Circulating palmitoleic acid is associated with cerebral glucose metabolism in healthy middle-aged individuals: results from the Progression of Early Subclinical Atherosclerosis prospective cohort study

BACKGROUND Excess energy intake upregulates de novo lipogenesis (DNL). Circulating palmitoleic acid (POA) is an objective DNL biomarker associated with higher cardiovascular risk, which has been linked to cerebral hypometabolism. Whether POA also relates to altered cerebral glucose metabolism in midlife remains unknown. OBJECTIVES To examine cross-sectional and longitudinal associations between circulating POA (predictor) and cerebral glucose hypometabolism (outcome), a neuroimaging marker linked to increased risk of subsequent cognitive decline. METHODS We studied 461 middle-aged (median age, 51 [47-54] years) individuals with subclinical atherosclerosis from the Progression of Early Subclinical Atherosclerosis (PESA) study, a longitudinal observational cohort of asymptomatic individuals (NCT01410318). Red blood cell (RBC) POA was quantified by gas-chromatography in blood samples collected at two visits of PESA participants that had undergone longitudinal cerebral 18F-fluorodeoxyglucose (FDG) positron emission tomography (4.9 years of follow-up time). Dietary data was derived from a validated food-frequency questionnaire. Associations were assessed using region-of-interest and voxelwise multiple regression models as well as mediation analysis. RESULTS Cross-sectionally, higher RBC POA was associated with widespread lower FDG uptake across the brain (β = -0.119 (95% confidence interval (CI) -0.206, -0.032), p = 0.007), even after adjusting for cardiovascular risk. Longitudinally, participants with sustained high RBC POA exhibited a 65% greater decline in cerebral FDG uptake compared to those with sustained low POA (β = -0.403 (-0.744, -0.063), p = 0.021), particularly in frontal and parietal regions. RBC POA levels were higher among individuals adhering to the pre-defined "Social-Business" dietary pattern and were significantly associated with increased alcohol intake. Furthermore, the association between alcohol intake and subsequent precuneus hypometabolism was partially mediated by RBC POA levels. CONCLUSIONS RBC POA, a marker of DNL, is associated with cerebral glucose hypometabolism, supporting that healthy dietary habits in midlife are key to preserving brain health.