Amyloid spatial extent with florbetapir-PET for early detection of preclinical Alzheimer’s disease - 25/02/26

Doi : 10.1016/j.tjpad.2026.100529

Emma G. Thibault ^a, Grace Del Carmen Montenegro ^a, J. Alex Becker ^a, Julie C. Price ^a, Brian C. Healy ^b,^c, Bernard J. Hanseeuw ^a,^d, Rachel F. Buckley ^b,^e,^f, Heidi I.L. Jacobs ^a, Michael J. Properzi ^b, Reisa A. Sperling ^b,^e,^f, Keith A. Johnson ^a,^b,^f,^⁎ , Michelle E. Farrell ^b,^⁎

^a Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA

^b Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114 USA

^c Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St Boston, MA, 02114, USA

^d Department of Neurology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Av. Hippocrate 10, 1200 Bruxelles, Belgium

^e Melbourne School of Psychological Sciences, University of Melbourne, Melbourne VIC 3052, Australia

^f CenterCenter for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue Boston, MA, 02115, USA

^⁎ Corresponding author. Michelle E. Farrell, Assistant Professor of Neurology, Massachusetts General Hospital, Harvard Medical School, Martinos Center for Biomedical Imaging, 149 13th St, Charlestown, MA 02129. Massachusetts General Hospital, Harvard Medical School, Martinos Center for Biomedical Imaging 149 13th St Charlestown MA 02129 ^⁎⁎ Corresponding author. Keith A. Johnson, Director, Molecular Neuroimaging, Department of Radiology, Massachusetts General Hospital, Professor in Radiology and Neurology, Harvard Medical School, Associate Neurologist, Department of Neurology, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, MA 02115. Molecular Neuroimaging, Department of Radiology, Massachusetts General Hospital, Professor in Radiology and Neurology, Harvard Medical School, Associate Neurologist, Department of Neurology, Brigham and Women’s Hospital 221 Longwood Avenue Boston MA 02115

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Highlights

•	Florbetapir spatial extent replicates PiB findings in preclinical AD
•	Spatial extent detects early amyloid-β spread below SUVR thresholds
•	EXT predicts early medial temporal tau accumulation and plasma pTau217 levels
•	Spatial extent improves early detection and could improve trial enrichment in AD

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Abstract

Background

Prevention of Alzheimer’s disease (AD) requires biomarkers sensitive to the earliest amyloid- β (Aβ) deposits.

Objectives

To characterize performance of a recently-developed Aβ-PET spatial extent metric (EXT) for early Aβ detection using ¹⁸ [F]-florbetapir (FBP)-PET, evaluating its sensitivity, reliability, and associations with plasma pTau217, tau-PET, and cognition .

Design

Longitudinal study with up to 5.5 years of PET, plasma and cognitive measures.

Setting

The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study and its companion screen-fail study Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) conducted across 67 international sites.

Participants

1,118 cognitively unimpaired older adults from the A4 placebo arm and LEARN.

Measurements

EXT (% of neocortex above region-specific thresholds), global Aβ SUVR, plasma pTau217, medial temporal (MTL) and temporal neocortical tau-PET SUVR, and Preclinical Alzheimer Cognitive Composite (PACC).

Results

EXT showed high cross-sectional reliability and longitudinal stability. Using EXT reclassified 21.4% of SUVR-participants from Aβ− to Aβ+ and predicted who would progress to SUVR+ 5.5 years later with 83% sensitivity and 94% specificity. In SUVR− individuals, higher pTau217 associated with greater SUVR only within EXT+ individuals. Baseline EXT outperformed SUVR in predicting MTL tau proliferation. For neocortical tau SUVR and PACC change, EXT was the better predictor in earlier Aβ stages (while Aβ spread) while SUVR was superior later (after Aβ was widespread).

Conclusions

EXT is a robust, generalizable PET metric that detects Aβ before global positivity and early Aβ-related changes in tau and cognition, supporting its relevance for trial enrichment and early therapeutic monitoring in AD prevention trials.

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Key words : amyloid, PET, preclinical Alzheimer’s disease, pTau217, early detection, amyloid staging

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Amyloid spatial extent with florbetapir-PET for early detection of preclinical Alzheimer’s disease - 25/02/26

Highlights

Abstract

Background

Objectives

Design

Setting

Participants

Measurements

Results

Conclusions

Plan

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