CNS Spectrums · Jul 29, 2026

Central sensitization syndromes as a neuropsychiatric risk state for dementia: Clinical and epidemiologic perspectives

By Hackshaw KV

Dementia prevention increasingly targets modifiable midlife risk states contributing to neurodegenerative vulnerability. While vascular and metabolic factors are established, a substantial proportion of risk remains unexplained. Central sensitization syndromes (CSS)-chronic conditions characterized by neural amplification-are highly prevalent, co-occur with depression and sleep disturbance, and involve neuroimmune and network-level mechanisms implicated in early Alzheimer's disease. To synthesize epidemiologic evidence linking CSS with incident dementia and evaluate competing causal explanations, including shared vulnerability, reverse causation, and medication-related confounding. A structured narrative review was conducted of longitudinal cohort and meta-analytic studies assessing incident dementia across CSS-related conditions. Multiple CSS-including migraine, fibromyalgia, irritable bowel syndrome, restless legs syndrome, and PTSD disorder-are associated with modest-to-moderate increases in dementia risk. Multisite chronic pain demonstrates dose-response relationships with hippocampal atrophy and incident dementia. However, many conditions lack dedicated longitudinal studies. Interpretation is limited by residual confounding, reverse causation, healthcare utilization bias, and medication effects. CSS are associated with increased dementia risk but causality remains unproven. Central sensitization may represent a clinically identifiable vulnerability state integrating pain, affective burden, and sleep disruption. This highlights a potentially high-risk population that may not be fully captured by traditional dementia risk models. Biomarker-integrated longitudinal studies and advanced causal modeling are needed to clarify mechanisms.

doi.org/10.1017/s1092852926101114Open accessPubMed 42522369Populations