"Food for thought": the role of dietary metabolism in the production and processing of the amyloid precursor protein of alzheimer's disease

The primary pathogen of Alzheimer’s disease (AD), beta amyloid (Aβ), is a small catabolic product of the amyloid precursor protein (AβPP). Whilst the Apolipoprotein E (APOE) ε4 allele is the major risk factor for roughly half of all late onset AD (LOAD) cases, it is not sufficient in itself to cause disease. Thus aetiological factors remain to be identified, not only for non-ε4 AD, but also for the 50% of cases that are APOE ε4 carriers. There is extensive in vitro, in vivo and epidemiological evidence linking dietary metabolism and sporadic AD pathogenesis. However, these results are of little validity if they do not occur in vivo, in homo, in a "real world" situation. Following the development of a novel method of AβPP purification and analysis, I compared AβPP homeostasis in normal subjects and those with various forms of AD. Different groups displayed different basal levels of AβPP and differed in their response to food ingestion. The separate roles of insulin and lipid metabolism in the homeostasis of AβPP and Aβ, both post-prandially and basally, were investigated using ingestion-based experiments. Changes in insulin and glucose metabolism stimulated an APOE-modulated effect on AβPP metabolism. Using glucose-clamp based experiments, I observed a relationship between insulin resistance and AβPP metabolism, but only in non-APOE ε4 LOAD subjects. In summary, this opus demonstrates in vivo, in homo, a reciprocal relationship between lipid metabolism and AβPP and Aβ homeostasis, supporting previous evidence that disorders of lipid metabolism promote sporadic AD. This study also describes in vivo, in homo, a reciprocal relationship between carbohydrate metabolism and AβPP and Aβ homeostasis and the existence of, and a role for, insulin resistance in non-APOE ε4 LOAD. Based on this research I propose a pathological paradigm for sporadic AD based upon insulin resistance and errors of lipoprotein/lipid metabolism.