Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status

Sanders-Brown Center on Aging, Department of Pathology, University of Kentucky, Lexington 40536-0230, USA.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 3.8). 04/2012; 71(5):362-81. DOI: 10.1097/NEN.0b013e31825018f7
Source: PubMed


Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.


Available from: James B Leverenz
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    • "Unlike the evolution of tau-related pathology, which corresponds to the development of the neurocognitive phenotype, the nexus between amyloid-␤ (A␤) and cognition is not well established. When measures of A␤-related pathology are compared directly to tau-related pathology with regard to their respective contributions to global cognitive dysfunction, A␤ consistently accounts for less variance [9] [10]. "
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    ABSTRACT: Alzheimer’s disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifying therapeutic trials.
    Journal of Alzheimer's disease: JAD 05/2015; 47(4):965-975. DOI:10.3233/JAD-142643 · 4.15 Impact Factor
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    • "With the current knowledge, it remains undefined if it can be used effectively in symptomatic AD where there is preexisting pathology. Many studies have shown that, even at the mild cognitive impairment stage of AD, extensive amyloid and tau pathologies are already present (Nelson et al., 2012). Also, it has been proposed that, in sporadic LOAD, tau pathology is not simply downstream of Ab-related pathology, but that these pathologies could be generated by dual pathways that can interact synergistically (Small and Duff, 2008; Yoshiyama et al., 2013). "
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    ABSTRACT: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. It is characterized by an imbalance between production and clearance of amyloid β (Aβ) and tau proteins. Oligomeric forms of Aβ and tau are believed to be the most toxic. Dramatic results from AD animal models showed great promise for active and passive immune therapies targeting Aβ. However, there is very limited evidence in human studies of the clinical benefits from these approaches. Immunotherapies targeting only tau pathology have had some success but are limited so far to mouse models. The majority of current methods is based on immunological targeting of a self-protein; hence, benefits need to be balanced against risks of stimulating excessive autoimmune toxic inflammation. For greater efficacy the next generation of vaccines needs to focus more on concurrently targeting all the intermediate toxic conformers of oligomeric Aβ and tau species. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 03/2015; 85(6):1162-1176. DOI:10.1016/j.neuron.2014.12.064 · 15.05 Impact Factor
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    • "The main hallmarks already described by Dr. Alzheimer are extracellular amyloid-␤ (A␤) plaques and intraneuronal neurofibrillary tangles (NFTs) [2] [3]. Amyloid plaques consist mainly of 40-and 42-amino-acid A␤ peptides. "
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    ABSTRACT: In Alzheimer's disease (AD), molecular changes are observed not only in patients' neurons but also in peripheral cells, such as blood lymphocytes. These include changes in the level of oxidative stress markers, mitochondria impairment, and aberrant cell cycle regulation in AD blood lymphocytes. While the concepts of early causes of AD are currently highly controversial, these findings provide support for the cell cycle hypothesis of AD pathomechanism and emphasize the systemic nature of the disease. Moreover, because of difficulties in studying dynamic processes in the human brain, lymphocytes seem to be useful for readout of AD molecular mechanisms. In addition, lymphocytes as easily accessible human cells have potential diagnostic value. We summarize current perspectives for the development of new therapeutic strategies based on oxidative stress and cell cycle dysregulation in AD, and for diagnostic methodologies involving new markers in AD lymphocytes.
    Journal of Alzheimer's disease: JAD 03/2015; 46(2). DOI:10.3233/JAD-141977 · 4.15 Impact Factor
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