title: A systematic review of biomarkers for disease progression in Alzheimer's disease.
abstract: BACKGROUND
  Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true slowing of the neurodegenerative process. A systematic review was undertaken to determine what biomarkers for disease progression in Alzheimer's disease exist and how well they perform.
  
  
  METHODS
  MEDLINE and Embase (1950-2011) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with probable Alzheimer's disease diagnosed by formal criteria were included. We made no restriction on age, disease duration, or drug treatment. We only included studies with a longitudinal design, in which the putative biomarker and clinical measure were both measured at least twice, as this is the only appropriate study design to use when developing a disease progression biomarker. We included studies which attempted to draw associations between the changes over time in the biomarker used to investigate disease progression and a clinical measure of disease progression.
  
  
  RESULTS
  Fifty-nine studies were finally included. The commonest biomarker modality examined was brain MRI (17/59, 29% of included studies). Median follow-up in included studies was only 1.0 (IQR 0.8-1.7) year and most studies only measured the putative biomarker and clinical measure twice. Included studies were generally of poor quality with small numbers of participants (median 31 (IQR 17 to 64)), applied excessively restrictive study entry criteria, had flawed methodologies and conducted overly simplistic statistical analyses without adjusting for confounding factors.
  
  
  CONCLUSIONS
  We found insufficient evidence to recommend the use of any biomarker as an outcome measure for disease progression in Alzheimer's disease trials. However, further investigation into the efficacy of using MRI measurements of ventricular volume and whole brain volume appeared to be merited. A provisional 'roadmap' to improve the quality of future disease progression biomarker studies is presented.
authors.affiliation: Division of Applied Health Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors.forename: David J M
authors.initials: DJ
authors.lastname: McGhee
authors.affiliation: Centre for Mental Health, Imperial College London, London, England, United Kingdom.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Ritchie
authors.affiliation: Centre for Health and Environmental Statistics, Plymouth University, Plymouth, England, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Thompson
authors.affiliation: Centre for Health and Environmental Statistics, Plymouth University, Plymouth, England, United Kingdom.
authors.forename: David E
authors.initials: DE
authors.lastname: Wright
authors.affiliation: Clinical Neurology Research Group, Plymouth University, Plymouth, England, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Zajicek
authors.affiliation: Division of Applied Health Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors.forename: Carl E
authors.initials: CE
authors.lastname: Counsell
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D018450:Disease Progression; D006801:Humans
chemical_list: D015415:Biomarkers