Ethanol increases diffuse amyloid plaque load and impairs memory in the 5xFAD mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common age-related dementia. Lifestyle factors, including alcohol use, can increase the risk of AD. While human studies demonstrate that alcohol use can negatively impact AD risk and disease progression, the underlying alcohol-dependent mechanisms that increase Aβ burden and impair cognition remain elusive. We have recently shown that alcohol (ethanol) can acutely affect microglial dynamics, which are critical to microglial function, and many other studies have reported inflammatory activation of microglia after long-term alcohol exposure in both humans and animal models. Here, we administered 4 weeks of ethanol at dosages that mimic human binge drinking to 2.5-month-old male 5xFAD mice, a common mouse model of AD. After a two-week abstinence period, we performed behavior assays and analyzed amyloid pathology and microglial transcriptome in the hippocampus and morphology in the subiculum where amyloid pathology develops earlier than in other brain regions. We found that ethanol exposure facilitated amyloid pathology and worsened cognitive function in 5xFAD mice, while microglial transcriptomic landscape, arborization and phagocytosis appeared unchanged. Overall, our results suggest that pronounced ethanol exposure, when started early in the disease before amyloid pathology is established, can worsen AD progression in an amyloidosis model.