Substantial Doubt Remains about the Efficacy of Anti-Amyloid Antibodies

Alzheimer's disease (AD) is a prevalent, progressive, and ultimately fatal neurodegenerative disorder that is defined pathologically by the accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. There remains an unmet need for therapies that can halt or slow the course of AD. To address this need, the FDA has provided a mechanism, under its Accelerated Approval pathway, for potential therapeutics to be approved based in part on their ability to reduce brain amyloid. Through this pathway, two monoclonal anti-amyloid antibodies, aducanumab and lecanemab, have been approved for clinical use. More recently, another amyloid-lowering antibody, donanemab, generated a statistically significant outcome in a phase 3 clinical trial and will shortly come under FDA review. While these monoclonal antibodies are not yet routinely used in clinical practice, the series of recent positive clinical trials has fostered enthusiasm amongst some AD experts. Here, we discuss three key limitations regarding recent anti-amyloid clinical trials: (1) there is little to no evidence that amyloid reduction correlates with clinical outcome, (2) the reported efficacy of anti-amyloid therapies may be partly, or wholly, explained by functional unblinding, and (3) donanemab in its phase 3 trial had no effect on tau burden, the pathological hallmark more closely related to cognition. Taken together, these observations call into question the efficacy of anti-amyloid therapies.Comment: 11 pages, 2 figures; Update 11/18/2023: Added subheadings to manuscript to improve readability, added a new data point to Figure 1A and Figure 2 for the recently published A4 clinical tria

Women can bear a bigger burden: ante- and post-mortem evidence for reserve in the face of tau.

In this study, we aimed to assess whether women are able to withstand more tau before exhibiting verbal memory impairment. Using data from 121 amyloid-β-positive Alzheimer's Disease Neuroimaging Initiative participants, we fit a linear model with Rey Auditory Verbal Learning Test score as the response variable and tau-PET standard uptake value ratio as the predictor and took the residuals as an estimate of verbal memory reserve for each subject. Women demonstrated higher reserve (i.e. residuals), whether the Learning (t = 2.78, P = 0.006) or Delay (t = 2.14, P = 0.03) score from the Rey Auditory Verbal Learning Test was used as a measure of verbal memory ability. To validate these findings, we examined 662 National Alzheimer's Coordinating Center participants with a C2/C3 score (Consortium to Establish a Registry for Alzheimer's Disease) at autopsy. We stratified our National Alzheimer's Coordinating Center sample into Braak 1/2, Braak 3/4 and Braak 5/6 subgroups. Within each subgroup, we compared Logical Memory scores between men and women. Men had worse verbal memory scores within the Braak 1/2 (Logical Memory Immediate: β = -5.960 ± 1.517, P < 0.001, Logical Memory Delay: β = -5.703 ± 1.677, P = 0.002) and Braak 3/4 (Logical Memory Immediate: β = -2.900 ± 0.938, P = 0.002, Logical Memory Delay: β = -2.672 ± 0.955, P = 0.006) subgroups. There were no sex differences in Logical Memory performance within the Braak 5/6 subgroup (Logical Memory Immediate: β = -0.314 ± 0.328, P = 0.34, Logical Memory Delay: β = -0.195 ± 0.287, P = 0.50). Taken together, our results point to a sex-related verbal memory reserve

Tau and atrophy: domain-specific relationships with cognition.

BackgroundLate-onset Alzheimer's disease (AD) is characterized by primary memory impairment, which then progresses towards severe deficits across cognitive domains. Here, we report how performance in cognitive domains relates to patterns of tau deposition and cortical thickness.MethodsWe analyzed data from 131 amyloid-β positive participants (55 cognitively normal, 46 mild cognitive impairment, 30 AD) of the Alzheimer's Disease Neuroimaging Initiative who underwent magnetic resonance imaging (MRI), flortaucipir (FTP) positron emission tomography, and neuropsychological testing. Surface-based vertex-wise and region-of-interest analyses were conducted between FTP and cognitive test scores, and between cortical thickness and cognitive test scores.ResultsFTP and thickness were differentially related to cognitive performance in several domains. FTP-cognition associations were more widespread than thickness-cognition associations. Further, FTP-cognition patterns reflected cortical systems that underlie different aspects of cognition.ConclusionsOur findings indicate that AD-related decline in domain-specific cognitive performance reflects underlying progression of tau and atrophy into associated brain circuits. They also suggest that tau-PET may have better sensitivity to this decline than MRI-derived measures of cortical thickness

Tau and atrophy: domain-specific relationships with cognition.

BackgroundLate-onset Alzheimer's disease (AD) is characterized by primary memory impairment, which then progresses towards severe deficits across cognitive domains. Here, we report how performance in cognitive domains relates to patterns of tau deposition and cortical thickness.MethodsWe analyzed data from 131 amyloid-β positive participants (55 cognitively normal, 46 mild cognitive impairment, 30 AD) of the Alzheimer's Disease Neuroimaging Initiative who underwent magnetic resonance imaging (MRI), flortaucipir (FTP) positron emission tomography, and neuropsychological testing. Surface-based vertex-wise and region-of-interest analyses were conducted between FTP and cognitive test scores, and between cortical thickness and cognitive test scores.ResultsFTP and thickness were differentially related to cognitive performance in several domains. FTP-cognition associations were more widespread than thickness-cognition associations. Further, FTP-cognition patterns reflected cortical systems that underlie different aspects of cognition.ConclusionsOur findings indicate that AD-related decline in domain-specific cognitive performance reflects underlying progression of tau and atrophy into associated brain circuits. They also suggest that tau-PET may have better sensitivity to this decline than MRI-derived measures of cortical thickness

Gene‐ and age‐informed screening for preclinical Alzheimer's disease trials

IntroductionElevated β-amyloid is used to enroll individuals into preclinical Alzheimer's disease trials, but the screening process is inefficient and expensive. Novel enrichment methods are needed to improve efficiency of enrollment.MethodsAlzheimer's disease incidence rates and a polygenic hazard score were used to create a gene- and age-defined ADAge. An ADAge cutpoint was chosen to optimally predict β-amyloid positivity among clinically normal Alzheimer's Disease Neuroimaging Initiative participants and applied to an independent Alzheimer's Disease Research Center validation cohort. The impact of ADAge enrichment on screening costs was evaluated in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease trial data.ResultsIn the validation cohort, the ADAge-enriched sample had a higher proportion of individuals with elevated β-amyloid (difference [95% CI] 0.19[0.07 to 0.33]) than the unenriched sample. ADAge enrichment lowered screening costs by $4.41 million (31.00%) in the real-world clinical trial scenario.DiscussionADAge enrichment provides for a more efficient and cost-effective means to enroll clinically normal individuals with elevated β-amyloid in clinical trials

A Multicompartmental Diffusion Model for Improved Assessment of Whole-Body Diffusion-weighted Imaging Data and Evaluation of Prostate Cancer Bone Metastases.

Purpose To develop a multicompartmental signal model for whole-body diffusion-weighted imaging (DWI) and apply it to study the diffusion properties of normal tissue and metastatic prostate cancer bone lesions in vivo. Materials and Methods This prospective study (ClinicalTrials.gov: NCT03440554) included 139 men with prostate cancer (mean age, 70 years ± 9 [SD]). Multicompartmental models with two to four tissue compartments were fit to DWI data from whole-body scans to determine optimal compartmental diffusion coefficients. Bayesian information criterion (BIC) and model-fitting residuals were calculated to quantify model complexity and goodness of fit. Diffusion coefficients for the optimal model (having lowest BIC) were used to compute compartmental signal-contribution maps. The signal intensity ratio (SIR) of bone lesions to normal-appearing bone was measured on these signal-contribution maps and on conventional DWI scans and compared using paired t tests (α = .05). Two-sample t tests (α = .05) were used to compare compartmental signal fractions between lesions and normal-appearing bone. Results Lowest BIC was observed from the four-compartment model, with optimal compartmental diffusion coefficients of 0, 1.1 × 10-3, 2.8 × 10-3, and >3.0 ×10-2 mm2/sec. Fitting residuals from this model were significantly lower than from conventional apparent diffusion coefficient mapping (P < .001). Bone lesion SIR was significantly higher on signal-contribution maps of model compartments 1 and 2 than on conventional DWI scans (P < .008). The fraction of signal from compartments 2, 3, and 4 was also significantly different between metastatic bone lesions and normal-appearing bone tissue (P ≤ .02). Conclusion The four-compartment model best described whole-body diffusion properties. Compartmental signal contributions from this model can be used to examine prostate cancer bone involvement. Keywords: Whole-Body MRI, Diffusion-weighted Imaging, Restriction Spectrum Imaging, Diffusion Signal Model, Bone Metastases, Prostate Cancer Clinical trial registration no. NCT03440554 Supplemental material is available for this article. © RSNA, 2023 See also commentary by Margolis in this issue

Correcting B0 inhomogeneity-induced distortions in whole-body diffusion MRI of bone.

Diffusion-weighted magnetic resonance imaging (DWI) of the musculoskeletal system has various applications, including visualization of bone tumors. However, DWI acquired with echo-planar imaging is susceptible to distortions due to static magnetic field inhomogeneities. This study aimed to estimate spatial displacements of bone and to examine whether distortion corrected DWI images more accurately reflect underlying anatomy. Whole-body MRI data from 127 prostate cancer patients were analyzed. The reverse polarity gradient (RPG) technique was applied to DWI data to estimate voxel-level distortions and to produce a distortion corrected DWI dataset. First, an anatomic landmark analysis was conducted, in which corresponding vertebral landmarks on DWI and anatomic T2-weighted images were annotated. Changes in distance between DWI- and T2-defined landmarks (i.e., changes in error) after distortion correction were calculated. In secondary analyses, distortion estimates from RPG were used to assess spatial displacements of bone metastases. Lastly, changes in mutual information between DWI and T2-weighted images of bone metastases after distortion correction were calculated. Distortion correction reduced anatomic error of vertebral DWI up to 29 mm. Error reductions were consistent across subjects (Wilcoxon signed-rank p < 10-20). On average (± SD), participants' largest error reduction was 11.8 mm (± 3.6). Mean (95% CI) displacement of bone lesions was 6.0 mm (95% CI 5.0-7.2); maximum displacement was 17.1 mm. Corrected diffusion images were more similar to structural MRI, as evidenced by consistent increases in mutual information (Wilcoxon signed-rank p < 10-12). These findings support the use of distortion correction techniques to improve localization of bone on DWI