Predicting Preclinical Cognitive Decline Using Plasma P-tau217 and APOE Genotype in 8,582 Individuals From Different Ethnic Groups

Le résumé fourni par la source

ABSTRACT 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 non-carriers (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 Research in context Evidence before this study Plasma P-tau217 has emerged as a blood biomarker of AD, and APOE -ε4 carrier status is the most common genetic risk factor for AD. Prior studies have shown that elevated P-tau217 levels are associated with greater risk of cognitive decline and may be elevated years before overt symptoms. However, four important questions remain unresolved. First, analytic models using P-tau217 have only estimated when cognitive impairment might occur. Second, although prior studies have examined APOE- ε4 and P-tau217 together in the context of amyloid pathology, it remains unclear whether APOE- ε4 carrier status modifies the prognosis at a given P-tau217 level, particularly for the risk and timing of cognitive impairment. Third, most prior studies have been conducted predominantly in non-Hispanic white populations, limiting the generalizability across diverse ancestry groups. Fourth, studies addressing timing have largely relied on model-based predicted age at symptom onset rather than directly observed clinically documented time-to-event. Added value of this study Using data from 8,582 individuals across several multi-ethnic cohorts, we examined whether APOE- ε4 carrier-status influenced the clinical prognosis using plasma P-tau217 for future cognitive impairment. By using observed clinical follow-up rather than predicted age at onset, we were able to evaluate both risk and timing in a more clinically relevant setting. Higher P-tau217 levels were associated with increased risk of cognitive impairment and earlier progression, with significantly stronger effects among APOE- ε4 carriers. Compared with non-carriers, APOE- ε4 carriers showed a higher likelihood of progression and a shorter symptom-free interval at similar P-tau217 levels. Clinically meaningful differences in impairment-free survival emerged approximately three to four years before symptom onset. Across conventional discrimination analyses and out-of-sample survival prediction, P-tau217 showed its strongest prognostic performance among APOE- ε4 carriers. Implications of all the available evidence Plasma P-tau217 appears to provide prognostic information not only about whether cognitive impairment is likely to occur, but also about the likely time window before symptom onset. APOE- ε4 carrier status refines this interpretation. Together, these findings support a more personalized prognostic framework in which the clinical meaning of a given P-tau217 level depends in part on genetic background, with potential relevance for risk stratification, trial enrichment, and timing of early intervention in diverse population groups.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.