The causative role of amyloidosis in the cardiac complications of Alzheimer's disease: a comprehensive systematic review

Alzheimer's disease (AD), the leading cause of dementia, is characterised by cerebral amyloid-beta (Aβ) and tau deposition, impairing cognition. While cardiovascular diseases exacerbate AD, the reverse association is underappreciated. This systematic review examined clinical and experimental studies that explored the cardiogenic dementia hypothesis and mechanisms by which amyloidosis in AD contributes to cardiovascular complications. A review of PubMed, Ovid Embase/Medline, and CINAHL conducted in August 2024 identified 252 studies meeting the selection criteria. Evidence links cerebral hypoperfusion from cardiac arrest, heart failure, or orthostatic hypotension to AD pathology, while atherosclerosis and hypertension drive neurodegeneration and cerebral amyloidosis. Vascular scoring tools, such as the Framingham Risk Score, may predict an individual's risk of cognitive impairment. Cardiac amyloidosis correlated with ECG abnormalities, aortic valve calcification, cardiomyopathy and atrial fibrillation. Aβ peptides and AD-related genes exacerbate cardiac fibrosis, negative inotropy and heart rate changes, reduce nitric oxide-mediated vasodilatation, and increase oxidative stress. Preclinical studies revealed that β-secretase impacts cardiac repolarisation by interfering with delayed rectifier current, although clinical evidence for arrhythmogenesis remains conflicting. AD-related autonomic dysregulation, particularly parasympathetic dysfunction, predisposes to arrhythmias. Additionally, hypercortisolaemia observed in AD has been associated with increased arterial stiffness. Diminished melatonin levels in AD were also linked to endothelial and mitochondrial dysfunction. This review enhances our understanding of how cerebral and cardiac amyloidosis, autonomic dysfunction, and endocrinopathy contribute to cardiac complications in AD, paving the way for research into targeted therapies. (Figure presented.). © 2025 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.