Candesartan's Effects on Alzheimer's Disease And Related Biomarkers

This is a double-blind placebo-control randomized clinical trial that compares candesartan to
placebo in individuals with mild cognitive impairment (MCI) who also have positive
Alzheimer's Disease (AD) biomarkers. The investigators will assess if blocking the effect of
Ang II, a crucial mediator of neuro-vascular injury, using angiotensin receptor blockers
(ARBs) will address shortcomings of current treatment regimens. They will also assess the
safety and dose-response of target engagement for treatment with escalating doses of
candesartan in this study.

Inclusion Criteria:

- Mild Cognitive Impairment, defined by:

- Subjective memory concern

- Abnormal memory function documented using the Logical Memory subscale (Delayed
Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale-Revised (the
maximum score is 25): [<11 for 16 or more years of education; <9 for 8-15 years
of education; <6 for <7 years of education]

- Montreal Cognitive Assessment (MoCA) < 26

- Clinical Dementia Rating scale /Memory sum Box score=0.5

- General functional performance sufficiently preserved (Functional Assessment
Questionnaire<9)

- Amyloid positivity determined by measuring the amyloid content in the brain. This can
be determined by either CSF amyloid level or an amyloid scan (PIB-PET)

Exclusion Criteria:

- Intolerance to ARBs

- Current use of ARBs, angiotensin-converting enzyme inhibitors (ACEIs) (use of
antihypertensive medications other than ACEI or ARBs for other indications is allowed)

- Current diagnosis of hypertension or current use of antihypertensive medication that
is prescribed specifically for hypertensive therapy

- SBP less than 110 or DBP less than 40 mm Hg

- Renal disease (Creatinine >2.0 mg/dl), hyperkalemia (K>5.5 meq/dl),
platelets<50,000/μl, or international normalized ratio (INR)>1.9

- Active medical or psychiatric diseases that in the judgment of the investigator would
affect the safety of the subject or scientific integrity of the study

- Uncontrolled congestive heart failure reflected by poor exercise tolerance and
shortness of breath

- History of stroke in the past 3 years

- Inability to have MRI (eg metal implants or cardiac pacemaker) with an exception for
those who cannot have an MRI, if all other parts of the study are obtained
successfully they may still be enrolled in the study, or cognitive assessment or
inability to assess amyloid positivity (no LP and no amyloid scan)

- History of increased intracranial pressure (ICP) or bleeding diathesis (from disease
states or from use of anticoagulants such as warfarin, heparin and related products,
rivaroxaban or Xarelto, apixaban or Eliquis, edoxaban or Savaysa, dabigatran or
Pradaxa)

- Women of childbearing potential (non-menopausal)

- In those who are unable to demonstrate that they understood the details of the study
(ie lack of decisional-capacity to consent), a study partner/surrogate who can sign on
their behalf will be required, otherwise they will be excluded

- Current use of Lithium, as candesartan may increase lithium concentration to toxic
levels