Early Presymptomatic Stages

Despite the existence of a variety of neurotransmitters and modulator substances, each of the non-thalamic nuclei with diffuse ascending projections is highly susceptible to the AD-associated pathological process (Tomlinson et al. 1981; Whitehouse et al. 1981, 1985; Mann et al. 1982; Mann 1983; German et al. 1987, 1992; Zweig et al. 1988; Chan-Palay and Asan 1989; Hertz 1989; Busch et al. 1997; Rub et al. 2000; Sassin et al. 2000; Parvizi et al. 2001; Zarow et al. 2003; Mesulam et al. 2004; Haglund et al. 2006; Grudzien et al. 2007; Weinshenker 2008; Grinberg et al. 2009; Simic et al. 2009; Braak and Del Tredici 2011; Elobeid et al. 2011; Vana et al. 2011; Trillo et al. 2013). The long and poorly myelinated axons of these nuclei might be capable of reverting to an earlier and less well differentiated state with a higher degree of tau phosphorylation more readily than heavily myelinated axons.