The mechanism of actions of caffeine in Alzheimer’s disease: a systematic review of preclinical studies

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder and the most prevalent form of dementia, characterized clinically by progressive memory decline and other cognitive impairments. Due to the long incubation period between disease onset and diagnosis, current AD drugs primarily manage symptoms and provide only marginal benefits, highlighting the urgent need for effective prevention strategies. Nutraceuticals have gained significant attention for their accessibility and acceptability among the general public. Among these, caffeine, the most widely consumed psychostimulant, has been reported in numerous epidemiological studies to counteract cognitive decline. However, other studies report no beneficial or harmful effects of caffeine consumption. Caffeine intake is typically estimated from coffee, tea, or energy drink consumption, and the interplay of complex lifestyle factors and genetic backgrounds makes it challenging to interpret findings related to caffeine’s impact on AD risk. Given the controversial findings and the lack of understanding of the underlying mechanisms, we aimed to systematically review preclinical experimental studies utilizing AD models, focusing on the mechanisms of action of caffeine. We searched PubMed, Web of Science, and Scopus for studies with the title search terms: caffeine and Alzheimer’s. Evidence from in vitro , in silico , ex vivo , and in vivo studies collectively supports the neuroprotective properties of caffeine in AD across molecular, cellular and systems levels. Despite this evidence, further investigation is necessary to comprehensively elucidate caffeine’s mechanisms of action in a translational context and its therapeutic potential in AD.