Terazosin And Metabolic Engagement in Alzheimer's Disease

1. Male or female, aged 50-80 years (inclusive) at the time of consent.

2. Diagnosis of Alzheimer's disease meeting the 2011 NIA-AA clinical criteria for mild cognitive impairment due to Alzheimer's disease or probable Alzheimer's disease dementia, with the clinical syndrome attributable to AD as the primary etiology in the judgment of the site investigator.

3. Alzheimer's disease pathology confirmed by an eligible biomarker: Amyloid PET scan, Cerebrospinal Fluid (CSF) Alzheimer's disease panel or blood Alzheimer's disease panel.

4. If receiving an acetylcholinesterase inhibitor (AChEI) and/or memantine, the participant must have been on a stable dose for at least 4 weeks before the baseline visit.

5. Early symptomatic AD - that is, mild cognitive impairment due to AD or mild AD dementia - as evidenced by a global Clinical Dementia Rating (CDR) score of 0.5 or 1.0 at screening, with a Memory box score ≥ 0.5

A participant meeting any of the following at screening is not eligible:

Consent and study conduct

1. Unwilling or unable to provide written informed consent or - where decisional capacity is impaired - unwilling or unable to provide assent alongside written consent from a legally authorized representative.

2. Receipt of an investigational agent, or participation in an interventional trial, within 30 days or 5 half-lives (whichever is longer) prior to screening.

3. Contraindication to MRI or otherwise unable to undergo MRI (non-compatible implanted device, retained ferromagnetic material, severe claustrophobia, body habitus exceeding scanner limits).

4. Any circumstance that, in the investigator's judgment, would prevent the participant from attending scheduled study visits or completing study procedures.

Neurological

5. Cognitive impairment attributable to a cause other than AD, including dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease, progressive supranuclear palsy, vascular dementia, normal pressure hydrocephalus, intracranial mass, or chronic subdural hematoma.

6. History of traumatic brain injury with loss of consciousness > 30 minutes, post-traumatic amnesia > 24 hours, or resulting in persistent cognitive or neurological deficit.

7. Stroke or TIA within 12 months prior to screening, or MRI evidence of significant cerebrovascular disease (territorial infarct, more than one lacunar infarct in a strategic location, or confluent white-matter hyperintensity [Fazekas grade 3]).

8. Seizure disorder requiring ongoing antiepileptic therapy.

9. Untreated vitamin B12 deficiency, untreated hypothyroidism, or another unresolved reversible contributor to cognitive impairment.

Psychiatric

10. Major depressive disorder, bipolar affective disorder, schizophrenia or other psychotic disorder, post-traumatic stress disorder, or another psychiatric condition of sufficient severity to increase adverse event risk or confound neurological and cognitive assessment, in the opinion of the site principal investigator.

11. Beck Depression Inventory-II score > 21 at screening.

12. Beck Anxiety Inventory score > 22 at screening.

13. Suicidal ideation within 12 months prior to baseline, as evidenced by a "yes" response to item 4 or 5 of the ideation subscale of the Columbia-Suicide Severity Rating Scale, or any suicidal behavior within 2 years prior to baseline.

14. Alcohol or substance use disorder (DSM-5 criteria) within 2 years prior to screening.

Cardiovascular and hemodynamic

15. Orthostatic hypotension, defined as a fall of ≥ 20 mmHg systolic or ≥ 10 mmHg diastolic within 3 minutes of standing from supine, with or without symptoms.

16. Seated systolic blood pressure < 110 mmHg or diastolic < 60 mmHg at screening.

17. History of syncope or near-syncope, or ≥ 2 falls, within 12 months prior to screening.

18. Clinically significant cardiovascular disease: myocardial infarction or unstable angina within 6 months, NYHA class III-IV heart failure, hemodynamically significant aortic or mitral stenosis, or uncontrolled arrhythmia.

19. Known autonomic failure or neurogenic orthostatic hypotension.

Concomitant medications

20. Current use of any α1-adrenergic antagonist (terazosin, doxazosin, prazosin, alfuzosin, tamsulosin, silodosin), or use within 4 weeks prior to randomization.

21. Current use of a phosphodiesterase-5 inhibitor (sildenafil, tadalafil, vardenafil, avanafil), including tadalafil prescribed for benign prostatic hyperplasia or pulmonary hypertension.

22. Known hypersensitivity to terazosin or other quinazoline derivatives.

23. Current treatment with - or planned initiation of, or receipt within 24 months prior to screening of - an anti-amyloid monoclonal antibody (aducanumab, lecanemab, donanemab, or any other approved or investigational agent of this class), or active evaluation for such treatment.

24. Initiation of, or change in dose of, any CNS-active medication (benzodiazepine, antidepressant, antipsychotic, hypnotic, or anticonvulsant) within 30 days prior to baseline.

General medical and laboratory

25. Acute or unstable medical, psychiatric, or orthopedic condition that in the investigator's judgment would confound assessment or compromise safety. Stable, adequately controlled chronic conditions common to this age group - including hypertension, diabetes mellitus, hyperlipidemia, and osteoarthritis - are permitted provided the treatment regimen has been unchanged for ≥ 30 days.

26. Hepatic impairment: ALT or AST > 3 × ULN, total bilirubin > 1.5 × ULN, or known cirrhosis (Child-Pugh class B or C).

27. eGFR < 30 mL/min/1.73 m².

28. Cataract or other intraocular surgery planned during the treatment period.

29. Active malignancy, or treatment for malignancy within 2 years, excluding non-melanoma skin cancer and in-situ cervical carcinoma.

Reproductive

30. Pregnancy, breastfeeding, or intention to become pregnant during the study period.