Alzheimer disease (AD) is a devastating neurodegenerative disorder, affecting almost 6 million people in the United States alone, characterized by abnormal accumulation of an aggregation-prone, variable-length peptide known as the amyloid-β protein (Aβ). Considerable progress has been made elucidating the molecular pathogenesis of rare forms of early-onset AD (EOAD) attributable to autosomal-dominant mutations, which in all cases have been found to affect the production of Aβ either by elevating the levels of all forms of Aβ or by increasing the relative proportion of longer, more amyloidogenic species (e.g., Aβ42) to shorter, less aggregation-prone species (e.g., Aβ40). Nevertheless, these familial forms of the disease account for <2% of all AD diagnoses, and the precise mechanistic cause(s) of the remaining >98% of late-onset AD (LOAD) cases remains poorly understood, apart from the identification of certain genetic and environmental factors affecting AD risk. This proposal explores the overall hypothesis that LOAD can be triggered by defective clearance of Aβ by one or more Aβ-degrading proteases (AβDPs). More specifically, we investigate the hypothesis that a transient increase in Aβ early in life can serve as a common pathogenic mechanism for LOAD risk factors. We demonstrate that a severe traumatic brain injury in novel model of LOAD, which lacks the genetic mutations associated with EOAD, can trigger an acute rise in Aβ as well as accumulation of Aβ fibrils by 1-day post-injury. Additionally, we identify cathepsin D (CatD), a lysosomal protease, as a novel AβDP, demonstrating that it is the most important in vivo regulator of intracellular, insoluble Aβ yet identified. Intriguingly, we discovered that CatD degrades Aβ42 and Aβ40 with markedly different kinetics, resulting in increases to the Aβ42/40 ratio resembling those produced by EOAD-linked mutations. Finally, we detail the successful development of high-throughput assays to measure the proteolytic degradation of different substrates for insulin-degrading enzyme (IDE). We use these assays, in combination with other methods, to discover novel peptidic and zinc-targeting inhibitors of IDE, which can serve as novel pharmacological tools to help elucidate the role of IDE in the pathogenesis of LOAD.

Dietary supplements have been extensively studied for their beneficial effects on cognition and AD neuropathology. The current study examines the effect of a medical food cocktail consisting of the dietary supplements curcumin, piperine, epigallocatechin gallate, α-lipoic acid, N-acetylcysteine, B vitaminsvitamin C, and folate on cognitive functioning and the AD hallmark features and amyloid-beta (Aβ) in the Tg2576 mouse model of the disease.

The study found that administering the medical food cocktail for 6 months improved cortical- and hippocampal- dependent learning in the transgenic mice, rendering their performance indistinguishable from non-transgenic controls. Coinciding with this improvement in learning and memory, we found that treatment resulted in decreased soluble Aβ, including Aβ oligomers, previously found to be linked to cognitive functioning.

In conclusion, the current study demonstrates that combination diet consisting of natural dietary supplements improves cognitive functioning while decreasing AD neuropathology and may thus represent a safe, natural treatment for AD.