Late life depression as a disconnection syndrome: a RAMESES realist synthesis of neurocognitive and neurofunctional correlates

Jorge D. López-Sánchez, Faculty of Psychology-Xalapa, Psychobiology Laboratory; Institute of Neuroethology. Universidad Veracruzana, Xalapa, Ver., Mexico
Dora E. Granados-Ramos, Faculty of Psychology-Xalapa, Psychobiology Laboratory, Universidad Veracruzana, Xalapa, Ver., Mexico
Blandina Bernal-Morales, Institute of Neuroethology. Universidad Veracruzana, Xalapa, Ver., Mexico

Background: Late-life depression (LLD) is a prevalent syndrome in older adults, characterized by neuropsychiatric symptoms and multidomain cognitive impairments. Objective: To examine how contexts and mechanisms interact to generate cognitive outcomes in LLD, and how these patterns support its conceptualization as a disconnection syndrome. Method: Following the RAMESES publication standards, we performed iterative searches in PubMed for articles published between January 2013 and January 2024. Inclusion was based on relevance (contribution to theory-building or testing) and rigour (credibility of the data). Forty-eight studies were retained. Results: Findings consistently showed impairments in global cognition, executive functions, processing speed, and memory. These deficits emerged through distinct context-mechanism-outcome (C-M-O) configurations. For example, in older adults with late-onset depression and vascular comorbidity (C), white matter hyperintensities (M) disrupted fronto-subcortical connectivity, leading to executive dysfunction and cognitive slowing (O). In cases of persistent depression (C), hypothalamic-pituitary-adrenal-axis hyperactivation and inflammation (M) produced memory decline and increased dementia risk (O). Importantly, neurofunctional disruptions also played a key role: in women with moderate-severe depression (C), hyper-synchronization of the default mode network (M) impaired sustained attention and cognitive flexibility (O); while in patients with limited SSRI response (C), inefficiency of the cognitive control network (M) explained persistent deficits in planning and judgment (O). Conclusion: These C-M-O patterns demonstrate that LLD involves interconnected neuroanatomical and neurofunctional mechanisms. Recognizing LLD as a disconnection syndrome has significant implications for tailoring pharmacological and psychotherapeutic interventions and for preventive strategies aimed at strengthening cognitive reserve in late life.

Keywords: Late-life depression. Cognitive impairment. Aging. Connectivity. Brain networks.