Adesuyan, Matthew; (2024) Exploring Novel Applications of Existing Drugs for Dementia Risk Reduction. Doctoral thesis (Ph.D), UCL (University College London).

Text Matthew_Adesuyan PhD Thesis_UCL Discovery_Deposit.pdf - Accepted Version Access restricted to UCL open access staff until 1 October 2025. Download (6MB)

Abstract

Aim To investigate if drugs with cardiovascular effects and different pharmacological properties can be repurposed as candidates to reduce the risk of dementia. Methods A systematic review with meta-analysis was conducted to assess the literature pertaining to the repurposing of antihypertensive agents to reduce the risk of Alzheimer’s disease (AD). Using real-world data from IQVIA Medical Research Database, the annual trends in the incidence of dementia in adults with hypertension was reported. A series of four cohort studies was then conducted to investigate the comparative risk of dementia between patients prescribed five different antihypertensive drug classes. This was followed by two novel cohort studies exploring the risk of AD in angiotensin-converting enzyme inhibitors (ACEI) with different pharmacological properties. Lastly, a cohort study was carried out to investigate the repurposing possibilities of phosphodiesterase type 5 inhibitors (PDE5I) on AD risk reduction. In all analytical studies, propensity score-inverse probability of treatment weighting was used to minimise confounding due to non-randomisation and create balance in the observed characteristics between treatment groups, so that fair comparisons can be evaluated. Results The meta-analysis identified angiotensin II receptor blockers (ARB) as a potential candidate that may reduce the risk of developing AD. Over the last 22 years, there was an average annual increase of 4.1% (95% CI 3.3-5.0) in the incidence of dementia in people with hypertension. The series of four antihypertensive cohort studies found evidence that ARB, beta-blockers and diuretics were associated with a lower risk of dementia compared to ACEI. However, there was no strong evidence to suggest that pharmacologically different ACEI have a differential impact on the risk of dementia. Nevertheless, a separate cohort study found evidence that PDE5I were associated with a reduced risk of AD. Conclusion This thesis has provided new evidence on the potential repurposing possibilities of routinely used drugs beyond their cardiovascular effects. Specifically, ARBs, BB, diuretics and PDE5I were identified as drugs associated with a reduced risk of dementia. These findings contribute evidence towards drug repurposing strategies and the advancement of dementia risk reduction efforts.

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