The time interval from amyloid to tau PET positivity varies by age, sex and APOE-ε4 status - 02/06/26

Doi : 10.1016/j.tjpad.2026.100622

Marta Milà-Alomà ^1,^2,^⁎ , Isabella Hausle ¹, Kellen K. Petersen ³, Pamela Thropp ¹, Suzanne E. Schindler ³, Duygu Tosun ^1,^2,^⁎
for the
Alzheimer’s Disease Neuroimaging Initiative ^{^†}
Alzheimer’s Disease Neuroimaging Initiative (ADNI): Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: ADNI_Acknowledgement_List.pdf

¹ Northern California Institute for Research and Education, San Francisco, CA, USA 94141

² Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA 94143

³ Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA

^⁎ Corresponding Author. Duygu Tosun, PhD, Department of Radiology and Biomedical Imaging, University of California San, Francisco, 505 Parnassus Ave M-391, San Francisco, CA 94121 USA Department of Radiology and Biomedical Imaging University of California San Francisco, 505 Parnassus Ave M-391 San Francisco CA 94121 USA ^⁎⁎ Corresponding Author. Marta Milà-Alomà, PhD, Department of Radiology and Biomedical Imaging, University of California San, Francisco, 505 Parnassus Ave M-391, San Francisco, CA 94121 USA Department of Radiology and Biomedical Imaging University of California San Francisco, 505 Parnassus Ave M-391 San Francisco CA 94121 USA

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Abstract

Background

Alzheimer’s disease (AD) progression varies widely among individuals. Identifying factors influencing timing of pathology and clinical progression is crucial for optimizing early intervention trials.

Objectives

To investigate how the estimated age at amyloid and tau PET positivity, and the time interval between these two key events (“amyloid–tau time interval”), relate to symptom onset and clinical progression, and to assess the effects of APOE -ε4 status and sex on these associations.

Design

This analysis used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Harvard Aging Brain Study (HABS).

Setting

The ADNI is a multicenter observational cohort conducted at 55 sites across the United States; The HABS is a longitudinal, single-center, population-based observational cohort.

Participants

This study included participants with at least one positive amyloid PET scan (ADNI n=792; HABS n=104) or at least one positive tau PET scan (ADNI n=212; HABS n=48). All participants had information on sex, APOE- ε4 status, and longitudinal cognitive assessments.

Measurements

We examined the influence of APOE -ε4 status, sex, and their interaction on the estimated age at biomarker positivity and the amyloid-tau time interval. Accelerated Failure Time (AFT) models were used to predict time to symptom onset (CDR > 0) based on estimated biomarker positivity age and the amyloid-tau time interval. Linear mixed-effects (LME) models evaluated differences in the rate of cognitive decline as measured with CDR-SB over five years following symptom onset by estimated biomarker positivity age and amyloid-tau time interval duration. Additional models included interaction terms with sex or APOE -ε4 status.

Results

The amyloid-tau time interval varied markedly between individuals and was shorter in APOE- ε4 carriers, women, and those with older age at amyloid PET positivity. APOE- ε4 carriers and women became amyloid and tau PET positive at younger ages. Following amyloid PET positivity, a shorter time to tau PET positivity predicted earlier symptom onset. After symptom onset, faster cognitive decline was observed in individuals with younger ages at amyloid or tau PET positivity. The time until symptom onset following tau PET positivity, or the rate of cognitive decline after symptom onset were not influenced by the amyloid-tau time interval.

Conclusions

After becoming amyloid PET positive, APOE- ε4 carriers, women and older individuals may have a shorter window for detection and treatment before they become tau PET positive and develop symptoms. These findings should guide the identification of individuals at highest risk of rapid AD progression, enabling more efficient participant selection for clinical trials.

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Keywords : Alzheimer’s disease, Amyloid PET positivity, Tau PET positivity, biological clock, clinical trials