One of the patients had well documented mild cognitive impairment (MCI), with a strongly positive amyloid-PET (positron emission tomography) scan, positive FDG-PET scan (fluorodeoxyglucose PET scan), abnormal neuropsychological testing, and hippocampal
volume reduced to 17th percentile; after 10 months on the MEND protocol (Metabolic Enhancement for Neurodegeneration), his hippocampal volume had increased to 75th percentile, in association with a reversal of cognitive decline. During his 10 months on the
MEND protocol, he interrupted his otherwise good compliance once, and this was associated with an episode of memory loss, in which he failed to remember that he had left his car in the driveway while he was working in his house. He returned to the protocol at that time, and after 10 months in total, he demonstrated not only a marked symptomatic improvement (which
had begun after approximately three months on the protocol), but also a dramatic increase in hippocampal volume. More modest hippocampal volumetric increases have been described with exercise and with a brain-training program, but to our knowledge the magnitude of hippocampal volume increase that occurred with this patient has not been reported previously.
This is very encouraging & showed that overall metabolic enhancement improves cognitive decline associated with Alzheimer's. Critics will surely say this is anecdotal, but Bredesen has mechanistic model to explain the findings, so I personally think it has great potential for future development of Alzheimer treatment. However, big Pharma may not like this idea because it is based mainly on lifestyle changes, so not so good for business.
In the case of APP signaling, binding of a trophic ligand such as netrin-1 increases the production of sAPPα, which inhibits BACE cleavage, with the complementary fragment, αCTF, inhibiting γ- secretase cleavage; thus cleavage at the α-site produces fragments that inhibit cleavage at the β-site and γ-site rather than feeding back to reduce α-site cleavage. Similarly, cleavage at the β-site and γ-site to produce Aβ feeds back positively to increase APP-C31 production, thus favoring the pro-AD, anti-trophic processing of APP. Moreover, Aβ itself has been shown to exhibit prionic properties, although the mechanism by which it does so has not been clarified. Thus APP processing displays positive feedback, and therefore APP and its derivative peptides function as a molecular switch. This has critical implications for therapeutic development, since it offers a mechanism by which a threshold effect occurs. We have taken advantage of this phenomenon to develop drug candidates that increase the anti-AD, trophic APP signaling, while reducing the pro-AD, anti-trophic APP signaling and enhancing cognition.