Biomarkers.

Background: Cardiovascular disease and dementia often co-exist at advanced stages. Yet, midlife longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health are scarce. We aimed to determine the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis and cardiovascular risk factors in middle-aged asymptomatic individuals.

Method: The Progression of Early Subclinical Atherosclerosis (PESA) is a longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54. Participants with subclinical atherosclerosis underwent longitudinal cerebral [F]fluorodeoxyglucose (FDG)-PET (outcomes). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with 3D vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess outcome-exposure associations through region-of-interest and voxelwise approaches. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses performed.

Result: This longitudinal study included 370 participants (median age: 49·8 [IQR=46·1-52·2] years; 84% men; follow-up: 4·7 [4·2-5·2] years). Persistent high-risk of cardiovascular disease was associated with an accelerated decline of cortical FDG uptake compared to low-risk (β=-0·008 [95% CI -0·013 to -0·002]; p=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; p=0·050) (Figure 1). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (β=-0·269 [95% CI -0·509 to -0·027]; p=0·029) (Figure 2).

Conclusion: Middle-aged asymptomatic individuals with sustained cardiovascular risk and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintaining cardiovascular health during midlife may be key to reducing neurodegenerative disease burden later in life.