Neurons on the rocks: A case of alcohol use and early onset Alzheimer's disease

Abstract

A 46-year-old female was admitted to the hospital for confusion, cognitive decline, and hallucinations with alcohol withdrawal. Her history was notable for Alcohol use disorder (AUD) and family history of Alzheimer's disease (AD). Comprehensive workup was unrevealing for metabolic encephalopathy, infection, or nutritional deficiencies. Phosphatidyl ethanol level was 1181, indicating severe alcohol misuse. Phospho-Tau 217 testing raised suspicion of AD and FDG-PET scan confirmed patterns consistent with early onset AD. AUD can precipitate earlier or more severe onset of AD. Phospho-Tau 217 can be a useful screening marker to identify people at risk of AD to prompt intensive treatment.

Introduction

Alzheimer's disease (AD) affects nearly 6.7 million Americans aged 65 + with earlier onset AD increasing in prevalence. Alcohol use is one of the few modifiable risk factors for disease progression and multiple studies reveal heavy alcohol use is associated with increased risk of AD. Unfortunately, <10% of people with alcohol use disorder (AUD) receive appropriate treatment of any kind and there are few current screening measures to identify at risk individuals to guide early intervention.

Case presentation

A 46-year-old female presented to the Emergency Department (ED) for altered mental status in the setting of alcohol withdrawal. She initially presented to the Connections and Referral Unit for monitoring of withdrawal symptoms then transferred to the ED due to altered mental status and dizziness. Her husband reported that for multiple years, she was regularly consuming 6–7 beers daily. He also endorsed an 18-month history of hallucinations, severe nightmares as well as memory and cognitive decline, including repetition and disorientation. Her past medical history was notable for major depressive disorder managed with citalopram and a 10-pack year history of tobacco use. Her family history was remarkable for three maternal generations of dementia with onset in the late 1950s and early 1960s felt due to Lewy body dementia versus AD.

In the ED, laboratory evaluation was notable for elevated liver enzymes with ALT 77 and AST 54. A CT head showing generalized parenchymal volume loss, but no acute abnormalities. Neurology was consulted and recommended treatment for likely Wernicke's encephalopathy or thiamine deficiency, as well as evaluation for additional vitamin deficiencies, Brain MRI, EEG, and lumbar puncture with cerebrospinal fluid analysis. The Kokmen Short Test of Mental Status score at the time of presentation was 9/38.

She weas admitted and monitored for alcohol withdrawal by the Clinical Institute Withdrawal Assessmentprotocol and initiated on 100 mg intravenous (IV) thiamine. She remained encephalopathic and became profoundly agitated and physically aggressive requiring 4-point restraints and intramuscular olanzapine on multiple occasions. After attempting to leave against medical advice, a capacity assessment was completed, and she was deemed not to possess medical decision-making capacity, necessitating a 72-h medical hold. While admitted, her phosphatidyl ethanol (PEth) level was 1181 (a level greater than 400 indicates severe alcohol misuse). ¹

The remaining workup into potential causes for her neurocognitive change and metabolic encephalopathy were unrevealing with no acute signs of infection with normal urinalysis and culture. Toxic ingestions were ruled out with a negative urine drug screen. Viral causes were less likely with negative tests for HIV and syphilis. Nutritional deficiencies were not noted with normal levels of vitamin B12, thiamine, IgG, zinc, copper, and folate. In the absence of a definitive cause, neurocognitive disorders were higher on the differential, and further imaging and testing was pursued.

Brain MRI demonstrated T2 hypersensitivities and atrophy in the medial temporal lobes concerning for Herpes Simplex Virus (HSV) encephalitis, and she was subsequently initiated on acyclovir. A lumbar puncture was performed and showed elevated protein at 39, but otherwise normal opening pressure and negative testing for HSV1 and HSV2, encephalitis, meningitis, autoimmune and paraneoplastic panels. Without clear evidence of an infection, acyclovir was discontinued. An EEG revealed excess generalized beta activity consistent with benzodiazepine treatment (as part of alcohol withdrawal treatment) without epileptiform abnormalities. Due to concern for autoimmune limbic encephalitis, she was initiated on IV methylprednisolone, which was discontinued after 3 days after rapid independent improvement of agitation and aggression, clinically most consistent with resolution of alcohol withdrawal and possibly post-ictal encephalopathy. Further imaging included a CT chest, abdomen and pelvis showing presumed infectious/inflammatory 0.5 cm nodule in the anterior lower right lung, probable hepatic steatosis, and moderate distended bladder, but no obvious signs of infection or anatomic changes consistent with her clinical picture.

Psychiatry was consulted, who recommended a continued focus on delirium prevention strategies and further neurologic evaluation. A chemical health assessment was performed, and she qualified for inpatient alcohol rehabilitation treatment. Unfortunately, this was cost prohibitive, and she was discharged home with naltrexone, thiamine, and folate.

At outpatient follow up 22 days later, her Kokmen improved to 14/38, and the cause of the persistent cognitive impairment remained unclear. We suspected that the partial improvement was explained by resolution of hospital acquired delirium, alcohol withdrawal, post-seizure delirium, and improvement in social supports. A repeat EEG was abnormal consistent with focal epilepsy involving the left temporal region. Repeat MRI two months after discharge revealed persistent, subtle, nonspecific, chronic signal abnormalities involving the medial temporal lobes, with overall global profound volume loss for her age, more than two standard deviations below normal affecting all lobes, including the temporal lobes (Figure 1). Of note, her hippocampal and amygdalae volumes were also at the first and second age-adjusted percentile, respectively (Figure 2). AD biomarker plasma phospho-Tau 217 was elevated at 0.890, consistent with the pathological changes of AD. FDG-PET confirmed a pattern of abnormality consistent with AD including hypometabolism involving bilateral parietal lobes, including precuneus and posterolateral temporal lobes (Figure 3).

Figure 1.

Brain MRI with volumetric analysis. Signs of global profound volume loss for age affecting all lobes, hippocampus, and amygdala.

Figure 2.

Brain MRI with volumetric analysis. Age-adjusted volume percentiles were globally reduced more than two standard deviations below normal (red box) for frontal lobe (1%), temporal lobe (1%), parietal lobe (1%), occipital lobe (1%), hippocampus (1%), and amygdala (2%), consistent with Alzheimer's disease.

Figure 3.

FDG-PET Z-score map comparing the FDG-PET uptake compared to a normative sample, ranging from blue (z-score = 0, normal) to red (z-score = −7, or 7 SD below normal). Consistent with Alzheimer's disease, there is relatively symmetric hypometabolism involving bilateral parietal lobes (white arrow) including precuneus (yellow arrow) and posterolateral temporal lobes (red arrow).

The insidious onset and gradual cognitive decline with persistent predominantly amnestic cognitive impairment, abnormal AD biomarkers, hippocampal atrophy, and FDG PET all supported an underlaying diagnosis of AD. The diagnosis was further complicated by alcohol dependence and evidence for probable subclinical seizure activity. She was transitioned to sertraline for mood disorder, continued on naltrexone to help maintain alcohol cessation, and initiated lacosamide and donepezil. Due to her new diagnosis and inability to continue with certain activities of daily living, she met criteria for dementia and full disability.

Discussion

As of 2023, AD impacts approximately 6.7 million Americans aged 65 years or older, an additional estimated 200,000 Americans have early onset AD.^2,3 The pathophysiology of AD is complex, as it represents an interplay of genetic, biological and environmental factors, characterized by its classical features of amyloid-beta plaques and hyperphosphorylated tau protein deposition in the brain. ⁴ The risk for AD increases with both modifiable and non-modifiable factors, and, while the most notable non-modifiable risk factors are age and female sex, additional modifiable factors include cardiovascular and metabolic disease, sensory loss, psychosocial stresses, and lifestyle factors such as smoking, physical inactivity and alcohol use. ⁵ This specific case illustrates the complexities of AD and its pathophysiology, but the most notable aspect of this case that one might choose to highlight is the diagnosis of AD at just 46 years old. Age is seen as the strongest overall risk factor with prevalence increasing exponentially after age 65,^4,5 so it brings her significant alcohol use to the forefront as a possible contributor to her earlier onset of disease.

AUD is a highly prevalent, highly comorbid, disabling disorder that often goes untreated in the United States with a lifetime prevalence being estimated at 29.1%. ⁶ Heavy and chronic alcohol use (>14 units/week) is consistently associated with an increased risk of cognitive impairment and all types of dementia, ⁷ including an 18–29% increased risk of AD. Unfortunately, fewer than 10% of individuals with past-year AUD receive treatment of any kind.^8,9 The harm caused by heavy alcohol stems from its neurotoxic effects, nutritional deficiencies, and neuroinflammation. In AD, excessive alcohol consumption can lead to the destruction of cholinergic neurons and enhance tau protein deposition. ¹⁰ Further alcohol use can lead to thiamine deficiencies that also disrupt neurotransmitter systems. ¹¹ The tau protein deposition and synaptic dysfunction lead to progressive neuronal decline and ultimately the development of AD. Phospho-Tau 217 is a plasma biomarker with approximately 82–89% sensitivity and 86–96% specificity depending on the specific assay and population studied. Chronic kidney disease is the most common reason for false positivity^12–14

Interestingly, multiple meta-analyses reveal that while heavy alcohol consumption increases the risk for AD, light to moderate alcohol consumption is associated with reduced risk of cognitive decline and dementia. ¹⁵ In fact, those who abstain from alcohol in midlife increased their risk by 47% ⁸ and this is thought to be due to vascular and neurological pathophysiology. Light to moderate consumption may reduce platelet aggregation and lipid deposition, reducing vascular decline, while also enhancing acetylcholine release, primarily in the hippocampus, thus preventing decline in learning and memory. ¹⁶ However, recent genetic analyses demonstrated a monotonic increase in dementia risk with higher alcohol consumption, and Mendelian randomization analyses showed no evidence of protective effects at any level of alcohol use. ¹⁷

Our patient used alcohol heavily, which predisposed her to its neurotoxic effects, and unfortunately the neuropsychiatric presentation of alcohol use and AD makes it difficult to delineate neurodegenerative impairment from impairment related to alcohol use. In fact, alcohol use and AD can both show similar patterns of brain atrophy, which further complicates the diagnosis, ¹⁶ and there is a paucity of reliable biomarkers and advanced imaging in those with AUD. ¹⁸

Lysine acetylation of tau has emerged as an important player in AD, with studies demonstrating that acetylation can impair tau degradation, promoting accumulation, and subsequent neurotoxicity. ¹⁹ Chronic alcohol exposure has been shown to disrupt cellular acetylation and deacetylation pathways, providing a plausible link by which AUD may exacerbate tau pathology. ²⁰ Further, although basal forebrain volumetrics were not specifically assessed in this case, degeneration of the cholinergic muscarinic receptors is another well-established feature of AD and has also been reported in the setting of chronic alcohol exposure and could represent future areas of research to correlate. ²¹

The diagnosis and delineation of these two processes is difficult in this group, which leads to mismanagement of symptoms that inevitably could lead to reduced quality of life as seen in this specific patient case. Phospho-Tau 217 proved a good screening test for AD in this clinical scenario with the clinical history of progressive predominately amnestic cognitive impairment despite abstinence from alcohol, no proven thiamine deficiency, absence of uncontrolled seizures.

Conclusion

This case appropriately highlights the need to focus on early identification and prevention of heavy alcohol use, not only as it relates to acute cognitive impairment, but also its long-lasting impact on cognitive and executive function. Additional consideration should be given to those with additional risk factors that may predispose them to AD. For example, there is evidence to suggest that heavy drinkers with APOE4 carrier status, which is associated with increased risk of early onset AD, have significantly poorer cognitive outcomes, increased dementia risk, and younger age of cognitive impairment onset.^22,23

Given the prevalence of alcohol use in the community, we may be underappreciating a larger group of at-risk individuals. Nevertheless, further research including population-based studies are required to more clearly elucidate the relationship between early onset AD and AUD. These data could then be used to identify those that would benefit from early screening for AD with phospho-Tau 217 testing and more aggressive management of AUD to prevent cognitive decline early in life.