Abstract Background The positron emission tomography (PET) radiotracer [18F]MK‐6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within‐brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK‐6240 use to identify and stage AD subjects versus non‐AD and controls. Methods Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter‐reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30‐scan set, providing initial validation. Inter‐rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Results Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter‐rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131‐scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. Discussion This four‐class [18F]MK‐6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. Highlights A visual read method has been developed for [18F]MK‐6240 tau positron emission tomography. The method is readily trainable and reproducible, with inter‐rater kappas of 0.98. The read method has been applied to a diverse set of 1842 [18F]MK‐6240 scans. All scans from a spectrum of disease states and acquisitions could be classified. Read classifications are consistent with histopathological neurofibrillary tangle staging literature.

Supplementary Figures 1-4 from Inhibition of Tumor Growth Progression by Antiandrogens and mTOR Inhibitor in a Pten-Deficient Mouse Model of Prostate Cancer

The BACE inhibitor verubecestat was previously found to reduce amyloid load as assessed by 18F-flutemetamol positron emission tomography (PET) composite cortical standard uptake value ratio (SUVr) in patients with mild-to-moderate Alzheimer’s disease (AD) in a substudy of the EPOCH trial. Here, we report on additional analyses relevant to the EPOCH PET data, to help inform on the use of PET for assessing amlyloid load in AD clinical trials. The analyses addressed (1) identification of an optimal 18F-flutemetamol reference region, (2) determination of the threshold to characterize the magnitude of the longitudinal change, and (3) the impact of partial volume correction (PVC). Pons and subcortical white matter were evaluated as reference regions. The SUVr cutoffs and final reference region choice were determined using 162 18F-flutemetamol PET scans from the AIBL dataset. 18F-flutemetamol SUVrs were computed at baseline and at Week 78 in EPOCH participants who received verubecestat 12 mg (n = 14), 40 mg (n = 20), or placebo (n = 20). Drug effects on amyloid load were computed using either Meltzer (MZ), or symmetric geometric transfer matrix (SGTM) PVC and compared to uncorrected data. The optimal subcortical white matter and pons SUVr cutoffs were determined to be 0.69 and 0.62, respectively. The effect size to detect longitudinal change was higher for subcortical white matter (1.20) than pons (0.45). Hence, subcortical white matter was used as the reference region for the EPOCH PET substudy. In EPOCH, uncorrected baseline SUVr values correlated strongly with MZ PVC (r2 = 0.94) and SGTM PVC (r2 = 0.92) baseline SUVr values, and PVC did not provide improvement for evaluating treatment effects on amyloid load at Week 78. No change from baseline was observed in the placebo group at Week 78, whereas a 0.02 and a 0.04 decrease in SUVr were observed in the 12 mg and 40 mg arms, with the latter representing a 22

The Down syndrome (DS) population is aging rapidly with a life expectancy of nearly 60 years of age compared to 25 years of age in 1980. There are approximately 210,000 people with DS in the USA and about 85,000 are >30 years of age. 1 With longevity comes a high risk of Alzheimer’s disease (AD). The lifetime risk of AD is estimated to be >90% , 2 and is the leading cause of death for adults with DS. 3 Symptoms of DS associated AD (DS-AD) appear at approximately 45 to 55 years of age with early biomarker changes occurring a decade or more earlier at about 35 years of age. 4 Recent fluid biomarker and amyloid imaging data show that AD pathogenesis in individuals with DS are similar to AD biomarkers in individuals with late-onset AD. 5 Published data using the tau positron emission tomography (PET) imaging agent flortaucipir provide data on tau accumulation in DS-AD that correlates with amyloid burden 6 and cognitive decline 7 . The LIFE-DSR study is a multi-center natural history study recruiting 270 adults with DS. Participants, age 25 or older, are followed at 16-month intervals over 32-months. Data collected includes cognitive, behavioral, and functional from a range of common developmental disability assessment tools. Plasma and buffy coat samples are banked for prospective molecular and genetic analyses. Two longitudinal sub-studies will be added to the LIFE-DSR protocol. First is a tau PET sub-study using the tracer 18 F-MK-6240. Second is a cerebrospinal fluid (CSF) biomarkers sub-study. Both sub-studies will enroll 30 LIFE-DSR participants with similar demographics (age >= 35 years), collecting data twice every 16 months. Data from the tau PET and CSF sub-studies will be compared with the clinical and fluid biomarker data collected under the LIFE-DSR protocol. Inclusion of PET and CSF sub-studies will enrich the LIFE-DSR study and improve our ability to understand and assess clinical features, imaging, and genetic markers of DS-AD progression and provide a basis for the development of endpoints for clinical trials to potentially develop more effective treatments. This is the first use of the next generation PET tau radiotracer, 18 F-MK-6240 in DS.

Background [ 18 F]MK-6240 is a PET tracer with sub-nanomolar affinity for neurofibrillary tangles. Therefore, tau quantification is possible with [ 18 F]MK-6240 PET/CT scans, and it can be used for assessment of Alzheimer’s disease. However, long acquisition scans are required to provide fully quantitative estimates of pharmacokinetic parameters. Therefore, on the present study, dual-time-window (DTW) acquisitions was simulated to reduce PET/CT acquisition time, while taking into consideration perfusion changes and possible scanning protocol non-compliance. To that end, time activity curves (TACs) representing a 120-min acquisition (TAC 120 ) were simulated using a two-tissue compartment model with metabolite corrected arterial input function from 90-min dynamic [ 18 F]MK-6240 PET scans of three healthy control subjects and five subjects with mild cognitive impairment or Alzheimer’s disease. Therefore, TACs corresponding to different levels of specific binding were generated and then various perfusion changes were simulated. Next, DTW acquisitions were simulated consisting of an acquisition starting at tracer injection, a break and a second acquisition starting at 90 min post-injection. Finally, non-compliance with the PET/CT scanning protocol were simulated to assess its impact on quantification. All TACs were quantified using reference Logan’s distribution volume ratio (DVR) and standardized uptake value ratio (SUVR 90 ) using the cerebellar cortex as reference region. Results It was found that DVR from a DTW protocol with a 60-min break between two 30-min dynamic scans closely approximates the DVR from the uninterrupted TAC 120 , with a regional bias smaller than 2.5%. Moreover, SUVR 90 estimates were more susceptible (regional bias ≤ 19%) to changes in perfusion compared to DVR from a DTW TAC (regional bias ≤ 10%). Similarly, SUVR 90 was affected by late-time scanning protocol delays reaching an increase of 8% for a 20-min delay, while DVR was not affected (regional bias < 1.5%) by DTW protocol non-compliance. Conclusions Therefore, such DTW protocol has the potential to increase patient comfort and throughput without compromising quantitative accuracy and is more reliable against SUVR in terms of perfusion changes and protocol deviations, which could prove beneficial for drug effect assessment and patient follow-up using longitudinal [ 18 F]MK-6240 PET imaging.

The Worldwide Alzheimer's Disease Neuroimaging Initiative (WW-ADNI) is a collaborative effort to investigate imaging and biofluid markers that can inform Alzheimer's disease treatment trials. It is a public-private partnership that spans North America, Argentina, Australia, Canada, China, Japan, Korea, Mexico, and Taiwan. In 2004, ADNI researchers began a naturalistic, longitudinal study that continues today around the globe. Through several successive phases (ADNI-1, ADNI-GO, ADNI-2, and ADNI-3), the study has fueled amyloid and tau phenotyping and refined neuroimaging methodologies. WW-ADNI researchers have successfully standardized analyses and openly share data without embargo, providing a rich data set for other investigators. On August 26, 2020, the Alzheimer's Association convened WW-ADNI researchers who shared updates from ADNI-3 and their vision for ADNI-4.

BACKGROUND:We performed exploratory analyses of retinal thickness data from a clinical trial of the AβPP cleaving enzyme (BACE) inhibitor verubecestat in patients with Alzheimer's disease (AD).OBJECTIVE:To evaluate: 1) possible retinal thickness changes following BACE inhibition; and 2) possible association between retinal thickness and brain atrophy.METHODS:Retinal thickness was measured using spectral-domain optical coherence tomography in a 78-week randomized placebo-controlled trial of verubecestat in 1,785 patients with mild-to-moderate AD. Changes from baseline in retinal pigment epithelium, macular grid retinal nerve fiber layer, central subfield retinal thickness, and macular grid volume were evaluated for verubecestat versus placebo. Correlation analyses were performed to investigate the potential association between macular grid retinal nerve fiber layer and central subfield retinal thickness with brain volumetric magnetic resonance imaging (vMRI) data at baseline, as well as correlations for changes from baseline at Week 78 in patients receiving placebo.RESULTS:Verubecestat did not significantly alter retinal thickness during the trial compared with placebo. At baseline, mean macular grid retinal nerve fiber layer and central subfield retinal thickness were weakly but significantly correlated (Pearson's r values≤0.23, p-values < 0.01) with vMRI of several brain regions including whole brain, hippocampus, and thalamus. At Week 78, correlations between retinal thickness and brain vMRI changes from baseline in the placebo group were small and mostly not statistically significant.CONCLUSION:BACE inhibition by verubecestat was not associated with adverse effects on retinal thickness in patients with mild-to-moderate AD. Correlations between retinal thickness and brain volume were observed at baseline.TRIAL REGISTRATION:Clinicaltrials.gov NCT01739348 (registered December 3, 2012; https://clinicaltrials.gov/ct2/show/NCT01739348).

Background [ 18 F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation as either negative (equating to none or sparse amyloid plaques) or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of nuclear medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases. Methods A total of 2770 [ 18 F]flutemetamol images were collected from 3 clinical studies and 6 research cohorts with available visual reading of [ 18 F]flutemetamol and quantitative analysis of images. These were assessed further to examine both the discordance and concordance between visual and quantitative imaging primarily using thresholds robustly established using pathology as the standard of truth. Scans covered a wide range of cases (i.e. from cognitively unimpaired subjects to patients attending the memory clinics). Methods of quantifying amyloid ranged from using CE/510K cleared marked software (e.g. CortexID, Brass), to other research-based methods (e.g. PMOD, CapAIBL). Additionally, the clinical follow-up of two types of discordance between visual and quantitation (V+Q- and V-Q+) was examined with competing risk regression analysis to assess possible differences in prediction for progression to Alzheimer’s disease (AD) and other diagnoses (OD). Results Weighted mean concordance between visual and quantitation using the autopsy-derived threshold was 94% using pons as the reference region. Concordance from a sensitivity analysis which assessed the maximum agreement for each cohort using a range of cut-off values was also estimated at approximately 96% (weighted mean). Agreement was generally higher in clinical cases compared to research cases. V-Q+ discordant cases were 11% more likely to progress to AD than V+Q- for the SUVr with pons as reference region. Conclusions Quantitation of amyloid PET shows a high agreement vs binary visual reading and also allows for a continuous measure that, in conjunction with possible discordant analysis, could be used in the future to identify possible earlier pathological deposition as well as monitor disease progression and treatment effectiveness.

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.

[18F]MK-6240 is a selective, high-affinity PET radiotracer for imaging neurofibrillary tangles (NFT) in Alzheimer’s disease (AD). Herein, we report test–retest (T–RT) reproducibility of [18F]MK-6240 in AD and healthy volunteers (HV). Twelve subjects with AD and three cognitively normal HV were enrolled in the study and dynamically scanned for 150 min with [18F]MK-6240 under a T–RT protocol. Two radioactivity doses were investigated: 165 ± 3 MBq (n = 6) and 300 ± 40 MBq (n = 9). Serial arterial blood samples were taken for each scan to obtain metabolite-corrected input functions. Following intravenous administration of [18F]MK-6240, the tracer rapidly partitioned into the brain and its heterogenous distribution pattern was consistent with known NFT pathology in AD. In contrast, uptake in HV was low and uniform across the brain parenchyma. Across all subjects, average T–RT variabilities in NFT-rich regions were ∼21%, ∼14% and ∼6% for various quantitative metrics: total distribution volume (VT), binding potential (BPND), and standardized uptake ratio (SUVR90–120), respectively. No significant differences in SUVR T–RT variability were observed between the high and low injected radioactivity groups (5.6% and 6.1%, respectively). This work suggests [18F]MK-6240 has adequate SUVR T–RT characteristics supporting the use of this outcome in future studies.

Treatment with BACE inhibitor verubecestat 12mg and 40mg failed to improve cognition in mild-to-moderate AD patients but was associated with reduced MRI brain volume on volumetric measures. To explore this observed effect, we performed kinetic analyses of volumetric MRI changes in different brain regions and assessed the contribution of amyloid load and disease-related neurodegeneration. Participants (age 55–85 years, inclusive) with probable AD and an MMSE score ≥15 and ≤26 were enrolled. MRI scans were obtained at baseline and at weeks 13, 26, 52 and 78 of the treatment period. 3D T1-weighted MRI images were segmented using Freesurfer and analyzed using a tensor based morphometry method. PET amyloid data were obtained with Vizamyl at baseline and week-78. SUVR values were generated with subcortical white matter as a reference region. Compared with placebo, kinetic analysis of 20 brain regions positive for amyloid showed an increased MRI volume loss in both verubecestat dose groups in all regions at week-13 with no evidence of further loss relative to placebo through week-78. Correlation analysis did not show a relationship between verubecestat-related volume reductions at week-13 and week-78 and amyloid burden at baseline. Analysis of 29 brain regions categorized by Vizamyl imaging as amyloid positive or negative showed that verubecestat-related volume loss at week-13 was present only in amyloid positive regions. The degree of AD-related neurodegeneration in the placebo group (change in MRI volume from baseline at week-78) was estimated in 31 brain regions. Verubecestat-related volume loss at week-13 within a region was not related to the magnitude of disease-related regional neurodegeneration in the placebo group. Finally, MRI volume changes at week-13 showed no conclusive relationship with ADAS-Cog11 total score. Kinetic analyses of verubecestat-induced brain volume loss demonstrate that this effect occurs rapidly and only in brain regions with amyloid pathology. However, this regional effect does not appear to be correlated with the magnitude of disease-related neurodegeneration or cognitive impairment. These results suggest that verubecestat is not associated with a generalized, widespread or progressive neurotoxic effect but may exert specific effects on amyloid related processes.

[18F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first-in-human whole-body biodistribution and dosimetry studies of [18F]MK-6240 for its potential application in human brain imaging studies. MK-6240 was administered intravenously (IV) in a 7-day rat toxicity study at × 50, × 100, and × 1000 dose margins relative to projected highest clinical dose of 0.333 μg/kg. The IV formulation of MK-6240 for clinical use and the formulation used in the 7-day rat toxicity study was tested for hemolysis potential in human and Wistar rat whole blood. Sequential whole-body positron emission tomography scans were performed in three healthy young subjects after IV bolus injection of 180 ± 0.3 MBq [18F]MK-6240 to characterize organ biodistribution and estimate whole-body radiation exposure (effective dose). MK-6240 administered IV in a 7-day rat toxicity study did not show any test article-related changes. The no-observed-adverse-effect level in rats was ≥ 333 μg/kg/day which provides a margin 1000-fold over an anticipated maximum clinical dose of 0.333 μg/kg. Additionally, the MK-6240 formulation was not hemolytic in human or Wistar rat blood. [18F]MK-6240 activity was widely distributed to the brain and the rest of the body, with organ absorbed doses largest for the gall bladder (202 μGy/MBq). The average (±SD) effective dose was 29.4 ± 0.6 μSv/MBq, which is in the typical range for F-18 radiolabeled ligands. Microdoses of [18F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [18F]MK-6240 is anticipated to result in a total human effective dose of 5.4 mSv and thus allows multiple positron emission tomography scans of the same subject per year.

In a recent Phase-3 trial (APECS) verubecestat was associated with poorer clinical outcomes compared with placebo in prodromal AD subjects. The subjects were screened using amyloid PET imaging and a subgroup of patients participated in a tau PET substudy. Here we report on the characteristics of neurofibrillary tangle (NFT) distribution in these prodromal AD subjects. Participants 50–85 years of age with prodromal AD/amnestic mild cognitive impairment due to AD were randomized in a double-blind, 24-month, placebo-controlled trial of verubecestat (12mg and 40mg). Subjects had a MMSE score between 24–30 and a positive Aβ imaging PET scan at screening. After 1 year in the trial, thirteen participants (3 females and 10 males) participated in a tau PET imaging substudy. Participants underwent 30 min (80 – 110 min post-tracer injection) brain PET scans with [18F]MK-6240. PET scans were obtained at multiple sites, but centrally collected and quality controlled by Bioclinica. The image processing including motion correction, spatial coregistration to 3D T1 MRI, normalization and smoothing were performed consistently across subjects. Cortical and subcortical SUVRs were calculated with cerebellar gray matter as reference. At the time of scanning 4 subjects were on placebo, 3 and 6 subjects had received 12 mg or 40 mg verubecestat for 12 months, respectively. Subjects age ranged between 55–87 year old and MMSE score between 23-29. There was no significant difference in cortical gray matter, parahippocampal and ambient gyri SUVRs between treatment groups. A positive [18F]MK-6240 signal was observed in hippocampal and limbic regions of all patients with SUVR ranging from 1 to > 3. Different patterns of NFT cortical distribution were observed, with 6 subjects showing levels consistent with Braak V-VI in typical brain regions known for NFT accumulation while the other subjects showed less NFT. In this limited sample size, both higher global and regional SUVRs tended to correlate with worse cognitive scores. In the APECS trial, prodromal amyloid positive subjects exhibited positive [18F]MK-6240 PET scan indicating the presence of NFT pathology. The diversity of brain NFT distribution pattern suggests that these prodromal subjects were at different stages on the AD pathological continuum.

BACKGROUND Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered β‐site amyloid precursor protein–cleaving enzyme 1 (BACE‐1) inhibitor that blocks production of amyloid‐beta (Aβ). The drug did not prevent clinical progression in a trial involving patients with mild‐to‐moderate dementia due to Alzheimer's disease. METHODS We conducted a randomized, double‐blind, placebo‐controlled, 104‐week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale–Sum of Boxes (CDR‐SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12‐mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40‐mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR‐SB score was 1.65 in the 12‐mg group, 2.02 in the 40‐mg group, and 1.58 in the placebo group (P=0.67 for the comparison between the 12‐mg group and the placebo group and P=0.01 for the comparison between the 40‐mg group and the placebo group), suggesting a worse outcome in the higher‐dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient‐years in the 12‐mg group, the 40‐mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.)