Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease

Department of Anatomy and Neurobiology, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
Neurobiology of aging (Impact Factor: 5.01). 05/2009; 30(7):1026-36. DOI: 10.1016/j.neurobiolaging.2009.04.002
Source: PubMed


To determine the frequency and possible cognitive effect of histological Alzheimer's disease (AD) in autopsied older nondemented individuals.
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.
Washington University Alzheimer's Disease Research Center.
Ninety-seven nondemented participants who were age 60 years or older at death (mean=84 years).
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.
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.

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Available from: Walter A Kukull, Oct 06, 2015
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    • "One the other hand, critics have found to focus on limitations in the methodology of clinical trials and on bias in the way the data are introduced, especially in trials sponsored by drug companies, and have concluded that efficay of drugs are inflated (Casey et al., 2010). One of the most important problems leading to difficulty in disease management is AD pathology existed in brain cells many years before the appearance of clinical symptoms (Price et al., 2009). AD is distinguished mainly by neuronal loss. "
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    • "By itself the ε4 allele does not doom one to certain death by AD or vascular disease, nor does the accumulation of plaques and tangles lead to dementia in all cases. Post mortem analyses of brains have uncovered many cases in which AD type plaques and tangles are present without the expected deficits in cognitive function (Davis et al., 1999; Price et al., 2009; Balasubramanian et al., 2012). Conversely, in studies of very old adults—individuals 80 to 100+ years old—up to 50% of dementias previously diagnosed as AD were later determined to be of unknown etiology (i.e., postmortem analysis failed to identify brain pathology typical of AD or other dementias; Crystal et al., 2000; Imhof et al., 2007; Middleton et al., 2011). "
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    • "The incidence of NFT formation increases with age [73], [82]–[84], and the difference between demented and non-demented subjects is mainly due to greater tangle densities and the spread of tangles across the neocortex in AD [85]. Likewise, we found that the NFT score was very low in non-demented MA subjects which was matched by a Braak stage of I, while in the OO, without the symptoms of dementia and without amyloid deposits, the NFT scores reached an intermediate average value of 5.8 (out of a maximum score of 15) with Braak scores of III–IV. "
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