Jessica Gong

Alzheimer’s disease and related dementias (ADRD) pose a growing global health challenge, with early detection critical to slowing cognitive decline and prevent ADRD. We analyzed high-throughput plasma proteomics in 2,460 cognitively healthy adults from the English Longitudinal Study of Ageing (ELSA) to identify proteins linked to 15-year cognitive trajectories, including verbal fluency, episodic memory, and orientation. Mixed-effect linear models revealed 34 proteins associated with faster orientation decline and 18 with accelerated episodic memory decline. Enrichment analyses implicate extracellular matrix remodeling, immune signaling, apoptosis, and lysosomal-autophagic pathways in cognitive deterioration. Subgroup analyses showed sex-specific effects, highlighting heterogeneity in proteomics signatures in cognitive aging. Notably, ten identified proteins are targets of drugs under clinical investigation, suggesting opportunities for therapeutic repurposing. These findings define a plasma proteomic signature associated with decline in domain-specific cognitive functions, offering promising biomarkers and druggable targets to prevent or slow age-related cognitive decline.

A deeper understanding of the molecular processes involved in psychological wellbeing in older adults is essential for advancing knowledge of underlying biological mechanisms. Leveraging proteomics data from 3,262 older adults (mean age = 63.5 years, 55% female) of the English Longitudinal Study of Ageing (ELSA), we investigated the cross-sectional and longitudinal associations (before and after protein measurement) between 276 proteins and eudaimonic wellbeing, hedonic wellbeing, life satisfaction, and depressive symptoms, over 20-year span. For positive wellbeing, two proteins (DEFB4A and ECE1) were longitudinally associated with subsequent eudaimonic wellbeing trajectory. We further identified higher concentrations of 7, 8, and 2 proteins were linked to subsequent lower eudaimonic wellbeing, hedonic wellbeing, and life satisfaction, respectively. Sex differences in XCL1 and SLAMF7 were observed, associated with subsequent lower eudaimonic and hedonic wellbeing in males. These findings link human psychological wellbeing to regulation of several biological pathways, particularly involving cytokine regulation, neurotrophic signaling, inflammatory and immune systems.

Cognitive decline and dementia represent some of the most pressing challenges to global public health, especially amid rapidly ageing populations worldwide

Population-based proteomics offers a groundbreaking avenue to predict future disease risks, enhance our understanding of disease mechanisms, and discover novel therapeutic targets and biomarkers. The role of plasma proteins in dementia, however, requires further exploration. This study investigated 276 protein-dementia associations in 229 incident all-cause dementia, 89 Alzheimer’s disease, and 41 vascular dementia among 3249 participants (55% women, 97.2% white ethnicity) from the English Longitudinal Study of Ageing (ELSA) over a median 9.8-year follow-up. We used Cox proportional hazard regression for the analysis. Receiver operating characteristic analyses were conducted to assess the precision of the identified proteins from the fully adjusted Cox regression models in predicting incident all-cause dementia, both individually and in combination with demographic predictors, APOE genotype, and memory score, to estimate the area under the curve. Additionally, the eXtreme Gradient Boosting machine learning algorithm was used to identify the most important features predictive of future all-cause dementia onset. These associations were then validated in 1506 incident all-cause dementia, 732 Alzheimer’s disease, 281 vascular dementia, and 111 frontotemporal dementia cases among 52 745 individuals (53.9% women, 93.3% White ethnicity) from the UK Biobank over a median 13.7-year follow-up. Two-sample bi-directional Mendelian randomization and drug target Mendelian randomization were further employed to determine the causal direction between protein concentration and dementia. NEFL (hazard ratio [HR] [95% confidence intervals (CIs)]: 1.54 [1.29, 1.84]) and RPS6KB1 (HR [95% CI]: 1.33 [1.16, 1.52]) were robustly associated with incident all-cause dementia; MMP12 (HR [95% CI]: 2.06 [1.41, 2.99]) was associated with vascular dementia in ELSA, after correcting for multiple testing. Additional markers EDA2R and KIM1 were identified from subgroup and sensitivity analyses. Combining NEFL and RPS6KB1 with other predictors yielded high predictive accuracy (area under the curve = 0.871) for incident all-cause dementia. The eXtreme Gradient Boosting machine learning algorithm also identified RPS6KB1, NEFL, and KIM1 as the most important protein features for predicting future all-cause dementia. Sex difference was evident for the association between RPS6KB1 and all-cause dementia, with stronger association in men (P for interaction = 0.037). Replication in the UK Biobank confirmed the associations between the identified proteins and various dementia subtypes. The results from Mendelian randomization in the reverse direction indicated that several proteins serve as early markers for dementia, rather than being direct causes of the disease. These findings provide insights into putative mechanisms for dementia. Future studies are needed to validate the findings on RPS6KB1 in relation to dementia risk.

A deeper understanding of the molecular processes involved in psychological wellbeing in older adults is essential for advancing knowledge of underlying biological mechanisms. Leveraging proteomics data from 3,262 older adults (mean age=63.5 years, 55% female) of the English Longitudinal Study of Ageing (ELSA), we investigated the cross-sectional and longitudinal associations (before and after protein measurement) between 276 proteins and eudaimonic wellbeing, hedonic wellbeing, life satisfaction, and depressive symptoms, over 20-year span. For positive wellbeing, two proteins (DEFB4A and ECE1) were longitudinally associated with subsequent eudaimonic wellbeing trajectory. We further identified higher concentrations of 7, 8, and 2 proteins were linked to subsequent lower eudaimonic wellbeing, hedonic wellbeing, and life satisfaction, respectively. Sex differences in XCL1 and SLAMF7 were observed, associated with lower eudaimonic and hedonic wellbeing in males. These findings link human psychological wellbeing to regulation of several biological pathways, particularly involving cytokine regulation, neurotrophic signaling, inflammatory and immune systems.

The understanding of biological pathways related to loneliness and social isolation remains incomplete. Cutting-edge population-based proteomics offers opportunities to uncover novel biological pathways linked to social deficits. This study employed a proteome-wide and data-driven approach to estimate the cross-sectional associations between objective measures of social connections (i.e., social isolation) and subjective measures (i.e., loneliness) with protein abundance, using the English Longitudinal Study of Ageing. Greater social isolation was associated with higher levels of 11 proteins (TNFRSF10A, MMP12, TRAIL-R2, SKR3, TNFRSF11A, VSIG2, PRSS8, FGFR2, KIM1, REN, and NEFL) after minimal adjustments; and three proteins were significantly associated after full adjustments (TNFRSF10A, TNFRSF11A, and HAOX1). Findings from two-sample Mendelian randomization indicated that a lower frequency of in-person social contact with friends or family causally increased levels of TNFRSF10A, TRAIL-R2, TNFRSF11A, and KIM1, and decreased the level of NEFL. The study also highlighted several enriched biological pathways, including necrosis and cell death regulation, dimerization of procaspase-8, and inhibition of caspase-8 pathways, which have previously not been linked to social deficits. These findings could help explain the relationship between social deficits and disease, confirming the importance of continuing to explore novel biological pathways associated with social deficits.