Modulation of Endothelial Function in Alzheimer's Disease by 18kDa Translocator Protein

The aim of this study is to determine whether pharmacological modulation of TSPO (with XBD173, 90mg twice daily, orally, for 28 days) improves neurovascular coupling (NVC) in AD relative to placebo. The main questions it aims to answer are:

Does pharmacological modulation of TSPO (with XBD173, 90mg twice daily, orally, for 28 days) improve neurovascular coupling (NVC) in people with AD compared to placebo? NVC will be defined as the change in hippocampal cerebral blood flow (CBF) that follows a memory task (ΔCBF(h)).

Does pharmacological modulation of TSPO (with XBD173, 90mg twice daily, orally, for 28 days): Increase cerebral blood flow (CBF); Reduce blood brain barrier leak (rate and volume) determined by Gd enhanced DCE-MRI; Increase plasma Amyloid 40/42; Reduce soluble markers of endothelial cell activation(sVCAM1, sICAM1, PECAM1, E-selectin, vWF); Improve markers of peripheral endothelial cell function; Cerebrovascular reactivity in response to CO2 inhalation

The first six participants will undergo a dose escalation phase. The first 3 participants will receive XBD173 (90mg, once daily, 28 days) and the subsequent 3 participants will receive XBD173 (90mg, twice daily, 28 days). This phase will be open label. Participants will have 1 safety visits and 2 assessment visits. Each Assessment visit will involve clinical tests, a blood test and an MRI scan. Participants in the Randomisation phase participants will be given either 90mg of XBD173, twice daily or a placebo (dummy drug) for 4 weeks, have 2 safety visits and 4 assessment visits. Each Assessment visit will involve clinical tests, a blood test and an MRI scan. Healthy Volunteers will be recruited and undergo a screening visit and MRI scan.