Effects of Tadalafil on Cognition and Cerebral Hemodynamics in Elderly Patients With Mild Cognitive Impairment

• The participant is between the ages of 60-90 years old.
• The participant must demonstrate a MoCA score ≥ 18 and ≤ 25.
• The participant has consented for his/herself.
• The participant has a caregiver, family member, or qualified individual to help with study tasks
• The participant is fluent in the English language.
• The participant is proficient in comprehending verbal and written English.

Exclusion Criteria:

1. Any of the aforementioned CMP values meet the exclusion threshold.
2. Absence of a caregiver, family member, or other appropriately qualified individual that will be available for the entire experimental duration to assist the participant with study tasks, including supervision of medication intake, recording blood pressure, and noting adverse events.
3. Current use of any form of organic nitrates or nitrite-containing medications, or planned nitrate use within 48 hours of tadalafil dosing.
4. Known hypersensitivity to tadalafil or to any component of the formulation.
5. Recent (within prior 3 months) acute cardiovascular events - e.g., myocardial infarction, unstable angina, stroke, or life-threatening cardiac arrhythmia - or decompensated/unstable heart failure according to the New York Heart Association (NYHA) class II-IV.
6. Resting hypotension (systolic BP \<90 mmHg) or clinically significant symptomatic orthostatic hypotension, or uncontrolled severe hypertension (e.g., systolic BP >170 mmHg or diastolic BP >110 mmHg).

7. Concurrent use of potent CYP3A4 inhibitors, including but not limited to:

   i. Amiodarone ii. Aprepitant iii. Azamulin iv. Cimetidine v. Ciprofloxacin vi. Clarithromycin vii. Diltiazem viii. Erythromycin ix. Fedratiib x. Fedratinib xi. Fluconazole xii. Itraconazole xiii. Ketoconazole xiv. Letermovir xv. Nirmatrelvir-Ritonavir xvi. Posaconazole xvii. Troleandomycin xviii. Voriconazole xix. Verapamil xx. Grapefruit and Grapefruit Juice xxi. Seville Orange Juice xxii. Pomelo Juice xxiii. Green tea extract xxiv. Curcumin/tumeric xxv. Black pepper extract xxvi. Goldenseal xxvii. Gingko Biloba xxviii. Kava xxix. Kratom xxx. CBD oil xxxi. Ginger xxxii. Elderberry Extract

8. Concurrent use of alpha-adrenergic blockers (unless on a stable dose and the investigator documents that coadministration is acceptable and that BP monitoring and dosing separation strategies are in place).
9. Severe renal impairment or end-stage renal disease (ESRD) on hemodialysis, and other renal dysfunction that, per the tadalafil product labeling, would contraindicate or require specific dosing changes for the intended tadalafil regimen.
10. Documented hepatic impairment, defined by Child Pugh Class A, B, or C.
11. History of non-arteritic anterior ischemic optic neuropathy (NAION), prior vision loss attributed to a PDE-5 inhibitor, or hereditary retinal disorders (e.g., retinitis pigmentosa).
12. Conditions that predispose to priapism (e.g., sickle cell disease, multiple myeloma, leukemia) if sexually active participants are at risk from prolonged erections.
13. Medical, neurologic, or psychiatric conditions (including advanced dementia) that, in the investigator's judgment, would preclude safe participation, study compliance, or the ability to provide informed consent.
14. Participants on guanylate cyclase (GS) stimulators such as riociguat (Adempas)
15. Participants with left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis).
16. Participants with severe autonomic dysfunction.
17. Participants with known or suspected pulmonary veno-occlusive disease.
18. Participants with known hereditary degenerative retinal disorders, including retinitis pigmentosa, and those with underlying non-arteritic anterior ischemic optic neuropathy (NAION) risk factors.
19. Participants with active peptic ulceration or significant bleeding disorders.
20. Participants on other phosphodiesterase-5 (PDE5) inhibitors (sildenafil, vardenafil, avanafil).
21. Participants with an anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease).
22. Participants with any uncontrolled arrhythmia, as determined by the screening electrocardiogram.
23. Participants with a creatinine clearance less than 30 mL/min.
24. Participants with a history of substantial alcohol consumption (≥ 5 units per day)