Iron Overload, Microbleeding and the Role of Bilirubin in Alzheimer's Disease Brain: Revisiting the Vascular Hypothesis.

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most prevalent forms of dementia, sharing overlapping clinical features yet distinct pathophysiological mechanisms. While AD is primarily driven by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles, VaD results from cerebrovascular pathology, including ischemic lesions and chronic hypoperfusion. However, accumulating evidence suggests that vascular dysfunction is a crucial contributor to both conditions, bridging neurodegenerative and cerebrovascular pathologies. In this review, we explore the interplay between AD and VaD, focusing on shared pathways such as blood-brain barrier (BBB) breakdown, neuroinflammation, and microvascular damage. Notably, cerebral microbleeds have emerged as a common feature in both AD and VaD, further linking vascular pathology to neurodegeneration. Microbleeding contributes to BBB disruption, iron deposition, and exacerbated oxidative stress, creating a vicious cycle that accelerates cognitive decline. We highlight the role of iron dysregulation as a key driver in AD, exacerbating Aβ accumulation, tau hyperphosphorylation, and ferroptosis. Conversely, bilirubin emerges as a molecule with theranostic potential, acting as both a biomarker and a neuroprotective agent due to its antioxidant and anti-inflammatory properties. Despite its protective role, bilirubin's dysregulation under pathological conditions may contribute to oxidative damage and neurovascular dysfunction. In this context, the accumulation of iron from recurrent microbleeds may further disrupt bilirubin homeostasis, amplifying oxidative injury and inflammation. We propose a vascular hypothesis that integrates iron metabolism and bilirubin homeostasis, suggesting that their imbalance plays a central role in AD pathogenesis and worsening. Understanding the intricate molecular interplay between neurodegeneration and vascular dysfunction could provide novel insights into targeted interventions aimed at mitigating cognitive decline. Finally, we discuss the potential of bilirubin-based therapeutic strategies, including its role in counteracting oxidative stress and modulating neuroinflammatory pathways, offering promising avenues for future research and precision medicine in dementia.