**4. Therapeutic modalities in treating pathogenic angiogenesis in AD**

Angiogenesis, as stated by the studies mentioned in this chapter, can be viewed as that stage in AD pathology where all the different pathways (hypoperfusion, BBB dysfunction, inflam‐ mation) merge, leading to the AD pathology. Observations showing increased cerebrovascular permeability prior to the appearance of the hallmarks of AD, sprout a novel paradigm for integrating vascular remodelling (angiogenesis) with the pathophysiology of the disease. Targeting this integral step in the pathophysiology of AD and developing a novel therapeutic intervention using anti‐angiogenic drugs can help to alleviate the global societal burden of AD.

## **4.1. Anti‐angiogenics: small molecule tyrosine kinase inhibitors**

Anti‐angiogenics, including small molecule tyrosine kinase inhibitors have been tested and approved as anti‐cancer therapeutics and have shown to maintain normal vascular [75–77]. Sunitinib is a broad spectrum tyrosine kinase inhibitor. This is known to inhibit the phosphor‐ ylation of multiple receptor tyrosine kinases and is a potent inhibitor of VEGF as well as platelet‐derived growth factor (PDGF‐β). Currently, it is in use for gastrointestinal stromal tumours, renal cell cancer and pancreatic cancer. Sunitinib was shown to decrease the amyloid burden and reverse cognitive decline in AD model mice, suggesting that if we target angio‐ genesis, we can revert the increase in the accumulation of Aβ and abate the cognitive decline associated with AD [76].

## **4.2. Biologics and small molecule VEGFR inhibitors**

We now know that VEGF is the prime and central component of pathological blood vessel formation. There are biologics and small molecules that specifically target the ligand or its receptor. This specific‐targeted therapy could prove more efficient and less deleterious due to avoidance of unwanted 'off target' effects. A potential therapeutic is Bexarotene, a retinoid X receptor agonist, is shown to facilitate Aβ clearance via activation of apolipoprotein (APOE) expression and promoting microglial phagocytosis [78]. Bexarotene counteracts VEGF‐ mediated angiogenesis by decreasing blood vessel density and reversing cognitive deficits in AD mice [78].

These are examples of some of the therapeutic routes that could target angiogenesis; however, understanding the molecular mechanism behind angiogenesis causing eventual AD pathology is of utmost importance in order to look for safe and effective novel therapeutics for AD and other vascular diseases.

## **5. Concluding remarks**

As the Western world ages, AD represents an ailment that will place a significant burden on all the aspects of society. This burden, primarily placed on family caregivers, has been estimated to cost billions in lost productivity and healthcare costs (both direct and indirect). Currently, there is a lack of understanding regarding the cause(s) of the disease that translates into a lack of viable treatments or cures. Over the years, limited progress has been made with regards to the clinical translation of the popular amyloid hypothesis for treating AD and hence new thinking towards AD pathogenesis is required. Vascular risk factors and neurovascular dysfunction associated with hypotension, hypertension, cholesterol levels, type II diabetes mellitus, smoking, oxidative stress and iron overload have been found to play integral roles in the pathogenesis of stroke and AD. Observations showing increased cerebrovascular permeability prior to the appearance of the hallmarks of AD, sprout a novel paradigm for integrating vascular remodelling (angiogenesis) with the pathophysiology of the disease. Taking this into account, research focused on understanding the molecular mechanism behind the pathophysiology of angiogenesis leading to AD pathology will mediate in developing novel therapeutic interventions targeting this pathological blood vessel formation help to alleviate the global societal burden of AD.
