Year: 2026
Type: preprint
Study design: Observational Study
Abstract: STRUCTURED ABSTRACT BACKGROUND Chronological age and plasma p⍰tau217 each predicts cognitive decline, but whether their prognostic associations interact is unclear. In this study, we examined their joint associations in a memory-clinic cohort. METHODS We included 3,741 participants from the Pittsburgh ADRC, with up to 28 years of follow-up (3.0 [IQR 2.0-6.0]). The primary outcome was increase in Clinical Dementia Rating global score (CDR-GS). Secondary outcomes included clinical-stage progression and longitudinal change in CDR Sum of Boxes. Plasma p-tau217 cut-off value was derived and externally validated in amyloid-beta-PET and autopsy sub-cohorts, respectively. Cox proportional hazards and linear mixed-effects models tested age-by-p-tau217 interactions while repeated cross-validation evaluated prognostic performance. RESULTS Age and plasma p-tau217 interacted in their associations with CDR-GS progression (χ(1) 2 =23.94; p=9.81×10 -7 ). Comparing the oldest displayed age with the youngest reference age, the adjusted hazard ratio was 4.80 (95% CI 2.74-8.27) in the lowest vs. 1.05 (95% CI 0.69-1.47) in the highest p-tau217 quartile. Older age was associated with clinical progression at low-p-tau217 (HR=1.97; 95% CI 1.58-2.45) but not at high-p-tau217 (HR=1.10; 95% CI 0.95-1.26) concentrations; adjusted 5-year risk differences were 19.3 and 3.3 percentage points, respectively. Adding plasma p-tau217 improved 5-year discrimination most accurately among participants younger than 60 years (AUC 0.66-0.81). DISCUSSION Prognostic association between age and clinical progression varies by plasma p-tau217 concentration. Age stratifies risk at low plasma p-tau217 levels, whereas elevated p-tau217 identifies higher risk across age groups and attenuates the age-related gradient. These findings support further evaluation of age-contextualized plasma p-tau217 interpretation for prognosis and trial enrichment.
Source: medRxiv
Authors: Ruyu Shi, Lamia T. Choity, Shayna T. Brodman, Xuemei Zeng, Marissa F. Farinas, Michel N. Nafash, Alexandra Gogola, Brian Lopresti, Dana L. Tudorascu, Sarah B. Berman, Robert A. Sweet, Victor L. Villemagne, Julia Kofler, C. Elizabeth Shaaban, Milos D. Ikonomovic, Tharick A. Pascoal, Ann D. Cohen, Oscar L. Lopez, Beth E. Snitz, M. Ilyas Kamboh, Thomas K. Karikari
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1058046096, Genetic Architecture of Alzheimer’s disease Proteinopathies, G2001687549, The role of astrogliosis in aging and the pathological and clinical progression of Alzheimer's Disease, G2442294994, Deep Resequencing of Candidate Gene Regions in Late-onset Alzheimer's Disease, Myosteatosis, Cognition and Blood Biomarkers of Alzheimer's Disease in Persons of African Ancestry, Neurobiology of Mild Cognitive Impairment in the Elderly, G3880778400, Search for the Alzheimers Genes, G5989133034, G707218699, Alzheimer Diagnosis in older Adults with Chronic Conditions ADACC Network, Examining the Persistence of Neurocognitive Benefits of Exercise, Mild Cognitive Impairment: A Prospective Community Study, Alzheimer Disease Research Center, Longitudinal multicenter head-to-head harmonization of tau PET tracers, Head-to-head comparisons of high-performance plasma phospho-tau epitopes for the detection of Alzheimer's disease, Plasma brain-derived tau: a novel Alzheimer’s disease-type neurodegeneration biomarker with potential to complete the AT(N) scheme in blood, Brain CHEC-AC (Brain and Cognitive Health Equity Campaign for Allegheny County), Analytical characterization and validation of blood-biomarkers for monitoring TBI evolution, Predictors of Altered CNS Structure, Function, and Connectomics in the Elderly using a Health Disparities Framework, Roles of Gray Matter Brain Aging and Small Vessel Disease in AD Pathophysiology
OpenAlex ID: W7202285738