Figure 1

Hypothetical model of the pathological processes in Alzheimer's disease (AD), focusing on the amyloid β peptide (Aβ) cascade. (Other relevant mechanisms have been omitted or presented in a secondary perspective for didactic purposes.) Dotted arrows indicate possible or secondary mechanisms affecting core pathological processes within the amyloid cascade. Background shades of gray separated by dotted lines are a schematic representation to integrate the progression of pathological events along with the development of the cognitive syndrome of AD (these thresholds are arbitrary and not experimentally validated, and represent the authors' point of view of the disease process). Three clinical phases of the disease are defined: presymptomatic (or preclinical) AD may last for several years or decades until the overproduction and accumulation of Aβ in the brain reaches a critical level that triggers the amyloid cascade; in the predementia phase, compatible with the definition of mild cognitive impairment secondary to AD, early stage pathology is present in varying degrees, from mild neuronal dystrophy to early stage Braak pathology, according to individual resilience and brain reserve. Finally, in the clinically defined dementia phase, there is a progressive accumulation of the classical pathological hallmarks of AD (that is, neuritic plaques and neurofibrillary tangles), bearing relationship with the progression of cognitive deficits and the magnitude of functional impairment. APP = amyloid precursor protein; PS1/2 = presenilin 1/2; TAU = microtubule-associated protein Tau.