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Alzheimer's Association International Conference (AAIC) · 2024:Poster Tue-17 · Hendrix, Dickson et al.
Companies recently identified clinical study sites engaging in fraudulent practices, reducing success in Alzheimer's disease (AD) clinical trials. Successful trials are reliable…
When the sample size a conventional design demands is larger than the trial you can run, a Global Statistical Test lets the clinical-endpoint hypotheses be tested anyway. The paper sets out when GST applies, how it is pre-specified, and how it has been received in review.
10 publications
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2026 · Alzheimers Dement.
Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), remains undiagnosed in > 90% of individuals, delaying access to timely evaluation and interventions. Self-administered digital cognitive assessments (SA-DCAs) offer scalable approaches for early detection, yet their real-world validation and clinical readiness remain uncertain. We developed a use-case-specific framework to evaluate SA-DCAs intended for community and primary-care MCI screening and applied it to a comprehensive scoping review of published evidence (2012-2025). Among 79 identified SA-DCAs, only four tools met predefined framework criteria across nine eligible studies. Common limitations included restricted population representativeness, inconsistent diagnostic performance reporting, limited biomarker anchoring, and reliance on prefiltered cohorts. Overall, the current evidence base is methodologically heterogeneous and incomplete for clinical deployment. The proposed framework characterizes requirements including anchoring strength, prevalence-adjusted performance reporting, and representative sampling establishing a foundation for advancing robust real-world evidence needed to translate SA-DCAs from research to clinical practice.
2026 · Front Med Technol.
Dickson, Samuel · Durrant, Abe · Dayley, Caleb · Christensen, Joshua · Mallinckrodt, Craig · Hendrix, Suzanne
Introduction: Choice of the primary outcome can be problematic in 1) diseases with heterogeneous signs and symptoms, 2) trials of disease-modifying treatments (DMTs) that are expected to affect all aspects of the disease, 3) in complex and rare diseases with minimal data on clinical trial outcomes. In such situations, a single outcome measuring a single domain of disease will rarely suffice as a primary outcome. To address this issue, regulatory bodies often suggest co-primary endpoints or require efficacy on both primary and key secondary endpoints for confirmatory trials, to ensure that at least two different domains of disease are affected by treatment. However, obtaining statistical significance on two outcomes is a much stricter requirement than on a single primary outcome. Global statistical tests (GST) combine multiple outcomes into a single score and could provide a viable alternative to the co-primary approach. Importantly for rare diseases, combining multiple assessments reduces the risk of selecting a poorly performing outcome simply because it has not been studied extensively. Methods: We conducted simulations to compare GST to single primary and co-primary endpoint approaches with two moderately or highly correlated outcomes with various effect sizes. Results: For scenarios with the same true effect size on both outcomes, the GST had greater power than single primary and co-primary approaches, regardless of the correlation level between outcomes. This was also true with different effect size combinations at the same correlation level. With an effect observed on one outcome only, GST was more likely to yield statistical significance than the co-primary approach. Unlike the co-primary approach, The GST yielded lower p-values in scenarios with lower correlation between the outcomes due to the independence of the information from each endpoint. Conclusions: Using GST as a prespecified endpoint is appropriate in trials where a clear primary endpoint has not been identified, sample sizes are insufficient to support multiple primary endpoints, and/or more comprehensive assessments across multiple endpoints are needed to fully evaluate outcomes.
2026 · Stat Med.
Mallinckrodt, Craig · Dickson, Samuel · Hendrix, Suzanne
In progressive diseases such as Alzheimer's, treatments that slow progression should start early to preserve higher levels of functioning for a longer period. In corresponding clinical trials, treatment effects are usually expressed as mean differences on a clinical scale at fixed time points. Early in the disease course, however, these mean differences may appear small but may nonetheless correspond to an important slowing of disease progression. This complicates the appreciation of the relevance of observed treatment effects. We introduce a class of target parameters that quantify treatment effects on the time scale in longitudinal studies; for instance, in terms of time saved or percentage slowing of progression. We focus on data from randomized trials where the target parameters are identified under regularity assumptions. These target parameters remain well defined if treatment was not randomized, but additional untestable assumptions are required for identification. We propose general two-step estimators. In the first step, the data can be analyzed with standard methods for longitudinal data and standard software can thus be used. In the second step, summary statistics from the first step are used for inferences about the target parameters. The second step has been implemented in the TCT R package. We study the asymptotic properties and efficiency of these two-step estimators, and evaluate them in an extensive simulation study. These estimators are used in a phase 2/3 clinical trial for Alzheimer's disease, leading to important additional insights into the treatment effect.
2026 · Stroke Vasc Interv Neurol
Nicodemus-Johnson, Jessie · Anderson, Landon
Background: Adjunct therapies are needed for patients with acute ischemic stroke who fare poorly, despite standard-of-care endovascular thrombectomy (EVT). RESCUE (A Randomized, Blinded, Placebo-Controlled, Parallel Group Design to Determine the Safety of RNS60 in Large Vessel Occlusion Stroke Patients Undergoing Endovascular Thrombectomy) tested the cytoprotective experimental drug RNS60 in patients with acute ischemic stroke, adjunct to EVT with or without prior standard-of-care thrombolytic treatment. Methods: RESCUE, a randomized, placebo-controlled, double-blind, phase 2 study, enrolled 83 participants eligible for EVT within 24 hours since last known well, assigned 1:1:1 to 48-hour infusion of RNS60 0.5 mL/kg per hour, RNS60 1.0 mL/kg per hour, or placebo 1.0 mL/kg per hour. A post hoc analysis evaluated safety and efficacy in a subpopulation of 62 participants enrolled within 12 hours since last known well. Efficacy end points included modified Rankin Scale score, post-EVT infarct growth, National Institutes of Health Stroke Scale score, Barthel Index score, EuroQoL, and duration of hospitalization and discharge disposition. Results: In this subpopulation, RNS60 1.0 mL/kg per hour was generally safe and well tolerated and reduced post-EVT infarct growth compared with placebo (least squares mean difference, 22.2; P=0.05). Of the participants treated with RNS60 1.0 mL/kg per hour, 72.2% achieved a 90-day modified Rankin Scale score of 0 to 2, and 72.2% achieved a Barthel Index score ≥95, compared with 36.8% (for both measures) of those receiving placebo, although the differences were not statistically significant (P=0.09 for both modified Rankin Scale and Barthel Index scores). Consistent but smaller differences to placebo were seen in the RNS60 0.5 mL/kg per hour group, which suggests a dose-dependent effect of RNS60. Participants in the RNS60 1.0 mL/kg per hour group were also released earlier from the hospital than those in the placebo group (mean [SD]: 6.0 [5.10] days versus 10.8 [6.84] days; mean difference [SE], -4.8 [1.99]; P=0.02). Final infarct volumes at 48 hours post-EVT correlated with modified Rankin Scale scores at day 90 for RNS60 1.0 mL/kg per (Pearson r=0.65; P=0.005) and placebo (r=0.65; P=0.007). Conclusions: Effects of RNS60 were favorable compared with placebo in the analyzed subpopulation, warranting further investigation in this population.
2026 · Nat Med
Despite advances in understanding the mechanisms, risk factors and treatment strategies for Alzheimer's disease (AD), no approved therapies exist to prevent or delay onset in at-risk individuals or those with elevated biomarkers who do not yet show symptoms. Multiple candidate interventions are now being evaluated in clinical trials in these settings, raising key questions around which populations are most appropriate and what criteria should guide regulatory and clinical decision-making. Data are expected within 1-2 years, underscoring the need for stakeholder alignment on clinically meaningful and acceptable characteristics of preventative therapies or other products. To address this need, the Global CEO Initiative on Alzheimer's Disease convened an international group of experts to develop target product profiles for therapies designed to delay or prevent the onset of clinical symptoms in AD. These target product profiles outline minimum and preferred characteristics, including intended use, target populations, safety expectations and efficacy benchmarks. This effort provides a foundational framework to accelerate therapeutic development and guide researchers, regulators and patients in the evaluation of emerging therapies for preventing symptomatic AD.
2026 · Neurol Ther
Dickson, Samuel · Hendrix, Suzanne
Introduction: The spinocerebellar ataxia composite score (SCACOMS) comprises items from the functional Scale for the Assessment and Rating of Ataxia (f-SARA) and the Clinician Global Impression of Change (CGI-C). In the derivation of SCACOMS, weights reflecting 1-year responsiveness were assigned to each item using partial least squares (PLS) regression modeling. The current objective was to incorporate patient-feedback into the SCACOMS item weights, examine corresponding responsiveness of the composite scale, and discuss potential implications for future use. Methods: Item weights derived by PLS regression were compared to each item's relative importance as assigned by 16 patients with SCA during semi-structured interviews. SCACOMS item weights were adjusted using the following combinations: (1) 50/50 weighted combination of PLS and patient weights and (2) reducing the weight of CGI-C to 20% and averaging individual item weights obtained from each perspective. The 1-year mean to standard deviation ratios (MSDRs) for the resulting reweighted scales were compared, with larger MSDRs indicating greatest sensitivity to disease progression. Results: The PLS-derived SCACOMS had the highest MSDR (0.99). When item weights were averaged across the two sources, the resulting MSDR was 0.91. When the weight of CGI-C was set to 20%, reflecting patient preferences for higher weights on the discrete symptoms, the MSDR was 0.79. Conclusions: This study took a novel approach to enhance the face validity of SCACOMS by incorporating patient feedback into the statistically optimized item weights. The result is the merging of objectively derived item weightings (reflecting optimal scale responsiveness) with patient-assigned relevance. While this update may increase the patient centricity of a composite measure, this comes at the expense of reduced sensitivity. This potential trade-off in sensitivity to detect change should be evaluated in the context of the composite measure's intended use.
2026 · Pharm Stat
Mallinckrodt, Craig · Dickson, Samuel · Hendrix, Suzanne
Participants who are randomized to treatment but have no post-baseline data pose a unique challenge. These participants need to be included to preserve randomization. Because there is no information about the outcome or the intercurrent event(s) that led to missing data, an estimand of interest, and the focus of this study, is a hypothetical strategy to estimate what would have been observed if participants had not discontinued. Various imputation-based and likelihood-based analyses were compared in simulated and real clinical trial data. Models that used baseline as a covariate or constrained baseline values to be equal yielded similar results and had greater power than an unconstrained analysis that fit baseline as a response. Assigning change to the first post-baseline visit as 0 and applying an analysis with baseline as a covariate controlled Type I error at the nominal level and had power equal to or greater than other methods. Treatment contrasts were not biased when the reason for missing all post-baseline data was random or treatment related. Within-group bias occurred with outcome-related missingness of all post-baseline data, but the bias was nearly equal in the two arms, leading to unbiased treatment contrasts. Bias occurred when missing all post-baseline data was related to treatment and outcome. Given the idiosyncratic nature of clinical trials, no universally best analytic approach exists for dealing with participants that have a baseline but no post-baseline data. Analysts can choose among the methods to tailor an approach to the situation at hand.
2026 · Alzheimers Dement
Nicodemus-Johnson, Jessie · Christensen, Joshua
Introduction: Alzheimer's disease (AD) study participants may present with cognitive impairment who do not have brain amyloid deposits (Aβ-). Identifying predictive biomarkers for non-amyloid-related CI may provide better screening tests for trials seeking only CI Aβ+ participants and new therapy targets. Methods: Analysis of the Bio-Hermes biomarker database identified subpopulations of clinically normal, CN Aβ- (n = 313), CI Aβ- (n = 296), and CI Aβ+ (n = 258), and CN Aβ+ (n = 84) participants. Comparative analysis of demographics, clinical assessments, biomarkers, cytokines, and proteomics results was conducted. Results: Subgroup comparison of CI Aβ- versus CN Aβ- found that neurofilament light most clearly differentiated CI Aβ- from CN Aβ- participants. No other biomarker analysis reached a level of differential significance. Discussion: Analyses showed many novel biomarkers do not differentiate CI Aβ- from CN Aβ-. New biomarkers are needed to best determine the neuropathology of the clinical presentation of AD. Highlights: NfL differentiated CN Aβ- versus cognitively impaired Aβ-. Proteomics (two platforms) did not differentially assess cognitively impaired Aβ--. Many novel biomarkers did not differentially assess cognitively impaired Aβ-. New biomarkers are needed to determine the neuropathology of AD clinical presentation.
2026 · The Journal of Prevention of Alzheimer's Disease
Hendrix, Suzanne · Mallinckrodt, Craig
Background: Soluble amyloid β1–42 (Aβ42) signals via the α7 nicotinic acetylcholine receptor to hyperphosphorylate tau in Alzheimer's disease (AD). Simufilam disrupts this pathogenic signaling by binding filamin A and disrupts its linkages with inflammatory receptors to reduce neuroinflammation. We assessed simufilam in two Phase 3 clinical trials in mild-to-moderate AD. Methods: Participants were age 50–87 with Stage 4 or 5 CE, a mini-mental state exam (MMSE) ≥16 and ≤27 and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5, 1 or 2. The criterion supporting AD pathology was plasma phosphorylated (p)-tau181 or prior amyloid PET. RETHINK randomized participants to simufilam 100 mg or placebo for 52 weeks. REFOCUS evaluated simufilam 50 and 100 mg versus placebo for 76 weeks. Co-primary endpoints were change from baseline on ADAS-Cog12 and ADCS-ADL. Sub-studies assessed exploratory plasma biomarkers and, in REFOCUS only, CSF and imaging biomarkers. Results: Both trials failed to meet co-primary, secondary or exploratory biomarker endpoints. REFOCUS was terminated early, with 22% of participants still active in the trial. In the predefined mild subgroup in REFOCUS, simufilam was associated with slower cognitive decline than placebo through Week 64 (p = 0.019). This finding disappeared at Week 76 with 45% missing data and did not replicate in RETHINK. Favorable nominal exploratory post-hoc findings amongst participants with the highest half of screening plasma p-tau181 levels occurred in RETHINK but not REFOCUS. The plasma p-tau181 entry criterion did not reliably exclude amyloid PET negativity in the sub-study. Conclusions: Simufilam did not meet co-primary or secondary endpoints in these Phase 3 trials. Simufilam was safe and well tolerated. Trials registered at clinicaltrials.gov: NCT04994483 and NCT05026177
2026 · J Prev Alzheimers Dis
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease driven by pathological depositions of proteins that accumulate over decades. Compelling genetic and neurobiological evidence suggests that amyloid accumulation in the brain initiates and drives early-stage AD. Measurement of fibrillar amyloid has been pivotal to the development and approval of disease-slowing treatments. Various biomarkers of AD pathophysiology provide evidence of target engagement and downstream effects on disease progression, and their use as surrogate endpoints may help identify and expeditiously bring new treatments to patients. In clinical trials, a surrogate endpoint serves as a substitute for a direct measurement of a patient's clinical status, and its use can provide ethical, logistical, and economic advantages. Establishing biomarkers as surrogate endpoints involves evaluating scientific evidence through diverse statistical approaches to demonstrate their predictivity of clinical benefit. This article evaluated evidence supporting amyloid β plaque reduction as a surrogate endpoint in symptomatic AD by exploring regulatory considerations and guidelines for surrogate endpoints, examining the amyloid hypothesis and the current therapeutic landscape in AD, and presenting supporting evidence of surrogate endpoints from a recent clinical development program of AD.
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