Inclusion Criteria

• Patient meets all inclusion criteria:

  1. Adults aged ≥55 years on the day of screening, no upper age limit 2. Either:

  1. Confirmed clinical diagnosis of Alzheimer's Disease (AD)
  2. Confirmed clinical diagnosis of Mixed Dementia consisting of Alzheimer's Disease and Vascular Dementia 3. Mini Mental State Examination score of ≥17 4. Confirmatory blood biomarker testing (pTau-217) (positive or intermediate via validated assays) ≤ 365 days prior to screening or between screening and randomisation or a positive amyloid PET scan (if available) or a positive amyloid CSF test (if available) 5. Randomisation should ideally take place within 4 weeks of the screening visit but no later than 8 weeks after the screening visit 6. Must be able and willing to comply with the treatment and assessment schedule and requirements including being able to start trial treatment ≤ 2 weeks after randomisation 7. Willing and able to have MRI scans in accordance with the assessment schedule unless participant is clinically contraindicated due to:
  1. Pacemakers or defibrillators (unless MRI-conditional models)
  2. Aneurysm clips, stents or metal implants (unless MRI safe)
  3. Cochlear implants (unless MRI-conditional models)
  4. Metal fragments in the body
  5. Severe claustrophobia 8. Negative pregnancy test ≤4 weeks prior to randomisation for women of child-bearing potential 9. Normal liver function at screening consisting of all the following:
  1. Total serum bilirubin <1.5 x ULN (except for participants with Gilbert's disease, for whom the upper limit of total serum bilirubin is 51.3 μmol/l or 3mg/dl)
  2. Alanine aminotransferase (ALT) <3 x ULN;
  3. Alkaline phosphatase <3 x ULN 10. Documented participant and study partner informed consent 11. If a participant is being re-randomised into the trial, additional timing of entry requirements must also be met:

  1. For participants being re-randomised after completing 18 months' follow-up and the arm was not closed due to lack of activity, a 12-week washout period from last dose of IMP must be completed before their screening visit. If the efficacy analysis indicates that the IMP was ineffective then this washout period can be reduced to 6 weeks.

  2. For participants being re-randomised following treatment arm termination due to lack of activity, a 6-week washout period from their last dose of IMP must be completed prior to screening assessment

     Study Partner inclusion criteria:

     1. Participant that meets the AD-SMART eligibility criteria has consented to participation in the trial
     2. Has at least twice-weekly contact with participant
     3. Be 18 years or older at the time of providing consent
     4. Willing to complete study partner questionnaires as outlined in visit schedule
     5. Willing to attend remote and in-person study visits with participant
     6. Documented informed consent

     Exclusion Criteria:

• Patient meets none of the exclusion criteria:

  1. Fazekas Score =3 reported from an MRI taken at any time prior to randomisation, if an MRI is not clinically contraindicated (reasons specified in Inclusion Criteria 7) A. MRI does not need to be repeated if Fazekas score = 0, 1 or 2 reported from an MRI performed ≤365 days to screening visit (if Fazekas score has not been reported, refer to Section 7.4) b. MRI should be conducted if participant is not clinically contraindicated to MRIs and previous MRI where Fazekas score = 0, 1 or 2 was >365 days or previous MRI scan is not available for Fazekas score reporting or participant has never had an MRI
  2. Clinical diagnosis of Dementia with Lewy bodies
  3. Clinical diagnosis of Parkinson's disease
  4. Clinical diagnosis of Frontotemporal Dementia
  5. Cardiac failure (American Heart Association Stage C or D)
  6. Significant respiratory comorbidity (hospitalisation within the previous ≤6 months due to respiratory comorbidity)
  7. Renal failure (CKD IV or eGFR ≤45 mL/min/1.73m²) at any time point prior to randomisation
  8. Malignancy (except if in complete remission) e.g. solid organ or haematological or melanoma
  9. Score of ≥1 on C-SSRS at screening visit
  10. Individuals without an identified study partner (refer to Section 4 for further details on study partners)
  11. Individuals who have an Alzheimer's Disease or Central Nervous System medication (e.g. antidepressant) change or dose change ≤28 days prior to screening
  12. Use of an Investigational Medicinal Product (IMP) or Investigational Medical Device (IMD) ≤26 weeks prior to randomisation (except for AD-SMART participants that are being re-randomised. See Section 5.4 for further information).
  13. Receiving antibody-based amyloid clearing treatment for Alzheimer's Disease within 26 weeks prior to randomisation
  14. Unable or unwilling to comply with study procedures
  15. Unable to swallow whole capsules
  16. Individuals who are living in the same household as an AD-SMART participant who is actively taking trial medication
  17. Female participants that are pregnant or breastfeeding
  18. Women of child-bearing potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception (see acceptable methods of contraception) whilst on trial treatment and up to 12 weeks after the last dose of study drug
  19. Male participants with a partner of child-bearing potential unwilling or unable to use an acceptable method of contraception whilst on trial treatment and up to 12 weeks after the last dose of the study drug.
  20. Male participants unwilling to desist from sperm donation during the trial and for 12 weeks after the last dose of trial treatment
  21. Current or previous exposure to any of the currently recruiting AD-SMART IMPs ≤26 weeks before randomisation.
  22. History of alcohol and/or drug abuse and/or dependence within the 5 years prior to screening visit.
  23. Any concurrent medical condition, abnormal laboratory tests or uncontrolled, clinically significant systemic disease that, in the opinion of the Investigator, could cause study participation to be detrimental to the participant.
  24. Participants who are not eligible for any of the trial IMPs, according to the eligibility criteria listed in the individual drug appendices. Please note that participants can enter the trial if they are eligible for at least one of the trial treatment arms, but do not need to be eligible for all.

Arm-specific eligibility criteria:

Atomoxetine-specific exclusion eligibility criteria:

In addition to the core inclusion and exclusion criteria, refer to section 2.2 of AD-SMART Appendix 1 Atomoxetine' for the arm-specific exclusion eligibility criteria for the Atomoxetine arm which must also be met.

Metformin-specific exclusion eligibility criteria:

In addition to the core inclusion and exclusion criteria, refer to section 2.2 of AD-SMART Appendix 2 Metformin' for the arm-specific exclusion eligibility criteria for the metformin arm which must also be met.