In recent years, the intricate relationship between major depressive disorder (MDD) and the heightened risk of Alzheimer’s disease and related dementias (ADRD) has drawn increasing scientific attention. Despite wide recognition of this connection, the biological underpinnings that link these two prevalent and debilitating conditions remain elusive. A groundbreaking investigation leveraging data from the UK Biobank now sheds critical light on this complex interplay, unveiling proteogenomic signatures that underlie ADRD susceptibility in individuals with a history of MDD. This pioneering research not only elucidates molecular pathways that may drive neurodegeneration in this vulnerable population but also offers promising avenues for early detection and preventive strategies.
Using a comprehensive proteomic approach, the study meticulously analyzed plasma protein profiles in participants both with and without a history of major depressive disorder to delineate biomarkers predictive of subsequent ADRD development. In participants devoid of baseline MDD, an extensive array of 493 proteins emerged as significantly associated with incident ADRD risk, reflecting the multifactorial biological processes implicated in Alzheimer’s pathology. Contrastingly, in individuals who had experienced MDD, the protein signature linked to dementia risk was remarkably more focused, consisting of only six key proteins: neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), pregnancy-specific beta-1 glycoprotein 1 (PSG1), neurosecretory protein VGF, GPS2 effector transcript 3 (GET3), and hematopoietic prostaglandin D synthase (HPGDS). Within this select group, GET3 stood out as a protein uniquely associated with ADRD risk specifically in the MDD cohort, suggesting a distinctive mechanistic role in the depressive brain’s vulnerability to dementia.
The identification of such a refined proteomic signature is of profound significance, as it hints at an underlying biological milieu in MDD that potentially primes neural substrates for accelerated neurodegenerative processes. Proteins like NfL and GFAP are already well-established biomarkers reflecting ongoing neuroaxonal injury and astroglial activation, respectively, processes fundamental to Alzheimer’s disease progression. The presence of VGF, a neuropeptide associated with synaptic plasticity and neurogenesis, alongside inflammatory mediators such as HPGDS and PSG1, further implicates disrupted neuronal maintenance and immune dysregulation in the depressive brain’s trajectory towards dementia.
Beyond proteomic associations, the study integrated cutting-edge genetic analyses through two-sample Mendelian randomization, advancing the understanding of causality in the MDD-ADRD nexus. Notably, genetic variants in apolipoprotein E (APOE), long recognized as the strongest genetic risk factor for late-onset Alzheimer’s disease, and the interleukin-10 receptor subunit B gene (IL10RB), pivotal in modulating anti-inflammatory responses, were causally linked to incident ADRD. This novel insight emphasizes inflammation’s critical role, modulated by genetic background, in mediating risk, especially among those burdened by the systemic and neuroinflammatory consequences of depression.
The investigation further culminated in the development of a proteomic risk score, termed PrRS_MDD-ADRD, designed to discriminate with high precision individuals with MDD at greatest risk for developing dementia. Achieving an impressive C statistic of 0.84, this score integrates weighted contributions from the MDD-specific proteins, embodying a powerful predictive tool. Such a score is not merely of diagnostic interest but carries significant implications for clinical practice, potentially guiding individualized monitoring and early interventional strategies in psychiatric patients predisposed to neurodegeneration.
This proteogenomic amalgamation bridges gaps in current understanding by revealing how peripheral biomarkers related to inflammation and amyloid-β metabolism intertwine in depression-associated dementia risk. The convergent evidence from proteomics and genomics reinforces the hypothesis that MDD fosters a distinct biological environment that accelerates typical neurodegenerative pathways implicated in Alzheimer’s disease. Notably, the overlap in inflammatory mediators and markers of neuronal injury suggests a feedforward cycle where depressive states enhance vulnerability to ADRD, possibly through chronic glial activation and dysregulated immune responses.
Importantly, these findings resonate with the emerging paradigm positioning neuroinflammation not merely as a consequence but as a driver of neurodegenerative pathology in depression-affected brains. The unique association of GET3—a less characterized protein—in the MDD group points to unexplored molecular mechanisms that may mediate crosstalk between neuroimmune functions and synaptic dynamics. Future research elucidating GET3’s cellular role could unlock novel therapeutic targets aimed at disrupting the incipient stages of dementia in depressed individuals.
The study’s utilization of the UK Biobank’s extensive dataset exemplifies the power of large-scale, population-based cohorts in disentangling complex disease relationships. The richness of this resource enabled robust statistical modeling and validation across diverse demographic strata, enhancing the generalizability of the findings. Moreover, the longitudinal design afforded prospective risk assessment, essential for developing clinically actionable biomarkers that precede overt cognitive decline.
Beyond scientific novelty, the implications of this research extend to public health and clinical psychiatry. With MDD being highly prevalent globally and dementia’s insurmountable burden growing with aging populations, tools like PrRS_MDD-ADRD could revolutionize risk stratification paradigms. Early identification of high-risk individuals enables timely deployment of preventive measures, lifestyle modifications, and cognitive interventions aimed at altering disease trajectories before the onset of irreversible neurodegeneration.
Furthermore, the integration of proteomic and genomic markers reflects an advancing era of precision psychiatry and neurology, where molecular signatures refine diagnostic categories traditionally defined by behavioral symptomatology. Such an approach promises greater specificity in understanding pathophysiology, paving the way for personalized therapeutics targeting distinct biological pathways in neuropsychiatric and neurodegenerative disorders.
In conclusion, this study presents a compelling narrative that major depressive disorder is not merely a comorbid condition occurring alongside Alzheimer’s disease and related dementias, but rather a potent modifier of dementia risk through distinct proteogenomic mechanisms. The identification of a concise set of plasma proteins intricately linked to neuroinflammation, amyloid metabolism, and neurodegeneration—coupled with causal genetic insights—charts a new course for research and clinical practice. It invites a paradigm shift toward integrated biomarker assessment in vulnerable psychiatric populations, fostering early detection and prevention of one of the most devastating age-related brain disorders.
As science progresses, the hope is that these findings will catalyze multidisciplinary efforts encompassing neurobiology, immunology, genetics, and psychiatry to unravel the enigmatic links between depression and dementia. Advancing such knowledge not only deepens our grasp of brain aging but also heralds novel avenues for therapeutic innovation aimed at preserving cognitive health in millions worldwide.
Subject of Research: The biological mechanisms linking major depressive disorder to increased Alzheimer’s disease and related dementia risk, focusing on proteomic and genomic predictors.
Article Title: Proteogenomic signature of Alzheimer’s disease and related dementia risk in individuals with major depressive disorder.
Article References:
Diniz, B.S., Chen, Z., Steffens, D.C. et al. Proteogenomic signature of Alzheimer’s disease and related dementia risk in individuals with major depressive disorder. Nat. Mental Health (2025). https://doi.org/10.1038/s44220-025-00460-0
Image Credits: AI Generated
