Cannabidiol in Alzheimer's disease: evidence-weighted molecular mechanisms and translational challenges.

Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder in which amyloid-β accumulation, tau dysregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, synaptic loss and neurodegeneration interact to drive memory loss and cognitive decline. Despite advances in symptomatic therapies and anti-amyloid agents, clinical benefit remains modest, supporting interest in polypharmacological approaches. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that interacts with several signalling systems relevant to AD, including cannabinoid-related pathways, peroxisome proliferator-activated receptor-γ (PPARγ), transient receptor potential vanilloid 1 (TRPV1) channels, 5-HT1A signalling, fatty acid-binding proteins involved in anandamide transport, GPR55 and adenosine transporters. The most consistent preclinical findings indicate that CBD attenuates neuroinflammatory and oxidative responses and improves selected behavioural outcomes. Evidence for amyloid-related effects is supportive but heterogeneous. Direct evidence for tau modulation has expanded in transgenic and chemically induced models, but findings remain model-dependent, whereas mitochondrial rescue and adult hippocampal neurogenesis are less firmly established. Methodological variability in CBD source, formulation, dose, route, treatment window, sex, age and outcome selection limits direct comparison between studies. Work on other cannabinoids and CBD:Δ9-THC combinations is discussed for context, and current evidence does not establish CBD as a disease-modifying treatment in AD. Overall, current preclinical evidence supports continued investigation of CBD as a multi-target neuroprotective candidate in AD, provided that future studies use standardized, mechanism-focused and translationally relevant designs. This review compares preclinical evidence across pathological domains and identifies translational research priorities.