Alzheimer's disease-related pathology

Since 1907, when Alois Alzheimer identified neuritic plaques and neurofibrillary tangles (NFTs) as the principal pathological change in AD, much has been learned of these entities. Notable discoveries include the understanding of the ultrastructure of NFTs and neuritic plaques and their

correlation with dementia in AD. Equally important has been the discovery of the hyperphos- phorylated tau protein as the major constituent of paired helical filaments and the discovery of the amyloid-beta (Ap) peptide as the major component of amyloid plaques [15] (see Fig. 15.1). These findings have led to the classification of diseases in terms of their immunoreactivity for these proteins and have changed the way we think about these entities clinically. We now use the term amyloidopathy to refer to AD (both familial and sporadic forms), Down’s syndrome, and a few others. Similarly, we use the term tauopathy to refer to frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and several other diseases. Other proteins have also been implicated in neurodegenerative diseases, including progranulin, transactive response DNA-binding protein 43, and others [16].

Plaques and tangles are clearly present relatively frequently in PD-D, but they are less often significant contributors to dementia. Many cases have been reported of a clinical and pathological picture of PD-D without any ARP. Furthermore, multiple studies have found them to be weak correlates for dementia in PD-D, as opposed to LRP [13]. However, subcortical accumulation of Ap has been reported in PD-D and it is also linked to the faster progression to dementia [17, 18]. Although it correlates highly with LRP burden [19], the level of Ap is unlikely to be a single neuropathological substrate in the progression to dementia. Cognitive impairment occurring at a later phase of PD and advanced age increase the likelihood of multiple pathologies being present. The brains of such patients are likely to demonstrate Ap and tau pathologies as well as a-synuclein. Variants of two highly investigated genes, APOE and MAPT, linked to the risk of PD-D [19, 20], are also associated with Ap aggregation [21] and increased tau expression [22], respectively, thereby suggesting a strong association of all three pathologies. A synergistic role has been proposed for Lewy body pathology as well as associated Ap and tau pathology in the neurodegeneration causing PD-D [23]. The lower levels of ARP in comparison with AD and the predominance of Lewy body pathology in PD-D suggest that the observed ARP may be a factor contributing to Lewy body pathology, which is the central mechanism in the development of dementia.

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