Intérêt de la TEP au [11C]-PIB dans les stades précoces de la maladie d'Alzheimer

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Solanezumab in- depth outcomes

BackgroundSolanezumab is a monoclonal antibody targeting soluble forms of β- amyloid protein important in the pathogenesis of Alzheimer- s disease (AD). Three previous 18- month double- blind placebo- controlled trials of low- dose solanezumab in late- onset sporadic AD found inconsistent benefits on cognitive and functional assessments. Dominantly- inherited mutation- associated AD subjects both before and after onset of symptoms form an ideal population to study potential benefits of solanezumab therapy.MethodMutation- carrying asymptomatic (CDR 0, N=41) or mildly symptomatic (CDR 0.5 - 1, N=28) patients were treated for a minimum of 4 years and up to 7 years in a double- blind 3 to 1 active versus placebo randomized clinical trial that measured disease progression by clinical, neuropsychological and biomarker evaluations. The trial was initiated with a dose of 400 mg every 4 weeks and escalated to 1600 mg when low dose trials in sporadic AD did not meet their primary endpoints. The primary cognitive outcome measure was DIAN- MCE, composed of Delayed Recall Score of the International Shopping List Test, the Delayed Recall score of the Logical Memory IIa subtest from the Wechsler Memory Scale- Revised, the Digit Symbol Substitution Test total score from the WAIS- R and the MMSE total score. Secondary outcomes included a battery of other cognitive and functional measures. The study was powered to detect delay of cognitive disease progression in the DIAN- MCE. Biomarkers include imaging modalities (volumetric MRI, FDG, amyloid and Tau PET). CSF markers included β- amyloid, Tau and PhosphoTau species. NfL was measured in both CSF and plasma. The study used a pre- specified Bayesian multivariate disease progression model, which included dynamic borrowing of control subjects from the DIAN Observational study.ResultThe topline efficacy, safety and biomarker results will be reported.ConclusionThis study provides the first test of targeting soluble abeta forms in DIAD. It addresses the efficacy of early initiation of higher doses of solanezumab targeting soluble forms of amyloid as a disease modifying therapy. While these results are specific to DIAD, they have the potential to inform the application of anti- amyloid therapy in sporadic AD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163859/1/alz038028.pd

Gantenerumab in- depth outcomes

BackgroundGantenerumab is a humanized anti- amyloid- beta monoclonal antibody in clinical development for the treatment of several stages of Alzheimer disease (AD). Gantenerumab was evaluated in a phase 2/3 clinical trial program designed to evaluate its efficacy in autosomal dominant AD based on a combination of clinical and biomarker evidence.MethodThe study enrolled both mutation carriers (n=69 with 3:1 randomization of treatment (n=52) vs placebo (n=17)) and non- carriers (n=28, all on placebo) from 15 years before to 10 years after the expected age of onset inclusive. Patients were both asymptomatic (CDR 0 and MMSE >25) and symptomatic (CDR 0.5- 1 and MMSE >16). There were 41 asymptomatic and 28 symptomatic mutation carriers. The initial dose of gantenerumab was 225 mg monthly administered subcutaneously. The dose was titrated to 1200 mg/month following a protocol amendment based on the increased amyloid lowering seen at higher doses in the gantenerumab program in symptomatic AD. The treatment duration was a minimum of 4 years (range 48- 80 months). The primary outcome was change from baseline in the DIAN- TU multivariate cognitive endpoint. Secondary clinical outcomes included the DIAN- TU cognitive composite, Cogstate multivariate cognitive endpoint, CDR SB, and time to CDR progression of >0.5 points. Change from baseline in amyloid PET was the primary biomarker outcome. Other biomarker outcomes included MRI, tau PET, CSF amyloid, tau and phosphotau, and CSF and plasma neurofilament light (NfL). Safety outcomes including ARIA were compared between drug and placebo groups.ResultWe will report change from baseline on the DIAN- TU multivariate cognitive endpoint, DIAN- TU cognitive composite, CDR- SB and other secondary efficacy endpoints. We expect significant lowering on amyloid PET with PIB and florbetapir based on the results from recent anti- amyloid antibodies, including Gantenerumab, in sporadic AD. We will also present the results of change in other key imaging and fluid biomarkers. The frequency, duration, and severity of ARIA will be reported and compared with studies in sporadic AD.ConclusionThis clinical trial was designed to inform future for ADAD and will provide new insights on the role of amyloid reduction in both pre- symptomatic and clinical AD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163780/1/alz038049.pd

Overview of dominantly inherited AD and top- line DIAN- TU results of solanezumab and gantenerumab

BackgroundAlzheimer- s disease (AD) prevention trials aim to intervene prior to significant neuronal loss, brain damage, and symptom onset to delay or slow cognitive decline. In dominantly inherited AD (DIAD), mutation carriers develop symptomatic AD at predictable ages with near 100% penetrance. In 2012, the Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial (DIAN- TU APT) platform launched a double- blind, randomized, placebo- controlled, parallel group trial of two anti- amyloid- beta monoclonal antibodies with two different antigenic targets, gantenerumab and solanezumab (NCT01760005). The DIAN- TU scientific development, implementation of the first AD prevention trial, trial challenges and opportunities, including dose escalation, and top- line results will be presented.MethodDIAN was established in 2008 in response to a call from the National Institute of Aging to establish a network to study DIAD and enable future clinical trials. Successive breakthroughs in understanding disease processes enabled the launch of the DIAN- TU adaptive prevention trial, a global adaptive platform trial supporting testing multiple drugs in parallel. The DIAN- TU partners include patients and families at risk for DIAD, global academic researchers, the NIH, Alzheimer- s Association, philanthropic supporters, the DIAN- TU Pharma Consortium, and pharmaceutical companies with drugs being tested. Important milestones include developing a platform to enable a comprehensive efficient treatment trial for this rare population, adding tau PET as part of AMP AD, adapting dosing mid- trial and extending the original biomarker trial to continue randomized dosing to test a cognitive endpoint until the last patient reaches 4 years, developing a disease progression statistical model and inclusion of DIAN observational data to increase the power to determine drug effects.ResultThe primary and key secondary outcomes of the DIAN- TU trial will be presented for each therapy in the context of targeting amyloid- beta at pre- clinical and clinically symptomatic stages of disease.ConclusionThese results inform about AD hypotheses, timing of treatment and the prospect of slowing, or preventing AD in DIAD and sporadic AD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163864/1/alz041129.pd

SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease

International audienceThe SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history

Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

International audienceAbstract Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE -ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1 -LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1- LoF variants, stratified by APOE-ε4 , derived from the Rotterdam study ( N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1- LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE -ε4-stratified SORL1- LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1- LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE -ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1- LoF variant carriers in case-control study data. Conclusions We conclude that SORL1- LoF variants should be interpreted in light of APOE genotypes for future clinical applications