Abstract
BACKGROUND: Cognitive decline (CD) is an age-related process exacerbated by metabolic syndrome (MetS), which may be mitigated by lifestyle interventions. Plasma biomarkers hold promise for early CD detection, but prospective evidence is limited. Therefore, we aimed to prospectively determine associations between peripheral neurology-related proteins and CD, and to assess whether the lifestyle intervention of the PREDIMED-Plus trial could modify these associations. METHODS: A 6-year observational study including 314 PREDIMED-Plus participants with overweight/obesity and MetS (mean age: 65 years, 44% women) were randomised to an intensive weight-loss intervention or a control group. At baseline and 3-year follow-up, plasma neurological and inflammatory proteins were quantified using proximity extension assay (OLINK neurology panel, n = 92), ELISA (C-reactive protein, amyloid-beta 40, phosphorylated tau 231 and adiponectin, n = 4) and Luminex (interleukin-6, n = 1). Cognitive performance was assessed at baseline, 2, 4, and 6 years. Elastic net regression identified proteins predictive of four cognitive domains, and protein composite scores of cognitive function were generated. Linear-mixed models assessed their associations with 6-year CD and tested for interactions with intervention. FINDINGS: Distinct baseline protein composite scores, including 18, 18, 16, and 17 proteins, were identified for global cognitive function (GCF), attention, executive function, and general cognitive function (GenCF), respectively. Of these, seven proteins (RSPO1, CD200, EDA2R, VWC2, GDNF, CD38, and ADAM23) were consistently associated across all cognitive domains. Protein composite scores of GCF and GenCF were significantly associated with 6-year CD, with PREDIMED-Plus interventions modulating these associations only for changes in GCF (P = 0·01). INTERPRETATION: This study identified protein signatures that are associated with CD and observed that a weight loss, energy-reduced Mediterranean diet, and physical activity may influence the relationship between these protein signatures and cognitive outcomes in older adults with MetS. However, further research is needed to confirm these findings and clarify causal relationships. FUNDING: Instituto de Salud Carlos III (ISCIII) co-funded by the European Union, CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), European Union's Horizon 2020 research and innovation programme, UCD Ad Astra Programme, ICREA Academia program, Sociedad Española de Endocrinología y Nutrición (SEEN), Agència Catalana de Recerca i Universitats (AGAUR).