Sex Differences and Heart-Brain Axis Dysfunction in Alzheimer's Disease: Unraveling the Complexity of Pathophysiology

Alzheimer’s disease (AD), the most common form of dementia, is a devastating neurodegenerative disease that causes progressive deterioration. Although the critical pathological mechanisms include amyloid plaques and neurofibrillary tangles, heart-brain axis impairment is also gaining attention. Heart-brain axis is a physiological and biomolecular bidirectional crosstalk between the heart and brain. The relationship between cardiovascular disorders and neurodegenerative diseases is apparent. Epidemiological studies reveal that both conditions share similar genetic and biochemical characteristics, pathogenic mechanisms, and risk factors. Cardiovascular diseases are claimed to increase the risk of cognitive dysfunction and AD by inducing pathological pathways in the brain. Although our understanding of the progression of neurological conditions has advanced, differences in organ functions between males and females remain a mystery. Sex is a key biological variable that causes differences in disease incidence, pathophysiology, symptoms, and prognosis. Males and females with AD show distinct cognitive and psychiatric symptoms. The prognosis of AD is poorer in females than in males, and females exhibit faster cognitive decline after diagnosis of AD. Clinical data also points to the sex-related differences in heart-brain axis regulation. A higher prevalence of AD in females is believed to be due to sexrelated differences in cardiovascular disease risk factors, complications, and treatment. However, systematic studies are required to confirm the effect of sex differences on AD. Developing novel individualized treatment approaches targeted at heart-brain axis regulation can only be achieved by filling the gap in the sex-based neurocardiology knowledge. Despite the enormous number of ongoing preclinical and clinical research, an effective pharmacological treatment for AD is yet to be available. Drug repositioning or repurposing are designed to accelerate new treatment strategies for the disease. This chapter focuses on the relationship between sex differences and heartbrain axis regulation in AD. Considering that cardiovascular diseases are among the reasons for the higher prevalence of AD in females than males, we also aim to evaluate the potential repositioning or repurposing of medications in the management of AD.

Keywords: Alzheimer’s disease, Cardiogenic dementia, Cardiovascular diseases, Cognition, Dementia, Drug repositioning, Drug repurposing, Heart-brain axis, Individualized treatment, Neurocardiology, Neurodegeneration, Sex differences.