, 2006, Giannakopoulos et al., 2003 and Näslund et al., 2000). The criticism that follows is Aβ deposition itself does not necessarily predict or cause clinical AD. Such observations, however, can be understood in several other ways. First, there may be a threshold effect that involves the MK 2206 density and duration, or even rate of Aβ accumulation that together with the age of onset of the pathological processes determines the onset of the clinical

manifestations of AD. Second, as with other illnesses, there are almost certainly genetic, pathological, epigenetic, and environmental mediators that modulate progression, disease course, and manifestation of illness. For Decitabine chemical structure example, one proposed mediator involves the concept of “cognitive reserve’ that hypothesizes that factors that enhance neuroplasticity and synaptogenesis, may make an individual more resistant to the clinical manifestations of the underlying

neuropathology, thereby delaying onset of the clinical expression of the illness (Cummings et al., 1998 and Stern et al., 1999). Third, it is also possible that early subtle cognitive impairment of AD that we might now refer to as preclinical stage 3 is often not recognized in elderly people who die and come to autopsy. Some evidence for this is from the Religious Order Study where those who died without cognitive impairment and who had intermediate or high likelihood of AD based on neuropathological

examination scored 0.25 standard deviation lower on episodic memory tests than those without pathology (Bennett et al., 2006), worsening of episodic memory being the earliest and most characteristic cognitive phenotype for AD (Dubois and Albert, 2004). Finally, it has become common to explain the results from failed AD therapeutic trials with presumptive anti-Aβ therapies as evidence that the hypothesis is wrong. This is clearly inaccurate, as to date, such trials were not definitive tests of the cascade hypothesis, but rather expedient ways to test potentially disease-modifying AD therapeutics in the current clinical, regulatory, and fiscal environment. None of the putative anti-Aβ agents that have failed in pivotal phase 3 therapeutic Calpain trials were optimal or even optimized agents within their class of anti-Aβ therapeutics: Alzhemed (tramiprosate, homotaurine) was a weak aggregation inhibitor; Flurizan (tarenflurbil, R-flurbiprofen) was a γ-secretase modulator with low potency and poor brain penetration; and semagacestat, a nonselective γ-secretase inhibitor (GSI), had significant mechanism-based toxicity limiting its dosage and efficacy with respect to lowering Aβ production (Golde et al., 2010). None of these drugs showed efficacy against primary endpoints in phase 2 trials but were advanced to phase 3 nonetheless. Other anti-Aβ therapies (e.g.