Numerous epidemiological studies indicate that populations exposed to environmental toxicants such as heavy metals have a higher likelihood of developing Alzheimer's disease (AD) compared to those unexposed, indicating a potential association between heavy metals exposure and AD. The aim of this review is to summarize contemporary mechanistic research exploring the associations of four important metals, arsenic (As), manganese (Mn), lead (Pb), and cadmium (Cd), with AD and possible pathways, processes, and molecular mechanisms on the basis of data from the most recent mechanistic studies. Primary research publications published during the last decade were identified via a search of the PubMed Database. A thorough literature search and final screening yielded 45 original research articles for this review. Of the 45 research articles, 6 pertain to As, 9 to Mn, 21 to Pb, and 9 to Cd exposures and AD pathobiology. Environmental exposure to these heavy metals induces a wide range of pathological processes that intersect with well-known mechanisms leading to AD, such as oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, autophagy dysfunction, and tau hyperphosphorylation. While exposure to single metals shares some affected pathways, certain effects are unique to specific metals. For instance, Pb disrupts the blood-brain barrier (BBB) and mitochondrial functions and alters AD-related genes epigenetically. Cd triggers neuronal senescence via p53/p21/Rb. As disrupts nitric oxide (NO) signaling, cortical, and synaptic function. Mn causes glutamate excitotoxicity and dopamine neuron damage. Our review provides a deeper understanding of biological mechanisms showing how metals contribute to AD. Information regarding the potential metal-induced toxicity relevant to AD may help us develop effective therapeutic AD intervention, treatment, and prevention.
Keywords: Alzheimer’s disease; arsenic; cadmium; heavy metals; mechanistic studies; neurodegenerative diseases.