Compiling evidence strongly suggests the involvement of environmental toxicants, including heavy metals (aluminum, arsenic, lead, copper, cadmium, mercury, and manganese), pesticides, and solvents, as the prime culprits of neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. The pathogenesis of environmental toxicant–induced neurodegenerative disease remains elusive. Studies carried out in the last decade suggest that dysfunctional mitochondria are increasingly recognized as a key factor in the progression of neurodegenerative diseases. Mitochondria, the essential organelles that regulate cellular energy production, are particularly vital in neurons, which have high energy demands and depend on proper mitochondrial function for survival. Environmental toxicants have been shown to impair mitochondrial membranes, disrupt the electron transport chain, increase oxidative stress, and damage mitochondrial DNA, leading to progressive neurodegeneration, with mitochondrial fragmentation and oxidative stress that worsens neurodegeneration. There are currently no disease-modifying treatments available for most neurodegenerative disorders, largely due to the lack of suitable molecular targets. Targeting mitochondria presents a rational strategy for neuroprotective therapy, with the potential to slow or halt disease progression. In view of this, this review highlights the central role of mitochondria in environmental toxicant–induced neurodegeneration, emphasizing how environmental exposures drive mitochondrial dysfunction and accelerate disease progression. Understanding these mechanisms is crucial for identifying environmental risk factors and developing targeted interventions. This will provide a foundation for future research targeting mitochondria and developing suitable therapeutic interventions for neurodegenerative diseases.

Alzheimer's disease (AD), one of the most challenging neurodegenerative disorders, with high prevalence worldwide, is characterized by progressive cognitive decline and accumulation of amyloid-β plaques and neurofibrillary tau tangles. Despite significant research, the limited efficacy of current treatments underscores the critical need to identify novel pathogenic mechanisms and therapeutic targets. Necroptosis, a regulated and highly inflammatory form of programmed cell death, has emerged as one of the key contributors to AD pathogenesis. This systematic review comprises 25 high-quality in vivo, in vitro, and autopsy studies, published between 2015 and 2025, extracted from PubMed, Scopus, and Science Direct databases. The keywords include "necroptosis", "RIPK1", "RIPK3", "MLKL", "pMLKL", "necroptosis inhibitors", "Alzheimer’s disease", and "neurodegeneration". The review summarizes the multiple molecular mechanisms, including TNF-α/TNFR1 signaling, TRIF-mediated RIPK3 activation, and RHIM-dependent MLKL phosphorylation, associated with necroptosis in the pathogenesis of AD. All the studies converge on necroptosis as a central pathogenic pathway linking key molecular and cellular abnormalities observed in AD. The accumulated evidence strongly supports prioritizing the development of brain-penetrant necroptosis inhibitors and clinical validation of associated biomarkers. These insights signal a significant shift in AD therapeutics, moving from symptomatic treatment to mechanistically targeted interventions that can alter disease progression.