Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease

Price, Joseph L.; McKeel, Daniel W.; Buckles, Virginia D.; Roe, Catherine M.; Xiong, Chengjie; Grundman, Michael; Hansen, Lawrence A.; Petersen, Ronald C.; Parisi, Joseph E.; Dickson, Dennis W.; Smith, Charles D.; Davis, Daron G.; Schmitt, Frederick A.; Markesbery, William R.; Kaye, Jeffrey; Kurlan, Roger; Hulette, Christine; Kurland, Brenda F.; Higdon, Roger; Kukull, Walter; Morris, John C.

doi:10.1016/j.neurobiolaging.2009.04.002

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Volume 30, Issue 7 , Pages 1026-1036, July 2009

Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease

Joseph L. Price
- Department of Anatomy and Neurobiology, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Daniel W. McKeel Jr.
- Department of Pathology and Immunology, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
- Retired.
Virginia D. Buckles
- Department of Neurology, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Catherine M. Roe
- Department of Neurology, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Chengjie Xiong
- Division of Biostatistics, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Michael Grundman
- Elan Pharmaceuticals, San Diego, CA, United States
Lawrence A. Hansen
- Department of Neuroscience, University of California – San Diego, La Jolla, CA, United States
Ronald C. Petersen
- Department of Neurology, Mayo Clinic, Rochester, MN, United States
Joseph E. Parisi
- Department of Anatomic Pathology and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
Dennis W. Dickson
- Neuro-Oncology Program and Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, United States
Charles D. Smith
- Department of Neurology, University of Kentucky, Lexington, KY, United States
Daron G. Davis
- Pathology Department, Central Baptist Hospital, Lexington, KY, United States
Frederick A. Schmitt
- Sanders-Brown Center on Aging, Alzheimer's Disease Center, University of Kentucky, Lexington, KY, United States
William R. Markesbery
- Sanders-Brown Center on Aging, Alzheimer's Disease Center, University of Kentucky, Lexington, KY, United States
Jeffrey Kaye
- Layton Aging & Alzheimer Disease Center, Oregon Health Sciences University, Portland, OR, United States
Roger Kurlan
- Department of Neurology, University of Rochester School of Medicine, Rochester, NY, United States
Christine Hulette
- Department of Pathology and Division of Neurology, Duke University Medical Center, Durham, NC, United States
Brenda F. Kurland
- Clinical Statistics, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Roger Higdon
- The BIATECH Institute, Seattle, WA, United States
Walter Kukull
- Department of Epidemiology, University of Washington, Seattle, WA, United States
John C. Morris
- Department of Pathology and Immunology, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
- Department of Neurology, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
- Department of Physical Therapy, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
- Corresponding author at: 4488 Forest Park Avenue, Suite 130, St. Louis, MO 63108, United States. Tel.: +1 314 286 2881; fax: +1 314 286 2763.

Received 13 February 2009; received in revised form 3 April 2009; accepted 6 April 2009. published online 20 April 2009.

Abstract

Objective

To determine the frequency and possible cognitive effect of histological Alzheimer's disease (AD) in autopsied older nondemented individuals.

Design

Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer's Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions.

Setting

Washington University Alzheimer's Disease Research Center.

Participants

Ninety-seven nondemented participants who were age 60 years or older at death (mean=84 years).

Results

About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs.

Conclusions

Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80–85 years, many nondemented older adults have substantial AD pathology.

Keywords: Preclinical Alzheimer's disease, Nondemented aging, Neuropathological Alzheimer's disease