Amyloid β instigates cardiac neurotrophic signaling impairment, driving Alzheimer's associated heart disease.

While a link between cardiovascular risk factors and increased Alzheimers disease (AD) risk has been reported, it remains unclear whether AD pathology has a direct effect on cardiac function and myocardial innervation. AD and amyloidosis are known to impair neuronal function and affect brain neurotrophic factors (NGF and BDNF) expression. Amyloid aggregates and neuro-signaling impairments may also expose AD patients to peripheral nervous system deficits, promoting cardiac disorders. Here, we characterize cardiac physiology, amyloid pathology, neurotrophic factors loss, and the impoverishment of cardiac neuronal fibers in Tg2576-AD mice hearts, human cardiomyocytes in culture, and human AD post-mortem left ventricular (LV) heart tissue. We reveal that Tg2576 animals exhibit increased myocardial fibrosis, amyloid {beta} (A{beta}) deposition, and brain/heart-axis neurotrophic deficiencies, resulting in myocardial denervation and cardiac dysfunction. A{beta} oligomers reduce BDNF expression in both human immortalized and iPSC-derived cardiomyocytes, by disrupting TrkB/CREB signaling. Analysis of human LV AD post-mortem tissue confirmed cell and animal results. Our findings elucidate a previously unknown mechanism of A{beta}-induced cardiac neurotrophic signaling dysregulation, underscoring the relevance of heart degeneration in AD. Translational PerspectiveThis research identified cardiac amyloid pathology, neurotrophic factor depletion, and reduced myocardial nerve function in a transgenic model of cerebral amyloidosis (Tg2576) and in human AD heart tissue. These findings carry significant diagnostic and therapeutic implications, emphasizing the role of neuro-signaling disruption in cardiac physiology impairment linked to AD. Our study advocates for considering cardiac complications in AD management and paves the way for future precision medicine approaches to enhance systemic clinical strategies for treating AD, proposing the cardiac neurotrophic signaling pathway as a potential therapeutic target.