Rethinking Alzheimer’s clinical trials to include atypical forms of the disease

The study, which involved several international research centres, was coordinated by Dr Neus Falgàs, researcher in the Alzheimer’s disease and other cognitive disorders group at IDIBAPS and a member of the Alzheimer’s Unit at Hospital Clínic, together with Dr Nick Corriveau-Lecavalier, from the Department of Neurology at Mayo Clinic. Dr Rema Raman, from the University of Southern California, is the senior co-author of the study. From Clínic-IDIBAPS, Dr Albert Lladó, head of the Alzheimer’s Unit, also contributed to the work.

A heterogeneous disease beyond memory loss

Alzheimer’s disease is commonly associated with progressive memory loss, particularly in older adults. However, this is not always how the disease begins. In some cases—especially in individuals under 65—the earliest symptoms may affect other cognitive domains, such as language, vision, executive function or behaviour. These presentations, known as atypical variants, usually progress to a more generalized cognitive decline that also includes memory impairment.

These variants show distinct clinical profiles and patterns of brain involvement and may be associated with a faster progression. They often affect individuals during their working years and with family responsibilities, which increases their social and economic impact.

Underrepresentation in clinical trials

The article highlights that Alzheimer’s clinical trials have traditionally focused on the typical form of the disease, characterized by memory impairment. As a result, common inclusion criteria—based on memory tests, age thresholds or biomarkers focused on specific brain regions—may limit the participation of patients with atypical variants.

Consequently, there is limited evidence regarding the effectiveness of new treatments in these populations, including disease-modifying therapies targeting proteins such as amyloid.

Relevant clinical and biological differences

Although all variants share the core neuropathological features of Alzheimer’s disease, atypical forms differ in how the disease affects the brain. Instead of primarily involving memory-related regions, they impact specific brain networks linked to language, vision or other cognitive functions.

These differences have direct implications for clinical trial design, both in terms of participant selection and in the definition of outcome measures used to track disease progression.

Towards more tailored clinical trials

The study outlines several key aspects to improve the design of Alzheimer’s clinical trials.

It emphasizes the need to broaden inclusion criteria to incorporate younger individuals and a wider range of clinical presentations beyond memory-dominant forms. It also highlights the importance of adapting outcome measures to capture different cognitive domains, including language, visuospatial abilities and executive functions.

The article further underlines the role of biomarkers in confirming diagnosis and better characterising study participants. In addition, it encourages the development of new trial designs that can either include multiple phenotypes within the same study or focus on specific clinical variants.

The potential of emerging tools—such as digital cognitive testing, artificial intelligence and remote assessment models—is also highlighted, as they may facilitate data collection and improve participation in research.

Implications for research and clinical practice

According to the authors, accounting for atypical variants is essential both to strengthen the available scientific evidence and to ensure a more accurate evaluation of new treatments for all patients with Alzheimer’s disease.

Adapting current approaches to the different clinical and biological profiles of the disease is key to improving both clinical trial design and the interpretation of their results.

Study reference: Corriveau-Lecavalier N, Falgàs N, Putcha D, et al. Improving the clinical trial landscape for patients with atypical variants of Alzheimer's disease: a call to action. Alzheimer's Dement. 2026;22:e71521. https://doi.org/10.1002/alz.71521

Image: Neus Falgàs and Albert Lladó, authors of the study from Clínic‑IDIBAPS.