solanezumab (LY2062430) / Eli Lilly - LARVOL DELTA

Baseline Amyloid PET Burden, but Not Longitudinal Change Predicts ARIA-H Risk in the A4 Study (EANM 2026) - "Materials and We conducted a secondary analysis of data from the A4 study, a randomised, placebo-controlled trial of solanezumab, using multivariable logistic regression... Baseline amyloid burden and APOE ε4 homozygosity are strong risk factors for the development of ARIA-H. Longitudinal change in amyloid burden evaluated between baseline and post therapy PET was non-significant in predicting the risk of ARIA-H. These findings suggest that ARIA-H is driven by pre-existing vascular vulnerability related to established amyloid deposition, rather than dynamic changes in amyloid over time."

Amyloid PET • Alzheimer's Disease • CNS Disorders • APOE

Dynamic imaging markers of incident microhemorrhages and superficial siderosis in the A4 study: A longitudinal person-interval analysis. (PubMed, Alzheimers Dement) - P3 | "Temporal imaging variables may provide independent prognostic information beyond baseline risk, supporting a dynamic model of hemorrhagic risk in Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • Hematological Disorders

Surrogate Endpoint Evaluation with Causal Mediation: Lessons from the A4 Trial. (PubMed, medRxiv) - "Using the A4 Study of solanezumab, we evaluate multiple formulations of the Prentice Criteria using causal mediation...Confidence interval widths varied by up to a factor of 17 across specifications. Causal mediation analysis of individual-level randomized trial data may contribute to quantitative surrogate endpoint evaluation, but our findings indicate this is only the case when analytic choices are biologically justified, prespecified, and interpreted with attention to uncertainty."

Journal

Multi-organ AI endophenotypes chart the heterogeneity of brain, eye and heart pan-disease. (PubMed, Nat Ment Health) - "Crucially, in data from an anti-amyloid AD drug (solanezumab), heterogeneity in cognitive decline trajectories was observed across treatment groups. Finally, Heart 1 and Heart 2 had the highest mortality risk and unique medication history profiles, with Heart 1 showing favorable responses to antihypertensive medications and Heart 2 to digoxin treatment. The 11 MAEs provide novel AI dimensional representations for precision medicine and highlight the potential of AI-driven patient stratification for disease risk monitoring, clinical trials, and drug discovery."

Heterogeneity • Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Heart Failure • Migraine • Oncology • Pain

Relationships between longitudinal retinal amyloid imaging and amyloid PET in the A4 Trial. (PubMed, Alzheimers Dement (Amst)) - "Curcumin-based retinal amyloid labeling shows promise but needs standardized protocols and validation in larger cohorts to understand its relationship to amyloid PET."

Journal • Alzheimer's Disease • CNS Disorders • Retinal Disorders

Clinico-biological trajectories stratified by combined tau biomarkers in preclinical Alzheimer's disease. (PubMed, Alzheimers Res Ther) - "Integrating plasma p-tau217 with tau-PET visual assessment reveals clinically meaningful tau-biomarker heterogeneity in preclinical AD. Our findings highlight the value of combining these biomarkers to refine early risk prediction and support prioritization strategies for prevention trials. The frequency of discordance also motivates refining tau-PET visual assessments beyond binary classification (e.g., ordinal/semi-quantitative staging) to better capture subtle early tau signal."

Biomarker • Clinical • Journal • Preclinical • Alzheimer's Disease • CNS Disorders

Neuroanatomical normative modelling in a preclinical Alzheimer’s disease trial cohort (OHBM 2026) - P3 | "Methods The A4 Study (NCT02008357) enrolled cognitively unimpaired, amyloid-positive adults aged 65–85 across 67 sites, randomised 1:1 to solanezumab (1600 mg IV every four weeks) or placebo, with the primary endpoint of Preclinical Alzheimer Cognitive Composite (PACC) change...We would like to acknowledge the dedication of all the participants, the site personnel, and all of the partnership team members who continue to make the A4 and LEARN Studies possible. The complete A4 Study Team list is available on: www.actcinfo.org/a4-study-team-lists."

Preclinical • Alzheimer's Disease • CNS Disorders

Mapping U.S. POINTER Cognitive-Slope Gains Onto Predicted Clinical Progression: An External-Cohort Translation Analysis With Exploratory Economic Thresholds. (PubMed, medRxiv) - "ADNI and LEARN were observational longitudinal cohorts, whereas A4 was a randomized solanezumab trial; the present analysis did not estimate solanezumab treatment effects...The absolute clinical delay was generally modest and varied with cohort risk structure, biomarker/genotype enrichment, and analytic framework. Exploratory economic-threshold results suggested more favorable margins in higher-risk ADNI subgroups under low incremental-cost and high willingness-to-pay assumptions, but these findings should be interpreted as hypothesis-generating translation estimates rather than empirical cost-effectiveness evidence."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • APOE

Longitudinal Associations Between Plasma GFAP, Cognition, Amyloid Burden, and Neurodegeneration in Preclinical Alzheimer’s Disease (AAN 2026) - "Design/Methods Data were analyzed from 949 cognitively unimpaired participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Study, a 240-week, multicenter, placebo-controlled trial of solanezumab in amyloid-positive older adults, and the companion amyloid-negative LEARN cohort...Among males, associations were weaker, limited to PACC slope (β = –0.14 ± 0.06, p = 0.018), and not significant for clinical progression or imaging outcomes. Conclusions Our findings identify astrocytic activation as an early contributor to neurodegeneration and support GFAP as a candidate biomarker for precision prevention in preclinical AD."

Preclinical • Alzheimer's Disease • CNS Disorders • FAP • GFAP

Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease. (PubMed, Cochrane Database Syst Rev) - "The effect of amyloid-beta-targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer's disease is trivial, while on functional ability, it is small at best. Amyloid-beta-targeting monoclonal antibodies increase the risk of amyloid-related imaging abnormalities. Both desirable outcomes and adverse events were inconsistently reported in the studies included in the review. Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Future research on disease-modifying treatments for Alzheimer's disease should focus on other mechanisms of action."

Clinical • Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Late-life body mass index and amyloid interaction on cognitive decline in unimpaired older adults. (PubMed, J Prev Alzheimers Dis) - "Our cross-sectional findings support a negative association between obesity and cognitive aging up to late-life. Longitudinally, we observed an "obesity paradox", where higher/obese BMI was associated with more favorable cognitive trajectories in the presence of advanced amyloid pathology. Together, our findings suggest that future trials targeting obesity to slow late-life cognitive decline may benefit from preferentially enrolling younger individuals or those without substantial amyloid accumulation."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Genetic Disorders • Obesity

DECODING HETEROGENEITY IN A4: EXPLAINABLE ML FINDS SOLANEZUMAB RESPONSIVE SUBGROUPS IN PRECLINICAL AD (ADPD 2026) - "An explainable ML strategy identified clinically interpretable profiles that may be preferential responders to solanezumab, despite the overall negative A4 result. These exploratory findings, based on limited sample sizes, suggest that greater regional brain volume and stronger psychomotor speed/attention at baseline may enrich for treatment benefit. Independent replication, presentation of absolute subgroup counts, and adjustment for multiplicity are warranted; if confirmed, this approach could support precision enrichment in future preclinical AD trials."

Heterogeneity • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

EFFICACY AND SAFETY OF IMMUNOTHERAPIES FOR ALZHEIMER'S DISEASE: A NETWORK META-ANALYSIS (ADPD 2026) - "The results found that monoclonal antibodies such as aducanumab and solanezumab consistently ranked higher in terms of Surface Under the Cumulative Ranking (SUCRA) score. However, this contrasts with the outlier of shorter-term treatments as AN-1792 with QS-21, a vaccine, is found to be the better treatment option. For heightened comprehension on the efficacy and safety choice of immunotherapies, future well-conducted and designed large studies encompassing specific safety outcomes, financial analysis is highly recommended. Also, as monoclonal antibodies are seen as demonstrating a higher efficacy, it is imperative for more focus driven towards further increasing the safety of these specific types of immunotherapies in the future."

Retrospective data • Alzheimer's Disease • CNS Disorders

PRE-RECORED: TIME TO REGIONAL TAU POSITIVITY – A NOVEL APPROACH FOR ASSESSING LONGITUDINAL TAU ACCUMULATION AND TREATMENT RESPONSE (ADPD 2026) - P2/3, P3 | "The T2RT+ was defined as an event for each composite and analyzed using Kaplan-Meier (KM) estimates for solanezumab and placebo groups... The T2RT+ approach captures the tau staging patterns in preclinical AD cohorts and might serve as a clinically meaningful, complementary endpoint to conventional SUVR approach for assessing treatment efficacy. Additional analyses exploring the baseline characteristics associated with progression to tau-PET positivity will be presented at the conference."

Alzheimer's Disease • CNS Disorders

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU-001 (clinicaltrials.gov) - P2/3 | N=438 | Active, not recruiting | Sponsor: Washington University School of Medicine | N=210 ➔ 438 | Trial primary completion date: Sep 2019 ➔ Sep 2023

Biomarker • Enrollment change • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU-001 (clinicaltrials.gov) - P2/3 | N=210 | Recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Dec 2016 ➔ Mar 2017

Biomarker • Trial completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU-001 (clinicaltrials.gov) - P2/3 | N=438 | Recruiting | Sponsor: Washington University School of Medicine | Active, not recruiting ➔ Recruiting

Biomarker • Enrollment open • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU-001 (clinicaltrials.gov) - P2/3 | N=490 | Recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Jul 2022 ➔ Oct 2027 | Trial primary completion date: Jul 2022 ➔ Oct 2027

Biomarker • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU-001 (clinicaltrials.gov) - P2/3 | N=490 | Recruiting | Sponsor: Washington University School of Medicine | Completed ➔ Recruiting | N=194 ➔ 490 | Trial completion date: Mar 2020 ➔ Jul 2022 | Trial primary completion date: Nov 2019 ➔ Jul 2022

Biomarker • Enrollment change • Enrollment open • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU-001 (clinicaltrials.gov) - P2/3 | N=490 | Recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Oct 2027 ➔ Jul 2028 | Trial primary completion date: Oct 2027 ➔ Apr 2028

Biomarker • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU-001 (clinicaltrials.gov) - P2/3 | N=194 | Completed | Sponsor: Washington University School of Medicine | Recruiting ➔ Completed | N=490 ➔ 194 | Trial completion date: Mar 2021 ➔ Mar 2020 | Trial primary completion date: Dec 2020 ➔ Nov 2019

Biomarker • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU-001 (clinicaltrials.gov) - P2/3 | N=490 | Active, not recruiting | Sponsor: Washington University School of Medicine | Recruiting ➔ Active, not recruiting

Biomarker • Enrollment closed • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU-001 (clinicaltrials.gov) - P2/3 | N=210 | Active, not recruiting | Sponsor: Washington University School of Medicine | Recruiting ➔ Active, not recruiting

Biomarker • Enrollment closed • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU-001 (clinicaltrials.gov) - P2/3 | N=210 | Recruiting | Sponsor: Washington University School of Medicine | Not yet recruiting ➔ Recruiting

Biomarker • Enrollment open • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU-001 (clinicaltrials.gov) - P2/3 | N=490 | Recruiting | Sponsor: Washington University School of Medicine | Active, not recruiting ➔ Recruiting

Biomarker • Enrollment open • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia