Assessing clinical meaningfulness in clinical trials for Alzheimer's disease: A U.S. regulatory perspective

Abstract

In the context of recent approvals of amyloid‐directed monoclonal antibodies for the treatment of Alzheimer's disease (AD) by the United States (U.S.) Food and Drug administration (FDA), there has been much public discussion regarding the meaningfulness of the treatment effects demonstrated with these drugs in clinical trials. There are a variety of regulatory approaches to evaluate how results on a clinical endpoint reflect a meaningful effect of an intervention, including qualitative and quantitative methodologies. This article will discuss regulatory considerations for clinical benefit across the stages of AD, approaches to the assessment of clinical meaningfulness in clinical trials, and FDA's assessment of clinical benefit in the recent traditional approvals of amyloid‐directed monoclonal antibodies for the treatment of AD.

Highlights

• Assessment of clinical benefit will depend on the stage of Alzheimer's disease (AD) being studied, the clinical symptoms or findings that occur at that stage of disease, and the mechanism of the drug and its anticipated effects.

• It is critical to obtain input from patients and caregivers with lived experience to understand their perspectives on clinical benefit.

• The Food and Drug Administration (FDA) encourages the use of clinically meaningful within‐patient change, which captures the assessment of improvement or decline based on the perspective of the individual patient, to assess meaningful score differences.

1. INTRODUCTION

Between 2021 and 2024, Food and Drug Administration (FDA) approved three amyloid‐directed monoclonal antibodies for the treatment of Alzheimer's disease (AD). Aducanumab and lecanemab received accelerated approval in June 2021 and January 2023, respectively, based on reductions of brain amyloid beta burden on positron emission tomography (PET) as a surrogate endpoint that was found to be reasonably likely to predict clinical benefit; the biologics licensing application for aducanumab was subsequently withdrawn in November 2024 for commercial reasons. ¹ The accelerated approval of lecanemab was subsequently converted to traditional approval in June 2023 based on verification of clinical benefit demonstrated in an adequate and well‐controlled confirmatory study. Donanemab received traditional approval in July 2024 based on clinical benefit demonstrated in two adequate and well‐controlled trials. In the context of these approvals, there has been much public discussion of the meaningfulness of the treatment effects demonstrated with these drugs in clinical trials.

2. U.S. REGULATORY REQUIREMENTS FOR DRUG APPROVAL

For FDA to approve a drug, the development program must provide data that meet the regulatory standard of substantial evidence of effectiveness and demonstrate that the drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling. The term “substantial evidence” is defined in section 505(d) of the Food, Drug, and Cosmetic Act as evidence consisting of adequate and well‐controlled investigations conducted to evaluate the effectiveness of the drug on the basis of which it could fairly and responsibly be concluded by experts that the drug will have the effect it is purported to have under the conditions of use described in the labeling.

Adequate and well‐controlled investigations are further defined in FDA regulations (21 CFR 314.126) as those capable of “detecting the effect of a drug from other influences, such as spontaneous change, placebo effect, or biased observation” and possessing various characteristics, including measures to minimize bias and well‐defined and reliable methods of assessing a subject's response.

Approval of a drug under the traditional approval pathway (also known as full approval) requires that there is substantial evidence of effectiveness that the drug provides therapeutic benefit to patients for the proposed indication. Benefit may be demonstrated either with an endpoint that is a direct measure of clinical benefit, or with a surrogate endpoint that is not, itself, a direct measure of the clinical benefit of interest, but instead has a strong and established evidence for its ability to predict clinical benefit (i.e., validated surrogate endpoint).

FDA may also grant accelerated approval for a drug intended to treat a serious or life‐threatening disease or condition based on a demonstrated effect on a surrogate endpoint or an intermediate clinical endpoint that is determined to be reasonably likely to predict a clinical benefit but lacks sufficient data to be used as a validated surrogate endpoint (i.e., reasonably likely surrogate endpoint). The ability to use the accelerated approval pathway takes into consideration the unmet need in the disease, including the adequacy of available treatments or lack of available treatments. It is important to note that the same standard for substantial evidence of effectiveness applies to accelerated approval as it does for approval under the traditional approval pathway. Postapproval trials have generally been required to verify and describe clinical benefit.

Although the statutory standard for effectiveness does not refer to particular endpoints or state a preference for clinical endpoints over surrogate endpoints, it is well established that the effect shown in the adequate and well‐controlled clinical investigations, must be, in FDA's judgment, clinically meaningful. ²

Consistent with regulations (CFR 312.84), FDA conducts a benefit‐risk analysis as part of its evaluation of each marketing application for drug products for life‐threatening and severely‐debilitating diseases. The meaningfulness of clinical trial results is an important consideration in the context of the analysis of whether the benefits outweigh the known and potential risks of the drug. As part of this evaluation, and consistent with FDA regulations (CFR 312.80), FDA takes into consideration the severity of the disease and the absence of satisfactory alternative therapy, recognizing that physicians and patients are generally willing to accept greater risks or side effects from products that treat life‐threatening and severely‐debilitating illnesses than they would accept from products that treat less serious illnesses.

3. CLINICAL BENEFIT IN AD

3.1. Defining clinical benefit

Although there is no statutory definition of clinical benefit, FDA has long interpreted clinical benefit to be a clinically meaningful effect of an intervention on how an individual feels, functions, or survives. ³ In other words, a clinical benefit may be assessed based on survival or on an outcome measure that assesses how a patient feels (e.g., pain, mood) or functions in daily life (e.g., ability to perform relevant tasks or functions impacted by the disease).

Undoubtedly, the most desirable clinical benefits for a drug that treats AD would be to restore cognitive losses or halt disease progression in those with symptoms, or to prevent the onset of symptoms in individuals at‐risk but who do not yet have symptoms. The field continues to strive for those goals. An achievable goal, however, is slowing of disease progression which can prolong time spent in a higher state of functioning in cognitive abilities and daily activities. Such slowing is clearly beneficial and meaningful for patients in a progressive neurodegenerative disease such as Alzheimer's disease. ⁴ Treatment of symptoms of AD (e.g., cognition, behavior) is also a meaningful therapeutic goal.

Assessment of clinical benefit will depend on the stage of Alzheimer's disease being studied, the clinical symptoms or findings that occur at that stage of disease, and the mechanism of the drug and its anticipated effects. Although there is a broad understanding of the clinical impacts of AD and desired outcomes with treatment, it is critical to obtain input from patients and caregivers with lived experience to understand the perspective of clinical benefit for the individual. In AD, it is anticipated that input from patients will be most informative during the earliest stages of disease when insight may still be relatively preserved, while input from caregivers will be more informative for later stages of disease. Patient experience data are very informative for this purpose. Under Section 3001 of 21^st Century Cures Act, the term “patient experience data” is defined as “…data that are collected by any persons and are intended to provide information about patients’ experience with a disease or condition” (Title III, section 3001 of the 21st Century Cures Act, as amended by section 605 of the FDA Reauthorization Act of 2017). Patient experience data can be particularly informative for understanding disease burden, aspects of the disease that are meaningful to patients and caregivers, and perspectives on risk to inform benefit‐risk considerations. FDA participates in a variety of stakeholder engagement activities to incorporate patient input into its regulatory decision making, including FDA patient listening sessions, externally led patient focused drug development meetings, and scientific and multi‐stakeholder meetings that include patient representation. ⁵ , ⁶

3.2. Clinical benefit across the stages of AD

As noted in Section 3.1, assessment of clinical benefit will depend on the stage of the disease. FDA has outlined its thinking on the selection of appropriate endpoints for the stage(s) of AD proposed to be enrolled in a clinical trial in the Draft Guidance for Industry – Early Alzheimer's Disease: Developing Drugs for Treatment. ⁷ Key concepts from that guidance are briefly summarized here. References to disease stages in this article refer to the stages of Alzheimer's disease defined in that guidance document.

In stages of the disease where deficits in cognition and daily functioning are detectable and readily measurable (Stages 3 and later, roughly corresponding to mild cognitive impairment and dementia stages of disease), it is anticipated that clinical benefit will be demonstrated using assessments of the concepts of interest of both cognition and daily functioning. Historically, cognition has been assessed with performance outcomes (e.g., neuropsychological testing) and observer‐ or clinician‐reported outcomes (e.g., activities of daily living scales or clinical global impression scales) as co‐primary endpoints. Integrated assessments of cognition and daily functioning (e.g., Clinical Dementia Rating scale ‐Sum of Boxes [CDR‐SB]) have also been used. This approach is intended to ensure that a change on a sensitive cognitive test is accompanied by an observed functional benefit, and alternately, that any observed functional benefit can be attributed to a benefit on cognition and not to changes in other medical conditions or lifestyle changes. Although not specifically discussed in the Guidance, a reduction in neuropsychiatric symptoms of dementia may also be a meaningful benefit for some patients with AD and these symptoms are typically assessed with observer‐ or clinician‐reported outcomes based on observations of behavior.

At the current time, FDA has not accepted any biomarkers as a validated surrogate endpoint to support traditional approval for AD. As noted in Section 1, FDA has used a reduction of the brain amyloid beta burden assessed by PET as a reasonably likely surrogate endpoint to support accelerated approval in clinical trials that enrolled participants with Stage 3 and Stage 4 AD for monoclonal antibodies directed against aggregated forms of amyloid beta. It is important to note that the acceptability of a surrogate endpoint for a particular development program is context dependent, and may rely on factors that include the disease, studied patient population, therapeutic mechanism of action, and availability of current treatments. A surrogate endpoint that is determined to be appropriate for use in a particular clinical development program may not be appropriate for use in a different program that is in a different clinical setting. The approach to establishing that a surrogate endpoint can predict clinical benefit can be complex and is beyond the scope of this article.

FDA recognizes that it may be difficult to assess clinical benefit in the earliest stages of AD where there may be no deficits (Stage 1) or only subtle deficits in cognition with no detectable impact on daily functioning (Stage 2). Although impacts on daily functioning are anticipated to develop over time, assessment of a change in daily functioning would require trials of long duration in these early stages. In this situation, FDA will consider whether persuasive changes on cognitive assessments (i.e., neuropsychological testing) alone will be sufficient to establish clinical benefit. Important factors in considering the meaningfulness of changes on cognition alone include the magnitude of effect, breadth of effects across individual cognitive measures, and statistical robustness of the findings. Additionally, the benefit of changes observed on cognitive assessments in these early stages of disease should be supported by effects on biomarkers of pathophysiological changes of AD that reflect that that the drug impacts underlying disease pathology. Alternately, such biomarkers may be capable of serving as surrogate endpoints as described above.

It is important to have drugs that treat symptoms of AD and the underlying pathologic disease processes. However, the assessment of clinical benefit may depend on the mechanism and anticipated effects of the drug (e.g., size and type of effects), which may also influence the stage of disease that is selected for enrollment and evaluation in a clinical trial. Effect sizes and the timing of desired effects will likely differ for drugs that target symptoms compared to those that target pathologic disease processes. Clinical trials for therapies that are intended to treat symptoms would necessarily enroll patients in symptomatic stages of disease. A benefit on cognition or daily functioning or a reduction in neuropsychiatric symptoms (e.g., agitation) compared to a control group is the desired effect, and it may be possible to demonstrate such a benefit in a study of relatively short duration (e.g., 6 months or less). Therapies that target the underlying pathophysiology of AD are anticipated to show greatest benefit when initiated at the earliest stages of the disease, before substantial irreversible neurodegeneration has occurred, and may be initiated prior to the onset of symptoms or in early symptomatic stages of AD. Slowing disease progression (staying in “current state” longer) or delaying or preventing onset of symptoms is the desired effect for these therapies and longer duration trials (e.g., 18 months or longer) are typically needed to observe these effects. It is also anticipated that, for drugs that slow disease progression, the trajectory on clinical outcomes in the treated group will show a slower rate of decline, with an increasing divergence from the placebo group that continues to exhibit the expected rate of decline over the duration of the trial. The anticipated therapeutic effects will inform the design of clinical trials and the interpretation of the study results. However, FDA recognizes that it may not always be clear early in a drug development program if the effects of a drug are anticipated to be symptomatic or if the drug may impact underlying pathologic processes and alter the trajectory of decline; therefore, it is important to assess a variety of outcome measures in early clinical studies to inform the design and selection of endpoints for Phase 3 studies.

4. ASSESSMENT OF CLINICAL MEANINGFULNESS

4.1. Patient‐focused drug development and guidance series

FDA is committed to Patient‐Focused Drug Development (PFDD) and ensuring that a patient's lived experience with their disease is captured throughout drug development. PFDD is defined as the “systematic approach to help ensure that patients' experiences, perspectives, needs and priorities are captured and meaningfully incorporated into the development and evaluation of medical products throughout the medical product lifecycle.” ⁸

To assist drug development stakeholders, including the pharmaceutical industry, FDA developed and published a series of four PFDD methodological guidance documents. ⁹ These guidance documents present a stepwise approach on how stakeholders can collect, develop, and submit patient experience data in a systematic manner through robust patient and community input to inform drug development and regulatory decision making. Application of these approaches and methods can be utilized in the AD drug development space.

4.2. Qualitative methodologies

Leveraging the PFDD Guidance Series, stakeholders can conduct qualitative research to collect data on the lived experience of both patients and caregivers, which may include thoughts on what a meaningful clinical benefit from a therapy would look like, the experience of patients in their clinical journey with the disease (e.g., diagnosis and clinical care), and the potential risks they would be willing to accept. Qualitative methodologies can be informative in the AD population throughout the drug development program and are discussed in the first two guidance documents of the FDA PFDD Guidance Series, “Patient‐Focused Drug Development: Collecting Comprehensive and Representative Input” ¹⁰ and “Patient‐Focused Drug Development: Methods to Identify What Is Important to Patients.” ¹¹ Qualitative methodologies such as concept elicitation interviews can help to inform the selection of outcomes. In clinical trials, qualitative methods, such as exit interviews, can also be used to assess the patient's and care partner's experiences in the trials, perception of benefit, and assessment of the extent to which blinding methods were successful in a study. Qualitative methodologies should include perspectives from patients, caregivers, and clinicians.

4.3. Selection of clinical outcome assessments

Selection of study outcomes that capture meaningful and relevant disease concepts for patients and caregivers is the most critical aspect of designing a study that will provide interpretable and informative data on clinical benefit and meaningfulness of the results. A variety of clinical outcome assessments (COAs) are used and have been accepted by FDA to assess effectiveness in clinical trials for AD. Typically, a mix of fit‐for‐purpose COAs, observer‐reported outcomes, and performance outcomes have been used to support clinical trial endpoints in AD (Table 1). Although there are fit‐for‐purpose outcome assessments that have been used in clinical trials to support drug approvals, FDA is open to the development of new COAs and the use of innovative approaches (e.g., digital health technologies) to capture concepts that are relevant and meaningful to patients and sensitive to change, particularly in the earliest stages of AD (e.g., Stage 2). The third draft guidance of the FDA PFDD Guidance Series “Patient‐Focused Drug Development: Selecting, Developing, or Modifying Fit‐for‐Purpose Clinical Outcome Assessments” ¹² discusses approaches to selecting, modifying, developing, and evaluating COAs to measure outcomes of importance to patients in clinical trials.

TABLE 1.

Definitions of clinical trial outcome terminology.

Outcome	The measurable characteristic (clinical outcome assessment, biomarker) that is influenced or affected by an individuals’ baseline state or an intervention as in a clinical trial or other exposure.
Endpoint	A precisely defined variable intended to reflect an outcome of interest that is statistically analyzed to address a particular research question. A precise definition of an endpoint typically specifies the type of assessments made, the timing of those assessments, the assessment tools used, and possibly other details, as applicable, such as how multiple assessments within an individual are to be combined.
Clinical Outcome Assessment (COA)	Assessment of a clinical outcome can be made through report by a clinician, a patient, a non‐clinician observer, or through a performance‐based assessment. There are four types of COAs. ·Clinician‐reported outcome (ClinRO) ·Observer‐reported outcome (ObsRO) ·Patient‐reported outcome (PRO) ·Performance outcome (PerfO)
Context of use	A statement that fully and clearly describes the way the COA or biomarker is to be used (e.g., patient population, trial setting) for a specific drug development program.
Fit for purpose	A conclusion that the level of validation associated with a biomarker or COA is sufficient to support its proposed use.

Note: Adapted from BEST (Biomarkers, Endpoints, and Other Tools) Resource Glossary. ^{3 .}

A challenge in AD, as well as for many other diseases that impact cognition, is that patients may experience anosognosia, in which a patient may be unaware of, or have limited insight into, their cognitive deficits, limiting the ability to rely on patient‐reported outcomes. Therefore, reports from informants based on direct observation of the patient are typically needed to accurately assess symptoms of memory impairment and function in daily life. It remains an open question as to whether patient‐reported outcomes may be informative in clinical trials in the earliest stages of disease when patients may be able to report subjective memory complaints (e.g., Stage 2). Additional work would be necessary to understand patient insight into their deficits and when anosognosia develops to support the use of patient‐reported outcomes in the earliest stages of disease.

Prior to initiating studies, drug developers should review the potential COAs for their planned trials to determine if the COA is fit‐for‐purpose or if additional qualitative or quantitative evidence is needed for their use. Drug developers should evaluate if the assessments capture concepts that are important to patients and if there is existing evidence to support the interpretability of a change in the score. If evidence is lacking, drug developers should plan to generate this evidence during the development program. Although FDA recognizes the impacts that diseases such as Alzheimer's disease have on caregivers, clinical outcomes that are intended to support a drug approval must be based on the assessment of the patient. In addition, to ensure that a COA measures concepts meaningful to patients, it is important to consider the scoring of the COA and how it performs in the patient population enrolled in the clinical trials and in different stages of the disease. “Ceiling effects” or “floor effects” are commonly encountered with COAs in AD, and different COAs may be needed for different stages of disease. Additionally, if a scale is capable of being used across multiple stages of AD, it is important to consider if the meaningfulness of a score change will differ based on the stage of the disease. A scale may contain items that are not applicable to the particular stage of disease being evaluated in the clinical trial; in that case, the interpretation of the score change should take into consideration of the range of items that are applicable and are anticipated to change during the course of a study for the enrolled population. The potential impact of practice effects is also an important consideration when selecting a performance outcome, particularly for clinical trials in early stages of AD when practice effects may be more pronounced.

4.4. Quantitative methodologies

The fourth Draft Guidance of the FDA PFDD Guidance Series, “Patient‐Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision‐Making,” describes analytical approaches that can be used to assess meaningful score differences (MSD) on COA‐based endpoints. ¹³ FDA is aware that many terms have been used to describe approaches to making COA scores more interpretable and there has been continued debate about the best terms to use. MSD is often determined based on what patients would regard as a clinically meaningful within‐patient change, which captures the assessment of improvement or decline based on the perspective of the individual patient. The use of a “minimal” important difference or change, typically defined as the smallest change on a COA that is perceived as beneficial, can be challenging to interpret as the minimal difference identified will depend on the methodology used and specific population studied, and application of the threshold to group‐mean changes may not accurately reflect the experience of what is meaningful change to the individual patients. Anchor‐based methods are recommended as the primary analytical method to identify MSDs, with distribution methodology as a supportive approach. Other supportive analytical approaches may include pre‐specified sensitivity analyses of the COA‐based endpoint, exploratory analytical methods to examine heterogeneity of treatment effects, and descriptive or graphical methods to illustrate findings in alternative ways. The specific method(s) used to estimate MSDs and how they will be applied in a clinical trial should be specified in the statistical analysis plan.

5. RECENT U.S. DRUG APPROVALS FOR AD

Many of the concepts regarding clinical meaningfulness presented in this perspective are evident in FDA's assessment of the results of clinical trials of the anti‐amyloid monoclonal antibodies that received traditional approval for the treatment of early symptomatic stages of Alzheimer's disease. These drugs target amyloid‐beta, a defining pathophysiological feature of AD, and the clinical trials evaluated patients in mild cognitive impairment and mild dementia stages of AD (i.e., Stage 3 and Stage 4) over 18 months.

The pivotal clinical trials for lecanemab and donanemab demonstrated a statistically persuasive benefit on clinically meaningful endpoints, supporting traditional approval of these products. ¹⁴ , ¹⁵ Although the selection of an appropriate primary endpoint for a study is critical to designing an interpretable study, an assessment of clinical benefit is not limited to the primary endpoint. The assessment of benefit also considers the consistency of findings from multiple endpoints (e.g., primary and secondary) within a trial and across the trials within a development program. Primary and secondary endpoints in the studies assessed cognition and its impact on daily functioning to provide a comprehensive assessment of the patient's disease state and captured relevant concepts expressed by patients and their caregivers. These endpoints included a mix of observer‐reported outcomes, clinician‐reported outcomes, and performance outcomes that capture data from diverse and independent sources, including clinical judgement based on semi‐structured interviews, input from the patients and caregivers, and performance on cognitive tests. Biomarkers showed consistent findings of pharmacodynamic effects on disease pathology, reflecting target engagement, effects on downstream tau pathophysiology, and neurodegeneration. The biomarker changes provided additional lines of evidence to increase the persuasiveness of changes observed on the clinical endpoints. Results in the Phase 3 studies were also consistent with the clinical and biomarker findings obtained in each development program's early‐stage clinical trials.

When assessing a clinically meaningful change, it is important to bear in mind that some scales have a wide range because they are intended to capture the continuum of AD from no impairment to severe dementia, and thus, only a fraction of the scale is relevant for interpretation of treatment effects in patients with mild cognitive impairment or mild dementia. FDA also considered changes on the CDR‐SB and other endpoints in this stage of disease within the context of clinically meaningful within‐patient change. For example, the CDR‐SB ranges from 0 to 18, with a typical score in a population with early AD ranging from 0.5 to approximately 6. The observed placebo decline for CDR‐SB over 18 months in the lecanemab and donanemab studies was approximately 1.5 to 2 points. The observed treatment effects of approximately 0.4 to 0.7 points in the lecanemab and donanemab Phase 3 studies should be considered with respect to this limited decline in the placebo group. For this reason, interpretation of an absolute point difference on a COA needs to consider the anticipated effect of the drug, duration of the study, and the disease stage.

Once statistical significance was established for primary and secondary endpoints, complementary exploratory analyses considering meaningful within patient change were used to support clinical meaningfulness. FDA also considered changes on the CDR‐SB and other endpoints in this stage of disease within the context of clinically meaningful within‐patient change. For example, responder analyses accounted for the percentage of subjects who did not have a meaningful increase of at least 0.5 points on the CDR‐SB. Time to event analyses described the proportion of subjects who progressed by a clinically meaningful amount, defined as any increase in the CDR global score at two consecutive visits. The CDR global score is used for disease staging, and worsening of this score generally reflects progression to the next stage of the disease (e.g., mild cognitive impairment [MCI] to mild dementia or mild dementia to moderate dementia). Delaying progression to the next disease stage as defined by the CDR global score is clearly clinically meaningful as it indicates a marked decline in cognition and daily function. The time course of the treatment effect was also considered, including the delay in the time to progression, with exploratory analyses suggesting that disease progression may be delayed by up to 5 or 6 months. The clinical trials demonstrated that absolute treatment differences between drug and placebo increased over time, as expected for drugs that impact the underlying biology of disease.

FDA also considered patient perspectives from published literature, stakeholder engagement activities, and the open public hearing during the advisory committee meetings for lecanemab and donanemab. Additionally, the advisory committee members included clinicians with expertise in Alzheimer's disease and other neurodegenerative diseases and patient and consumer representatives. ¹⁶ , ¹⁷ Overall, these stakeholder perspectives and the unanimous vote from the advisory committees for both products supported that the observed effects on slowing disease progression were meaningful for patients.

6. CONCLUSION

In slowly progressive neurodegenerative diseases such as AD, prolonging time in the current disease state or slowing the rate of disease progression are clinically meaningful outcomes to patients and caregivers. Score changes on COAs that support clinical trial endpoints must be considered in the full context of the clinical trial data and an understanding of the pathophysiology of disease. Various sources of evidence should be generated to support these clinical trial results, which may include COAs and biomarkers of pathologic disease processes. Implementation of multiple fit‐for‐purpose COAs which have different methods and reporters generates broader and more diverse evidence for the assessment of clinical benefit. FDA encourages drug developers to consider all options and methods to explore clinical meaningfulness and clinically meaningful within‐patient change throughout their product's development.

CONFLICT OF INTEREST STATEMENT

The authors have no conflicts to disclose. Author disclosures are available in the supporting information.

DISCLAIMER

This article reflects the views of the authors and should not be construed to represent FDA's views or policies.

Supporting information

Supporting Information

Buracchio T, Campbell M, Krudys K. Assessing clinical meaningfulness in clinical trials for Alzheimer's disease: A U.S. regulatory perspective. Alzheimer's Dement. 2025;11:e70113. 10.1002/trc2.70113