title: New Genetic Approaches to AD: Lessons from APOE-TOMM40 Phylogenetics.
abstract: Clinical trials for Alzheimer's disease are now focusing on the earliest stages of the disease with the goal of delaying dementia onset. There is great utility in using genetic variants to identify individuals at high age-dependent risk when the goal is to begin treatment before the development of any cognitive symptoms. Genetic variants identified through large-scale genome-wide association studies have not substantially improved the accuracy provided by APOE genotype to identify people at high risk of late-onset Alzheimer's disease (LOAD). We describe novel approaches, focused on molecular phylogenetics, to finding genetic variants that predict age at LOAD onset with sufficient accuracy and precision to be useful. We highlight the discovery of a polymorphism in TOMM40 that, in addition to APOE, may improve risk prediction and review how TOMM40 genetic variants may impact the develop of LOAD independently from APOE. The analysis methods described in this review may be useful for other genetically complex human diseases.
authors.affiliation: Joseph and Kathleen Bryan Alzheimer's Disease Center, Department of Neurology, Duke University Medical Center, 2200 W Main Street, Suite A200, Durham, NC, 27705, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lutz
authors.affiliation: Zinfandel Pharmaceuticals, Inc., Durham, NC, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Crenshaw
authors.affiliation: Joseph and Kathleen Bryan Alzheimer's Disease Center, Department of Neurology, Duke University Medical Center, 2200 W Main Street, Suite A200, Durham, NC, 27705, USA. kwe@duke.edu.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Welsh-Bohmer
authors.affiliation: Zinfandel Pharmaceuticals, Inc., Durham, NC, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Burns
authors.affiliation: Joseph and Kathleen Bryan Alzheimer's Disease Center, Department of Neurology, Duke University Medical Center, 2200 W Main Street, Suite A200, Durham, NC, 27705, USA.|Zinfandel Pharmaceuticals, Inc., Durham, NC, USA.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Roses
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D010802:Phylogeny; D012307:Risk Factors
chemical_list: D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human
keywords: APOE; Alzheimer’s disease; Genetic analysis; Phylogenetic analysis; Randomized clinical trial; TOMM40