Mild cognitive impairment and pre-frailty show distinct plasma multi-omic signatures: a cross-sectional study

Frailty and cognitive impairments frequently co-occur in older adults. It remains unclear whether this overlap reflects shared underlying biological mechanisms or parallel but distinct disease pathways. We hypothesize that physical weakness and cognitive impairment share circulating markers already in an early disease stage. We therefore recruited and analyzed a relatively healthy population with partially overlapping pre-frailty and mild cognitive impairment (MCI), and applied a multi-omics approach to identify shared and distinct molecular signatures in plasma. Community-dwelling older adults were recruited, and frailty status was determined using the Fried frailty criteria. Cognitive function was assessed in all subjects using the Montreal Cognitive Assessment (MoCA) and MemTrax tests. Blood samples were collected in the fasted state, and plasma was used for multi-omics analyses, including proteomic profiling using the SomaLogic 11 k platform, Nightingale metabolomics, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 50 community-dwelling older adults (79.9 ± 0.5 years) were recruited, comprising 29 fit individuals (14 females, 15 males) and 21 pre-frail individuals (9 females, 12 males). Pre-frail individuals scored significantly lower on the MoCA test (- 12%, P = 0.006) and MemTrax accuracy (- 4%, P = 0.03), indicating worse cognitive performance. Proteomics analysis identified 21 biomarkers associated with MCI, including APP, ACHE, and ADGRB1, and 24 biomarkers associated with pre-frailty, including FABP2, KNG1, and MTMR14. Contrary to our hypothesis, no biomarkers were shared between the pre-frailty and MCI proteomic signatures. Metabolomics analyses identified two biomarkers associated with pre-frailty and ten associated with MCI, again with no overlap between the two conditions. LC-MS/MS identified C18:0 acylcarnitine as a biomarker for pre-frailty, but not MCI. Despite consistent differences in cognitive performance between fit and pre-frail individuals, pre-frailty and MCI were characterized by distinct proteomic and metabolomic signatures, with no detectable molecular overlap. These findings suggest that the frequently observed clinical co-occurrence of frailty and cognitive impairment arises from parallel but biologically distinct disease processes, at least in early disease stages. If confirmed in a larger cohort, this suggests that both conditions will benefit from disease-specific treatments.Trial registration: The FITAAL study was registered in the Dutch Trial Register, with registration code NTR6124.