Towards an understanding of the pathological basis of senile depression and incident dementia: Implications for treatment

Senile depression (SD) is a heterogeneous syndrome. Several clinical profiles are more likely to appear in SD than in early‐life depression, but it remains unclear whether the pathophysiology is different. The prevalence of dementia increases with aging, and the underlying pathophysiological processes in the preclinical phase begin even before cognitive deficits or neurological signs appear. SD may be either a risk factor for developing dementia or a prodromal stage of dementia. The inconsistent findings regarding the association between SD and incident dementia may be attributable to the neuropathological heterogeneity underlying SD. Most studies have focused on patients with the clinical diagnosis of Alzheimer disease (AD) as an outcome, but several clinicopathological studies suggest that primary age‐related tauopathy and argyrophilic grain disease may account for a proportion of cases clinically misdiagnosed as AD in the elderly population. Furthermore, most AD cases have additional neuropathologic changes such as cerebrovascular disease and Lewy body disease. Here, we review the neuropathological findings linking SD to incident dementia, focusing on common age‐related neuropathologies. In particular, the roles of disturbance of neural circuity, imbalance of monoaminergic systems, dysregulation of the hypothalamic–pituitary–adrenal axis, and elevated neuroinflammatory status are discussed. Finally, we review the current treatment of SD in the context of age‐related neuropathological changes.