The Association of Alzheimer’s Disease and Related Dementias Blood-Based Biomarkers With Depressive Symptoms

Why It Matters

The identification of GFAP as a biomarker for depressive symptoms highlights neuroinflammation’s role in early Alzheimer’s‑related changes, offering a target for screening and intervention in aging populations.

Key Takeaways

• Plasma GFAP linked to higher depressive symptoms in older adults
• Aβ42/40, p‑tau181, and NfL showed no independent association
• Association persisted after adjusting for demographics, health, cognition, and meds
• Effect strongest in men; APOE ε4 status showed no clear interaction

Pulse Analysis

Depressive symptoms affect a sizable portion of older adults and have long been suspected of heralding neurodegenerative disease. In Alzheimer’s research, blood‑based biomarkers (BBMs) such as amyloid‑beta (Aβ42/40), phosphorylated tau (p‑tau181), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) provide a minimally invasive window into brain pathology. While amyloid and tau have dominated diagnostic pipelines, emerging evidence suggests that markers of neuroinflammation may bridge the gap between mood disturbances and the earliest stages of Alzheimer’s disease. Understanding which BBMs correlate with depression could refine risk stratification and guide preventive strategies.

The ASPREE cohort, a large primary‑prevention trial of low‑dose aspirin, offered a unique dataset of 11,947 participants with both BBM measurements and CES‑D‑10 depression scores. After sequential adjustment for demographics, comorbidities, cognition and antidepressant use, only plasma GFAP retained a robust positive association with depressive symptom severity (β = 0.27, p = 0.002). Neither the Aβ42/40 ratio, p‑tau181 nor NfL reached significance in the fully adjusted model, suggesting that neurodegenerative markers alone do not explain mood changes. Sex‑stratified analysis hinted at a stronger GFAP‑depression link in men, though interaction terms fell short of conventional significance.

These results reinforce the hypothesis that astrocytic activation and neuroinflammation, captured by GFAP, may precede or coexist with depressive states in older adults at risk for Alzheimer’s disease. Clinically, GFAP could become part of a multimodal screening panel, prompting earlier mental‑health interventions that might also mitigate downstream cognitive decline. However, the study’s homogenous, predominantly White sample and cross‑sectional design limit generalizability; longitudinal studies in more diverse populations are needed to confirm causality and explore therapeutic implications. As the biotech industry expands its BBM portfolio, GFAP’s dual relevance to mood and neurodegeneration positions it as a promising target for next‑generation diagnostics.