Alzheimer’s Disease Clinical Trials and Emerging Therapies: Transforming Patient Care Through Innovation

Date

5th November, 2025

Executive Summary

Alzheimer’s disease (AD) is one of the most significant and pressing challenges in modern healthcare. Affecting more than 50 million people worldwide¹, AD places an immense and growing social and economic burden on societies as populations age. After decades of treatments that only addressed symptoms, the emergence of disease-modifying therapies (DMTs) has reshaped the therapeutic landscape, offering renewed hope for slowing or altering disease progression.

This white paper presents an updated, evidence-based overview of the evolving AD landscape, highlighting recent clinical and regulatory milestones, operational challenges in contemporary trials, and the ways specialized clinical research organizations (CROs), such as Pivotal, are advancing innovation through scientific and operational excellence.

The Evolving Paradigm of Alzheimer’s Disease: From Symptomatic Management to Disease Modification

Historically, AD was diagnosed primarily through clinical assessment, often confirmed only post-mortem. Early diagnostic frameworks such as the 1984 NINCDS-ADRDA criteria focused on cognitive and behavioral symptoms, which frequently delayed diagnosis until substantial neuronal loss had occurred².

Recent research has redefined AD as a biologically measurable continuum. The 2024 revised NIA-AA criteria now define the disease by the simultaneous presence of both amyloid-beta (Aβ) and tau pathology, which allows for diagnosis at pre-symptomatic stages and supports preventive strategies³. This conceptual shift has fundamentally transformed the design of clinical trials and the selection of patients.

Breakthroughs in Disease-Modifying Therapies: The Amyloid Hypothesis and Clinical Validation

The amyloid cascade hypothesis continues to serve as the foundation for current DMTs. Monoclonal antibodies, such as Lecanemab and Donanemab, specifically target Aβ aggregates aiming to reduce plaque burden and slow cognitive decline⁴.

Regulatory Milestones in Europe

Lecanemab (Leqembi®): Initially deferred by the EMA’s CHMP in July 2024; a positive opinion was issued in November 2024⁵, followed by final approval by the European Commission in April 2025⁶.

Donanemab (Kisunla®): Initially rejected by the CHMP in March 2025 due to considerations of the benefit-risk ratio; a revised positive opinion was issued in July 2025⁷ leading to the European Commission’s approval in September 2025⁸. This approval is limited to ApoE4 heterozygotes and non-carriers, reflecting the need for risk stratification related to ARIA.

Efficacy Data from Pivotal Trials

Lecanemab (Clarity AD): This trial demonstrated a 27% reduction in the CDR-SB after 18 months of treatment (translating to a 0.45-point difference; p<0.001), alongside substantial amyloid clearance⁹.

Donanemab (TRAILBLAZER-ALZ 2): In early-stage patients it showed a 35% reduction on the iADRS resulting in a 2.92 point difference (p<0.001)¹⁰.

Although statistically significant, these corresponding effect sizes (Cohen’s d ≈ 0.21–0.23) are considered modest, and their clinical relevance, particularly regarding functional independence and quality of life, remains under active discussion¹¹.

Safety and Monitoring

Amyloid-related imaging abnormalities (ARIA) continue to pose significant safety concerns in AD treatment:

ARIA-E: Occurs in 12–24% of treated patients.
ARIA-H: Affects 17–20% of patients.
Symptomatic ARIA: Observed in 3–6% of patients, with rare serious outcomes specifically noted in individuals who are homozygous for the ApoE4 allele.

These risks underline the necessity for vigilant MRI monitoring and careful risk-based patient selection, both of which significantly influence trial design and operational complexity.

Operational Challenges in Modern Alzheimer’s Trials

1. Biomarkers-Driven Recruitment: AD trials now require confirmation of amyloid pathology, leading to an increase in screening failure rates (30–50%). While PET imaging remains the gold standard for this confirmation, it is both costly and limited in capacity. CSF biomarkers are a less invasive alternative, but they encounter significant patient refusal rates. However, plasma biomarkers such as p-tau217, have been robustly validated as feasible and cost-effective tools for detecting Alzheimer’s pathology. Large-scale studies have demonstrated their diagnostic accuracy, achieving high concordance with amyloid PET results in relevant clinical settings, thereby supporting their use for screening and monitoring^12,13. Additionally, formal recommendations for their appropriate use now offer guidance on their integration into clinical trials and practice¹⁴.

2. Infrastructure Requirements: Trials must incorporate MRI, PET, CSF, and plasma biomarker pipelines, which require close collaboration among the different stakeholders: clinical sites, imaging vendors, and CROs.

3. Patient Retention: The high burden of clinical visits and infusion schedules necessitate patient-centric strategies. These can include eConsent, decentralized monitoring, and active community engagement.

Next-Generation Therapeutic Strategies

The development pipeline is expanding beyond amyloid-targeting to include interventions aimed at tau, neuroinflammation, and synaptic resilience. Tau aggregation inhibitors and anti-tau antibodies are progressing through Phase 2 and 3 development pathways¹⁵. Additionally, therapies targeting microglial regulation (such as, TREM2 agonists) represent a promising avenue of research¹⁶.

Prevention-focused trials, such as AHEAD 3–45, are investigating early interventions in cognitively normal individuals who have elevated amyloid burden¹⁷. Furthermore, precision approaches that integrate genetic profiling (APOE) with biomarker analysis are redefining how patients are stratified and how safety oversight is conducted.

Implementation and Readiness in Europe

A 2023 survey conducted by the European Academy of Neurology (EAN) identified critical and significant gaps in readiness for the rollout of DMT: More than 50% of the European neurologists who responded reported feeling unprepared to implement these treatments, citing, as major barriers, the limited access to biomarker diagnostics and MRI monitoring. Additionally, 93% of respondents expressed the need for training on managing ARIA¹⁸.

Pivotal’s Role: Bridging Science and Operations

Our Global CRO, Pivotal, combines medical expertise with operational excellence to accelerate AD trials. Our comprehensive approach includes, among others:

Strategic Protocol Design: We develop scientifically robust and operationally feasible protocols, that incorporate biomarker strategies from the very beginning.
Expert Regulatory Guidance: We provide end-to-end support navigating through complex European regulatory frameworks, leveraging our extensive deep experience with EMA and national bodies to ensure efficient submission and approval processes.
Site optimization: Pivotal’s operational and medical team leverages a vetted network of experienced neurology centers to enhance trial site performance.
Data-Driven Oversight & Risk Management: Using our proprietary Danah platform, Pivotal’s team conducts centralized monitoring and apply predictive analytics to enhance trial oversight.
Patient engagement: We foster partnerships with patients advocacy groups (PAGs) and utilize digital tools to minimize participant burden and reduce dropout rates.

Shaping the Future of Alzheimer’s Research

Pivotal is leading the way in next-generation Alzheimer’s studies by facilitating:

Advanced Therapeutic Strategies: We are prepared to support complex trials, that include combination therapies targeting amyloid, tau, and inflammatory pathways simultaneously, paving the way for more comprehensive treatment options.
Equitable access initiatives: We are committed to ensuring representation across Europe and elsewhere, implementing strategies that promote equitable access to clinical trials and research participation for diverse populations.

Conclusion

The evolution of Alzheimer’s research signifies both a remarkable scientific achievement and an operational challenge. The modest clinical benefits of DMTs must be carefully weighed against considerations of real-world feasibility, cost, and safety. Success in this new era will depend on collaboration among all stakeholders, robust infrastructure, and specialized expertise.

Pivotal’s integrated model—combining board-certified neurologists, standardized imaging protocols, advanced data platforms, and solid site partnerships—positions us to lead this transformative journey. Whether we are advancing anti-amyloid programs, tau-targeted therapies, or prevention studies, Pivotal is committed to delivering the scientific rigor and operational precision that are essential for achieving success in Alzheimer’s Disease research and development of specific treatments.

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