Relationship Between Depression and Neurodegeneration: Risk Factor, Prodrome, Consequence, or Something Else? A Scoping Review

Abstract

Background: The link between depression and neurodegeneration is complex and unclear. It is debated whether depression is a risk factor, a prodrome, a consequence, or unrelated. Objectives: This review examines these possibilities to clarify their connection, focusing primarily on Alzheimer's disease, vascular dementia, Parkinson's disease, and other highly comorbid neurodegenerative diseases. Methods: Eligibility criteria: The studies included in this review focused on neurodegenerative diseases with high comorbidity with depression, published in peer-reviewed English-language journals, providing empirical evidence on the link between the two conditions or theoretical frameworks that point to other studies. Non-human studies and those irrelevant to this connection were excluded. Source of evidence: AI-supported tools identified relevant articles. Results: Most studies suggest depression may contribute to neurodegeneration, but clinical, neuroimaging, and longitudinal evidence also support its role as a prodrome or consequence, indicating a bidirectional relationship. Conclusions: Despite extensive research, the connection remains unclear, highlighting the need for further investigation into underlying mechanisms and interdependencies, focusing on longitudinal studies by examining causality.

Keywords: Alzheimer’s disease; Parkinson’s disease; comorbidity; depression; neurodegeneration; prodrome; risk factor.

Figure 1

A flowchart illustrating the research strategy employed for this scoping review in accordance with PRISMA-ScR guidelines [44].

Figure 2

Ganguli’s causal network model illustrates the shared biological mechanisms and bidirectional pathways connecting depression and neurodegeneration.

Figure 3

A graphical representation of the four trajectories influenced by possible common variables. The diagram illustrates how these trajectories may coexist and interact rather than being mutually exclusive.