Doctoral candidate Marta Arbizu Gómez discusses the impact of atypical Alzheimer’s disease variants on clinical trials, the challenge of early differential diagnosis, and how to address them through multidomain cognitive stimulation.
Atypical Alzheimer’s disease variants (dysexecutive, posterior cortical atrophy, logopenic aphasia, behavioral, and corticobasal) begin without the characteristic memory impairment, requiring a rethinking of clinical care and research:
– Inclusion bias: Criteria focused on amnesia exclude these patients from clinical trials of anti-amyloid drugs such as lecanemab or donanemab.
– Sensitive assessment: Go beyond traditional memory tests by integrating biomarkers, digital assessments, and artificial intelligence technology.
– Adapted rehabilitation: Requires multidomain cognitive stimulation focused on the specific neuropsychological profile of each variant through NeuronUP.
Why do Alzheimer’s clinical trials need to be rethought?
Alzheimer’s disease is almost automatically associated with memory loss. And, indeed, in its most common form, the first symptoms are usually related to difficulty remembering recent information, repeating questions, or becoming disoriented in everyday situations.
However, Alzheimer’s disease does not always begin this way.
There are atypical forms of the disease in which the initial symptoms do not primarily affect memory, but rather language, vision, planning, behavior, or even movement. A person may first have difficulty finding words, reading, interpreting what they see, organizing tasks, controlling impulses, or coordinating certain movements, and still be developing Alzheimer’s disease.
This clinical diversity poses a significant challenge: if clinical trials are designed almost exclusively around the typical form of the disease, many people with atypical variants may be left out of research and the evidence on new treatments.
A recent article published in Alzheimer’s & Dementia raises precisely this issue: clinical trial designs need to be adapted to better represent the full heterogeneity of Alzheimer’s disease.
What are atypical forms of Alzheimer’s disease?
Atypical forms of Alzheimer’s disease are clinical presentations in which the disease does not begin with predominantly memory-related decline. Although they share the same biological basis as Alzheimer’s disease—the accumulation of beta-amyloid and tau—their initial symptoms can be very different.
Main clinical variants and predominant symptoms
The main atypical variants include:
- Dysexecutive Alzheimer’s disease, characterized by difficulty planning, organizing, making decisions, or solving problems.
- Logopenic variant primary progressive aphasia, characterized by language problems, such as difficulty finding words or repeating sentences.
- Posterior cortical atrophy, also known as the visual variant of Alzheimer’s disease, in which initial symptoms affect visual and visuospatial processing.
- Behavioral variant Alzheimer’s disease, characterized by changes in personality, behavior, empathy, motivation, or impulse control.
- Corticobasal syndrome associated with Alzheimer’s disease, which may involve motor symptoms, rigidity, clumsiness, movement abnormalities, or difficulty performing learned gestures.
These forms are especially common in people with early-onset Alzheimer’s disease, meaning those whose symptoms appear before age 65. In addition, they may progress more rapidly and have a substantial impact on a person’s work, family, and social life.
| Alzheimer’s variant | Predominant symptoms |
|---|---|
| Typical amnestic Alzheimer’s disease | Progressive memory loss |
| Dysexecutive Alzheimer’s disease | Difficulty planning, organizing, and making decisions |
| Logopenic variant primary progressive aphasia | Difficulty finding words and repeating sentences |
| Posterior cortical atrophy | Visual and visuospatial impairments |
| Behavioral variant Alzheimer’s disease | Changes in personality, behavior, empathy, or motivation |
| Corticobasal syndrome associated with Alzheimer’s disease | Rigidity, clumsiness, motor impairments, or apraxia |
Bias in Alzheimer’s clinical trials: The memory problem
For years, major clinical trials in Alzheimer’s disease have been designed primarily for people with the most typical form of the disease: the form characterized by memory loss.
This has important consequences. Many studies use inclusion criteria focused on memory impairment, clinical scales that primarily assess amnestic symptoms, or age limits that may exclude younger people. In addition, some cognitive tests or biomarkers used in trials may not adequately capture the main symptoms of atypical variants.
For example, a person with posterior cortical atrophy may have great difficulty reading, navigating visually, or interpreting objects, while relatively preserving memory in the early stages. Similarly, a person with progressive aphasia may have severe language problems, even though their scores on standard memory tests do not adequately reflect the actual impact of the disease.
This means that the tools used to measure disease progression or treatment efficacy may not be sensitive enough for these variants.
Why is it important to include these atypical forms in trials?
Including people with atypical Alzheimer’s disease in clinical trials is not just a methodological issue. It is also an issue of equity.
If these people are excluded from studies, there will be less evidence about whether new treatments work for them, the best time to administer them, and the most appropriate measures for assessing their efficacy.
This issue has become even more relevant with the advent of disease-modifying therapies targeting beta-amyloid, such as lecanemab or donanemab. These treatments have been shown to slow decline in the early stages of Alzheimer’s disease, but the available evidence comes mostly from studies focused on typical forms with predominantly memory-related symptoms.
Therefore, although these therapies may potentially be useful for people with atypical variants, their efficacy in these clinical profiles remains uncertain.
The article argues that people with atypical Alzheimer’s disease should not be considered a marginal exception, but rather an important part of the clinical diversity of the disease.
Subscribe
to our
Newsletter
New strategies for research on early-onset Alzheimer’s disease
The authors propose several strategies to improve the inclusion of atypical forms of Alzheimer’s disease in clinical research.
- First, they propose broadening trial inclusion criteria. This means not always requiring memory loss to be the main symptom and reducing age barriers, since many people with atypical variants develop the disease before age 65.
- Second, they highlight the need to create cohorts ready for clinical trials. These are well-characterized groups of patients with longitudinal follow-up, appropriate cognitive tests, and biomarkers confirming Alzheimer’s pathology. These cohorts would make it easier to quickly identify people eligible to participate in studies.
- Third, the authors emphasize the need to adapt outcome measures. It does not make sense to assess someone whose main symptom is memory loss in the same way as someone whose primary problem is language or vision. Trials should include measures specific to each variant, together with functional scales that better reflect the impact on daily life.
Finally, the article proposes exploring more flexible trial designs, such as phenotype-based trials, platform trials, basket trials, or emulated trials using real-world data. These approaches could help study less common populations without sacrificing scientific rigor.
An opportunity to better understand Alzheimer’s disease
Although atypical forms pose significant challenges, they also offer a unique opportunity to better understand Alzheimer’s disease.
These variants clearly show that Alzheimer’s disease does not affect everyone in the same way. Depending on which brain networks are most vulnerable, symptoms may present as problems with memory, language, vision, behavior, executive function, or movement.
In addition, in many early-onset cases, the disease may be less influenced by other conditions associated with aging, such as vascular lesions or other neurodegenerative diseases. This could make atypical forms especially valuable models for studying Alzheimer’s progression and responses to new treatments.
For this reason, rather than excluding them because of their complexity, the authors argue that research should actively include them.
What role can new technologies play?
The article also highlights the potential of new technologies to improve the assessment of these variants.
Digital cognitive tests, automated language analyses, artificial intelligence-based tools, and advanced neuroimaging techniques could help detect and track symptoms that traditional tests do not always capture effectively.
For example, in people with language difficulties, speech analysis can provide information about disease progression. In people with visual impairments, digital tests can help measure changes in perception or visuospatial orientation. In neuroimaging, artificial intelligence-based methods could identify patterns of brain involvement specific to each variant.
In addition, remote assessments and hybrid follow-up models can make it easier for people to participate in trials if they are young, actively employed, or live far from specialized centers.
What role can NeuronUP play?
This approach also connects with the role that digital tools such as NeuronUP can play. If Alzheimer’s disease does not always affect the same cognitive domains, assessment and intervention should not focus solely on memory either.
In atypical forms, it may be necessary to assess and address areas such as language, attention, executive functions, visuospatial skills, or activities of daily living. Flexible, multidomain programs make it possible to better tailor therapeutic work to each person’s profile.
In this respect, NeuronUP can contribute to more personalized care by facilitating the assessment of different cognitive abilities and the design of interventions tailored to each patient’s actual needs.
Conclusions on the clinical diversity of Alzheimer’s disease
Alzheimer’s disease is far more diverse than traditionally thought. Although memory loss remains the best-known symptom, not everyone with Alzheimer’s disease begins by forgetting.
Some people first have problems speaking, reading, interpreting what they see, staying organized, behaving as they did before, or moving normally. These atypical forms are also part of the disease and should be represented in clinical research.
Rethinking clinical trials to better include them is essential to generate evidence that is fairer, more precise, and more useful. Only then can therapeutic advances benefit the full range of people living with Alzheimer’s disease.
References
- 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. doi:10.1002/alz.71521.
Frequently asked questions about atypical Alzheimer’s disease variants
1. What are the main differences between typical and atypical Alzheimer’s disease?
Typical Alzheimer’s disease primarily begins with progressive loss of recent memory. In contrast, atypical variants begin with changes in other cognitive domains, such as language (logopenic aphasia), visuospatial processing (posterior cortical atrophy), executive functions (dysexecutive variant), behavior, or movement (corticobasal syndrome). Both profiles share the same underlying neuropathology (beta-amyloid and tau).
2. Why are people with atypical Alzheimer’s disease often excluded from clinical trials?
Most trials are designed using inclusion criteria focused on amnestic symptoms, traditional psychometric scales that are not sensitive to other domains, and age limits that exclude patients younger than 65. Because atypical variants are more prevalent in early-onset Alzheimer’s disease, these patients are left out of the validation phases of new disease-modifying treatments.
3. How does atypical Alzheimer’s disease affect traditional neuropsychological assessment?
Standardized psychometric tests designed to measure amnestic impairment may underestimate or miss the symptoms of atypical variants. A patient with posterior cortical atrophy or logopenic aphasia may score relatively well on initial verbal memory tests despite severe functional limitations in reading, spatial navigation, or naming.
4. How can cognitive stimulation be adapted for patients with nonamnestic variants?
Intervention should not be limited to memory training. Digital tools such as NeuronUP make it possible to design personalized programs tailored to a patient’s areas of difficulty: visuospatial praxis and gnosis exercises for posterior cortical atrophy, language stimulation and verbal fluency for logopenic aphasia, or reasoning and inhibitory control tasks for the dysexecutive or behavioral variant.
5. What role do new anti-amyloid drugs (lecanemab and donanemab) play in atypical variants?
Although these biologic therapies slow decline in the early stages of the disease, most clinical evidence comes from populations with an amnestic phenotype. Their exact efficacy in nonamnestic phenotypes remains uncertain because these variants were not adequately represented in the initial research cohorts.
A Guide to Evaluating and Treating Primary Progressive Aphasia (PPA) for Clinicians
Leave a Reply