Genome Instability and Cellular Stress Responses in Alzheimer’s Disease: From Molecular Mechanisms to Translational Insight

Alzheimer’s disease (AD) is the leading cause of dementia worldwide and remains without therapies that meaningfully alter its long-term course. Research over the past decade has moved beyond a strictly amyloid-centred view, framing AD as a multifactorial disorder in which neuronal vulnerability is shaped by impaired genome maintenance and chronic activation of cellular stress response pathways. Post-mitotic neurons accumulate oxidative base lesions and single- and double-strand DNA breaks, and show defects in base excision repair, single-strand break repair and DNA damage response signalling, all of which have been linked to synaptic dysfunction and cognitive decline.Recent advances have reinforced this view. Single-cell genomics and long-read sequencing have revealed somatic mutational burden and structural variation in AD brain, while studies in induced pluripotent stem cell-derived neurons and brain organoids have connected DNA damage, mitochondrial dysfunction and proteostasis collapse to early neuronal phenotypes. In parallel, environmental epidemiology has strengthened the link between air pollution and other exposures and AD risk, pointing to the exposome as a modifiable contributor.Several questions remain open. The temporal sequence between genome damage, mitochondrial failure and proteotoxic stress in human neurons is not resolved, the cell-type-specific contribution of glial damage responses is underexplored, and translational pipelines connecting these mechanisms to biomarkers and human-relevant testing remain limited. Addressing these gaps is scientifically important and has direct public health relevance, supporting earlier detection, more accurate risk assessment and the design of intervention strategies that target neuronal resilience rather than late-stage pathology alone.In this Research Topic, we aim to address key aspects of genome instability and cellular stress responses in Alzheimer’s disease in order to promote discussion around this theme and to increase our understanding of how these mechanisms drive neuronal vulnerability. Specific goals include clarifying the contribution of DNA damage and repair pathways to AD initiation and progression, characterising the crosstalk between mitochondrial integrity, proteostasis and integrated stress signalling, and evaluating how environmental exposures modulate these processes. A longer-term goal is to translate these mechanistic insights into biomarkers and intervention strategies suitable for early-stage AD.We particularly welcome submission of Original Research, Review, Mini Review, Methods, Hypothesis and Theory, and Perspective articles on the following sub-topics:• DNA damage and repair in neurons and glia in Alzheimer’s disease, including base excision repair, single-strand break repair and double-strand break signalling.• Mitochondrial DNA integrity, mitophagy and bioenergetic failure in AD-relevant models.• Integrated stress response, unfolded protein response and proteostasis collapse, and their crosstalk with amyloid-β and tau pathology.• Oxidative stress, redox signalling and cellular senescence in the ageing brain.• Environmental and exposome contributions to AD risk, including air pollution and neurotoxicants.• Application of new approach methodologies (NAMs), including iPSC-derived neurons, brain organoids and microphysiological systems, to AD mechanism discovery and biomarker development. Topic editors: TANIMA SENGUPTA, Linbin Dai Source: https://www.frontiersin.org/research-topics/81288/genome-instability-and-cellular-stress-responses-in-alzheimers-disease-from-molecular-mechanisms-to-translational-insight