Controversies and Inconsistencies Within the Current Amyloid Hypothesis. 1. Aβ deposition occurs in cognitively normal individuals; 2. There is a weak correlation between plaque load and cognition; 3. The biochemical nature and presence of Aβ oligomeric assemblies in vivo is unclear; 4. Pre-clinical AD models based on EOAD-linked mutations are biased toward the amyloid hypothesis; 5. Pathological heterogeneity and comorbidities are unexplained by the amyloid hypothesis; 6. Aβ has a normal physiological role and targeting Aβ may disrupt these roles over the long term; 7. Genetic factors linked to AD can be interpreted independently of amyloid; 8. APP cleavage and function is more complex than solely the production of Aβ, indicating other APP family members may play a role in disease progression; 9. The triggers of synapse loss, neuronal loss and neuroinflammation in AD are still unclear; 10. The relationship between Aβ and tau pathologies is unclear; 11. The onset of dementia in Down’s Syndrome is highly variable, despite the presence of fibrillar plaques in 100% of Down’s individuals by the fifth decade; 12. The APOE4 genotype has numerous functional effects, rather than solely relating to reduced Aβ clearance, including links to enhanced inflammatory phenotypes. Each of these points are discussed in detail in the text.