Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study

Abstract

Background: In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease.

Methods: In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (¹⁸F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid.

Findings: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease.

Interpretation: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression.

Funding: None.

Figure 1:. Tau spatial staging in people with Down syndrome and autosomal-dominant Alzheimer’s disease

Spatial staging shows the magnitude of tau spread in regions of the brain. Stage 1 indicates little spread across the brain, and stage 4 indicates that tau has spread to virtually all parts of the brain. The frequency of abnormally increased tau PET is shown for people with Down syndrome (A) and autosomal-dominant Alzheimer’s disease (C). The spatial pattern of abnormally increased tau PET across the brain is shown for people with Down syndrome (B) and autosomal-dominant Alzheimer’s disease (D). Within people with Down syndrome, the earliest changes in tau burden occurred subcortically (amygdala, hippocampus, and pallidum) and were followed by changes in the entorhinal cortex (B). With autosomal-dominant Alzheimer’s disease participants, the earliest changes in tau burden were seen in the medial temporal lobe with subcortical changes occurring later (D).

Figure 2:. Tau PET burden versus cortical amyloid burden for selected brain regions in people with Down syndrome and autosomal-dominant Alzheimer’s disease

Three representative regions of interest—the entorhinal cortex (A), precuneus (B), and fusiform gyrus (C)—showed a similar pattern for tau burden (measured as SUVR) as a function of amyloid burden (measured as centiloids). For individuals who had very high amyloid burden, the tau PET burden was greater for people with Down syndrome than for those with autosomal-dominant Alzheimer’s disease. Individual dots show individual tau concentrations relative to amyloid and the centred line represents the generalised additive model fit. Shaded regions indicate 95% CIs. SUVR=standardised uptake value ratio.

Figure 3:. Temporal pattern of pathological changes in amyloid and tau within selected brain regions in people with Down syndrome and autosomal-dominant Alzheimer’s disease

Plots show differences in tau burden (measured as SUVR) between familial controls and people with Down syndrome (A, B, C) and autosomal-dominant Alzheimer’s disease (D, E, F) in three representative regions of interest—the entorhinal cortex (A, D), precuneus (B, E), and fusiform gyrus (C, F). For both Down syndrome and autosomal-dominant Alzheimer’s disease, the timepoint when the burden of amyloid or tau was greater than that of familial controls was calculated with regards to EYOs. When the CI crossed 0, participants with Down syndrome (A, B, and C) and those with autosomal-dominant Alzheimer’s disease (D, E, and F) had greater pathological burden of amyloid or tau compared with familial controls. Cortical amyloid was significantly higher for people with Down syndrome compared with familial controls at EYOs −12 (A, B, C), and at EYOs −17 for people with autosomal-dominant Alzheimer’s disease compared with familial controls (D, E, F). For all regions considered, people with Down syndrome accumulated amyloid and tau PET more closely together temporally compared with people with autosomal dominant Alzheimer’s disease. EYO=estimated years until symptom onset. SUVR=standardised uptake value ratio.