Temporal sequence of amyloid and tau PET positivity: APOE-ϵ4 and sex effects, and implications for Alzheimer's disease progression

ImportanceAlzheimers disease (AD) progression varies widely among individuals. Identifying factors influencing timing of pathology and clinical progression is crucial for optimizing early intervention trials. ObjectiveTo investigate how estimated age at amyloid and tau PET positivity, and the time interval between amyloid and tau PET positivity ("amyloid-tau interval"), relate to symptom onset and clinical progression, and whether APOE-{varepsilon}4 status and sex modify these associations. DesignLongitudinal observational study. SettingMulticenter study using data from the Alzheimers Disease Neuroimaging Initiative (ADNI). ParticipantsADNI participants with at least one positive amyloid PET scan (n=792) or at least one positive tau PET scan (n=212) were included. Both cognitively unimpaired and impaired individuals were included and all had information on sex, APOE-{varepsilon}4 status, and longitudinal cognitive assessments. Exposures18F-florbetapir or 18F-florbetaben amyloid PET, 18F-flortaucipir tau PET, CDR global, CDR-SB. Main outcomes and measuresWe examined the influence of APOE-{varepsilon}4 status, sex, and their interaction on the age at biomarker positivity and the amyloid-tau interval. Accelerated Failure Time (AFT) models were used to predict time to symptom onset based on biomarker positivity age and the amyloid-tau interval. Linear mixed-effects (LME) models evaluated differences in the rate of cognitive decline over five years following symptom onset, by biomarker positivity age and amyloid-tau interval duration. Additional models included interaction terms with sex or APOE-{varepsilon}4 status. ResultsAPOE-{varepsilon},4 carriers and women had earlier amyloid and tau PET positivity ages. APOE-{varepsilon},4 carriers, women, and those with older age at amyloid PET positivity had a shorter amyloid-tau interval. An older age at amyloid or tau PET positivity and a shorter amyloid-tau interval predicted earlier symptom onset. An older age at amyloid or tau PET positivity was also associated with slower rate of cognitive decline after symptom onset. The amyloid-tau interval did not influence time until symptom onset after tau PET positivity or rate of cognitive decline. Conclusions and relevanceAPOE-{varepsilon}4 and sex influenced the timing of amyloid and tau PET positivity and the amyloid-tau interval, which in turn affected symptom onset and clinical progression. These factors should guide the identification of amyloid-positive individuals at highest risk of rapid AD progression, enabling more efficient selection of participants for clinical trials.