Tobey James Betthauser

Tau positron emission tomography (PET) staging is increasingly used to stratify Alzheimer’s disease (AD), yet cross-tracer interchangeability remains unestablished. In a prospective head-to-head study of 682 individuals across the aging-to-AD continuum, we compared tau PET Braak staging derived from [ ¹⁸ F]Flortaucipir and [ ¹⁸ F]MK6240. While both tracers showed high internal adherence to hierarchical Braak patterns (89-92%), cross-tracer agreement was limited (43%, weighted κ = 0.54) and fell to 14- 23% at early-to-intermediate stages, a key window for therapeutic intervention. Discordance was strongly directional: in over 90% of discordant cases [ ¹⁸ F]MK6240 assigned a higher stage, on average approximately one stage above [ ¹⁸ F]Flortaucipir. [ ¹⁸ F]MK6240 upstaging was associated with greater Aβ burden, adverse plasma biomarker profiles, and worse cognitive performance. Stage-frequency benchmarking against an external neuropathological cohort (N = 4,422) revealed that PET staging lags neuropathology by ∼2 Braak stages for [ ¹⁸ F]MK6240 and ∼3 for [ ¹⁸ F]Flortaucipir in the early phases of disease, with progressive convergence at later stages. Tau PET Braak staging is internally coherent within tracers but not interchangeable across them, with [ ¹⁸ F]MK6240 systematically assigning higher stages than [ ¹⁸ F]Flortaucipir. This biologically meaningful discordance, most pronounced at early stages, has direct implications for patient selection and staging for clinical trials and practice, necessitating tracer- aware harmonization strategies.

Background: Up to 30% of individuals harboring core Alzheimer’s disease (AD) neuropathology—amyloid-β (Aβ;A) and tau (T)—remain cognitively unimpaired. Objective: We examine whether MRI measures of cerebral blood flow (CBF) and white matter hyperintensities (WMH) differentiate cognitively impaired (AD or mild cognitive impairment (MCI);AD+MCI) from non-demented individuals with (NDAN) and without (Controls) core AD neuropathology. Methods: A retrospective cohort study (2018-2023) using data from The Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center studies employed linear models comparing group differences in regional gray matter (GM) CBF and whole brain WMH volume. Participants (N=500) underwent 3T MRI, Aβ-( ¹¹ C-Pittsburgh Compound B) and tau-( ¹⁸ F-MK6240) PET, and neuropsychological assessments. We categorized participants based on PET and cognitive status as Controls (n=416; cognitively unimpaired, A-T-), NDAN (n=38; cognitively unimpaired, A+T+), or AD+MCI (n=46; cognitively impaired, A+T+). Results: Participants were 67 years old (mean), 68% female, and 37% APOE ε4+. NDAN, like Controls, had significantly higher CBF than AD+MCI in GM regions susceptible to neurofibrillary tangle formation in early AD (frontal and temporal cortices, and limbic regions ( p sp =0.002) but not NDAN ( p =0.16). Conclusion: CBF differentiated NDAN from AD+MCI, highlighting vascular contributions to cognitive resilience. Most pronounced CBF preservation in NDAN was observed in parietal and occipital cortices, regions typically free of tau until late stages of AD progression.

This study examines associations between brain levels of amyloid-β and tau with representational pattern similarity in amygdalar reactivity to negative and neutral images in older adults without dementia. 81 participants viewed affective images during functional magnetic resonance imaging (fMRI). Participants rated the images on valence and arousal outside the scanner. Amyloid-β and tau were measured with ¹¹ C-Pittsburgh compound B and ¹⁸ F-MK-6240 positron emission tomography (PET) imaging. Representational pattern similarity analyses compared amygdalar responses to negative and neutral stimuli, while preserving the voxel-wise pattern of fMRI activation. Greater differentiation in the pattern of responding across the amygdala was indicated by lower similarity between negative and neutral stimuli. Greater tau levels in the entorhinal cortex and amygdalae were associated with less pattern similarity in left amygdalar reactivity to negative and neutral images in participants whose tau level was below standard positivity thresholds. Less pattern similarity in right amygdalar reactivity to negative and neutral images was also associated with the participants’ valence and arousal ratings of the stimuli. No associations were found with global amyloid levels and only the association between entorhinal tau and amygdalar similarity remained significant after Bonferroni correction. Greater amygdalar pattern separation in response to negative and neutral stimuli with higher levels of entorhinal tau suggest greater amygdalar sensitivity to negative compared to neutral information as tau accumulates in the brain, suggesting a potential underlying mechanism for the disrupted emotional processes often observed in preclinical Alzheimer’s Disease and other Related Dementias.

This longitudinal study including four independent cohorts assessed the spatiotemporal dynamics of tau extent and load changes in Alzheimer's disease using tau positron emission tomography data from 2,459 participants, including 898 followed for up to 7 years. Regional standardized uptake value ratios indexed tau load, whereas the spatial extent of tauopathy (SEOT) (proportion of abnormal voxels) measured tau extent. We observed burden-dependent longitudinal dynamics of tau progression: SEOT showed greater sensitivity to increases over time in regions with low baseline tau burden, whereas the standardized uptake value ratio was more informative for tracking accumulation once regional burden was established. This pattern was consistent across Braak regions and cohorts and was reflected in differential associations with other Alzheimer's disease severity markers. These findings refine models of tau propagation by suggesting that tau positron emission tomography changes may be differentially captured by extent-based and load-based metrics at different stages of disease progression, highlighting SEOT as a promising surrogate outcome for trials.

To efficiently implement plasma and cerebrospinal fluid (CSF) biomarkers for staging and prognosis of Alzheimer disease (AD), we must understand their dynamics across disease progression. We analyzed participants from the Swedish BioFINDER-2 study with mass spectrometry measurements of plasma and CSF tau species, including eMTBR-tau243/MTBR-tau243 and phosphorylation occupancies (%p-tau). Disease duration was estimated using Aβ-PET and tau-PET with the SILA algorithm. Bootstrapped LOESS models showed that %p-tau217 changes earliest, increasing just before Aβ-PET positivity. Other p-tau species changed later, with smaller dynamic ranges and earlier ceiling effects. %p-tau205 and MTBR-tau243 changes aligned with tau-PET positivity onset, while MTBR-tau243—especially plasma eMTBR-tau243—tracked cortical tau burden in later stages. Non-phosphorylated mid-region tau may serve as a late-stage biomarker. Taken together, concurrent assessments of plasma or CSF %p-tau217, %p-tau205, and (e)MTBR-tau243 provides information about different biological events in the disease cascade, which can benefit clinical trials and patient management in clinical practice.

Understanding the time course of Alzheimer’s disease biomarkers of amyloid and tau pathology and their temporal relation to clinical symptoms is key to identifying optimal windows for disease intervention and planning future drug trials. The goal of this work was to determine the extent to which Sampled Iterative Local Approximation (SILA), an algorithm extensively validated for amyloid PET, is capable of modeling longitudinal tau (T) PET trajectories and estimating person-level tau positivity onset ages in two commonly analyzed brain regions and two tracers from two different cohorts Methods: 385 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; mean (SD) age = 73.4 (7.3) years) with longitudinal flortaucipir tau PET and 288 participants from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center (collectively referred to as WISC; mean (SD) age = 67.4 (6.7) years) with longitudinal MK-6240 tau PET were included in the study. Standard uptake value ratios (SUVRs) in the entorhinal cortex and a meta-temporal ROI were modeled with SILA separately, for each cohort and region. Forward and backward SUVR and T+/- prediction were characterized with ten-fold cross-validation and in-sample validation techniques. Accuracy of estimated T+ onset ages (ETOA) was characterized in T- to T+ converters. Differences in ETOA were tested between APOE-e4 carriers and non-carriers, as well as differences in time T+ between levels of cognitive impairment. Results: SILA was able to accurately estimate retrospective change in tau SUVR in the meta-temporal region regardless of age, sex, APOE-e4 carriage, tau SUVR, and dementia (p >0.05) whereas dementia was associated with model residuals in entorhinal cortex (p ≤0.05; ADNI). In subsets of observed T- to T+ converters, the difference between “observed” and estimated meta-temporal T+ onset age [95% CI] was 0.12 [-0.27, 0.52] years for ADNI and -0.09 [0.93, 0.74] years for WISC. ETOA was significantly earlier, and odds of SILA-estimated T+ status were higher amongst APOE-e4 carriers (p <0.05) and those with dementia (p <0.05). Conclusions: Our results suggest SILA can be used to accurately model longitudinal tau PET trajectories and retrospectively estimate individual T+ onset ages in the meta-temporal region. The accuracy of SILA time estimates in entorhinal cortex worsened amongst those with dementia in ADNI suggesting entorhinal cortex may only be suitable for studying the temporal progression of tau during the preclinical time frame.

Plasma phosphorylated tau 217 (p-tau217) levels have been shown to parallel neurofibrillary tangle and cognitive decline over time. Although recent clinical trials have demonstrated exploratory drug effects on plasma p-tau217, little is known about plasma p-tau217 effect size and performance as an endpoint in Alzheimer disease (AD) clinical trials. Therefore, the objective of this study was to assess the longitudinal performance and potential utility of plasma p-tau217 as a primary endpoint in early-stage AD clinical trials. This retrospective study included participants from 4 cohorts: ADNI (a multisite observational study), BICWALZS (a South Korean memory clinic-based cohort), MYHAT-NI (a Southwestern Pennsylvania population-based cohort), and WRAP (older adults at risk for AD). Eligible participants had plasma p-tau217 measurements at least at 2 timepoints, along with baseline Aβ PET imaging and clinical assessments. Linear mixed-effects models were used to assess associations between plasma p-tau217 trajectories and clinical or biomarker outcomes. Effect size was defined as the mean annual rate of change in p-tau217 divided by its standard deviation. We calculated the sample size required for a hypothetical clinical trial designed to detect a 25% drug effect with 80% power at a 0.05 test level. A total of 716 individuals were included in the analysis: 413 cognitively unimpaired (CU) participants (58.6% female; mean age = 70.6 years, SD = 7.9) and 303 cognitively impaired (CI) participants (54.7% female; mean age = 73.2 years, SD = 7.4). In Aβ-positive individuals, the annual rate of change in plasma p-tau217 was similar between CU (0.07 pg/mL/y, SD = 0.11) and CI (0.08 pg/mL/y, SD = 0.13) groups. Effect size was 0.64 and 0.62 in CU and CI Aβ-positive individuals, respectively. The minimum sample size required per study group to detect a 25% drug effect was 610 for the CU Aβ-positive and 664 for the CI Aβ-positive group. Notably, selecting individuals with intermediate Aβ levels (Centiloid 20-40) yielded higher effect sizes (CU: 0.85; CI: 0.72), which reduced the required sample sizes per study group to 342 for CU and 492 for CI. Our findings support that changes in plasma p-tau217 represent a robust endpoint for clinical trials targeting CU or CI individuals with Aβ pathology.

Background: Recent studies demonstrate tau burden is heterogeneous after A+ onset and is temporally proximal to clinical impairment in sporadic AD. This study uses temporal modeling and neuroimaging data from three cohorts to investigate common factors that may hasten amyloid‐related tau accumulation. Methods: Participants with available amyloid and tau PET imaging were included from ADNI ( n = 880), OASIS ( n = 445), and University of Wisconsin (WISC: WRAP and Wisconsin ADRC; n = 739) cohorts. The following steps were completed separately for each cohort. Amyloid and tau were quantified, respectively, using Centiloids (CL) and medial temporal and temporal neocortex standard uptake value ratios (SUVR). A+ and T+ thresholds were defined as the mean plus two standard deviations (SDs) of lower Gaussian mixture model distributions. Sampled iterative linear approximation (SILA) was used to estimate A+ onset age (EAOA) and A+ time (age at observation minus EAOA). To understand moderators of the relationship between A+ time and tau SUVR's, we excluded those deemed confidently A‐ (APOE‐e4 carriage, sex, or education category explained additional variation in tau, both as main effects and interactions with A+ time. Results: Cohort characteristics are shown in Table 1. Results (Figure 1) were mostly consistent between OASIS and WISC cohorts with A+ time having a significant positive association with tau SUVR in both medial temporal and temporal neocortex, and APOE‐e4 carriage having a significant interaction with A+ time for the medial temporal SUVR ( APOE‐e4 carriers had faster tau trajectories). These effects were also significant in ADNI, and additionally interactions of A+ time by baseline tau age and by sex (females had faster tau trajectories) were significant for medial temporal tau, and A+ time by baseline tau age for temporal neocortex (younger age had faster tau trajectories). The education by A+ time interaction did not reach significance in any cohort/region. Conclusion: In three longitudinal cohorts, APOE‐e4 carriage consistently accelerated tau trajectories relative to A+ onset. Future work will further investigate these relationships and cohort differences that may contribute to mixed findings.

Characterizing the timing and progression of Alzheimer’s disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer’s disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium–Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer’s Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analysed on the Lilly Meso Scale Delivery Platform were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modelling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4–6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help to identify optimal treatment windows for these individuals.