Modifiable risk factors of dementia linked to excitation-inhibition imbalance

Recent evidence identifies 12 potentially modifiable risk factors for dementia to which 40% of dementia cases are attributed. While the recognition of these risk factors has paved the way for the development of new prevention measures, the link between these risk factors and the underlying pathophysiology of dementia is yet not well understood. A growing number of recent clinical and preclinical studies support a role of Excitation-Inhibition (E-I) imbalance in the pathophysiology of dementia. In this review, we aim to propose a conceptual model on the links between the modifiable risk factors and the E-I imbalance in dementia. This model, which aims to address the current gap in the literature, is based on 12 mediating common mechanisms: the hypothalamic-pituitary-adrenal (HPA) axis dysfunction, neuroinflammation, oxidative stress, mitochondrial dysfunction, cerebral hypo-perfusion, blood-brain barrier (BBB) dysfunction, beta-amyloid deposition, elevated homocysteine level, impaired neurogenesis, tau tangles, GABAergic dysfunction, and glutamatergic dysfunction. We believe this model serves as a framework for future studies in this field and facilitates future research on dementia prevention, discovery of new biomarkers, and developing new interventions.