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Background: Several radiotracers targeting tau pathology in Alzheimer's disease (AD) are being used in human studies. Although abundant imaging characterization data exist for individual tracers there are only sparse in vivo data directly comparing tracers in head‐to‐head studies. As the use of tau PET increases, it is of paramount importance to enable multi‐tracer, multi‐center, multi‐national observational and therapeutic trials. We present the direct in vivo comparison of [18F]GTP1 and [18F]PI2620. Methods: To date, 21 subjects (70±6 years; 12F) have completed imaging with both [18F]GTP1 and [18F]PI2620: 10 prodromal, 9 mild, one moderate AD subjects (Aβ+), and one Aβ‐ cognitively unimpaired subject. Thirty minutes images were acquired 60 and 45 min after [18F]GTP1 and [18F]PI2620 administration, respectively. SUVR was calculated using the inferior cerebellum and used to compare tau‐specific binding and off‐target signal characteristics between the two tracers. The choroid plexus was defined manually for each subject. The whole cortical gray (WCG) and cerebellum rims were defined using the gray and white‐matter SPM tissue segmentation images (Figure 1). Results: Tracer distribution was similar for both tracers (Figures 2 and 3). Hammer atlas cortical SUVRs were linearly correlated (r2=0.88). Higher cortical [18F]PI2620 SUVR were observed in some subjects and regions (Figure 3). A lower SUVR correlation was observed in subcortical regions (r2=0.57). Regional comparisons are shown in Figure 4. Conclusions: The tau pathology distribution was similar for both tracers although each tracer presents a distinct off‐target signal pattern. These preliminary results support the development of categorical and standardized quantification scales for using both tracers in future studies and bridging existing data sets. Figure 1. Delineation of cortex and cerebellum rims. The combined gray and white matter SPM segmentations were binarized and the ventricles and internal CSF spaces filled to create a mask. Figure 2. [18F]GTP1 and [18F]PI2620 SUVR images. Figure 3. [18F]GTP1 and [18F]PI2620 SUVR in WCG and in vivo Braak regions. Figure 4: [18F]GTP1 and [18F]PI2620 SUVR correlation in target cortical regions, and off‐target signal in choroid plexus (CP), WCG and cerebellum (CBL) rims, and subcortical structures (CAU: caudate; PUT: putamen; PAL: pallidum; THA: thalamus; NAc: nucleus accumbens; SN: substantia nigra) and centrum semiovale (WM). [ABSTRACT FROM AUTHOR]

Background: Several radiotracers targeting tau pathology in Alzheimer's disease (AD) are being used in human studies. Although abundant imaging characterization data exist for individual tracers there are only sparse in vivo data directly comparing tracers in head‐to‐head studies. As the use of tau PET increases, it is of paramount importance to enable multi‐tracer, multi‐center, multi‐national observational and therapeutic trials. We present the direct in vivo comparison of [18F]GTP1 and [18F]PI2620. Methods: To date, 21 subjects (70±6 years; 12F) have completed imaging with both [18F]GTP1 and [18F]PI2620: 10 prodromal, 9 mild, one moderate AD subjects (Aβ+), and one Aβ‐ cognitively unimpaired subject. Thirty minutes images were acquired 60 and 45 min after [18F]GTP1 and [18F]PI2620 administration, respectively. SUVR was calculated using the inferior cerebellum and used to compare tau‐specific binding and off‐target signal characteristics between the two tracers. The choroid plexus was defined manually for each subject. The whole cortical gray (WCG) and cerebellum rims were defined using the gray and white‐matter SPM tissue segmentation images (Figure 1). Results: Tracer distribution was similar for both tracers (Figures 2 and 3). Hammer atlas cortical SUVRs were linearly correlated (r2=0.88). Higher cortical [18F]PI2620 SUVR were observed in some subjects and regions (Figure 3). A lower SUVR correlation was observed in subcortical regions (r2=0.57). Regional comparisons are shown in Figure 4. Conclusions: The tau pathology distribution was similar for both tracers although each tracer presents a distinct off‐target signal pattern. These preliminary results support the development of categorical and standardized quantification scales for using both tracers in future studies and bridging existing data sets. Figure 1. Delineation of cortex and cerebellum rims. The combined gray and white matter SPM segmentations were binarized and the ventricles and internal CSF spaces filled to create a mask. Figure 2. [18F]GTP1 and [18F]PI2620 SUVR images. Figure 3. [18F]GTP1 and [18F]PI2620 SUVR in WCG and in vivo Braak regions. Figure 4: [18F]GTP1 and [18F]PI2620 SUVR correlation in target cortical regions, and off‐target signal in choroid plexus (CP), WCG and cerebellum (CBL) rims, and subcortical structures (CAU: caudate; PUT: putamen; PAL: pallidum; THA: thalamus; NAc: nucleus accumbens; SN: substantia nigra) and centrum semiovale (WM). [ABSTRACT FROM AUTHOR]

Background: Previous work from our group has shown that a model using a limited number of common clinical, demographic and MRI features can robustly predict CDR‐SB progression (Hibar et al. CTAD 2021) and that baseline Tau‐PET levels are associated with subsequent cognitive decline (Teng et al., 2021). However, the gain from combining these predictors has not previously been assessed. The aim of this work was to assess the additive prognostic value of including baseline [18F]GTP1 tau‐PET with the other common predictors. Method: Baseline [18F]GTP1 images and MRI features were available from two crenezumab (NCT02670083 and NCT03114657; n = 51) and two semorinemab (NCT03289143; n = 360 and NCT038287747 placebo arm; n = 113) randomized clinical trials in prodromal to moderate AD populations. The benchmark linear model included age, sex, APOE4 status, education, diagnosis, baseline ADAS‐Cog 11, ADCS‐ADL, CDR‐SB and MMSE and hippocampus, ventricles and whole brain volume as predictors. In addition, the extended model included the whole cortical grey and temporal meta‐ROI [18F]GTP1 SUVR. A gradient boosted decision tree ensemble (XGBoost) model aimed to uncover potential nonlinearities and interaction among the features. Model performance was evaluated by r2 using bootstrapped confidence intervals and calibration. Result: Our analyses included data from 524 participants (prodromal AD: 151, mild AD: 318, moderate AD: 55). The benchmark model yielded r2 = 0.175 [CI 0.122 – 0.241] with CDR‐SB in the overall sample. The [18F]GTP1 only model had r2 = 0.122 [0.071 – 0.185]. The extended linear model yielded r2 = 0.226 [0.163 – 0.299] and remained well calibrated. Point estimates of r2 were lower in the prodromal and mild versus the moderate subgroups. The performance of the XGBoost model on the holdout set (r2 = 0.230 [0.123 – 0.382]) was marginally better than the linear model, but results were variable among the diagnosis subgroups and further validation needs to be performed on a larger independent dataset. Conclusion: The extended model including [18F]GTP1 SUVR features showed increased performance relative to the benchmark model. Therefore, [18F]GTP1 SUVR features may provide additional, meaningful information about patient prognosis and may be used as covariate adjustment factors to enhance treatment efficacy estimates in clinical trials. Analysis using [18F]GTP1 SUVR in other brain regions is being evaluated. [ABSTRACT FROM AUTHOR]

Background: Over the past decade, several PET tracers were developed to visualise and quantify tau pathology in vivo. However, all these tracers have distinct off‐target binding, different dynamic ranges and likely different levels of non‐specific binding resulting in large variability in semiquantification. We propose to standardise the sampling and the quantification across all available tau tracers. Method: 549 participants underwent tau scans with either 18F‐FTP (Cognitively Unimpaired (CU) = 54/AD = 14), 18F‐MK6240 (CU = 186/AD = 89), 18F‐PI2620 (CU = 17/AD = 21), 18F‐PM‐PBB3 (CU = 30/AD = 28), 18F‐GTP1 (CU = 7/AD = 38) or 18F‐RO948 (CU = 35/AD = 30). All CU individuals were Aβ‐ and all AD were Aβ+. The tau scans were spatially normalized using CapAIBL and the cerebellar cortex was used as reference region. We constructed a "universal" tau mask from the intersection of all the specific tau tracer masks, after subtracting AD from CU. All tau PET studies were sampled with a Mesial Temporal (MTL) and a Meta Temporal (MetaT) composites constrained by the universal mask. For each tracer and in composite, the mean and standard deviation of the Aβ‐ CU SUVR for each tau tracer were used to generate z‐scores (CenTauRz). Result: Using a threshold of 2 CenTauRz in the MetaT regions, all tracers highly discriminated Aβ+ AD from Aβ‐ CU (ACC = [0.94‐1], sens = [0.84‐1], spec = [0.96‐1]) with mean CenTauRz for the different AD cohorts ranging from 8 to 14. Lower accuracy was observed in the MTL (ACC = [0.78‐1]) due to lower sensitivity in some cohorts [0.65‐1] however, the specificity was similar to that in the MetaT composite (spec = [0.94,1]). Conclusion: All tracers exhibited comparably high discriminative power to separate Aβ+ AD from Aβ‐ CU, where AD Aβ+ displayed a consistent range of CenTauRz across tracers. However, there were some differences between cohorts. For example, different PET scanners, with different sensitivities were used. For some cohorts, scans were selected as extreme representative cases, while for others the scans were more representative of clinical settings, with AD patients at early stages (with low or negative tau scans) or with suspected hippocampal sparing subtype that likely explains the lower accuracy in the MTL for some cohorts. Further studies with larger cohorts to validate the universal mask and CenTauRz scale are ongoing. [ABSTRACT FROM AUTHOR]

Background: Conventional measures of tau PET longitudinal change focus on SUVR. However, a small (n=57) observational [18F]GTP1 study including a broad range of Alzheimer's disease (AD) participants suggested tau Extent and Load could measure disease progression over 12 months with greater precision than SUVR. We assess the performance of these metrics in a larger 73‐week study in prodromal‐to‐mild AD. Methods: We analyzed 109 prodromal (pAD) and 180 mild (mAD) [18F]GTP1 scans in the semorinemab Phase 2 Tauriel study (NCT03289143). Quantification was performed using the cerebellum as reference. In a given ROI, extent was defined as the fraction of voxels above a scan‐specific threshold (mean cerebellar gray SUVR plus 2 standard deviations). Load was defined as Extant multiplied by the product of the mean SUVR of above‐threshold voxels. Analyses included the whole cortical gray (WCG), temporal meta‐ROI (excluding Braak 1/2, TMP), and Braak ROIs. As no treatment effects were observed with semorinemab, data were pooled across treatment and placebo arms. Relationships between endpoints were assessed with Spearman correlations (ρs), and endpoints changes were compared using Cohen's D effect size (ES). Results: At baseline, a slightly higher correlation was observed between SUVR and Load (ρs=0.89‐0.97) than between SUVR and Extent (ρs=0.64‐0.91) partly due to the smaller dynamic range for Extent in high‐tau burden regions (Figure 1). Longitudinal changes were correlated and consistent across endpoints (Figure 2). Extent ES values were lower than SUVR and Load ES, which showed similar performance (Table 1). Prognostic associations with baseline WCG measures were similar in pAD and mAD for predominantly cognitive measures ADAS‐COG and RBANS. Weaker prognostic associations were observed for CDR‐SB and ADCS‐ADL incorporating functional status (Table 2). Conclusion: Higher baseline tau burden was associated with faster clinical decline in pAD and mAD. There was not obvious advantage of using Extent or Load; [18F]GTP1 SUVR is a robust measurement for assessing longitudinal change in multi‐site clinical trials settings. Figure 1. Relationship between tau burden metrics. Figure 2. Relationship between change in tau burden. Table 1. Cohen's D ES±95%CI of imaging endpoints change over 73 weeks. Table 2. Prognostic associations of baseline WCG tau burden measurements with cognitive change measures. [ABSTRACT FROM AUTHOR]

Background: Prior studies of tau PET tracers in participants with normal cognition and/or a broad range of Alzheimer's disease (AD) severity suggest baseline tau PET signal is associated with subsequent rates of cognitive decline. However, the prognostic utility of tau PET imaging is less well‐established within more homogenous cohorts limited to specific AD stages and for cognitive versus functional decline. We addressed these questions by analyzing baseline [18F]GTP1 tau PET signal and longitudinal changes in cognitive and functional measures in the Phase 2 Tauriel study of semorinemab in prodromal‐to‐mild AD. Methods: We analyzed data from a subset of Tauriel participants with prodromal AD (pAD; n=127) or mild AD (mAD; n=233) who underwent baseline [18F]GTP1 tau PET and longitudinal assessments with the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB), Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and/or Alzheimer's Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL). As no treatment effects were observed with semorinemab in Tauriel, data were pooled across semorinemab and placebo arms. Associations between baseline [18F]GTP1 SUVRs and annualized longitudinal change on each measure were explored using Pearson correlations and multiple linear mixed effects regression models adjusting for relevant baseline covariates. Results: Baseline cortical [18F]GTP1 SUVRs and longitudinal decline on clinical measures were significantly greater in mAD relative to pAD cohort. Prognostic associations with baseline cortical [18F]GTP1 were similar in pAD and mAD and more robust for predominantly cognitive measures (ADAS‐Cog13: pAD rs=0.37, mAD rs=0.35; RBANS Total Index: pAD rs=‐0.40, mAD rs=‐0.41) than measures incorporating functional status (CDR‐SB: pAD rs=0.27, mAD rs=0.29; ADCS‐ADL: pAD rs=‐0.12, mAD rs=‐0.26). Analogous results were seen using temporal or Braak stage regions of interest. [18F]GTP1 associations with cognitive decline generally remained significant after adjusting for baseline cognitive score, age, hippocampal volume, and education. Conclusions: Higher baseline [18F]GTP1 tau PET signal was associated with faster subsequent clinical decline in both prodromal and mild AD. More robust associations were seen with cognitive relative to functional measures. These results bolster prior work that suggests a role for tau PET in patient selection/stratification in AD clinical trials. [ABSTRACT FROM AUTHOR]

Background: Prior studies of tau PET tracers in participants with normal cognition and/or a broad range of Alzheimer's disease (AD) severity suggest baseline tau PET signal is associated with subsequent rates of cognitive decline. However, the prognostic utility of tau PET imaging is less well‐established within more homogenous cohorts limited to specific AD stages and for cognitive versus functional decline. We addressed these questions by analyzing baseline [18F]GTP1 tau PET signal and longitudinal changes in cognitive and functional measures in the Phase 2 Tauriel study of semorinemab in prodromal‐to‐mild AD. Methods: We analyzed data from a subset of Tauriel participants with prodromal AD (pAD; n=127) or mild AD (mAD; n=233) who underwent baseline [18F]GTP1 tau PET and longitudinal assessments with the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB), Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and/or Alzheimer's Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL). As no treatment effects were observed with semorinemab in Tauriel, data were pooled across semorinemab and placebo arms. Associations between baseline [18F]GTP1 SUVRs and annualized longitudinal change on each measure were explored using Pearson correlations and multiple linear mixed effects regression models adjusting for relevant baseline covariates. Results: Baseline cortical [18F]GTP1 SUVRs and longitudinal decline on clinical measures were significantly greater in mAD relative to pAD cohort. Prognostic associations with baseline cortical [18F]GTP1 were similar in pAD and mAD and more robust for predominantly cognitive measures (ADAS‐Cog13: pAD rs=0.37, mAD rs=0.35; RBANS Total Index: pAD rs=‐0.40, mAD rs=‐0.41) than measures incorporating functional status (CDR‐SB: pAD rs=0.27, mAD rs=0.29; ADCS‐ADL: pAD rs=‐0.12, mAD rs=‐0.26). Analogous results were seen using temporal or Braak stage regions of interest. [18F]GTP1 associations with cognitive decline generally remained significant after adjusting for baseline cognitive score, age, hippocampal volume, and education. Conclusions: Higher baseline [18F]GTP1 tau PET signal was associated with faster subsequent clinical decline in both prodromal and mild AD. More robust associations were seen with cognitive relative to functional measures. These results bolster prior work that suggests a role for tau PET in patient selection/stratification in AD clinical trials. [ABSTRACT FROM AUTHOR]

Background: Over the past decade, several PET tracers were developed to visualise and quantify tau pathology in vivo. However, all these tracers have distinct off‐target binding, different dynamic ranges and likely different levels of non‐specific binding resulting in large variability in semiquantification. We propose to standardise the sampling and the quantification across all available tau tracers. Method: 549 participants underwent tau scans with either 18F‐FTP (Cognitively Unimpaired (CU)=54/AD=14), 18F‐MK6240 (CU=186/AD=89), 18F‐PI2620 (CU=17/AD=21), 18F‐PM‐PBB3 (CU=30/AD=28), 18F‐GTP1 (CU=7/AD=38) or 18F‐RO948 (CU=35/AD=30). All CU individuals were Aβ‐ and all AD were Aβ+. The tau scans were spatially normalized using CapAIBL and the cerebellar cortex was used as reference region. We constructed a "universal" tau mask from the intersection of all the specific tau tracer masks, after subtracting AD from CU. All tau PET studies were sampled with a Mesial Temporal (MTL) and a Meta Temporal (MetaT) composites constrained by the universal mask. For each tracer and in composite, the mean and standard deviation of the Aβ‐ CU SUVR for each tau tracer were used to generate z‐scores (CenTauRz). Result: Using a threshold of 2 CenTauRz in the MetaT regions, all tracers highly discriminated Aβ+ AD from Aβ‐ CU (ACC=[0.94‐1], sens=[0.84‐1], spec=[0.96‐1]) with mean CenTauRz for the different AD cohorts ranging from 8 to 14. Lower accuracy was observed in the MTL (ACC=[0.78‐1]) due to lower sensitivity in some cohorts [0.65‐1] however, the specificity was similar to that in the MetaT composite (spec=[0.94,1]). Conclusion: All tracers exhibited comparably high discriminative power to separate Aβ+ AD from Aβ‐ CU, where AD Aβ+ displayed a consistent range of CenTauRz across tracers. However, there were some differences between cohorts. For example, different PET scanners, with different sensitivities were used. For some cohorts, scans were selected as extreme representative cases, while for others the scans were more representative of clinical settings, with AD patients at early stages (with low or negative tau scans) or with suspected hippocampal sparing subtype that likely explains the lower accuracy in the MTL for some cohorts. Further studies with larger cohorts to validate the universal mask and CenTauRz scale are ongoing. [ABSTRACT FROM AUTHOR]

Background: Previous research has demonstrated that the injected dose in PET examinations can be reduced without substantial effects on quantitative outcomes. These reductions can lead to lower radiation burden for subjects, reduced costs for institutions and potential for additional research scans of the same subject. Here, we investigated the effect of reduced injected doses of [18F]RO948 and [18F]Flortaucipir (FTP) on standardised uptake value ratios (SUVRs) and associated outcomes. Method: Images were manipulated from list‐mode data to simulate injected doses of 70%, 50%, 25% and 12.5% of the true injected dose. Initial analyses were scan time reduction for RO948 and dose reduction for FTP with future harmonisation of processing intended. Inferior cerebellum‐grey was used to compute SUVRs in regions‐of‐interest (ROIs) corresponding to the in vivo Braak regions of tau spread. Differences between true and reduced injected doses (given as a percentage) were calculated in individual regions as the mean of [SUVRreduced – SUVRtrue] over the means of SUVRreduced and SUVRtrue values across subjects. Result: Previously reported test‐retest variability for RO948 and FTP are 2‐6% (±6%) and 1.5‐3.3% (±3%) respectively. Regionally, RO948 remained below this TRT variability at 25% injected dose, with an average SUVR difference of 2.3% (±8%) (figure 2), whereas FTP remained below TRT variability only at 70% injected dose with an average SUVR difference of 2.9% (±3%). However, differences were above TRT variability for FTP at lower injected doses. FTP average SUVR differences were observed to be higher in CN compared to AD patients at reduced injected doses but with greater variability in AD than CN. There were no differences observed between Ab+ and Ab‐ controls. Conclusion: Preliminary findings suggest that lower injected tracer‐doses for RO948 and FTP yield robust SUVRs. However, the degree to which injected doses can be reduced must be investigated further for different demographics and for different tracers. Ongoing work aims to harmonise the simulation list‐mode processing, add MCI/AD RO948 subjects, and evaluate dose reduction in [18F]GTP1 data. Further validation will be performed against demographic and clinical variables, as well as for longitudinal data. [ABSTRACT FROM AUTHOR]

Background: The Tauriel Study (NCT03289143) was a Phase 2 randomized, double‐blind, placebo‐controlled, parallel‐group clinical trial that assessed the safety and efficacy of semorinemab in patients with prodromal‐to‐mild Alzheimer's disease. We examined the concordance of fluid tau biomarkers with Tau PET for the identification of patients with high tau burden at enrollment. Method: Tau at baseline was assessed by [18F]GTP1 PET imaging and assays for multiple CSF and plasma tau indices, including pTau181 and mid‐domain tTau (Elecsys assays), tau peptides 2‐24 and 93‐105 (anti‐peptide capture mass‐spec assay), and phosphotau/unphosphorylated tau217 ratio (mass‐spec assay). The association between imaging and fluid tau levels were assessed with Spearman correlations. AUC, sensitivity and specificity are reported in the context of predicting tau burden with a single fluid biomarker, where 'high tau' is defined as GTP1 temporal meta‐ROI SUVR ≥1.3. Cutoffs were derived using Youden's index. Result: 354 participants had both PET and plasma samples; 68 subjects had paired PET and CSF data. GTP1 significantly correlated with each fluid marker, highly with pT217 (r = 0.78), moderately with other CSF assays (r = 0.44 ‐ 0.56) and weakly with plasma tTau (r = 0.19) (Table 1). Discrimination was highest for CSF pTau217 (AUC = 0.909). Specificity was 0.862 and 0.84 for pTau181 and pTau217 respectively, while sensitivity was 0.564 and 0.868 (Figure 1). Empirically defined cutoffs were 36.88 pg/mL for pTau181 and 0.052 for pT217. Conclusion: Baseline Tau PET is shown to be prognostic for future cognitive decline and thus could be included in enrollment criteria for future clinical studies in AD. Alternative approaches include the use of fluid biomarkers for tau. While pTau181 and n‐terminal tau indices can only be optimized for either high specificity or high sensitivity, both can be concurrently optimized using pTau217, thus positioning it as a potential alternative marker for Tau pathology. Additional CSF and plasma tau indices are pending similar analyses. [ABSTRACT FROM AUTHOR]

Background: The introduction of the AT(N) framework raised several issues in regards to the definition of T+. What brain regions should be sampled? Based on one or on multiple tracers? In this work, we developed a "universal" cortical tau mask for the AD continuum derived from all the major tau ligands. This "universal" cortical mask will serve as the common tau area for all tracers over which several different regional sampling VOI or composites can be then applied. Guaranteeing sampling of the same common regions is the first step to develop a common scale for all tau tracers: the CenTauR. Method: 464 participants underwent tau scans with either 18F‐AV1451 (CN=54/AD=24), 18F‐MK6240 (CN=157/AD=22), 18F‐PI2620 (CN=10/AD=21), 18F‐PM‐PBB3 (CN=30/AD=28), 18F‐GTP1 (CN=15/AD=38) or 18F‐RO948 (CN=35/AD=30). All CN were Aß‐ and all AD were Aß+. The tau scans were spatially normalized using CapAIBL and the cerebellar cortex was used as reference region. For each tracer, a difference image between the means of the Aß‐ CN and Aß+ AD patients was generated. Difference images were subsequently thresholded at 1/3 of the difference between Aß‐ CN and Aß+ AD in the inferior temporal lobe. A single tau specific mask was then constructed from the intersection of all the specific tau tracer masks. A MRI‐derived grey matter mask at PET resolution was applied to the composite mask only sampling grey matter regions. Finally, the mask was mirrored and fused to remove the hemispherical asymmetry of tau pathology. Agreement between masks was assessed by dice‐scores. Result: Visually, all the tracer‐specific masks appeared very similar. None of the known off‐target binding regions were discernible in the resulting masks (Figure 1). There was good agreement between all masks, with dice‐scores of 0.60 and 0.66 for cortical regions. Conclusion: We constructed an "universal" tau mask for the AD continuum based on all the commonly used tau tracers aiming at standardizing tau sampling and quantification across tracers and across centres. The "universal" tau mask demarcates a tau specific space that can then be sub‐segmented into smaller regions to focus on specific areas or composite regions that might better capture early tau deposition and spreading. [ABSTRACT FROM AUTHOR]

Background: In prior cross‐sectional studies using [18F]GTP1 or other tau PET tracers across a spectrum of Alzheimer's disease (AD) severity, tau PET signal has independently correlated with cognition, even after adjustments for β‐amyloid (Aβ) load and atrophy. However, it remains uncertain how robust these correlations are in more homogeneous patient populations (e.g., clinical trial participants) and after adjustment for MRI white‐matter hyperintensities (WMH). We sought to address this question by examining baseline data from the Phase 2 Tauriel study (NCT03289143), which is investigating the safety and efficacy of semorinemab (an anti‐tau antibody) in prodromal‐to‐mild AD. Method: We analyzed data from a subset of Tauriel participants who underwent baseline [18F]GTP1 tau PET imaging and met criteria for probable AD dementia (n=244) or mild cognitive impairment (MCI; n=137), with MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, significant Aβ pathology (PET or CSF), and significant episodic memory impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Other screening/baseline assessments included the 13‐item version of the Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13) and MRI (WMH scored with Fazekas scale). Relationships between cognitive indices, whole cortical gray (WCG) [18F]GTP1 SUVR, WMH, and age were assessed using Pearson correlations and multiple linear regression. Result: Univariate analyses revealed significant correlations between all cognitive indices [MMSE, CDR Sum of Boxes, ADAS‐Cog13, and RBANS] and [18F]GTP1 SUVR across the whole cortical gray (WCG; p's<0.001). Significant univariate correlations were also seen between WMH and ADAS‐Cog13 scores (p=0.035) and between age and RBANS scores (p<0.001). Multivariate linear regression analyses that included all three factors consistently identified both WCG [18F]GTP1 SUVR and WMH as independent predictors of cognitive performance across all indices (p's<0.05), with a much larger proportion of variance attributable to WCG [18F]GTP1 SUVR. Conclusion: Amongst participants with prodromal‐to‐mild AD enrolled in the Tauriel study, [18F]GTP1 tau PET signal was more strongly associated with baseline cognitive performance than the extent of WMH. These data suggest that even in AD participants with co‐morbid cerebral microvascular ischemic disease, therapeutic interventions targeting tau have the potential to ameliorate subsequent cognitive decline. [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities (WMH) on MRI are commonly seen in Alzheimer's disease (AD) and thought to represent co‐morbid microvascular ischemic disease. However, the relationship between WMH and tau pathology in AD remains incompletely understood. We explored this question using screening/baseline data from a Phase 2 study of the anti‐tau antibody semorinemab (Tauriel; NCT03289143), which included both MRI and [18F]GTP1 tau PET imaging. Method: Participants in the Tauriel study are aged 50‐80, meet criteria for AD dementia or mild cognitive impairment (MCI), have MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, evidence of significant amyloid pathology, and significant episodic memory impairment (RBANS delayed memory index < 85), and undergo screening MRIs, with WMH quantified using the Fazekas scale. Analyses were performed on a subset of participants (n=381) who received baseline [18F]GTP1 tau PET scans. Relationships between WMH, [18F]GTP1 SUVR in an AD‐specific temporal lobe ROI, age, and cognitive scales were assessed graphically and quantified using Pearson correlations, Cohen's D, t‐tests, and multiple linear regression. Result: Tauriel participants had Fazekas scores of zero (n=161), one (n=208), or two (n=12). Per the Figure, participants with Fazekas scores > 0 tended to be older (Cohen's D=0.69, p < 0.001) and have lower temporal [18F]GTP1 SUVR (Cohen's D=0.35, p<0.001). The relationship between temporal [18F]GTP1 SUVR and baseline ADAS‐Cog13 (r=0.39, p<0.001) remained significant after adjusting for Fazekas score and age via multiple regression (p<0.001). Conclusion: Given the circumscribed range of disease severity seen in prodromal‐to‐mild AD participants at screening/baseline in the Tauriel study, the relationships between MRI WMH and [18F]GTP1 tau PET suggest that these pathologies have additive and independent contributions to cognition that may be age‐related. Clinical trials of anti‐tau therapeutics in similar patient populations may need to account for cerebrovascular co‐morbidities in patient selection and/or efficacy analyses. [ABSTRACT FROM AUTHOR]

Background: In prior cross‐sectional studies using [18F]GTP1 or other tau PET tracers across a spectrum of Alzheimer's disease (AD) severity, tau PET signal has independently correlated with cognition, even after adjustments for β‐amyloid (Aβ) load and atrophy. However, it remains uncertain how robust these correlations are in more homogeneous patient populations (e.g., clinical trial participants) and after adjustment for MRI white‐matter hyperintensities (WMH). We sought to address this question by examining baseline data from the Phase 2 Tauriel study (NCT03289143), which is investigating the safety and efficacy of semorinemab (an anti‐tau antibody) in prodromal‐to‐mild AD. Method: We analyzed data from a subset of Tauriel participants who underwent baseline [18F]GTP1 tau PET imaging and met criteria for probable AD dementia (n=244) or mild cognitive impairment (MCI; n=137), with MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, significant Aβ pathology (PET or CSF), and significant episodic memory impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Other screening/baseline assessments included the 13‐item version of the Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13) and MRI (WMH scored with Fazekas scale). Relationships between cognitive indices, whole cortical gray (WCG) [18F]GTP1 SUVR, WMH, and age were assessed using Pearson correlations and multiple linear regression. Result: Univariate analyses revealed significant correlations between all cognitive indices [MMSE, CDR Sum of Boxes, ADAS‐Cog13, and RBANS] and [18F]GTP1 SUVR across the whole cortical gray (WCG; p's<0.001). Significant univariate correlations were also seen between WMH and ADAS‐Cog13 scores (p=0.035) and between age and RBANS scores (p<0.001). Multivariate linear regression analyses that included all three factors consistently identified both WCG [18F]GTP1 SUVR and WMH as independent predictors of cognitive performance across all indices (p's<0.05), with a much larger proportion of variance attributable to WCG [18F]GTP1 SUVR. Conclusion: Amongst participants with prodromal‐to‐mild AD enrolled in the Tauriel study, [18F]GTP1 tau PET signal was more strongly associated with baseline cognitive performance than the extent of WMH. These data suggest that even in AD participants with co‐morbid cerebral microvascular ischemic disease, therapeutic interventions targeting tau have the potential to ameliorate subsequent cognitive decline. [ABSTRACT FROM AUTHOR]