Differential neuropsychiatric associations of plasma biomarkers in older adults with major depression and subjective cognitive decline

Abstract

Older adults with major depressive disorder (MDD) or early cognitive decline during the subjective cognitive decline (SCD) stage may exhibit neuropsychiatric symptoms such as anxiety, depression, and subtle cognitive impairment. The clinicopathological features and biological mechanisms of MDD differ from those of SCD among older adults; these conditions thus require different treatment strategies. This study enrolled 82 participants above 50 years old with normal cognitive levels from the communities to examine biomarker-behavior correlations between MDD (n = 23) and SCD (n = 23) relative to a normal control (NC) group (n = 36). Multidomain assessments were performed for all participants, including immunomagnetic reduction tests to detect plasma beta-amyloid (Aβ), total tau (Tau), phosphorylated tau-181 (p-Tau181), neurofilament light chain, and glial fibrillary acidic protein (GFAP). This study observed that depressive symptoms in MDD were associated with amyloid pathology (plasma Aβ40 vs. HADS-D: R = 0.45, p = 0.031; Aβ42/Aβ40 vs. HADS-D: R = -0.47, p = 0.024), which was not observed in the NC (group difference p < 0.05). Moreover, cognitive decline in MDD was distinguished by a mixed neurodegenerative process involving amyloid (plasma Aβ42 vs. facial memory test: R = 0.48, p = 0.025), tau (Tau/Aβ42 vs. digit symbol substitution test (DSST): R = -0.53, p = 0.01), and astrocytic injury (plasma GFAP vs. Montreal cognitive assessment score: R = -0.44, p = 0.038; plasma GFAP vs. DSST: R = -0.52, p = 0.014), findings that did not apply to the NC (group difference p < 0.05). Moreover, this study revealed different biomarker-behavior correlations between individuals with SCD and the NC. Compared with the NC, cognitive decline in the SCD group might be unrelated to amyloid pathology and instead might be early manifestations of tau pathology. This study underscores the difference in clinicopathological features between MDD and SCD among older adults, which differ from those of the NC. These findings enhance our understanding of the mechanisms underlying MDD and SCD in older individuals.

Fig. 1. Enrollment and grouping of participants with major depressive disorder (MDD), subjective cognitive decline (SCD), or neither (NC).

Participants over 50 were included in the study, but only those without major organ failure (such as heart, renal, or liver failure) and unimpaired cognitive function were included. Using the Mini-International Neuropsychiatric Interview (MINI), participants with MDDs were segmented into an MDD group. Those without psychiatric disorders but with subjective cognitive problems (AD8 score ≥ 2) were segmented into an SCD group, whereas those without such problems were segmented into an NC group.

Fig. 2. Behavior–biomarker correlation matrix.

Lower plasma Aβ42 level is associated with more impaired cognitive performance in category fluency (CF-fruit). Higher plasma Aβ40 level and lower Aβ42/Aβ40 ratio are associated with lower global cognition (MoCA score) and worse working memory in the forward digit span test (DST-f). Additionally, cognitive tests have strong and consistent correlations with each other. Furthermore, anxiety and depression are positively associated with physical and mental fatigue. Higher mental fatigue is associated with lower cognitive performance in cognitive processing speed (DSST), and semantic fluency (CF-animal, color, and city), in addition to lower physical activity (IPAQ-SF MET). The matrix presents the correlation coefficients exceeding the false discovery rate (FDR) correction. Supplementary Fig. S1 depicts the correlation matrices of individual MDD, SCD, and NC groups.

Fig. 3. Differential biomarker–behavior correlations in individuals with MDD and NC.

Compared with the NC, participants in the MDD group exhibited a more pronounced association between blood amyloid levels and depression tendency, as indicated by the positive association of plasma Aβ40 with HADS-D (group difference p = 0.005; A left) and the negative association of the Aβ42/Aβ40 ratio with HADS-D (group difference p = 0.005; A right). Furthermore, the associations between biomarkers and cognition in the MDD group differed from those in the NC, showing a stronger positive association between plasma Aβ42 and facial recognition (FMT, p = 0.034; B left-upper) and a stronger negative association between the Tau/Aβ42 ratio and cognitive processing in coding compared with NC individuals (DSST, p = 0.030; B right-upper). Additionally, higher plasma GFAP levels were associated with poorer cognitive performance in MoCA (p = 0.039; B left-lower) and DSST (p = 0.012; B right-lower), an association not observed in NC participants. Notably, MDD participants engaging in more physical activity, indicated by a higher metabolic equivalent, exhibited higher plasma p-Tau181 levels (p = 0.014; C left) and a higher p-Tau181/Aβ42 ratio (p = 0.011; C right). Moreover, plasma biomarkers did not exhibit differential associations with total PFS mental and physical fatigue scores between the MDD and NC groups.

Fig. 4. Differential biomarker–behavior correlations in SCD and NC.

The biomarker–mental health correlation analysis comparing individuals with SCD and NC revealed a negative correlation between anxiety and plasma p-Tau181 in NC but not in those with SCD (group difference p = 0.044; A). In biomarker–cognition correlation studies, a trend of higher plasma Tau being associated with superior semantic fluency (CF-animal and fruit) in NC had the opposite direction among those with SCD; however, the correlations for those with SCD were not statistically significant (group differences all p < 0.05; B). Moreover, the negative correlation of plasma Aβ40 and the positive correlation of Aβ42/Aβ40 ratio with semantic fluency (CF-animal and color) and working memory (DST-f) were present in the NC group but not in the SCD group (group differences all p < 0.05; C). Additionally, no differences were observed between the SCD and NC groups in terms of correlations between physical biomarkers and fatigability (all group differences p > 0.05).