To identify plasma biomarkers predictive of amyloid- and tau-PET burden in cognitively healthy adults.
Dementia is a significant contributor to disability worldwide . In addition to neurodegeneration (Aβ and tau), other pathways (e.g. inflammation, vascular injury) likely play important roles in dementia pathogenesis. Identifying blood biomarkers for preclinical disease can inform our understanding of biological pathways underpinning dementia and identify opportunities for disease modification.
We measured 126 proteins in 279 dementia- and stroke-free Framingham Generation 3 cohort participants (136 women, mean age 45 [SD 8]) with available stored blood samples (2002-2005) and available 11C-Pittsburgh Compound-B (PiB)-PET and/or 18F-Flortaucipir (FTP)-PET scans completed a mean of 8.6 years after blood sampling. Linear mixed effect regression with family structure modelled as random effect between individual log transformed biomarkers and amyloid deposition (frontal, lateral temporal and retrosplenial cortices [FLR]; posterior cingulate (PC); and precuneus) and tau deposition (entorhinal cortex [ERC]; and global deposition was performed. Results were corrected for multiple testing (Bonferroni correction).
A total of 63 biomarkers demonstrated significant associations with amyloid- or tau-PET deposition. Plasma total tau (t-tau), serum receptor for advanced glycation products (sRAGE) and insulin predicted amyloid deposition in all measured regions (FLR (ß±SE, p): insulin [-0.15±0.06, p=0.008], sRAGE [-0.140±0.06, p=0.021], t-tau [0.10±0.05, .p= 0.036]).
9 biomarkers were associated with entorhinal and global tau, including growth differentiation factor-15 (ERC [ß±SE, p]: -0.014±0.07, p= 0.04), lysine deficient protein kinase-1 (WNK1) (ERC [ß±SE, p]: 0.52±0.25, p=0.03] and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (ERC [ß±SE, p]: 0.16±0.07, p=0.01).
Plasma t-tau, sRAGE (marker of hyperglycemia and inflammation) and insulin predicted pre-clinical amyloid-PET burden, while 9 biomarkers, including GDF-15, WNK-1 and nt-proBNP (markers of inflammation and vascular risk) predicted preclinical tau burden. These biomarkers offer potential in identifying preclinical stages of dementia but will require validation in other cohorts.