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. 2024 Jan;20(1):388-398.
doi: 10.1002/alz.13444. Epub 2023 Aug 29.

Characterizing the emergence of amyloid and tau burden in Down syndrome

Matthew D Zammit  1 , Tobey J Betthauser  2   3 , Andrew K McVea  1 , Charles M Laymon  4 , Dana L Tudorascu  5 , Sterling C Johnson  2   3 , Sigan L Hartley  1 , Alexander K Converse  1 , Davneet S Minhas  4 , Shahid H Zaman  6 , Beau M Ances  7 , Charles K Stone  3 , Chester A Mathis  5 , Annie D Cohen  5 , William E Klunk  5 , Benjamin L Handen  5 , Bradley T Christian  1   8 ; Alzheimer's Biomarker Consortium - Down Syndrome
Affiliations

Characterizing the emergence of amyloid and tau burden in Down syndrome

Matthew D Zammit et al. Alzheimers Dement. 2024 Jan.

Abstract

Introduction: Almost all individuals with Down syndrome (DS) will develop neuropathological features of Alzheimer's disease (AD). Understanding AD biomarker trajectories is necessary for DS-specific clinical interventions and interpretation of drug-related changes in the disease trajectory.

Methods: A total of 177 adults with DS from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) underwent positron emission tomography (PET) and MR imaging. Amyloid-beta (Aβ) trajectories were modeled to provide individual-level estimates of Aβ-positive (A+) chronicity, which were compared against longitudinal tau change.

Results: Elevated tau was observed in all NFT regions following A+ and longitudinal tau increased with respect to A+ chronicity. Tau increases in NFT regions I-III was observed 0-2.5 years following A+. Nearly all A+ individuals had tau increases in the medial temporal lobe.

Discussion: These findings highlight the rapid accumulation of amyloid and early onset of tau relative to amyloid in DS and provide a strategy for temporally characterizing AD neuropathology progression that is specific to the DS population and independent of chronological age.

Highlights: Longitudinal amyloid trajectories reveal rapid Aβ accumulation in Down syndrome NFT stage tau was strongly associated with A+ chronicity Early longitudinal tau increases were observed 2.5-5 years after reaching A.

Keywords: Down syndrome; PET; Tau; amyloid; amyloid chronicity; longitudinal; trajectory modeling.

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Conflict of interest statement

GE Healthcare holds a license agreement with the University of Pittsburgh based on the technology described in this manuscript. Dr. Klunk is a co‐inventor of PiB and, as such, has a financial interest in this license agreement. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of this manuscript. AVID Radiopharmaceuticals provided the precursor and reference standard to produce AV‐1451. S.C.J. has served on advisory committees to Roche, Merck, and Alzpath and has received research funding for unrelated work from Cerveau Technologies. All other authors have no conflicts of interest with this work and had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors have no conflicts of interest. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Longitudinal amyloid‐beta (Aβ) burden (represented as amyloid load [AβL] and equivalent centiloids [CL]) with respect to age (left). Sampled iterative local approximation (SILA) modeled fit of Aβ burden with respect to estimated Aβ‐positive (A+) chronicity (right). Single points represent participants with only one Aβ scan, while points connected by lines represent participants with longitudinal data. Each color represents a single individual.
FIGURE 2
FIGURE 2
Longitudinal rate of equivalent centiloids (CL) and amyloid load (AβL) (presented as change/year) with respect to amyloid‐beta (Aβ) burden (left) and Aβ‐positive (A+) chronicity (right). Shaded regions represent the standard deviation.
FIGURE 3
FIGURE 3
Tau burden (presented as AV‐1451 standardized uptake value ratios [SUVR]) within each neurofibrillary tau (NFT) stage with respect to chronological age and Aβ‐positive (A+) chronicity.
FIGURE 4
FIGURE 4
Longitudinal tau change (presented as standardized uptake value ratio change per year [SUVR/year]) across each neurofibrillary tau (NFT) stage region with respect to Aβ‐positive (A+) chronicity. Dashed lines represent zero tau change (horizontal) and an A+ chronicity of 0 years (vertical). Each colored point represents a single individual with Down syndrome (DS).
FIGURE 5
FIGURE 5
Annualized % change in tau burden within each neurofibrillary tau (NFT) stage region categorized by bin of Aβ‐positive (A+) chronicity. Error bars represent the 95% confidence interval.
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