Abstract
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 with18F-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 m2); mildly decreased (60–89 mL/min/1.73 m2); and moderately/severely decreased or failure (<60 mL/min/1.73 m2). 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.
Authors and Affiliations
Muge Akinci, PhD¹, Froogh Aziz, MSc¹, Diana Guzman, BA², Lina Cheung, BS², Jian X. Kong¹˒³, Stephanie Silver¹, Joseph Eimicke¹, Sabrina Simoes, PhD²˒⁴, Jeanne A. Teresi, EdD, PhD¹˒³˒⁵, Adam M. Brickman, PhD²˒⁴˒⁶, Patrick Lao, PhD²˒⁴˒⁶, and José A. Luchsinger, MD¹˒³˒⁷*
¹ Department of Medicine, College of Physicians and Surgeons, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, United States
² Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, 710 West 168th Street, New York, NY 10032, United States
³ Morris Stroud III Center for Study of Quality of Life in Health and Aging, Columbia University, 1051 Riverside Drive, New York 10032, NY, United States
⁴ Gertrude H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, United States
⁵ New York State Psychiatric Institute, 1051 Riverside Drive, New York 10032, NY, United States
⁶ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, 710 West 168th Street, New York, NY 10032, United States
⁷ Department of Epidemiology, Joseph P. Mailman School of Public Health, Columbia University Irving Medical Center, 722 West 168th Street, New York, NY 10032, United States
\* Corresponding author: José A. Luchsinger