Alcohol Modulation of Amyloid Precursor Protein in Alzheimer's Disease

Heavy alcohol use increases the risk of Alzheimer's Disease (AD); however, the underlying mechanisms are not addressed. The key chemical of alcohol beverages is ethanol (EtOH), and acetaldehyde is its key toxic metabolite. QIAGEN Ingenuity Pathway Analysis (IPA) bioinformatics tool was used to investigate and compare the holistic impact of EtOH and acetaldehyde on AD. An extensively researched biomarker of AD pathologies is amyloid-beta of which the precursor is amyloid precursor protein (APP). Molecules associated with APP or EtOH were collected from the QIAGEN Knowledge Base, and 313 molecules were overlapping between the molecule sets. Using the "Pathway Explorer" tool, 40 of the 313 molecules were found to change due to EtOH exposure and influence APP and were compared with acetaldehyde-mediated molecule expression changes. A pathway analysis of the findings related to these 40 molecules showed that EtOH increases APP expression at a confidence of p = 0.056 (z-score = 1.91, two-tailed). Among the top 10 IPA canonical pathways, ranked by the Benjamini-Hochberg corrected Fisher's Exact Test, identified through the "Core Expression Analysis" feature of IPA, revealed that neuroinflammation was associated at the highest confidence (p=5.97E-73). Our study suggests involvement of the neuroinflammation pathway in alcohol modulation of APP as a potential causal factor in AD.