example, the contributions of a genetic predisposition to Alzheimer's disease (i.e., presence of the apolipoprotein E epsilon4 allele, the major genetic risk factor) to the various metrics were not considered. 92,3955][366][367] One of these models was the 5XFAD mouse line, which expresses five human APP and PS1 transgenes and results in mice with A-beta pathology, gliosis, synaptic degeneration, neuronal loss, and progressive cognitive deficits as early as 4 months of age. 368Despite their aggressive phenotypes, these models also failed to develop neurofibrillary tangles.In efforts to replicate neurofibrillary tangle pathology, a mouse line was created that carried targeted insertions (knock-in mutations) of PS1, APP, and microtubule-associated protein tau (i.e., 3xTg-AD mice). 3694][375] Further, the amyloid peptides generated by mice are distinct from those produced by the human brain. 376

Rodent models of AUD and Alzheimer's disease
Only a few studies have evaluated how EtOH may exacerbate Alzheimer's-related behavior and brain pathology in wild-type rodents.Compared to unexposed mice, wild-type C57BL/6J mice exposed to EtOH (1 month, free access to water, 10% or 20% EtOH) showed impaired spatial memory and elevated hippocampal p-tau, but no change in total tau. 377Similarly, wild-type, male C57BL/6J mice exposed to both EtOH (via liquid diet for 7 weeks at 28% of total calories) and thiamine deficiency demonstrated nonspecific, whole-brain increases in A-beta (both A-beta-42 and A-beta-40 isoforms) protein levels compared to unexposed mice 378 (also see Zhao et al., 2011 379 ).Finally, compared with unexposed animals, Sprague Dawley rats exposed to EtOH (via liquid diet for 5 weeks at about 36% of total calories) showed increased expression of APP and beta-site APP-cleaving enzyme 1 (BACE1, which is critical for A-beta expression) in hippocampus, cerebellum, and striatum. 380Of note, nonspecific, elevated levels of A-beta also have been observed in response to other age-related pathologies (e.g., hypertension, diabetes 381,382 ), and elevations in p-tau can occur in response to other, particularly anesthetic, psychoactive agents. 383,384indings observed in wild-type animals appear to be exaggerated in transgenic mice.For example, APP/PS1 mice exposed to EtOH (drinking in the dark for 1 month), compared to vehicle-treated APP/PS1 animals, showed greater memory deficits (i.e., Morris water maze performance), higher wholebrain APP and BACE1 levels, and enhanced plaque formation. 385imilarly, compared with unexposed mice, APP/PS mice exposed to 10 weeks of moderate EtOH in a two-bottle choice design showed deficits in nest building (but not in an object location affected in Alzheimer's disease.The current literature analysis, however, agrees with a 2001 review published in this journal that alcohol misuse does not increase the risk for Alzheimer's disease per se. 399Whether alcohol misuse or AUD increase the risk for alcohol-related or other forms of dementia may be clarified by improvements in neuropsychological tests or biomarkers better able to differentiate dementias in vivo.

Table 1 . Literature Search Details
Such gaps have led to a program initiated by the National Institute on Aging-the Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (https://www.model-ad.org)-tofund development of Alzheimer's disease mouse models that better recapitulate the human disease.