Neuronal Cell Death Mechanisms in Alzheimer's Disease

Alzheimer’s disease is characterised by progressive loss of neurons in key regions of the brain, notably the hippocampus and cortex, resulting in cognitive decline and behavioural impairment. Central to this process are multiple regulated and unregulated cell death pathways that intersect with the defining pathological hallmarks of the disease: extracellular amyloid-β peptide accumulation and intraneuronal tau aggregation. In response to these misfolded proteins and accompanying neuroinflammatory signals, neurons may undergo apoptosis, a form of programmed cell death involving caspase activation, or necroptosis, a regulated necrotic pathway mediated by receptor-interacting protein kinases. Emerging evidence also implicates pyroptosis, an inflammatory cell death driven by inflammasome activation, and ferroptosis, an iron-dependent lipid peroxidation cascade. Impairment of autophagy and mitophagy exacerbates proteostatic stress and mitochondrial dysfunction, further lowering the threshold for neuronal demise. Chronic microglial activation and elevated cytokine levels, such as tumour necrosis factor-α, amplify these death signals. The interplay of these mechanisms determines the tempo of neuronal loss and offers multiple therapeutic targets to preserve synaptic integrity, slow neurodegeneration and ultimately modify disease progression.

Research from Nature Portfolio

Recent clinical evaluation of a small-molecule modulator of the p75 neurotrophin receptor demonstrated safety and favourable changes in imaging and fluid biomarkers in patients with mild to moderate Alzheimer’s, suggesting mitigation of synaptic and axonal degeneration without cognitive decline over six months. Complementary preclinical work has revealed that sequestration of nuclear Yes-associated protein by amyloid aggregates initiates a novel form of regulated neuronal necrosis during early, pre-symptomatic stages; restoration of nuclear YAP levels reduced early cell loss, lowered subsequent plaque burden and improved cognitive outcomes in model systems.

Neuronal Cell Death Mechanisms in Alzheimer's Disease publication trend

The graph below shows the total number of articles in neuronal cell death mechanisms in alzheimer's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Apoptosis: programmed cell death characterised by caspase activation, DNA fragmentation and membrane blebbing, with minimal inflammation.

Necroptosis: regulated necrotic cell death mediated by RIPK1, RIPK3 and MLKL, often triggered by death receptors in inflammatory contexts.

Autophagy: lysosome-mediated degradation pathway that clears damaged organelles and protein aggregates, essential for neuronal homeostasis.

Pyroptosis: inflammatory cell death driven by inflammasome activation and gasdermin pore formation, leading to cytokine release.

Ferroptosis: iron-dependent lipid peroxidation cascade causing cell membrane damage, implicated in neurodegenerative stress responses.

References

1. p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial. Nature Medicine (2024).
2. YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology. Nature Communications (2020).
3. Different amyloid β42 preparations induce different cell death pathways in the model of SH-SY5Y neuroblastoma cells. Cellular & Molecular Biology Letters (2024).
4. Neuronal cell death mechanisms in Alzheimer’s disease: An insight. Frontiers in Molecular Neuroscience (2022).
5. TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus. Acta Neuropathologica Communications (2021).