Early Symptomatic Alzheimer's Disease Research Articles

Memory impairment in Amyloidβ-status Alzheimer's disease is associated with a reduction in CA1 and dentate gyrus volume: In vivo MRI at 7T

IntroductionIn Alzheimer's disease (AD), early diagnosis facilitates treatment options and leads to beneficial outcomes for patients, their carers and the healthcare system. The neuropsychological battery of the Uniform Data Set (UDSNB3.0) assesses cognition in ageing and dementia, by measuring scores across different cognitive domains such as attention, memory, processing speed, executive function and language. However, its neuroanatomical correlates have not been investigated using 7 Tesla MRI (7T MRI). MethodsWe used 7T MRI to investigate the correlations between hippocampal subfield volumes and the UDSNB3.0 in 24 individuals with Amyloidβ-status AD and 18 age-matched controls, with respective age ranges of 60 (42–76) and 62 (52–79) years. AD participants with a Medial Temporal Atrophy scale of higher than 2 on 3T MRI were excluded from the study. ResultsA significant difference in the entire hippocampal volume was observed in the AD group compared to healthy controls (HC), primarily influenced by CA1, the largest hippocampal subfield. Notably, no significant difference in whole brain volume between the groups implied that hippocampal volume loss was not merely reflective of overall brain atrophy. UDSNB3.0 cognitive scores showed significant differences between AD and HC, particularly in Memory, Language, and Visuospatial domains. The volume of the Dentate Gyrus (DG) showed a significant association with the Memory and Executive domain scores in AD patients as assessed by the UDSNB3.0.. The data also suggested a non-significant trend for CA1 volume associated with UDSNB3.0 Memory, Executive, and Language domain scores in AD. In a reassessment focusing on hippocampal subfields and MoCA memory subdomains in AD, associations were observed between the DG and Cued, Uncued, and Recognition Memory subscores, whereas CA1 and Tail showed associations only with Cued memory. DiscussionThis study reveals differences in the hippocampal volumes measured using 7T MRI, between individuals with early symptomatic AD compared with healthy controls. This highlights the potential of 7T MRI as a valuable tool for early AD diagnosis and the real-time monitoring of AD progression and treatment efficacy. ClinicalTrials.govID NCT04992975 (Clinicaltrial.gov 2023)

At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. Phase 2, open-label, single arm study. Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-β antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Effects of the multidomain intervention with nutritional supplements on cognition and gut microbiome in early symptomatic Alzheimer's disease: a randomized controlled trial.

The SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at-risk elderly people (SUPERBRAIN) is a part of the World-Wide Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (WW-FINGERS) network. This study aimed to demonstrate the effects of the SUPERBRAIN-based multidomain intervention with nutritional supplements in amyloid positive emission tomography (PET) proven early symptomatic Alzheimer's disease patients. Forty-six participants who were diagnosed with mild cognitive impairment or mild dementia and were positive in the amyloid PET study randomized into three groups: group A, the multidomain intervention with nutritional supplements; group B, nutritional supplements only; and a control group. The primary outcome was a change in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total scale index score after an 8-week intervention. Secondary outcomes, including gut microbiome data, were also analyzed. The RBANS total scale index score improved significantly in group A compared with group B (p < 0.032) and compared with the control group (p < 0.001). After intervention, beta diversity of the gut microbiome between group A and the control group increased, and patients in group A were more enriched with Bifidobacterium. SUPERBRAIN-based multidomain intervention with nutritional supplements improves cognition and gut microbiota in patients with early symptomatic Alzheimer's disease who were amyloid-positive by PET.

Phase 3 study finds donanemab slowed progression of Alzheimer's disease

An 18‐month trial has found that the monoclonal antibody donanemab significantly slowed disease progression compared with placebo in adults with early symptomatic Alzheimer's disease. Slowing of clinical progression occurred in both a group with low to medium brain tau protein pathology and a group that included individuals with high tau pathology, the investigators reported. Study results were published online July 17, 2023, in JAMA.

Estimating prevalence of early symptomatic Alzheimer's disease in the United States.

Understanding the prevalence of treatment-eligible Alzheimer's disease (AD) is crucial for policy planning. We used a comprehensive literature review and population cascade approach to estimate the number of amyloid-positive, clinically diagnosed patients with mild cognitive impairment (MCI) or mild dementia due to AD in the United States. An estimated 666,646 individuals were identified as having MCI due to AD (range: 351,926-1,227,776) and 620,850 individuals as having mild dementia due to AD (range: 445,082-820,339). In a US population of 76 million individuals aged 60 or older in 2021, the estimates of MCI and mild dementia due to AD increased with age. As earlier diagnosis of AD and new disease-modifying treatments become available, accurate population estimates are required to reduce uncertainty in the number of clinically diagnosed patients eligible for amyloid-targeting therapies.

Donanemab in Early Symptomatic Alzheimer Disease

There are limited efficacious treatments for Alzheimer disease. To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. 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). 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. 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. 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. 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. ClinicalTrials.gov Identifier: NCT04437511.

Tau as a diagnostic instrument in clinical trials to predict amyloid in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the presence of both amyloid and tau pathology. In vivo diagnosis can be made with amyloid and tau positron emission tomography (PET) imaging. Emergent evidence supports that amyloid and tau accumulation are associated and that amyloid accumulation may precede that of tau. This report further investigates the relationship between amyloid and tau to assess whether elevated cortical tau can predict elevated amyloid in participants with early symptomatic AD. Florbetapir F18 and flortaucipir F18 uptake were evaluated from baseline PET scans collected in three multi-center studies with cognitively impaired participants, including A05 (N = 306; NCT02016560), TB (N = 310; TRAILBLAZER-ALZ; NCT03367403), and TB2 (N = 1165; TRAILBLAZER-ALZ 2; NCT04437511). Images were assessed using visual and quantitative approaches to establish amyloid (A+) and tau (T+) positivity, as well as a combination method (tauVQ) to establish T+. Associations between global amyloid and tau were evaluated with positive and negative predictive values (PPV, NPV) and likelihood ratios (LR+, LR-). Predictive values within subgroups according to ethnicity, race, cognitive score, age, and sex were also evaluated. The relationship between regional tau (four target and two reference regions were tested) and global amyloid was investigated in A05 participant scans using receiver-operating characteristic (ROC) curves. PPV for amyloid positivity was ≥93% for all three trials using various A+ and T+ definitions, including visual, quantitative, and combination methods. Population characteristics did not have an impact on A+ predictability. Regional analyses (early tau (Eτ) volume of interest (VOI), temporal, parietal, frontal) revealed significant area under the ROC curve in Eτ VOI compared to frontal region, regardless of reference region and consistent among visual and quantitative A+ definitions (p < 0.001). These findings suggest that a positive tau PET scan is associated (≥93%) with amyloid positivity in individuals with early symptomatic AD, with the potential benefits of reducing clinical trial and health care expenses, radiation exposure, and participant time. Positron emission tomography (PET) evaluates candidates for Alzheimer's disease (AD) research. A positive tau PET scan is associated (≥93%) with amyloid positivity.A positive amyloid PET is not necessarily associated with tau positivity.Tau PET could be the sole diagnostic tool to confirm candidates for AD trials.

APOE ε4's impact on response to amyloid therapies in early symptomatic Alzheimer's disease: Analyses from multiple clinical trials.

Apolipoprotein E (APOE) ε4 may interact with response to amyloid-targeting therapies. Aggregate data from trials enrolling participants with amyloid-positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression. 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. 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. 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.

Disease progression and costs at the 3-year follow-up of the GERAS-US study.

GERAS-US prospectively characterized clinical and economic outcomes of early symptomatic Alzheimer's disease (AD). Societal cost changes were examined in amyloid-positive patients with mild cognitive impairment due to AD (MCI) and mild dementia due to AD (MILD). Cognition, function, and caregiver burden were assessed using Mini-Mental State Examination (MMSE), Cognitive Function Index (CFI), and Zarit Burden Interview, respectively. Costs are presented as least square mean for the overall population and for MCI versus MILD using mixed model repeated measures. MMSE score and CFI worsened. Total societal costs (dollars/month) for MCI and MILD, respectively, were higher at baseline ($2430 and $4063) but steady from 6 ($1977 and $3032) to 36 months ($2007 and $3392). Direct non-medical costs rose significantly for MILD. Caregiver burden was higher for MILD versus MCI at 12, 18, and 24 months. Function and cognition declined in MILD. Non-medical costs reflect the increasing impact of AD even in its early stages. In the GERAS-US study, total societal costs for patients with mild cognitive impairment due to Alzheimer's disease (MCI) and mild dementia due to Alzheimer's disease (MILD) were higher at baseline but steady from 6 to 36 months.Mini-Mental State Examination (MMSE) and Cognitive Function Index (CFI) worsened; the rate of decline was significant for patients with MILD but not for those with MCI.There was a rise in direct non-medical costs at 36 months for patients with MILD.Caregiver burden was higher for MILD versus MCI at 12, 18, and 24 months.Slowing the rate of disease progression in this early symptomatic population may allow patients to maintain their ability to carry out everyday activities longer.

Meaningful Clinical Changes in Alzheimer Disease Measured With the iADRS and Illustrated Using the Donanemab TRAILBLAZER-ALZ Study Findings.

To provide relevant background of the Integrated Alzheimer's Disease Rating Scale (iADRS), with examples, to assist the reader with the interpretation of iADRS findings from the TRAILBLAZER-ALZ study. The iADRS is an integrated measure of global Alzheimer disease (AD) severity for use in the clinical trial environment. It provides a single score that captures commonalities across cognitive and functional ability domains, reflecting disease-related impairment, while minimizing noise not related to disease progression that may exist within each domain. In AD, disease-modifying therapies (DMTs) are expected to slow the rate of clinical decline, changing the trajectory of disease progression. The overall percent slowing of disease progression with treatment is a more informative outcome of effect than absolute point differences between treatment and placebo groups at any given time point because the latter is influenced by treatment period and disease severity. The TRAILBLAZER-ALZ trial was a phase 2 study designed to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD; the primary outcome measure was the change from baseline to 76 weeks on the iADRS. In the TRAILBLAZER-ALZ study, donanemab slowed disease progression by 32% at 18 months (p = 0.04 vs placebo), demonstrating clinical efficacy. At the patient level, one can assess whether the DMT effect is clinically meaningful by estimating the threshold of change consistent with clinically meaningful worsening; based on the TRAILBLAZER-ALZ findings, treatment with donanemab would delay reaching this threshold by approximately 6 months. The iADRS is capable of accurately describing clinical changes associated with disease progression and detecting treatment effects and is an effective assessment tool for use in clinical trials of individuals with early symptomatic AD.

Neurons derived from individual early Alzheimer's disease patients reflect their clinical vulnerability.

Establishing preclinical models of Alzheimer's disease that predict clinical outcomes remains a critically important, yet to date not fully realized, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-individual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimer's disease where we sought a match between individual disease characteristics in the cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-β burden in life, as measured by cognitive decline and brain activity levels, varies between individuals and this vulnerability rating correlates with the individual cellular vulnerability to extrinsic amyloid-β in vitro as measured by synapse loss and function. Our findings indicate that patient-induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimer's disease pathology but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an individual's in-life clinical vulnerability thus represent a tractable method of Alzheimer's disease modelling using clinical data in combination with cellular phenotypes.

Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease

Plasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures of treatment outcomes. To analyze the association of donanemab treatment with plasma biomarkers associated with Alzheimer disease. TRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to December 4, 2020, across 56 sites in the US and Canada. Exploratory biomarkers were prespecified with the post hoc addition of plasma glial fibrillary acidic protein and amyloid-β. Men and women aged 60 to 85 years with gradual and progressive change in memory function for at least 6 months were included. A total of 1955 participants were assessed for eligibility. Key eligibility criteria include Mini-Mental State Examination scores of 20 to 28 and elevated amyloid and intermediate tau levels. Randomized participants received donanemab or placebo every 4 weeks for up to 72 weeks. The first 3 doses of donanemab were given at 700 mg and then increased to 1400 mg with blinded dose reductions as specified based on amyloid reduction. Change in plasma biomarker levels after donanemab treatment. In TRAILBLAZER-ALZ, 272 participants (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) were randomized. Plasma levels of phosphorylated tau217 (pTau217) and glial fibrillary acidic protein were significantly lower with donanemab treatment compared with placebo as early as 12 weeks after the start of treatment (least square mean change difference vs placebo, -0.04 [95% CI, -0.07 to -0.02]; P = .002 and -0.04 [95% CI, -0.07 to -0.01]; P = .01, respectively). No significant differences in plasma levels of amyloid-β 42/40 and neurofilament light chain were observed between treatment arms at the end of treatment. Changes in plasma pTau217 and glial fibrillary acidic protein were significantly correlated with the Centiloid percent change in amyloid (Spearman rank correlation coefficient [R] = 0.484 [95% CI, 0.359-0.592]; P < .001 and R = 0.453 [95% CI, 0.306-0.579]; P < .001, respectively) following treatment. Additionally, plasma levels of pTau217 and glial fibrillary acidic protein were significantly correlated at baseline and following treatment (R = 0.399 [95% CI, 0.278-0.508], P < .001 and R = 0.393 [95% CI, 0.254-0.517]; P < .001, respectively). Significant reductions in plasma biomarkers pTau217 and glial fibrillary acidic protein compared with placebo were observed following donanemab treatment in patients with early symptomatic Alzheimer disease. These easily accessible plasma biomarkers might provide additional evidence of Alzheimer disease pathology change through anti-amyloid therapy. Usefulness in assessing treatment response will require further evaluation. ClinicalTrials.gov Identifier: NCT03367403.

Association of Amyloid Reduction After Donanemab Treatment With Tau Pathology and Clinical Outcomes

β-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease. To perform post hoc analyses of amyloid reduction after donanemab treatment and assess its association with tau pathology and clinical measures. The Study of LY3002813 in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ) was a phase 2, placebo-controlled, randomized clinical trial conducted from December 18, 2017, to December 4, 2020, with a double-blind period of up to 76 weeks and a 48-week follow-up period. The study was conducted at 56 centers in the US and Canada. Enrolled were participants from 60 to 85 years of age with gradual and progressive change in memory function for 6 months or more, early symptomatic Alzheimer disease, elevated amyloid, and intermediate tau levels. Donanemab (an antibody specific for the N-terminal pyroglutamate β-amyloid epitope) dosing was every 4 weeks: 700 mg for the first 3 doses, then 1400 mg for up to 72 weeks. Blinded dose-reduction evaluations occurred at 24 and 52 weeks based on amyloid clearance. Change in amyloid, tau, and clinical decline after donanemab treatment. The primary study randomized 272 participants (mean [SD] age, 75.2 [5.5] years; 145 female participants [53.3%]). The trial excluded 1683 of 1955 individuals screened. The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (Spearman correlation coefficient r, -0.54; 95% CI, -0.66 to -0.39; P &lt; .001). Modeling provides a hypothesis that amyloid would not reaccumulate to the 24.1-centiloid threshold for 3.9 years (95% prediction interval, 1.9-8.3 years) after discontinuing donanemab treatment. Donanemab slowed tau accumulation in a region-dependent manner as measured using neocortical and regional standardized uptake value ratios with cerebellar gray reference region. A disease-progression model found a significant association between percentage amyloid reduction and change on the integrated Alzheimer Disease Rating Scale only in apolipoprotein E (APOE) ε4 carriers (95% CI, 24%-59%; P &lt; .001). Results of post hoc analyses for donanemab-treated participants suggest that baseline amyloid levels were directly associated with the magnitude of amyloid reduction and inversely associated with the probability of achieving complete amyloid clearance. The donanemab-induced slowing of tau was more pronounced in those with complete amyloid clearance and in brain regions identified later in the pathologic sequence. Data from other trials will be important to confirm aforementioned observations, particularly treatment response by APOE ε4 status. ClinicalTrials.gov Identifier: NCT03367403.

EE263 Impact of Treatment Duration on the Potential Cost-Effectiveness of Disease-Modifying Therapies for the Treatment of Early Symptomatic Alzheimer's Disease

To examine potential cost-effectiveness of Alzheimer’s disease-modifying therapies (DMTs) of different treatment durations. BACKGROUND: Clinical trial results suggest the disease-modifying impact of a new class of anti-amyloid monoclonal antibodies. Optimal treatment duration is uncertain due to limited follow-up in clinical trials. A recent economic analysis of the first such agent approved questioned the economic value of treatments that slow progression of early symptomatic Alzheimer’s disease (AD) to more advanced states.

Aducanumab Use in Symptomatic Alzheimer Disease Evidence in Focus: A Report of the AAN Guidelines Subcommittee.

To identify the class of evidence for aducanumab use for the treatment of Alzheimer disease and present clinical considerations regarding use. The author panel systematically reviewed available clinical trial data detailing aducanumab use in individuals with early symptomatic Alzheimer disease. Level of evidence statements were assigned in accordance with the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed. Data were identified from 4 clinical trials, 1 rated Class I and 3 rated Class II. The Class I study showed that single doses of aducanumab up to 30 mg/kg were safe and well tolerated. All 3 Class II studies provided evidence that aducanumab (3-10 mg/kg) decreased amyloid deposition on brain PET at 1 year vs placebo. Efficacy data in the Class II studies varied by dose and outcome, but aducanumab either had no effect on mean change on the Clinical Dementia Rating Sum of Boxes scores or resulted in less worsening (vs placebo) that was of uncertain clinical importance. Adverse amyloid-related imaging abnormalities occurred in approximately 40% of individuals treated with aducanumab vs 10% receiving placebo. Administration of aducanumab will require expanded clinical infrastructure. Evidence-based guidance is needed to address key questions (e.g., safety in populations not enrolled in phase 3 studies, expected benefits on daily function, treatment duration) and critical issues relating to access to aducanumab (e.g., coverage, costs, burden of monthly infusions) that will inform shared decision making between patients and providers.

2021 marks a new era for Alzheimer's therapeutics

2021 marks a new era for Alzheimer's therapeutics

Reproducibility of applying multiple statistical analyses to data from the TRAILBLAZER‐ALZ clinical trial of donanemab in early symptomatic Alzheimer's disease

AbstractBackgroundThe Mixed Model for Repeated Measures (MMRM) is the most frequently used statistical analysis for clinical trial endpoints in Alzheimer’s disease (AD) but has the limitation of not efficiently leveraging data from intermediate time points due to the flexibility in the mean structure. In the TRAILBLAZER‐ALZ trial, donanemab, a humanized IgG1 antibody specifically targeting brain amyloid plaque, slowed disease progression in individuals with early symptomatic AD. The aim of this presentation is to apply different statistical models to clinical scale data gathered from this trial, as consistent conclusions following multiple methods would strengthen confidence in the results.MethodTRAILBLAZER‐ALZ (NCT03367403) was a randomized, placebo‐controlled, double‐blind, multi‐center Phase 2 study assessing the safety, tolerability, and efficacy of donanemab in patients with early symptomatic AD. The change from baseline to 76 weeks was assessed using the Integrated AD Rating Scale (iADRS), a composite tool measuring cognition and daily function (primary endpoint), and the Clinical Dementia Rating Scale‐Sum of Boxes (CDR‐SB; secondary endpoint). In addition to MMRM, three statistical models were fit: Bayesian Disease Progression Model (DPM), Natural Cubic Spline (NCS) model, and Quadratic Mixed Model (QMM). Each model has unique assumptions and data handling, for example, in treating time categorically or continuously, which can lead to differences in power while still controlling the false‐positive rate to an allowable margin.ResultThe percent slowing estimates and treatment differences at 18 months from the models are consistent in supporting a positive treatment effect across the clinical scales. The DPM, NCS, and QMM provide a reduction in the standard error, which leads to tighter intervals due to the model assumptions generally being met.ConclusionThe consistency of the results between the statistical models and across the clinical scales suggests the general robustness and strength of the data, regardless of the statistical model used. DPM, NCS, and QMM may provide a more detailed estimate of the longitudinal trajectory of each treatment group when there are small sample sizes and noisy data, and an MMRM model may not be an ideal choice in trial designs that may have sparse data at later time points.

Donanemab leads to less decline in early Alzheimer's disease

Patients with early symptomatic Alzheimer's disease showed less cognitive and functional decline with donanemab compared with placebo in a Phase 2 study offering up to 72 weeks of treatment. The study failed to show a significant difference from placebo on several secondary measures of efficacy, however. Results were published online March 13, 2021, in the New England Journal of Medicine.

Lanabecestat: Neuroimaging results in early symptomatic Alzheimer's disease.

IntroductionLanabecestat, a beta‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) inhibitor, was investigated as a potential Alzheimer's disease (AD)‐modifying treatment. As previously reported, amyloid beta (Aβ) neuritic plaque burden reduction did not result in clinical benefit. Lanabecestat's effects on neuroimaging biomarkers and correlations between neuroimaging biomarkers and efficacy measures are reported.MethodsAMARANTH and DAYBREAK‐ALZ were 104‐ and 78‐week, multicenter, randomized, double‐blind, placebo‐controlled studies of lanabecestat in early symptomatic AD (AMARANTH) and mild AD dementia (DAYBREAK‐ALZ). Patients randomly (1:1:1) received placebo, lanabecestat 20 mg, or lanabecestat 50 mg daily (AMARANTH, n = 2218; DAYBREAK‐ALZ, n = 1722). Florbetapir positron emission tomography (PET), fluorodeoxyglucose (FDG) PET, flortaucipir PET, and volumetric magnetic resonance imaging (MRI) were used to measure Aβ neuritic plaque burden, cerebral metabolism, aggregated tau neurofibrillary tangles, and brain volume, respectively. Additionally, florbetapir perfusion scans were performed in DAYBREAK‐ALZ. Efficacy measures included 13‐item Alzheimer's Disease Assessment Scale–Cognitive Subscale, Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, Clinical Dementia Rating–Sum of Boxes, Functional Activities Questionnaire, and Mini‐Mental State Examination. These studies stopped early due to futility.ResultsDespite previously observed annualized reduction in Aβ neuritic plaque burden, there were no treatment differences in annualized change of aggregated tau neurofibrillary tangle burden (AMARANTH, n = 284; DAYBREAK‐ALZ, n = 70), cerebral metabolism (AMARANTH, n = 260; DAYBREAK‐ALZ, n = 38) and perfusion (DAYBREAK‐ALZ, n = 213). Greater brain volume reduction (AMARANTH, n = 1697 [whole brain]; DAYBREAK‐ALZ, n = 650 [whole brain]) occurred on lanabecestat compared to placebo. Higher baseline aggregated tau neurofibrillary tangle burden, lower cerebral metabolism, and lower brain volumes correlated with poorer baseline efficacy scores and greater clinical worsening. Lower baseline cerebral perfusion correlated with poorer baseline efficacy scores. Reduction in cerebral metabolism or whole brain volume correlated with clinical worsening, regardless of treatment assignment.DiscussionTau pathology and cerebral metabolism assessments showed no evidence of lanabecestat slowing pathophysiologic progression of AD. Lanabecestat exposure was associated with brain volume reductions. Correlations between imaging measures and cognitive assessments may aid future study design.

Longitudinal change in cortical thickness and hippocampal volume predicts cognitive decline

AbstractBackgroundUsing biomarkers for early detection of Alzheimer disease (AD) is crucial for developing potential treatments. It has been hypothesized that longitudinal change in cortical thickness and hippocampal volume could be used to predict cognitive decline in individuals with AD. Here, using longitudinal MRI data, we evaluated whether changes in cortical thickness and hippocampal volume predicted changes in cognition, as measured by a battery of standardized tests.Method152 Participants (aged: 45‐86) who were enrolled in studies at the Knight ADRC at Washington University were included. Data was obtained through OASIS (www.oasis‐brains.org). Participants were classified as having normal cognition or early symptomatic AD, and were followed for 1‐8 years. Hippocampal volume was extracted, and cortical thickness measures were derived as an average of a set of FreeSurfer cortical regions (Figure 1). A random coefficient model was used to calculate longitudinal change in these biomarkers, and to assess whether these measures predict cognitive decline. Additional correlations between longitudinal changes in cognition and changes in cortical thickness, and hippocampal volume, were calculated using Spearman correlations.ResultWe found that longitudinal change in cortical thickness and hippocampal volume significantly predicted the rate of decline measured from a battery of standardized cognitive tasks (Figure 2). Furthermore, longitudinal changes in these structural biomarkers were strongly correlated with cognitive decline measured by the Logical Memory IIA‐Delayed (Figure 3).ConclusionLongitudinal changes in cortical thickness and hippocampal volume significantly predict cognitive decline on neuropsychological tests that address cognitive domains that are typically impacted by AD. To evaluate brain atrophy in a manner that could easily be examined in a clinical context, we did not limit the study to participants with known amyloid biomarker status. It has been postulated that once therapeutic agents for AD become available, we will have difficulty providing large scale screening tests in populations at risk due to limited availability of PET centers. As MRI is widely available, longitudinal volumetric MRI may potentially be used in the future to screen patients as a first step in a workup and evaluation for participation in clinical trials or, once approved, evaluation for therapy.