Key considerations for combination therapy in Alzheimer's clinical trials: Perspectives from an expert advisory board convened by the Alzheimer's drug discovery foundation.

There is growing consensus in the Alzheimer's community that combination therapy will be needed to maximize therapeutic benefits through the course of the disease. However, combination therapy raises complex questions and decisions for study sponsors, from preclinical research through clinical trial design to regulatory, statistical, and operational considerations. In January 2024, the Alzheimer's Drug Discovery Foundation convened an expert advisory board to discuss the key considerations in each of these areas.

Alzheimer's disease drug development in an evolving therapeutic landscape.

Unlabelled: The Alzheimer's disease (AD) research field has entered a new era, where our fundamental understanding of the pathophysiology of AD and advances in biomarkers have not only allowed for earlier, timely, and accurate detection and diagnosis of the disease, but that amyloid removal has been shown to be associated with signals of slowing cognitive and functional decline. Although recent FDA-approved amyloid plaque-lowering monoclonal antibody therapies have shifted the trajectory of AD, additional treatment options will be key to further slowing clinical decline or stopping disease progression. Thus, new and emerging therapies for AD have created an evolving therapeutic landscape.

Plasma pTau217 ratio predicts continuous regional brain tau accumulation in amyloid-positive early Alzheimer's disease.

Background: This study examines whether phosphorylated plasma Tau217 ratio (pTau217R) can predict tau accumulation in different brain regions, as measured by positron emission tomography (PET) standardized uptake value ratio (SUVR), for staging Alzheimer's disease (AD).

Methods: Plasma pTau217R was measured using immunoprecipitation-mass spectrometry. Models for predicting tau PET SUVR, developed with 144 early AD individuals using [F]MK6240, were validated in two validation sets, VS1 (98 early AD) and VS2 (47 preclinical/early AD with a different tracer, flortaucipir (Tauvid)), all amyloid-beta positive (Aβ+).

Clinical Meaningfulness in Alzheimer's Disease Clinical Trials. A Report from the EU-US CTAD Task Force.

Recent positive results of three phase III anti-amyloid monoclonal antibody trials are transforming the landscape of disease-modifying therapeutics for Alzheimer's disease, following several decades of failures. Indeed, all three trials have met their primary endpoints. However, the absolute size of the benefit measured in these trials has generated a debate on whether the change scores observed on clinical outcome assessments represent a clinically meaningful benefit to patients.

Benefits and risks of FDA-approved amyloid-targeting antibodies for treatment of early Alzheimer's disease: Navigating clinician-patient engagement.

The emergence of the United States Food and Drug Administration (FDA)-approved amyloid-targeting therapies for Alzheimer's disease challenges clinicians and healthcare providers with a transformative landscape. Effectively communicating the risks, benefits, burdens, costs, and available support associated with these novel disease-modifying treatments to patients, families, and other healthcare providers is essential but complex. In response, the Alzheimer's Association's Clinical Meaningfulness Workgroup has proposed language surrounding treatment eligibility, benefits, amyloid-related imaging abnormalities (ARIA), apolipoprotein E (APOE) genotyping, and treatment costs, serving as a resource to healthcare professionals in navigating discussions with patients and their families.

Plasma pTau181 enhances the prediction of future clinical decline in amyloid-positive mild cognitive impairment.

Abstract: Plasma pTau181, a marker of amyloid and tau burden, was evaluated as a prognostic predictor of clinical decline and Alzheimer's disease (AD) progression of amyloid-positive (Aβ+) patients with mild cognitive impairment (MCI). The training cohort for constructing the Bayesian prediction models comprised 135 Aβ+ MCI clinical trial placebo subjects. Performance was evaluated in two validation cohorts.

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.

Introduction: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis.

Methods: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data.

Plasma pTau217 predicts continuous brain amyloid levels in preclinical and early Alzheimer's disease.

Background: This study investigated the potential of phosphorylated plasma Tau217 ratio (pTau217R) and plasma amyloid beta (Aβ) 42/Aβ40 in predicting brain amyloid levels measured by positron emission tomography (PET) Centiloid (CL) for Alzheimer's disease (AD) staging and screening.

Methods: Quantification of plasma pTau217R and Aβ42/Aβ40 employed immunoprecipitation-mass spectrometry. CL prediction models were developed on a cohort of 904 cognitively unimpaired, preclinical and early AD subjects and validated on two independent cohorts.

Racial and ethnic differences in plasma biomarker eligibility for a preclinical Alzheimer's disease trial.

Introduction: In trials of amyloid-lowering drugs for Alzheimer's disease (AD), differential eligibility may contribute to under-inclusion of racial and ethnic underrepresented groups. We examined plasma amyloid beta 42/40 and positron emission tomography (PET) amyloid eligibility for the ongoing AHEAD Study preclinical AD program (NCT04468659).

Methods: Univariate logistic regression models were used to examine group differences in plasma and PET amyloid screening eligibility.

Lewy body dementia: Overcoming barriers and identifying solutions.

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements.

Predicting clinical progression trajectories of early Alzheimer's disease patients.

Background: Models for forecasting individual clinical progression trajectories in early Alzheimer's disease (AD) are needed for optimizing clinical studies and patient monitoring.

Methods: Prediction models were constructed using a clinical trial training cohort (TC; n = 934) via a gradient boosting algorithm and then evaluated in two validation cohorts (VC 1, n = 235; VC 2, n = 421). Model inputs included baseline clinical features (cognitive function assessments, APOE ε4 status, and demographics) and brain magnetic resonance imaging (MRI) measures.

Alzheimer's Targeted Treatments: Focus on Amyloid and Inflammation.

Alzheimer's disease (AD) is the major cause of dementia that is now threatening the lives of billions of elderly people on the globe, and recent progress in the elucidation of the pathomechanism of AD is now opening venue to tackle the disease by developing and implementing "disease-modifying therapies" that directly act on the pathophysiology and slow down the progression of neurodegeneration. A recent example is the success of clinical trials of anti-amyloid b antibody drugs, whereas other therapeutic targets, e.g.

Plasma Aβ42/Aβ40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease.

Introduction: Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve screening efficiency.

Methods: Plasma Aβ, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences.