Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease
Introduction
Senile plaques (SPs) and neurofibrillary tangles (NFTs), the neuropathological hallmarks of Alzheimer's disease (AD; Khachaturian, 1985) are not limited to individuals with dementia of the Alzheimer type (DAT) but also may be present in the brains of cognitively normal older adults (Tomlinson et al., 1968, Crystal et al., 1988, Katzman et al., 1988, Price et al., 1991, Dickson et al., 1992, Troncoso et al., 1996, Troncoso et al., 1998, Hulette et al., 1998, Schmitt et al., 2000, Knopman et al., 2003). Neuropathological criteria for AD rely on densities of SPs and NFTs to discriminate AD from aging, as the distinction between the two conditions has been thought to be quantitative rather than qualitative (Tomlinson et al., 1970, Arriagada et al., 1992). Alternatively, the presence of SPs and NFTs in nondemented older adults may represent AD at a stage prior to its clinical expression (Morris et al., 1996, Price and Morris, 1999, Troncoso et al., 1998, Hulette et al., 1998, Schmitt et al., 2000), in which the neuropathological lesions of AD accumulate over many years before sufficient synaptic and neuronal damage occurs to produce the symptoms of AD. This notion of a preclinical (presymptomatic) stage of AD is consistent with similar latent stages in other neurodegenerative disorders (Dickson et al., 2008). Although it is possible to explain the presence of SPs and NFTs without apparent dementia in other ways (Berlau et al., 2007), a continuous neuropathologic process for AD, regardless of clinical status, is supported by observations that the mechanisms responsible for SPs and NFTs in nondemented older adults appear identical to those found in AD (Haroutunian et al., 1998, Haroutunian et al., 1999) and the distribution of SPs and NFTs in nondemented older adults corresponds with the hierarchical topographical progression associated with symptomatic AD (Arriagada et al., 1992, Price and Morris, 1999, Price et al., 1991).
Previous studies of neuropathological AD in nondemented aging have been based on cases collected at a single site (Price and Morris, 1999, Galvin et al., 2005, Bennett et al., 2006), and comparison of results has been difficult because neuropathological methods and criteria differed in these studies. Such methodological differences, combined with relatively small sample sizes in all but one study (Bennett et al., 2006), may contribute to conflicting results on the relationships between SPs or NFTs and cognition in nondemented aging. Some studies have reported a negative effect for episodic memory only (Hulette et al., 1998, Schmitt et al., 2000, Bennett et al., 2006), without effects in other cognitive domains, while other studies found no relationship between AD pathology and any cognitive measure (Knopman et al., 2003, Driscoll et al., 2006). We therefore sought to provide a uniform assessment of neuropathological markers of AD in a large sample of nondemented older adults whose cognitive status had been evaluated antemortem at several Alzheimer's Disease Centers (ADCs) and to evaluate relationships between these markers and cognitive function.
Section snippets
Participants
This study capitalized on the National Alzheimer Coordinating Center-supported Neuropsychological Database Initiative (NDI; M Grundman, PI) that merged longitudinal clinical and cognitive data from more than 4000 cognitively normal older ADC participants. Individuals in the NDI who came to autopsy at 7 participating ADCs, with a Clinical Dementia Rating (CDR; Morris, 1993) of 0 (indicating the absence of dementia and of mild cognitive impairment) within 2 years of death, and were at least 60
Results
The 97 autopsied nondemented individuals had an average age ± S.D. at death of 84.3 ± 8.6 years. There were 55 women, the mean years of education was 15.4 ± 2.9, and the mean MMSE score at last assessment was 28.1 ± 2.1.
Discussion
There are three major findings from this study. First, consistent with previous reports, a substantial proportion of nondemented older adults were found to have npAD, with the frequency ranging from about 20% (when criteria are restricted to Probable/Definite CERAD and Intermediate/High NIA-Reagan) to about 40% (all levels of criteria). Second, diffuse SPs are a prominent feature of npAD in nondemented cases and discriminate cases with and without npAD. Third, AD lesions (including diffuse SPs)
Acknowledgments
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
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