Toward a multifactorial model of Alzheimer disease

Storandt, Martha; Head, Denise; Fagan, Anne M.; Holtzman, David M.; Morris, John C.

doi:10.1016/j.neurobiolaging.2011.11.029

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Toward a multifactorial model of Alzheimer disease

Martha Storandt
- Department of Psychology, Washington University, St. Louis, Missouri, USA
- Department of Neurology, Washington University, St. Louis, Missouri, USA
Denise Head
- Department of Psychology, Washington University, St. Louis, Missouri, USA
- Department of Radiology, Washington University, St. Louis, Missouri, USA
Anne M. Fagan
- Department of Neurology, Washington University, St. Louis, Missouri, USA
David M. Holtzman
- Department of Neurology, Washington University, St. Louis, Missouri, USA
John C. Morris
- Department of Neurology, Washington University, St. Louis, Missouri, USA
- Department of Pathology and Immunology, Physical Therapy, Occupational Therapy, Washington University, St. Louis, Missouri, USA
- Corresponding author. Tel.: +1-314 286 2881; fax: +1-314 286 2763

Received 17 October 2011; received in revised form 28 November 2011; accepted 28 November 2011. published online 20 January 2012.
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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 Aβ₄₂ and tau were minimally correlated, indicating they represent independent processes. Aβ₄₂, 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 Aβ₄₂ 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.

Keywords: Preclinical Alzheimer disease , Amyloid-β , Tau , PIB , Amyloid plaque , APOE , Brain volumetry , Memory , Biomarkers , Cerebrospinal fluid