Predicting Preclinical Cognitive Decline Using Plasma P-tau217 and APOE Genotype in 8,582 Individuals From Different
Yuexuan Xu1,2, Tamil Iniyan Gunasekaran1,2, Yian Gu1,2,3
1Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Background:
Plasma phosphorylated tau217 (P-tau217), a plasma biomarker of Alzheimer's disease (AD), can increase before overt symptoms. P-tau217 positivity is linked to the age at symptom onset in model-based predictions, not time to clinical event. Individuals with different genetic backgrounds, yet similar P-tau217 levels may differ in whether cognitive decline will occur or when it will emerge. Whether APOE-ε4 carrier status provides additional prognostic information beyond P-tau217 remains unclear.
Methods:
Using data from 8,582 individuals in several multi-ethnic cohorts, we evaluated how APOE-ε4 carrier status modifies the risk and time to cognitive impairment associated with plasma P-tau217. Plasma P-tau217 was analyzed as a continuous measure, with positivity analyses performed secondarily. Associations of baseline P-tau217 with prevalent and incident cognitive impairment were assessed using logistic regression and Cox models, stratified by APOE-ε4 and in interaction models. Adjusted survival curves, restricted mean survival time, and accelerated failure time model were used to predict time to event and risk. Prognostic performance was evaluated using discrimination measures, including the AUC, incremental R2, and Harrell's C-index, and nonparametric random survival forest models.
Findings:
Elevated P-tau217 levels were associated with subsequent cognitive impairment in both APOE-ε4 carriers and non-carriers, but the effects on risk and timing of cognitive impairment were significantly stronger among APOE-ε4 carriers. In stratified meta-analyses, increase in P-tau217 levels was associated with cognitive impairment at baseline and with incident cognitive impairment in APOE-ε4 carriers compared to noncarriers (OR = 2.25 vs 1.52; HR = 1.76 vs 1.26 for 1-SD increase of P-tau217 levels). Each 1-SD increase in P-tau217 levels was accompanied by a 23% shorter period to cognitive impairment among APOE-ε4 carriers, compared to 13% among non-carriers. Clinically relevant differences in cognitive-impairment-free survival emerged three to four years before symptom onset. Across parametric and nonparametric models, the prognostic value of P-tau217 was consistently greater among APOE-ε4 carriers.
Interpretation:
Plasma P-tau217 levels and APOE genotypes are commercially available and can be used to estimate the years before the onset of overt cognitive impairment. These findings may also determine optimal timing for therapeutic intervention, particularly during the preclinical phase of the disease.
Funding:
NIH.
