A diagnosis of major depressive disorder (MDD) has consistently been linked to an increased risk of cognitive decline and neurodegenerative disorders, including Alzheimer’s disease. However, the biological mechanisms underlying this connection have remained largely unclear. Recent research from the Translational Research Group in Neurological Diseases (ITEN) at the Santiago Health Research Institute (IDIS), in collaboration with the Neurology department of the Complexo Hospitalario Universitario de Santiago de Compostela (CHUS) and the Instituto de Investigación Sanitaria Galicia Sur (IISGS), has identified alterations in plasma levels of beta-amyloid peptides in patients diagnosed with MDD.
The study, published in the International Journal of Molecular Sciences, represents the first observational, cross-sectional study conducted in Spain – and likely globally – to simultaneously evaluate, using Single Molecule Array (SIMOA) technology, various markers related to amyloid metabolism and neuroaxonal and astroglial damage in the plasma of patients with MDD, compared to a healthy control group, and to assess their association with the severity of depressive symptoms, anhedonia, and cognitive status.
Blood-Based Biomarkers Offer New Avenues for Research
Traditionally, these markers have been measured in cerebrospinal fluid obtained through lumbar puncture, an invasive, costly, and often uncomfortable procedure for patients. “Analysis in peripheral blood allows us to obtain relevant biological information from a simple extraction and subsequent centrifugation, which represents a clear advantage for both patients and the healthcare system,” explains Dr. Roberto Agís-Balboa, co-leader of the ITEN group and head of the SIMOA HD-X platform at IDIS.
The research team measured four markers simultaneously using SIMOA technology: beta-amyloid 40 and 42 peptides, neurofilament light (NfL) – an indicator of neuroaxonal damage – and glial fibrillary acidic protein (GFAP), associated with astrocyte activation. After adjusting for age and sex, the results showed that patients with MDD had reduced plasma levels of the 40 and 42 peptides compared to healthy controls. No significant differences were detected in NfL and GFAP levels.
A Pioneering Study in Depression and Biomarkers
“To the best of our knowledge, This represents the first study in major depression that employs SIMOA to simultaneously measure all four markers in plasma,” notes Dr. Agís-Balboa. “The observed reduction in beta-amyloid peptides is consistent, but It’s not accompanied by the typical pattern seen in Alzheimer’s disease, where a reduction is observed in the relative rate of peptide 42 compared to peptide 40,” known as the Aβ42/Aβ40 ratio.
Researchers María de los Ángeles Fernández Ceballos and Lara Vidal Nogueira, the first co-authors of the study, emphasize that NfL and GFAP levels, as suggested by existing literature, are primarily associated with age and not with the presence of depression itself. “These markers tend to increase with age, regardless of depression diagnosis, although it is noteworthy to observe a slight increase in both markers in the depression group for each age range, although it does not reach statistical significance,” they explain.
Focus on Patients Without Cognitive Impairment
A particularly relevant aspect of the study is that the cohort of patients with MDD did not exhibit incipient cognitive impairment or belong to an advanced age group. Participants were evaluated for the severity of their depressive symptoms and underwent standardized cognitive testing. “Most studies analyzing depression as a risk factor focus on older individuals or those with mild cognitive impairment. In our case, this was not the situation, which makes the results particularly interesting,” points out Dr. Agís-Balboa.
However, the authors stress the need to interpret the findings with extreme caution and within a fundamentally exploratory framework. Carlos Fernández Pereira, also an investigator in the study, points out that the reduction in beta-amyloid levels could be related to other systemic or metabolic factors correlated with, or independent of, depression, and not necessarily linked to an underlying neurodegenerative process. The study’s hypothesis, he explains, was framed around analyzing peripheral markers that are altered in Alzheimer’s disease, and given that depression is a risk factor, it seemed interesting to see what happens with these markers in patients with a diagnosis, but without incipient cognitive impairment or advanced age.
Modest Sample Size and Future Directions
The researchers also acknowledge important limitations, including the modest sample size and the potential influence of confounding factors, including pharmacological treatment and body mass index. “Our study is cross-sectional and observational, so it does not allow us to establish causal relationships. It is essential to move towards prospective studies of peripheral measurements to better understand the complex interface between depression that may be associated in the future with a neurodegenerative disease such as Alzheimer’s,” says Dr. José María Prieto, head of the Neurology Service at CHUS. “This could allow us to see the evolution of these markers in the periphery from major depression to dementia.”
The work was funded by the Ministry of Science and Innovation and the Carlos III Health Institute, and highlights the importance of interdisciplinary collaboration between nursing, psychiatry, neurology, clinical psychology, and laboratory research personnel to advance the development of biomarkers in psychiatry.
The full article is available at https://www.mdpi.com/1422-0067/27/3/1474
