Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease

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

Research output: Contribution to journalArticlepeer-review

528 Scopus citations


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.

Original languageEnglish
Pages (from-to)1026-1036
Number of pages11
JournalNeurobiology of Aging
Issue number7
StatePublished - Jul 2009

Bibliographical note

Funding Information:
This study was supported by a National Institute of Aging (NIA) grant to the National Alzheimer Coordinating Center (U01AG16976; P.I., J.C. Morris), by NIA grants to individual Alzheimer Disease Centers (P50AG05681, P01AG03991, P50AG016574, P30AG028383, P30AG028377, P50AG005131, P30AG008017, and P30AG008665), by the Postdoctoral Program of 1UL1RR024992-01 from the National Center for Research Resources, and by the Charles and Joanne Knight Alzheimer Research Initiative of Washington University's Alzheimer's Disease Research Center (ADRC). At Washington University in St Louis, Hieu Van Luu, Javier Agraz, Jessica Church, Debra Carter and Kymberli Sykes provided excellent technical contributions, and Nigel Cairns PhD and James E. Galvin MD provided helpful comments on the manuscript. Geoffrey Murdoch MD, PhD of the University of Pittsburgh School of Medicine provided neuropathological assistance when he was at the Oregon Health Sciences University.


  • Neuropathological Alzheimer's disease
  • Nondemented aging
  • Preclinical Alzheimer's disease

ASJC Scopus subject areas

  • General Neuroscience
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


Dive into the research topics of 'Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease'. Together they form a unique fingerprint.

Cite this