Sporadic Alzheimer’s disease (AD) was first described by the physician Alois Alzheimer (Fig. 2.​1a) as an insidious and slowly progressive neurodegenerative disorder of the human central nervous system (CNS) (Alzheimer 1906; Alzheimer et al. 1995). Clinically, its earliest sign is a subtle decline in memory functions in a state of clear consciousness. Intellectual and practical skills gradually worsen, and personality changes manifest themselves, followed by deterioration of language functions, impairment of visuospatial tasks, and, in the end, dysregulation of autonomic functions and dysfunction of the motor system in the form of a hypokinetic hypertonic syndrome (Albert et al. 2011; Morris et al. 2014). Both the tempo of the cognitive decline and the duration of the disease as well as neurological symptoms can vary considerably from one individual to another (Franssen et al. 1993).

Clinically recognizable AD develops only in humans and is found in all ethnic groups worldwide, whereby its prevalence increases remarkably with age (Purohit et al. 2011). Of known diseases causing dementia, AD is the most frequent one and accounts for 60–70 % of cases. In societies with increasing life expectancy, it can be predicted that the number of demented individuals will quadruple by the year 2050, whereby this estimate rests on the reasonable assumption that no significant therapeutic breakthrough for AD will occur in the immediate future (Brookmeyer et al. 2007; Reitz et al. 2011; Mayeux and Stern 2012). As such, AD imposes an enormous socio-political and economic threat that makes the search for causal or symptomatic solutions an urgent medical priority (Mount and Downton 2006; Trojanowski and Hampel 2011; Mayeux and Stern 2012).

At present, only a provisional clinical diagnosis can be made for AD, and this usually takes place during the last phase of the underlying pathological process. Diagnoses based on ante mortem observation, even with the help of advancing ancillary disciplines, such as neuroimaging and biomarkers, are still too unreliable, thereby necessitating post mortem confirmation (Beach et al. 2012a; Montine et al. 2012; Toledo et al. 2012; Serrano-Pozo et al. 2013).

Cases of sporadic AD show the presence of the same pathological process that develops at specific CNS sites (Duyckaerts et al. 2009; Nelson et al. 2009, 2011). Currently, cross-sectional studies performed on cohorts of non-selected autopsy cases are the chief sources of information about the systematic progression of this process (Bouras et al. 1994; Giannakopoulos et al. 1994; Braak and Braak 1997b; Dickson 1997a; Duyckaerts and Hauw 1997; Braak et al. 2011). The present article is based on the results of such analyses performed on brains conventionally fixed by immersion in aqueous solutions of formaldehyde. The findings reported here involve established histological methods (immunohistochemistry, silver stains, dye-staining techniques) and can be reproduced by other laboratories.