Table 2.
Primary putative MOA class of AD compounds that failed in phase II or III, classified as disease-modifying versus symptomatic, and direct amyloid targets versus targets beyond amyloid
| DISEASE-MODIFYING COMPOUNDS |
| Direct amyloid targets |
| Reduction of Aβ production |
| Reduce cleavage of amyloid-β precursor protein to form the Aβ that eventually aggregates into senile plaques, by targeting enzymes such as β-secretase (BACE) or γ-secretase |
| Inhibition of Aβ plaque formation |
| Removal of soluble Aβ40/42 peptides before they aggregate into the senile plaques |
| Clearance of Aβ plaques |
| Removal of the plaques after their formation |
| Aβ vaccine |
| Active immunotherapy for Aβ |
| Targets beyond amyloid |
| Mitigation of tau pathology [25] |
| Tau is a core pathology in AD along with Aβ; tau pathway targets span its production to the formation of neurofibrillary tangle aggregates of hyperphosphorylated tau protein |
| Decrease of inflammation [9] |
| Neuroinflammation is emerging as another core pathology in AD, which can exacerbate both amyloid and tau pathologies |
| Reduction of cholesterol accumulation [7, 26] |
| Elevated cholesterol levels play a role in AD, as its presence is higher in AD patients and causes Aβ clusters to develop faster. Cholesterol-related gene polymorphisms in the APOE gene are linked to AD development: presence of one ɛ4 allele variant produces a four-fold increase, and two alleles produce a 12–15-fold increase |
| Improvement in brain energy utilization [10, 27–29] |
| Impaired cerebral glucose metabolism and insulin resistance are recognized features of AD. Epidemiological and pathophysiological studies have shown a link between AD and diabetes; diabetes is associated with greater risk of developing AD, and dementia in general |
| Decrease in vascular burden [30] |
| Disturbances of the vascular system are linked to AD disease progression, with epidemiological evidence suggesting that chronic high blood pressure may increase the risk for of dementia |
| Neuroprotectant/antioxidant [31–33] |
| Free radicals and oxidative stress may play a role in the brain changes that cause AD, as shown by brain lesions in individuals with AD that are typically associated with free radical exposure |
| Neural growth/regeneration [34, 35] |
| Since neuronal death is the resultant pathology of AD, treatments to promote neuronal growth and/or regeneration have received attention, encouraged by neuroplasticity and potential for neurogenesis |
| Hormone treatment [36] |
| Links between various female sex hormones and AD have been postulated by clinical observations. Prevalence of AD is higher in women than in men, which is not completely explained by their higher life expectancy; and earlier age of menopause (spontaneous or surgical) is associated with enhanced risk of developing AD |
| SYMPTOMATIC COMPOUNDS |
| Predominantly neurotransmitter based |