Multilocus genetic pro fi ling to empower drug trials and predict brain atrophy ☆ NeuroImage: Clinical

Designers of clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) are actively considering structural and functional neuroimaging, cerebrospinal fl uid and genetic biomarkers to reduce the sample sizes needed to detect therapeutic effects. Genetic pre-selection, however, has been limited to Apolipoprotein E (ApoE). Recently discovered polymorphisms in the CLU , CR1 and PICALM genes are also moderate risk factors for AD; each affects lifetime AD risk by ~10 – 20%. Here, we tested the hypothesis that pre-selecting subjects based on these variants along with ApoE genotype would further boost clinical trial power, relative to considering ApoE alone, using an MRI-derived 2-year atrophy rate as our outcome mea- sure. We ranked subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on their cumulative risk from these four genes. We obtained sample size estimates in cohorts enriched in subjects with greater aggregate genetic risk. Enriching for additional genetic biomarkers reduced the required sample sizes by up to 50%, for MCI trials. Thus, AD drug trial enrichment with multiple genotypes may have potential implications for the timeliness, cost, and power of trials.

[1]  Jason J. Corneveaux,et al.  Initial Assessment of the Pathogenic Mechanisms of the Recently Identified Alzheimer Risk Loci , 2013, Annals of human genetics.

[2]  Michael W. Weiner,et al.  Genome-wide analysis reveals novel genes in fl uencing temporal lobe structure with relevance to neurodegeneration in Alzheimer ' s disease , 2010 .

[3]  Jason H. Moore,et al.  Alzheimer's Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans , 2010, Alzheimer's & Dementia.

[4]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease: Report of the NINCDS—ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease , 2011, Neurology.

[5]  David M Holtzman,et al.  Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease. , 2011, Archives of neurology.

[6]  N. Jahanshad,et al.  Common Alzheimer's Disease Risk Variant Within the CLU Gene Affects White Matter Microstructure in Young Adults , 2011, The Journal of Neuroscience.

[7]  J. Haines,et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. , 1997, JAMA.

[8]  M. Harirchian,et al.  Pharmacogenetic Study on the Effect of Rivastigmine on PS2 and APOE Genes in Iranian Alzheimer Patients , 2011, Dementia and Geriatric Cognitive Disorders Extra.

[9]  Amalia M. Issa,et al.  Ethical perspectives on pharmacogenomic profiling in the drug development process , 2002, Nature Reviews Drug Discovery.

[10]  Norbert Schuff,et al.  Automated cross-sectional and longitudinal hippocampal volume measurement in mild cognitive impairment and Alzheimer's disease , 2010, NeuroImage.

[11]  Paul M. Thompson,et al.  Inverse Consistent Mapping in 3D Deformable Image Registration: Its Construction and Statistical Properties , 2005, IPMI.

[12]  Eric J Topol,et al.  Genotype-Based Risk and Pharmacogenetic Sampling in Clinical Trials , 2010, Journal of biopharmaceutical statistics.

[13]  M. Donohue,et al.  Enrichment through biomarkers in clinical trials of Alzheimer's drugs in patients with mild cognitive impairment , 2010, Neurobiology of Aging.

[14]  Carole Dufouil,et al.  Effects of ApoE-ɛ4 allele load and age on the rates of grey matter and hippocampal volumes loss in a longitudinal cohort of 1186 healthy elderly persons , 2010, NeuroImage.

[15]  Andrew J. Saykin,et al.  Hippocampal Atrophy as a Quantitative Trait in a Genome-Wide Association Study Identifying Novel Susceptibility Genes for Alzheimer's Disease , 2009, PloS one.

[16]  Hilkka Soininen,et al.  Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations , 2011, Neurobiology of Aging.

[17]  D. Blacker,et al.  Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database , 2007, Nature Genetics.

[18]  A D Roses,et al.  A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease , 2009, The Pharmacogenomics Journal.

[19]  Paco Martorell,et al.  Monetary costs of dementia in the United States. , 2013, The New England journal of medicine.

[20]  D. Selkoe.  Alzheimer's disease. , 2011, Cold Spring Harbor perspectives in biology.

[21]  K. Lunetta,et al.  Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. , 2010, Archives of neurology.

[22]  Paul M. Thompson,et al.  Robust Brain Extraction Across Datasets and Comparison With Publicly Available Methods , 2011, IEEE Transactions on Medical Imaging.

[23]  Michael Weiner,et al.  Unbiased tensor-based morphometry: Improved robustness and sample size estimates for Alzheimer's disease clinical trials , 2013, NeuroImage.

[24]  Mark E. Schmidt,et al.  The Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception , 2012, Alzheimer's & Dementia.

[25]  Katie Kingwell.  Alzheimer disease: BIN1 variant increases risk of Alzheimer disease through tau , 2013, Nature Reviews Neurology.

[26]  J. Haines,et al.  Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis , 1997 .

[27]  C. Jack,et al.  Boosting power for clinical trials using classifiers based on multiple biomarkers , 2010, Neurobiology of Aging.

[28]  Nick C Fox,et al.  Common variants at ABCA 7 , MS 4 A 6 A / MS 4 A 4 E , EPHA 1 , CD 33 and CD 2 AP are associated with Alzheimer ’ s disease , 2011 .

[29]  Mert Sabuncu,et al.  Genetic variation and neuroimaging measures in Alzheimer disease. , 2010, Archives of neurology.

[30]  Norbert Schuff,et al.  Longitudinal stability of MRI for mapping brain change using tensor-based morphometry , 2006, NeuroImage.

[31]  Michael Weiner,et al.  Voxelwise gene-wide association study (vGeneWAS): Multivariate gene-based association testing in 731 elderly subjects , 2011, NeuroImage.

[32]  Paul K Crane,et al.  Comprehensive search for Alzheimer disease susceptibility loci in the APOE region. , 2012, Archives of neurology.

[33]  Michael Weiner,et al.  Exhaustive Search of the SNP-SNP Interactome Identifies Epistatic Effects on Brain Volume in Two Cohorts , 2013, MICCAI.

[34]  R. Bartha,et al.  Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database. , 2008, Brain : a journal of neurology.

[35]  Jing Cui,et al.  Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score , 2009, The Lancet Neurology.

[36]  Paul M. Thompson,et al.  Reduced cortical thickness in hippocampal subregions among cognitively normal apolipoprotein E e4 carriers , 2008, NeuroImage.

[37]  Donald A. Wilson,et al.  ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models , 2012, Science.

[38]  P. Visser,et al.  Do MCI criteria in drug trials accurately identify subjects with predementia Alzheimer’s disease? , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[39]  J. Reisch,et al.  Implication of common and disease specific variants in CLU, CR1, and PICALM , 2012, Neurobiology of Aging.

[40]  C. Jack,et al.  Alzheimer's Disease Neuroimaging Initiative , 2008 .

[41]  Danielle J. Harvey,et al.  The Alzheimer's Disease Neuroimaging Initiative: Annual change in biomarkers and clinical outcomes , 2010, Alzheimer's & Dementia.

[42]  Nick C Fox,et al.  The clinical use of structural MRI in Alzheimer disease , 2010, Nature Reviews Neurology.

[43]  Alan C. Evans,et al.  A nonparametric method for automatic correction of intensity nonuniformity in MRI data , 1998, IEEE Transactions on Medical Imaging.

[44]  R. Katz,et al.  Regulatory innovation and drug development for early-stage Alzheimer's disease. , 2013, The New England journal of medicine.

[45]  C. Jack,et al.  Longitudinal MRI atrophy biomarkers: Relationship to conversion in the ADNI cohort , 2010, Neurobiology of Aging.

[46]  Norbert Schuff,et al.  Accurate measurement of brain changes in longitudinal MRI scans using tensor-based morphometry , 2011, NeuroImage.

[47]  Dave R. M. Langers,et al.  Enhanced signal detection in neuroimaging by means of regional control of the global false discovery rate , 2007, NeuroImage.

[48]  A. Roses,et al.  The Medical and Economic Roles of Pipeline Pharmacogenetics: Alzheimer's Disease as a Model of Efficacy and HLA-B*5701 as a Model of Safety , 2009, Neuropsychopharmacology.

[49]  Anders M. Dale,et al.  Reliability in multi-site structural MRI studies: Effects of gradient non-linearity correction on phantom and human data , 2006, NeuroImage.

[50]  Norbert Schuff,et al.  Validation Testing of the MRI Calibration Phantom for the Alzheimer's Disease Neuroimaging Initiative Study , 2006 .

[51]  Norbert Schuff,et al.  Optimizing power to track brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based morphometry: An ADNI study of 515 subjects , 2009, NeuroImage.

[52]  A. Fagan,et al.  APOE predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging , 2010, Annals of neurology.

[53]  Nick C Fox,et al.  The Alzheimer's disease neuroimaging initiative (ADNI): MRI methods , 2008, Journal of magnetic resonance imaging : JMRI.

[54]  Paul M. Thompson,et al.  Neuroimaging Measures as Endophenotypes in Alzheimer's Disease , 2011, International journal of Alzheimer's disease.

[55]  Dominic Holland,et al.  Neuroimaging Enrichment Strategy for Secondary Prevention Trials in Alzheimer Disease , 2010, Alzheimer disease and associated disorders.

[56]  Guillén Fernández,et al.  CR1 genotype is associated with entorhinal cortex volume in young healthy adults , 2011, Neurobiology of Aging.

[57]  J. Pankow,et al.  Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. , 2007, American journal of epidemiology.

[58]  Philippe Amouyel,et al.  The pursuit of susceptibility genes for Alzheimer's disease: progress and prospects. , 2010, Trends in genetics : TIG.

[59]  V. Pankratz,et al.  Replication of CLU, CR1, and PICALM associations with alzheimer disease. , 2010, Archives of neurology.

[60]  L. Kurlowicz,et al.  The Mini Mental State Examination (MMSE). , 1999, Director.

[61]  M. Sugishita,et al.  [Clinical Dementia Rating (CDR)]. , 2011, Nihon rinsho. Japanese journal of clinical medicine.