Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoas-say technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, withinperson analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.Reprints and permissions information is available at www.nature.com/reprints.

Evidence before this study Using PubMed and Google Scholar the authors reviewed prior work on longitudinal neuroimaging markers of Alzheimer pathology with a focus on autosomal dominant Alzheimer disease (ADAD). We searched for all articles prior to October 31 st , 2017 with no language restrictions for the keywords Alzheimer's, Alzheimer, longitudinal, positron emission tomography, PET, MRI, atrophy, FDG, hypometabolism, familial, and autosomal. Theories proposed initially in 2010 by Jack and colleagues and revised in 2013 posited temporal trajectories of Alzheimer biomarkers relative to each other and clinical decline. Work by Bateman and colleagues in 2012, Benzinger and colleagues in 2013, and Fleisher and colleagues in 2015 depict such temporal ordering of biomarkers in ADAD populations derived from cross-sectional analyses. There was also a small subset of longitudinal ADAD studies, but these had one or more limitation such as small populations (n<50), examination of only one biomarker, not accounting for regional differences or correlations in the brain, or had a short duration of longitudinal followup. Added value of this studyOur study presents the first known work examining both the longitudinal temporal trajectories and spatial patterns of Alzheimer pathology in ADAD cohorts using neuroimaging. This work also presents the largest known cohort to date of ADAD individuals studied longitudinally with multiple neuroimaging biomarkers. Longitudinal analyses can provide a more accurate and powerful way to model the temporal emergence of pathology in ADAD. We find that mutation carriers first display Aβ accumulation, followed by hypometabolism, and finally structural atrophy; this is consistent with theoretical models and cross-sectional estimates from ADAD. Most importantly we consider such temporal relationships not in one singular summary measure, but characterize these trajectories throughout the brain. We found that the accrual of pathology varied throughout the brain and by modality in terms of the time of initial emergence and the rates of longitudinal change. These findings suggest region specific vulnerabilities to β-amyloidosis, metabolic decline, and atrophy that change over the course of the disease. Implications of all the available evidenceOur results build upon existing evidence characterizing biomarkers in clinical and preclinical Alzheimer disease. Our findings suggest that imaging biomarkers follow a sequential pattern, with β-amyloidosis, hypometabolism, and structural atrophy emerging more than twenty, fifteen, and ten years respectively before the expected onset of dementia. Although there is a general hierarchical pattern, there was considerable regional heterogeneity. Most commonly, regions demonstrated an increase in β-amyloidosis and structural atrophy, but there was not evidence of metabolic declines. Further, rather than being homogenous, the same biomarker often demonstrates different longitudinal trajectories across brain regions. Characterizing the temporal and regional dynamics...

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 Prevention Trial (NexGen). METHODS In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the NIH, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen trial. RESULTS Our expanded trials toolbox consists of a Disease Progression Model for ADAD, primary endpoint 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.

These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.

Code availabilityAll code for data cleaning and analysis associated with the current submission is available upon request to the corresponding author and is provided as part of the replication package.

No abstract

BackgroundWe previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer’s disease (AD).MethodsA subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-β plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale.ResultsSixty-seven of the 89 patients initially enrolled had ≥ 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-β plaque levels below the amyloid-β positivity threshold.ConclusionResults from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-β plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-β plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit.Trial registrationClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Potential Conflicts of Interest S.E.S. has a family member with stock in Eli Lilly, which is developing drugs for Alzheimer disease. D.L.G. is a full time employee at Biogen, which funded this study and is developing drugs for Alzheimer disease. L.M.S. receives research support from Eli Lilly, Hoffman LaRoche, MJFox Foundation for Parkinson's Research for Biofind study and has served as consultant and/or advisory boards for Roche Diagnostics and Eli Lilly. He provides quality control oversight for Roche Elecsys immunoassays in the ADNI study. J.J.H. is on the advisory board and consults for both Biogen and Lundbeck A/S. T.L.S.B. consults for Eli Lilly and receives research funding from Avid Radiopharmaceuticals. J.L. reports personal fees from Aesku, Bayer Vital, the Willi Gross Foundation, Axon Neuroscience, and Ionis Pharmaceuticals. He has received non-financial support from AbbVie that is outside the submitted work. D.M.H. co-founded and is on the scientific advisory board of C 2 N Diagnostics. D.M.H. consults for Genentech, AbbVie, Eli Lilly, Proclara, and Denali. Washington University receives research grants to the lab of D.M.H. from C2N Diagnostics, Eli Lilly, AbbVie, and Denali. J.H.L. reports being named on patents related to the use of VILIP-1. These are being managed by Washington University in accordance with University policy. J.H.L. is a co-inventor on patent 11/630582 (2005) (Markers for brain damage) and patent 60957132 (2008) (Alzheimer's diagnosis). J.C.M. has or is currently participating in clinical trials of anti-dementia drugs sponsored by Janssen Immunotherapy, Eli Lilly and Company, and Pfizer. He has served as a consultant for or has received speaking honoraria from Eisai, Esteve, Janssen Alzheimer Immunotherapy Program/Elan, GlaxoSmithKline, Novartis, and Pfizer. He receives research support from Eli Lilly/Avid Radiopharmaceuticals. R.J.B. co-founded and is on the scientific advisory board of C 2 N Diagnostics. He consults for Roche, Genentech, AbbVie, Pfizer, Boehringer-Ingelheim, and Merck. A.M.F. has received research funding from Biogen, Fujirebio and Roche Diagnostics. She is a member of the scientific advisory boards for Roche, Genentech and AbbVie and also consults for Araclon/Griffols and DiamiR.