Molecular And Cellular Pathophysiology Of Preclinical Alzheimer'S Disease
Although the two pathological hallmarks of Alzheimer's disease (AD), senile plaques composed of amyloid-Î² (AÎ²) peptides and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau, have been studied extensively in postmortem AD and relevant animal and cellular models, the pathogenesis of AD remains unknown, particularly in the early stages of the disease where therapies presumably would be most effective. We and others have demonstrated that AÎ² plaques and NFTs are present in varying degrees before the onset and throughout the progression of dementia. In this regard, aged people with no cognitive impairment (NCI), mild cognitive impairment (MCI, a presumed prodromal AD transitional state, and AD all present at autopsy with varying levels of pathological hallmarks. Cognitive decline, a requisite for the clinical diagnosis of dementia associated with AD, generally correlates better with NFTs than AÎ² plaques. However, correlations are even higher between cognitive decline and synaptic loss. In this review, we illustrate relevant clinical pathological research in preclinical AD and throughout the progression of dementia in several areas including AÎ² and tau pathobiology, single population expression profiling of vulnerable hippocampal and basal forebrain neurons, neuroplasticity, neuroimaging, cerebrospinal fluid (CSF) biomarker studies and their correlation with antemortem cognitive endpoints. In each of these areas, we provide evidence for the importance of studying the pathological hallmarks of AD not in isolation, but rather in conjunction with other molecular, cellular, and imaging markers to provide a more systematic and comprehensive assessment of the multiple changes that occur during the transition from NCI to MCI to frank AD.
Behavioural Brain Research
Digital Object Identifier (DOI)
Mufson, Elliott J.; Ikonomovic, Milos D.; Counts, Scott E.; Perez, Sylvia E.; Malek-Ahmadi, Michael; Scheff, Stephen W.; and Ginsberg, Stephen D., "Molecular And Cellular Pathophysiology Of Preclinical Alzheimer'S Disease" (2016). Translational Neuroscience. 332.