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BackgroundMolecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer's disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer's disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly.MethodsTo determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.ResultsCLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.ConclusionsThe findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

Background: Medicare claims data enables broad characterization of United States (US) patients with Alzheimer's disease and related dementias (ADRD). Resulting insights can be used as a reference to describe this population and as a benchmark for generalizability of patients with ADRD enrolled in clinical trials. Objective: To characterize demographics, comorbidities, comedications, and healthcare resource utilization in US patients with newly diagnosed ADRD, focusing on differences across Medicare fee-for-service (FFS) and Medicare Advantage enrollees. Methods: This observational cohort study used complete (100%) Medicare claims data inclusive of both FFS and Medicare Advantage insurance types. Study patients were ≥65-years-old with ≥12 months of continuous pre-index enrollment and Medicare Part D coverage. Two cohorts of patients were selected in calendar year 2019; those newly diagnosed with ADRD and those with a new acetylcholinesterase inhibitor (AChEI) claim. Results: The newly diagnosed ADRD and new AChEI users cohorts included 861,727 and 395,319 patients, respectively. Demographics and comedications were generally similar across the two cohorts, supporting internal validity of the study results. Circulatory system-related comorbidities and mood disorders were common in both cohorts. Differences in race, inpatient claims and long-term care claims were observed between insurance types. Conclusions: The study results provide a reference for describing the ADRD population in the US and emphasize the importance of evaluating new Alzheimer's disease drugs in broad patient populations with comorbidities and concomitant medication use. [ABSTRACT FROM AUTHOR]

Dementia is often characterized as being caused by one of several major diseases, such as Alzheimer's disease (AD), cerebrovascular disease, Lewy body disease, or a frontotemporal degeneration. Failure to acknowledge that more than one entity may be present precludes attempts to understand interactive relationships. The clinicopathological studies of dementia demonstrate that multiple pathologic processes often coexist. How overlapping pathologic findings affect the diagnosis and treatment of clinical AD and other dementia phenotypes was the topic taken up by the Alzheimer's Association's Research Roundtable in October 2014. This review will cover the neuropathologic basis of dementia, provide clinical perspectives on multiple pathologies, and discuss therapeutics and biomarkers targeting overlapping pathologies and how these issues impact clinical trials.High prevalence of multiple pathologic findings among individuals with clinical diagnosis of AD suggests that new treatment strategies may be needed to effectively treat AD and other dementing illnesses.

INTRODUCTION: Apolipoprotein E (APOE) ε4 may interact with response to amyloid‐targeting therapies. METHODS: Aggregate data from trials enrolling participants with amyloid‐positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression. RESULTS: Pooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non‐carriers. Carrier and non‐carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale–Sum of Boxes (CDR‐SB) were –0.30 (–0.478, –0.106) and –0.20 (–0.435, 0.042) and AD Assessment Scale–Cognitive subscale (ADAS‐Cog) values were –1.01 (–1.577, –0.456) and –0.80 (–1.627, 0.018), respectively. Decline in the APOE ε4 non‐carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases. DISCUSSION: We hypothesize that APOE ε4 carriers have same or better response than non‐carriers to amyloid‐targeting therapies and similar or less disease progression with placebo in amyloid‐positive trials. HIGHLIGHTS: Amyloid‐targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers.Clinical decline is the same/slightly faster in amyloid‐positive APOE ε4 non‐carriers.Prevalence of non‐carriers in trial populations could impact outcomes. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does donanemab, a monoclonal antibody designed to clear brain amyloid plaque, provide clinical benefit in early symptomatic Alzheimer disease? Findings: In this randomized clinical trial that included 1736 participants with early symptomatic Alzheimer disease and amyloid and tau pathology, the least-squares mean change in the integrated Alzheimer Disease Rating Scale score (range, 0-144; lower score indicates greater impairment) at 76 weeks was −6.02 in the donanemab group and −9.27 in the placebo group for the low/medium tau population and −10.19 in the donanemab group and −13.11 in the placebo group in the combined study population, both of which were significant differences. Meaning: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab treatment significantly slowed clinical progression at 76 weeks. Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of.04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P <.001) in the low/medium tau population and −10.2 (95% CI, −11.22 to −9.16) with donanemab and −13.1 (95% CI, −14.10 to −12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P <.001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, −0.67 [95% CI, −0.95 to −0.40]; P <.001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, −0.7 [95% CI, −0.95 to −0.45]; P <.001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and Relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial Registration: ClinicalTrials.gov Identifier: NCT04437511 This randomized clinical trial examines the efficacy and adverse effects of donanemab, a monoclonal antibody designed to clear brain amyloid plaque, among patients with early symptomatic Alzheimer disease. [ABSTRACT FROM AUTHOR]

Introduction: An Alzheimer's disease (AD) dementia disease progression model was developed based on the integrated Alzheimer's Disease Rating Scale (iADRS). Methods: Data from 3483 placebo participants in six AD trials were used to develop the disease progression model with NONMEM (version 7.4.2) and examined for mild cognitive impairment, and mild and moderate dementia due to AD. Results: Baseline iADRS score was significantly influenced by AD symptomatic medication use, EXPEDITION2 enrollment (included moderate AD participants), age, and baseline Mini‐Mental State Examination (MMSE) score. Rate of disease progression increased across disease stage and was significantly influenced by AD medication use, age, and baseline MMSE score. Apolipoprotein E ε4 carrier status did not influence baseline iADRS score or disease progression. Discussion: These results demonstrate a disease progression model describing the time course of the iADRS across the AD severity spectrum. This model can assist future clinical trials in study design optimization and treatment effect interpretation. Highlights: A disease progression model described the integrated Alzheimer's Disease Rating Scale (iADRS) time course in mild cognitive impairment to moderate Alzheimer's disease.Using the linear regression model, iADRS scores can be calculated for Mini‐Mental State Examination scores.Results can help optimize future clinical trial design and aid in understanding treatment effects. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The safety and efficacy of donanemab has been evaluated in early Alzheimer's disease in TRAILBLAZER-ALZ and TRAILBLAZER- ALZ 2. The objective is to characterize the efficacy and safety associated with donanemab, a novel amyloid-targeting therapy (ATT). METHODS: TRAILBLAZER-ALZ (phase 2) and TRAILBLAZER-ALZ 2 (phase 3) were multicenter, randomized, double-blind, placebo-controlled, 18- month trials that assessed the safety and efficacy of donanemab in patients with early Alzheimer's disease. The primary outcome in both studies was change from baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS). Secondary outcomes included change from baseline on CDR-SB, ADAS-Cog13, ADCS-iADL, and MMSE. Amyloid-related imaging abnormalities of edema/effusion (ARIA-E), amyloid-related imaging abnormalities of microhemorrhages and hemosiderin deposits (ARIA-H), and infusion-related reactions were adverse events of special interest. RESULTS: TRAILBLAZER-ALZ 2 demonstrated a slowing of clinical progression at 76 weeks and had a safety profile consistent with TRAILBLAZER-ALZ. In the low/medium-tau population in TRAILBLAZER-ALZ 2, change in iADRS score demonstrated a 35% slowing of disease progression (difference, 3.25; 95% CI 1.88 to 4.62; P < 0.001), and change in CDR-SB demonstrated a 36% slowing (difference, -0.67; 95% CI -0.95 to -0.40; P < 0.001). Participants with low/medium-tau who received donanemab experienced a 39% lower risk of progressing to the next disease stage versus placebo over 76w (CDR-Global score, Hazard Ratio=0.61; P < 0.001). Significant, positive results across all clinical endpoints were also observed in the combined (low/medium and high tau) population. Adverse events with donanemab in TRAILBLAZER-ALZ 2 included ARIA-E (24.0%, 6.1% symptomatic); ARIA-H (31.4%); and infusion-related reactions (8.7%). CONCLUSION: TRAILBLAZER-ALZ and TRAILBLAZER-ALZ 2 trials demonstrated that donanemab significantly slowed cognitive and functional decline in amyloid-positive early symptomatic AD participants and lowered their risk of disease progression while adverse events were consistent with donanemab's well-characterized safety profile and known class risks. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To characterize the efficacy and safety associated with donanemab, a novel amyloid-targeting therapy (ATT). METHODS: TRAILBLAZER-ALZ (phase 2) and TRAILBLAZER-ALZ 2 (phase 3) were multicenter, randomized, double-blind, placebo-controlled, 18- month trials that assessed the safety and efficacy of donanemab in patients with early Alzheimer's disease. The primary outcome in both studies was change from baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS). Secondary outcomes included change from baseline on the CDR-SB, the ADAS-Cog13, the ADCS-iADL, and MMSE. Amyloid-related imaging abnormalities of edema/ effusion (ARIA-E), amyloid-related imaging abnormalities of microhemorrhages and hemosiderin deposits (ARIA-H), and infusion-related reactions were adverse events of special interest. RESULTS: TRAILBLAZER-ALZ 2 demonstrated a slowing of clinical progression at 76 weeks and had a safety profile consistent with TRAILBLAZER-ALZ. In the low/medium-tau population in TRAILBLAZER-ALZ 2, change in iADRS score demonstrated a 35% slowing of disease progression (difference, 3.25; 95% CI, 1.88 to 4.62; P < 0.001). Change in CDR-SB demonstrated a 36% slowing (difference -0.67; 95% CI -0.95 to -0.40; P < 0.001). Significant, positive results across all clinical endpoints were also observed in the combined (low/medium and high tau) population. Adverse events with donanemab in TRALBLAZER-ALZ 2 included amyloid-related imaging abnormalities ARIA-E (24.0%, 6.1% symptomatic); ARIA-H (31.4%); and infusion-related reactions (8.7%). Most events were transient and asymptomatic. Participants receiving donanemab experienced a 39% lower risk of progressing to the next disease stage versus placebo over 76w (CDR-Global score, Hazard Ratio=0.61; P < 0.001). CONCLUSION: TRAILBLAZER-ALZ and TRAILBLAZER-ALZ 2 trials demonstrated that donanemab significantly slowed cognitive and functional decline in amyloid-positive early symptomatic AD participants and lowered their risk of disease progression while key safety risks occurred primarily within the first 6 months and then declined. [ABSTRACT FROM AUTHOR]