Clinical nutrition (Edinburgh, Scotland) · 2026
Serum metabolite signature of the mediterranean diet adherence and cognitive function: Evidence from two cohorts.
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Papandreou Christopher, Skyfa Vasiliki-Amaryllis, Tsilidis Konstantinos K, Julvez Jordi, Sakka Paraskevi, Hadjigeorgiou George, Dardiotis Efthimios, Kosmidis Mary H, Yannakoulia Mary, Patas Kostas, Ntanasi Eva, Mamalaki Eirini, Brikou Dora, Drouka Archontoula, Chatzipanagiotou Stylianos, Charisis Sokratis, Gu Yian, Scarmeas Nikolaos
Аннотация
BACKGROUND AND AIMS: The Mediterranean diet (MD) has been consistently associated with favorable cognitive outcomes. However, reliance on self-reported dietary assessment limits accurate characterization of diet-health associations. Circulating metabolites may capture the endogenous metabolic imprint of habitual dietary patterns and provide complementary biological information beyond questionnaire-based measures. We aimed to identify a serum metabolite signature associated with MD adherence and to examine its cross-cohort reproducibility and associations with cognitive performance and trajectories.
METHODS: We analyzed 595 serum metabolites measured by mass spectrometry in 337 adults aged ≥65 years (cognitively normal or with mild cognitive impairment [MCI]) from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). MD adherence was estimated using a validated food-frequency questionnaire (FFQ). A two-stage penalized regression approach was used to derive a metabolite signature of MD adherence. External validation (applying the HELIAD-derived metabolites and coefficients) and recalibration (re-estimating coefficients) were performed in 148 adults aged ≥40 years from the Aiginition Longitudinal Biomarker Investigation of Neurodegeneration (ALBION) (cognitively normal or MCI), where MD adherence was assessed using four repeated 24-h dietary recalls. Associations with cognitive performance (global and five domain-specific scores) were examined cross-sectionally and prospectively (median follow-up: 2.8 years in HELIAD; 1.2 years in ALBION).
RESULTS: A 23-metabolite signature enriched in lysophospholipids, plasmalogen and ether-linked phospholipids, long-chain polyunsaturated phosphatidylcholines, and steroid hormone sulfates explained 28.7% of the variance in the MedDietScore in HELIAD (r = 0.54). Direct cross-cohort transferability was limited in ALBION (R2 = 0.02), but predictive performance improved following cohort-specific recalibration (R2 = 0.21). The metabolite signature was positively associated with memory performance cross-sectionally and with subsequent language change in HELIAD. Calibration analyses suggested attenuation of FFQ-based associations, with larger effect estimates after correction but wider confidence intervals.
CONCLUSION: A reproducible serum metabolite signature reflects diet-related metabolic variation associated with MD adherence and is linked to cognitive performance in older adults. Rather than functioning as a direct biomarker of adherence, this profile captures the endogenous metabolic imprint of habitual dietary patterns and may complement self-reported dietary measures in nutritional epidemiology.
METHODS: We analyzed 595 serum metabolites measured by mass spectrometry in 337 adults aged ≥65 years (cognitively normal or with mild cognitive impairment [MCI]) from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). MD adherence was estimated using a validated food-frequency questionnaire (FFQ). A two-stage penalized regression approach was used to derive a metabolite signature of MD adherence. External validation (applying the HELIAD-derived metabolites and coefficients) and recalibration (re-estimating coefficients) were performed in 148 adults aged ≥40 years from the Aiginition Longitudinal Biomarker Investigation of Neurodegeneration (ALBION) (cognitively normal or MCI), where MD adherence was assessed using four repeated 24-h dietary recalls. Associations with cognitive performance (global and five domain-specific scores) were examined cross-sectionally and prospectively (median follow-up: 2.8 years in HELIAD; 1.2 years in ALBION).
RESULTS: A 23-metabolite signature enriched in lysophospholipids, plasmalogen and ether-linked phospholipids, long-chain polyunsaturated phosphatidylcholines, and steroid hormone sulfates explained 28.7% of the variance in the MedDietScore in HELIAD (r = 0.54). Direct cross-cohort transferability was limited in ALBION (R2 = 0.02), but predictive performance improved following cohort-specific recalibration (R2 = 0.21). The metabolite signature was positively associated with memory performance cross-sectionally and with subsequent language change in HELIAD. Calibration analyses suggested attenuation of FFQ-based associations, with larger effect estimates after correction but wider confidence intervals.
CONCLUSION: A reproducible serum metabolite signature reflects diet-related metabolic variation associated with MD adherence and is linked to cognitive performance in older adults. Rather than functioning as a direct biomarker of adherence, this profile captures the endogenous metabolic imprint of habitual dietary patterns and may complement self-reported dietary measures in nutritional epidemiology.