The Systemic Nature of Alzheimer’s Disease: Mechanisms of Amyloid Spread and Multiorgan Pathology

Alzheimer9s Disease (AD) and Heart Failure (HF) were traditionally studied as separate conditions affecting the brain and heart, respectively. However, growing evidence reveals significant pathophysiological overlaps, suggesting that AD and HF share common molecular mechanisms. These include amyloid-beta (A³), phospho-tau deposition, and systemic inflammatory pathways, which mirror the pathological hallmarks observed in AD's brain pathology. This connection has led to the hypothesis of Alzheimer 9s-related cardiomyopathy (AC). This paradigm shift highlighted the role of A³ oligomers in cardiovascular aging, endothelial dysfunction, and myocardial remodeling. Notably, HF with preserved ejection fraction (HFpEF) has emerged as the clinical phenotype associated with both HF as a proteinopathy and AD. This overlap is unsurprising, as HFpEF represents the aging phenotype in the heart, paralleling the anticipated aging process in the brain observed in AD. Building on these findings, this dissertation defines AC as a novel clinical and biochemical entity characterized by HFpEF, along with cardiac deposition of A³ plaques and neurofibrillary tangles resembling those in the brain. Furthermore, this work explores the mechanisms involved in the metastasis of A³ pathology This research investigates two pivotal mechanisms underlying the systemic manifestation of Alzheimer's disease (AD) and Alzheimer's disease cardiomyopathy (AC). The first study focuses on the role of brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, in the development of AC. We propose that the widespread loss of BDNF across the body disrupts neuroprotective signaling, which in turn promotes the deposition of A³. This loss of neuroprotection is a key factor linking neuronal dysfunction to the cardiac manifestations of the disease. The second study explores the spreading hypothesis of AD/AC, suggesting that A³ aggregates, in the form of pre-amyloid oligomers (PAOs), can be internalized into extracellular vesicles (EVs) and transported through the bloodstream. These EVs, derived from red blood cells, enable the systemic dissemination of A³ to various organs, where it is internalized by cells and contributes to amyloid deposition, further extending the pathology beyond the brain and heart. Together, these studies reveal systemic and metastatic-like mechanisms in AC progression, redefining AD as a multi-organ disorder with cardiac implications.