14 Alzheimer’s Disease: Genetics, Pathogenesis, Models, and Experimental Therapeutics

Abstract

Alzheimer’s disease (AD), manifest as progressive loss of memory and cognitive impairments, affects more than 4 million individuals in the United States (Brookmeyer et al. 1998; Mayeux 2003; Cummings 2004; Wong et al. 2006). The index case, a middle-aged woman with behavioral disturbances and dementia, was described more than 100 years ago (Goedert and Spillantini 2006a; Hardy 2006a; Roberson and Mucke 2006; Small and Gandy 2006; Mandkelkow et al. 2007). Due to the postwar baby boom and increased life expectancy, the elderly are the most rapidly growing segment of our society and the number of persons with AD is predicted to triple over the next several decades. Prevalence, cost of care, impact on individuals and caregivers, and lack of mechanism-based treatments make AD one of the most challenging diseases of this new century (Price et al. 1998; Wong et al. 2002, 2006; Selkoe and Schenk 2003; Citron 2004a,b; Cummings 2004; Walsh and Selkoe 2004). This dementia syndrome results from dysfunction and death of neurons in specific brain regions/circuits, particularly those populations of neurons participating in memory and cognitive functions (Whitehouse et al. 1982; Hyman et al. 1984; Braak and Braak 1991, 1994; West et al. 1994, 2000, 2004; Price et al. 1998). The characteristic neuropathology of AD includes intracellular accumulations of phosphorylated Tau assembled in paired helical filaments (PHFs) within neurofibrillary tangles (NFTs) and abnormal neuritis, as well as extracellular Aβ peptide oligomers that, as aggregates, are at the core of neuritic amyloid plaques and represent sites of synaptic disconnection...