In the 1990s it was proposed that the depositions of β-amyloid (Aβ) protein and amyloid plaque formation in the brain were the main causes of the subsequent additional neuropathological hallmarks of AD, which are neurofibrillary tangles, vascular damage, an inflammatory response, and neuronal cell death [
20,
21]. This theory is still the basis for much research and treatment developments in AD [
22]. The association between early onset AD and mutations in the amyloid precursor protein (APP) and presenilin genes [
23] has been central to the promotion of the amyloid cascade hypothesis. The observations in DS and the high risk of early onset AD have also provided important support for this hypothesis, given that the gene for APP is located on chromosome 21 [
24] and therefore along with other genes on chromosome 21 it is inherited in triplicate by people with DS [
25]. Much is now known about the amyloid pathway with the subsequent cleavage of APP by two enzymes β and γ-secretase creating the soluble product of Aβ [
26]. Other factors, both in the general population and in people with DS, contribute to the extent of Aβ pathology, such as the status of the apolipoprotein E (ApoE) genotype. When ApoE4 (ε4) is present in DS, the risk for AD is even higher, with a two-fold increase in the amyloid load deposited in the brain [
27,
28]. In contrast, when ε2 allele is present, it is associated with increased longevity and the absence of dementia [
29]. Neuro-inflammation is also known to play a role in the pathogenesis of AD, especially through microglia activation [
30], and it may be more influential in DS as genes regulating inflammatory processes, such as
mir-155 and the s100 calcium-binding protein beta (S100B), are located on chromosome 21 [
25]. These latter gene products are thought to impact cognitive impairment and neurodegeneration [
31], as it has been proposed that inflammatory processes accelerate the development of AD in DS [
32].