Association of total and brain-derived Alzheimer's disease plasma biomarkers with brain amyloid deposition in a community-based sample.

BACKGROUND AND OBJECTIVES: Plasma biomarkers, particularly brain-derived phosphorylated-tau (BD-p-tau) species, hold promise as screening tools for Alzheimer's disease (AD). However, their ability to reflect AD pathology remains understudied in community settings. In a community-based sample, we examined associations between plasma biomarkers and cerebral amyloid (Aβ) deposition, and whether kidney function modified these associations. METHODS: This cohort study included cognitively unimpaired, late middle-aged adults with 18 F-Florbetaben PET imaging and NULISAseq-derived plasma biomarker measurements. Analyses were restricted to NULISAseq biomarkers related to AD pathology (Aβ38, Aβ40, Aβ42, ACHE, BACE1, BASP1, BD-p-tau181, BD-p-tau217, CD63, IGFBP7, KLK6, MAPT-tau, PSEN1, SFRP1, total p-tau181, p-tau217, and p-tau231). As a measure of kidney function, cystatin C-based estimated glomerular filtration rate was calculated and categorized by chronic kidney disease (CKD) stage as normal/high (≥90 mL/min/1.73 m 2 ); mildly decreased (60-89 mL/min/1.73 m 2 ); and moderately/severely decreased or failure (<60 mL/min/1.73 m 2 ). Bidirectional stepwise linear regression analysis was performed to identify plasma biomarkers associated with brain Aβ deposition. Linear regression models including plasma biomarker-by-CKD stage interactions tested effect modification by kidney function. RESULTS: A total of 541 Hispanic, non-Hispanic Black, and non-Hispanic White participants were included. Stepwise linear regression retained plasma BD-p-tau217 (B = 0.22; 95% CI 0.19 to 0.25; p < 0.001), which was positively associated with brain Aβ deposition, alongside Aβ42 (B = -0.08; 95% CI -0.11 to -0.06; p < 0.001), IGFBP7 (B = -0.05; 95% CI -0.08 to -0.02; p = 0.004), and BACE1 (B = -0.04; 95% CI -0.07 to -0.01; p = 0.009), which were negatively associated with brain Aβ deposition. A significant BD-p-tau217-by-CKD stage interaction demonstrated a weaker association between BD-p-tau217 and brain Aβ deposition among individuals with moderately/severely decreased kidney function or failure than those with normal/high kidney function (B = -0.17; 95% CI -0.25 to -0.08; p < 0.001). DISCUSSION: In a real-world sample, BD-p-tau217 emerged as the plasma biomarker most strongly associated with brain Aβ deposition, although this association may be attenuated in the presence of moderate/severe kidney dysfunction or kidney failure. IGFBP7 and BACE1 were identified as candidate plasma biomarkers of brain Aβ deposition, warranting replication in independent cohorts.