The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model.

INTRODUCTION: The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer's disease in autosomal dominant Alzheimer's disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation (NexGen) prevention trial. METHODS: In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the National Institutes of Health, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen prevention trial. RESULTS: Our expanded trial toolbox consists of a disease progression model for ADAD, primary end point DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion. CONCLUSION: These steps represent elements to improve efficacy of the adaptive platform trial and a continued effort to optimize prevention and treatment trials in ADAD.

Clinical and biomarker changes in dominantly inherited Alzheimer's disease.

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aß)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aß deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial.

Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] ß = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] ß = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] ß = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] ß = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] ß = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] ß = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] ß = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.

Evaluation of dose-dependent treatment effects after mid-trial dose escalation in biomarker, clinical, and cognitive outcomes for gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect. Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes. Results: Both gantenerumab and solanezumab demonstrated dose-dependent treatment effects (significant for gantenerumab, non-significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose-dependent treatment effects were observed in clinical or cognitive outcomes. Conclusions: Mid-trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases. Highlights: We evaluated the dose-dependent treatment effect of two different amyloid-specific immunotherapies.Dose-dependent treatment effects were observed in some biomarkers.No dose-dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations.

A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aß targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

Dominantly Inherited Alzheimer Network: facilitating research and clinical trials.

The Dominantly Inherited Alzheimer Network (DIAN) is an international registry of individuals at risk for developing autosomal dominant Alzheimer's disease (AD). Its primary aims are to investigate the temporal ordering of AD pathophysiological changes that occur in asymptomatic mutation carriers and to identify those markers that herald the transition from cognitive normality to symptomatic AD. DIAN participants undergo longitudinal evaluations, including clinical and cognitive assessments and measurements of molecular and imaging AD biomarkers. This review details the unique attributes of DIAN as a model AD biomarker study and how it provides the infrastructure for innovative research projects, including clinical trials. The recent design and launch of the first anti-amyloid-beta secondary prevention trial in AD, led by the related DIAN Trials Unit, also are discussed.

Effects of age and amyloid deposition on Aß dynamics in the human central nervous system.

BACKGROUND: The amyloid hypothesis predicts that increased production or decreased clearance of ß-amyloid (Aß) leads to amyloidosis, which ultimately culminates in Alzheimer disease (AD). OBJECTIVE: To investigate whether dynamic changes in Aß levels in the human central nervous system may be altered by aging or by the pathology of AD and thus contribute to the risk of AD. DESIGN: Repeated-measures case-control study. SETTING: Washington University School of Medicine in St Louis, Missouri. PARTICIPANTS: Participants with amyloid deposition, participants without amyloid deposition, and younger normal control participants. MAIN OUTCOME MEASURES: In this study, hourly cerebrospinal fluid (CSF) Aß concentrations were compared with age, status of amyloid deposition, electroencephalography, and video recording data. RESULTS: Linear increases were observed over time in the Aß levels in CSF samples obtained from the younger normal control participants and the older participants without amyloid deposition, but not from the older participants with amyloid deposition. Significant circadian patterns were observed in the Aß levels in CSF samples obtained from the younger control participants; however, circadian amplitudes decreased in both older participants without amyloid deposition and older participants with amyloid deposition. Aß diurnal concentrations were correlated with the amount of sleep but not with the various activities that the participants participated in while awake. CONCLUSIONS: A reduction in the linear increase in the Aß levels in CSF samples that is associated with amyloid deposition and a decreased CSF Aß diurnal pattern associated with increasing age disrupt the normal physiology of Aß dynamics and may contribute to AD.