The heterogeneity of late-life depression and its pathobiology: a brain network dysfunction disorder

Depression is frequent in older individuals and is often associated with cognitive impairment and increasing risk of subsequent dementia. Late-life depression (LLD) has a negative impact on quality of life, yet the underlying pathobiology is still poorly understood. It is characterized by considerable heterogeneity in clinical manifestation, genetics, brain morphology, and function. Although its diagnosis is based on standard criteria, due to overlap with other age-related pathologies, the relationship between depression and dementia and the relevant structural and functional cerebral lesions are still controversial. LLD has been related to a variety of pathogenic mechanisms associated with the underlying age-related neurodegenerative and cerebrovascular processes. In addition to biochemical abnormalities, involving serotonergic and GABAergic systems, widespread disturbances of cortico-limbic, cortico-subcortical, and other essential brain networks, with disruption in the topological organization of mood- and cognition-related or other global connections are involved. Most recent lesion mapping has identified an altered network architecture with "depressive circuits" and "resilience tracts", thus confirming that depression is a brain network dysfunction disorder. Further pathogenic mechanisms including neuroinflammation, neuroimmune dysregulation, oxidative stress, neurotrophic and other pathogenic factors, such as β-amyloid (and tau) deposition are in discussion. Antidepressant therapies induce various changes in brain structure and function. Better insights into the complex pathobiology of LLD and new biomarkers will allow earlier and better diagnosis of this frequent and disabling psychopathological disorder, and further elucidation of its complex pathobiological basis is warranted in order to provide better prevention and treatment of depression in older individuals.