Faculty Bibliography

Major depressive disorder (MDD) is a leading cause of disability worldwide, and depression in older adults is an increasingly urgent public health concern. While psychosocial contributors to late-life depression have been extensively studied, the underlying biochemical mechanisms remain less well understood. Mitochondria, critical for neuronal energy production, function, and survival, have been implicated in depression, and mitochondrial alterations have also been linked to changes in sex hormone levels. This is a secondary analysis of an observational study of cognitively unimpaired older adults with and without MDD (N = 112) who were followed for three years. We analyzed the baseline data of an observational study to examine the relationship between depression status and mitochondrial function, using plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) and mitochondrial DNA encapsulated in extracellular vesicles (EV-mtDNA). We also examined the association between mitochondrial function and biological sex as well as interactions with depression status. Across all participants, we observed moderately strong correlations (r = 0.42-0.53) between plasma levels of ccf-mtDNA and EV-mtDNA. Group-level analyses showed elevated levels of both EV-mtDNA and ccf-mtDNA in the depressed group, with depression severity positively associated with both measures in a sex-specific manner. Importantly, older depressed females exhibited higher EV-mtDNA levels compared to older depressed males, while older depressed males showed higher ccf-mtDNA levels compared to their female counterparts. These findings suggest that mitochondrial alterations in depression may be shaped by sex-specific biological pathways in the aging population.

Cognitive assessment and analysis of plasma biomarkers are lower-cost options for the early assessment of Alzheimer's disease (AD). In this study, we examined whether serial position markers in the Rey's AVLT were sensitive to plasma AD biomarkers in cognitively unimpaired older individuals. Participants (n = 327; mean age = 70.4, SD = 10.4) were free of dementia (MMSE = 24+) at baseline and recruited as part of the Memory Evaluation Research Initiative (MERI; Nathan Kline Institute, NY, USA). Data included plasma p-tau231, Aβ40 and Aβ42, AVLT scores and demographics. Bayesian linear and logistic regression analyses were carried out with plasma biomarkers as outcomes (including the Aβ42/40 ratio); memory scores, including traditional metrics and serial position scores, were predictors; and age, years of education, APOE ε4-status and reported gender were control variables. Results indicated that plasma p-tau231 was associated primarily with delayed primacy recall (first four words): the more primacy words were recalled, the lower the plasma p-tau231 levels were. This study confirms that serial position analysis of word-list recall data, and particularly delayed primacy, is a valuable tool for the identification of in vivo AD-related pathology in cognitively unimpaired individuals.

Neuroimaging studies have highlighted both hyperconnectivity and hypoconnectivity across the Alzheimer's disease (AD) continuum, alongside task-induced activity changes. These alterations may reflect compensatory mechanisms or network breakdowns. While connectivity-based measures are not yet established as clinical biomarkers, they hold promises for evaluating therapeutic efficacy and informing the design of targeted interventions. Leveraging these insights, this review explores the potential of off-label FDA-approved drug repositioning as a cost-effective strategy to identify therapeutic approaches for AD. We examine the neurophysiological effects of certain repurposed drugs that modulate synaptic activity, reduce inflammation, enhance metabolic pathways and gut-brain axis interactions, in preclinical and clinical models. Emerging evidence suggests that these drugs (e.g., anticonvulsants, anti-diabetics, anti-inflammatory, and gastrointestinal agents) can influence brain connectivity and activity, mitigating cognitive deficits. By integrating connectivity-focused biomarkers into clinical trials, researchers can advance the development of disease-modifying treatments. This review underscores the importance of a connectivity-driven framework for repurposing existing drugs to address need for new treatments for AD.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Vascular dysfunction contributes to Alzheimer disease (AD) and related dementias (ADRDs), but the underlying mechanisms remain unclear. Previous studies link midlife hemostasis and platelet aggregation measures to late-life dementia risk. We aimed to determine whether platelet aggregation in midlife is associated with imaging markers of AD pathology. METHODS:F-flortaucipir) PET uptake in dementia-free, middle-aged adults from the Framingham Heart Study. Co-primary outcomes included amyloid and tau uptake in AD-vulnerable regions. We also examined an MRI-based cortical thickness signature of AD risk as a secondary outcome. We used multivariable regression models adjusted for demographic and clinical factors, considering potential nonlinear associations. RESULTS:< 0.035), consistent with a neurodegenerative pattern. DISCUSSION/CONCLUSIONS:Our findings indicate that platelet aggregation is linked to PET and MRI markers of AD pathology as early as midlife. These findings support further investigation of platelet-mediated mechanisms in AD pathogenesis.

Major depressive disorder (MDD) is associated with Alzheimer's disease (AD) but the precise mechanisms underlying this relationship are not understood. While it is well established that cerebrospinal fluid (CSF) soluble levels of triggering receptor expressed on myeloid cells 2 (sTREM2) increase during early stages of AD, how sTREM2 levels behave in subjects with MDD is not known. In a longitudinal study, we measured CSF sTREM2 levels in 27 elderly cognitively intact individuals with late-life major depression (LLMD) and in 19 healthy controls. We tested the hypothesis that, similarly to what happens in early stages of AD, CSF sTREM2 would be elevated in MDD. In addition, we compared the associations of CSF sTREM2, pro- and anti- inflammatory, and AD biomarkers in LLMD and control subjects. Surprisingly, we found that mean CSF sTREM2 levels were significantly reduced in LLMD compared to controls. This reduction was no longer significant at the 3-year follow-up visit when depression severity improved. In addition, we found that CSF sTREM2 was associated with AD biomarkers and proinflammatory cytokines in controls but not in LLMD. These findings suggest that impaired microglia phagocytic response to AD pathology may be a novel link between MDD and AD.