title: Uncorking the truth
title: alcohol, serotonin, and the early stages of Alzheimer’s Disease
titleType: Subtitle
Creators: name: Pierson, Samantha
Publisher: name: University of Iowa
Year: 2026
Subjects: Alcohol
Dorsal Raphe
Serotonin
Tau
Aging
Dementia
Pathology

description: There are no effective treatments for Alzheimer’s disease (AD) and related dementias, and existing interventions require early implementation, before significant pathological accumulation occurs. Because AD pathology often precedes symptoms by several decades, early identification for treatment is challenging. Modifiable risk factors, including lifestyle adjustments, thus represent promising targets for disease prevention. Recent epidemiological studies have highlighted alcohol use as one such risk factor, particularly in early-onset dementia. Though the association between alcohol consumption and AD remains underexplored, both alcohol use and AD pathology have notable impacts on the serotonin system, which may underlie this risk. This dissertation investigates how alcohol exposure may influence AD-like pathology and neuropsychiatric symptoms (NPS), focusing on serotonergic dysfunction as a potential mediator. Understanding how alcohol might accelerate the pathophysiology of dementia could help to identify at-risk individuals for early interventions.
description: We hypothesize that alcohol-induced serotonergic dysfunction may drive vulnerability to AD-related neuropathology and NPS, such as depression. To test this, we first utilized post-mortem human tissue and a preclinical mouse model to examine the role of tau pathology within the serotonergic system in relation to NPS-like behavior and serotonin neuron function. Tau pathology was found in the dorsal raphe nucleus (DRN) in 9 of 19 human cases without reported cognitive impairment, and in 9 of 10 AD cases. While this pathology was not exclusive to serotonergic neurons, it did colocalize with them. In wildtype mice overexpressing P301L-tau in the DRN, tau spread to connected regions, and was accompanied by depressive-like behaviors and hyperexcitability in serotonergic cells, possibly driven by tau-induced astrocytic activation.
description: Next, we assessed the effects of chronic alcohol exposure in a preclinical mouse model of spontaneous tau pathology (htau) and in wildtype mice. Chronic alcohol vapor induced a depressive-like phenotype in both htau and wildtype groups. Additionally, blood alcohol concentration correlated with tau pathology, serotonergic staining intensity, and tau-serotonin colocalization specifically in htau mice exposed to alcohol. Differential gene expression changes post-alcohol exposure in htau and wildtype mice suggest that alcohol may uniquely impact AD-related gene expression. These findings indicate a potential dose-dependent relationship between alcohol exposure and AD-like pathology, with serotonergic alterations mediating this risk. This work expands our understanding for the role of serotonin dysfunction in linking alcohol use to dementia risk, and provides insights that could aid in identifying at-risk individuals for whom lifestyle adjustments or early therapeutic interventions may be beneficial.