title: Toward a multifactorial model of Alzheimer disease.
abstract: Relations among antecedent biomarkers of Alzheimer disease (AD) were evaluated using causal modeling; although correlation cannot be equated to causation, causation does require correlation. Individuals aged 43 to 89 years (N = 220) enrolled as cognitively normal controls in longitudinal studies had clinical and psychometric assessment, structural magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarkers, and brain amyloid imaging via positron emission tomography with Pittsburgh Compound B (PIB) obtained within 1 year. CSF levels of Aβ(42) and tau were minimally correlated, indicating they represent independent processes. Aβ(42), tau, and their interaction explained 60% of the variance in PIB. Effects of APOE genotype and age on PIB were indirect, operating through CSF markers. Only spurious relations via their common relation with age were found between the biomarkers and regional brain volumes or cognition. Hence, at least 2 independent hypothesized processes, one reflected by CSF Aβ(42) and one by CSF tau, contribute to the development of fibrillar amyloid plaques preclinically. The lack of correlation between these 2 processes and brain volume in the regions most often affected in AD suggests the operation of a third process related to brain atrophy.
authors.affiliation: Department of Psychology, Washington University, St. Louis, Missouri, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Storandt
authors.forename: Denise
authors.initials: D
authors.lastname: Head
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000209:etiology*; D000682:Amyloid / Q000032:analysis; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D000814:Aniline Compounds; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D003071:Cognition; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009929:Organ Size; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D049268:Positron-Emission Tomography; D013844:Thiazoles; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000682:Amyloid; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D001057:Apolipoproteins E; D015415:Biomarkers; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D016875:tau Proteins