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.

Inclusion criteria for AD:

• Subjects aged between 60-90 years old
• Male or postmenopausal female
• Fertile men are eligible to participate if they are willing to use the contraception methods listed in the PIS, during treatment and for 90 days after the last dose of treatment
• Able to provide written informed consent prior to any study-mandated procedures
• AA genotype at rs6971 (TSPO) locus
• Clinical diagnosis of AD by dementia specialist, fulfilling NIA-AA criteria
• Mild - moderate cognitive impairment (MMSE = 20-27 )
• AD biomarker positive MCI patients

Inclusion criteria for HV:

• Subjects aged 18 years or older
• Male or Female
• Female subjects of childbearing potential must be willing to have a pregnancy test before scanning
• Able to provide written informed consent prior to any study-mandated procedures
• Subjects willing to have blood samples collected for genotyping (ApoE and TSPO rs6971)
• AD biomarker positive

Exclusion criteria for AD:

• History of migraine (with attack frequency greater than 1 per month)
• Clinical history of suggestive of dementia with Lewy Bodies such as REM Sleep Behaviour Disorder
• Conditions affecting safe engagement in the intervention
• Conditions preventing completion of study procedures, e.g. severe loss of vision or hearing
• Clinically significant renal disease (eGFR <60 ml/min per 1.73m2)
• Clinically significant liver disease (abnormal serum transaminases)
• Contraindications to MRI scanning or exposure to gadolinium-based contrast agents
• Change of medications approved for AD (eg. Galantamine, rivastigmine, and donepezil) or antihypertensives within the last 28 days or planned during the timeframe of the study
• Severe respiratory disease with chronic hypoxia (sats <92%), known CO2 retention or need for home oxygen therapy
• Use of the following medications or therapies:
• Severe and moderate P450 CY3A4 inhibitors: Boceprevir, Clarithromycin, Cobicistat, Idelalisib, Itraconazole, Ketoconazole, Nelfinavir, Ritonavir, Saquinavir, Telaprevir, Telithromycin, Voriconazoleb, Aprepitant, Conivaptan, Crizotinib, Diltiazem, Dronedarone, Erythromycin, Fluconazole, Imatinib, Isavuconazole, Nefazodone, Netupitant, Nilotinib, Posaconazolee, Tofisopam, Verapamil, Delavirdine
• Severe and moderate P450 CY3A4 inducers: Carbamazepine, Enzalutamide, Fosphenytoin, Mitotane, Phenytoin, Rifampicin, Bosentan, Efavirenz, St John's wort, Barbiturates, Nevirapine, Primidone, Rifabutin, Rifapentine
• Oral contraceptives

Exclusion criteria for HV

• Contraindications to MRI scanning or exposure to gadolinium-based contrast agents
• Pregnancy in WOCBP
• eGFR<60 ml/min per 1.73 m2
• Severe respiratory disease with chronic hypoxia (sats <92%), known CO2 retention or need for home oxygen therapy

The first 6 participants will participate in an open label safety phase