**2. The amyloid cascade hypothesis**

The most widely accepted theory of AD etiology is the amyloid cascade hypothesis [1], which maintains that overproduction and/or decreased clearance leads to extracellular aggregation of the presumably toxic amyloid-beta (Aβ) peptide. These extracellular Aβ aggregates act to increase neuronal kinase activity, resulting in phosphorylation of the microtubule-associated protein tau. Hyperphosphorylation of tau induces formation of intracellular aggregates known as neurofibrillary tangles and alters intracellular transport along microtubule tracks. This in turn abolishes neuronal communication, resulting in cell death in a spatially conserved pattern and producing deficits in networks that subserve memory and cognition. Aggregation of Aβ and tau is well-established pathological characteristics of AD brain tissue at autopsy. It is also known that in familial forms of AD, mutations in amyloid precursor protein (APP), Presenilin 1, or Presenilin 2 accelerate Aβ production and accumulation and lead to cognitive decline at a much earlier age. Presinilins function as part of the gamma secretase protein complex, one of three proteolytic enzymes responsible for cleaving APP into Aβ or nonaggregating amyloid peptides. Autopsy samples from brain parenchyma of patients with familial AD, which account for less than 1% of all AD cases, present with exorbitant Aβ and Tau accumulation similar to sporadic AD. Additionally, since the APP gene is located on chromosome 21, individuals with Down syndrome (trisomy 21) invariably develop AD-like dementia, also at a younger age than sporadic cases. This intuitively makes sense: an extra copy of APP on chromosome 21 will inevitably lead to the generation of more Aβ. However, it is highly uncertain to what degree familial AD and Down syndrome recapitulate the initial stages of sporadic AD, which accounts for the vast majority of AD cases. This is the core of the debate surrounding the amyloid cascade hypothesis: Is Aβ aggregation the start of AD or a downstream effect of an earlier insult? Additionally, and of considerable concern, to the day of writing this chapter, multiple immunotherapy clinical trials that target and clear Aβ as well as trials to block the activity of the secretases have failed to reverse cognitive loss and, in some cases, have accelerated it [2]. In this chapter, we will describe Aβ aggregation only as surrogate for the final common pathway of multiple disease mechanisms leading to the established end pathology of AD and not as a direct, initiating cause of clinical demise.
