Safety and Modulation of ABCC9 Pathways by Nicorandil for the Treatment of Hippocampal Sclerosis of Aging

1. Men or women at least age 75 years

2. UPDRS ≤ 7

3. Hachinski Ischemic Score ≤ 4

4. CSF profile of "A-T-N+" defined as Aβ(1-42)>250pg/ml; Total Tau>50pg/ml; Phospho-tau<30pg/ml within 24 months, Aβ PET scan negative for Alzheimer's disease within 24 months, or plasma profile of Phospho-tau181 negative for Alzheimer's disease ; hippocampal volume ≤ 1 s.d. below age and gender adjusted mean. Plasma ptau181 levels below 3.0 pg/ml.

5. English-speaking, to ensure compliance with cognitive testing and study visit procedures

6. Involvement of a study partner to supervise medications and compliance with study visits/procedure

7. Stable medical conditions for three months prior to screening visit, with no clinically significant abnormalities of hepatic, renal, and hematologic function defined in the opinion of the investigator

8. Stable medications for 4 weeks prior to screening visit

9. Ability to ingest oral medications

10. Physically acceptable for this study as confirmed by medical history, physical exam, neurological exam and clinical tests

1. Significant neurologic disease such as Parkinson's disease, stroke, brain tumor, multiple sclerosis or seizure disorder

2. Major depression in past 12 months (DSM-IV criteria)

3. Recent (in past 12 months) substance abuse

4. History of cancer within the past two years, with the exception of non-metastatic prostate or non-melanoma skin cancers such as squamous cell and basal cell carcinomas

5. Contra-indications to lumbar puncture (bleeding disorder, platelet count < 100,000, anticoagulant treatment, major abnormality of the spine that would make LP technically difficult) will exclude the participant from engaging in this optional procedure, but the participant may still participate in the main study using plasma p-tau181 and/or amyloid-PET for Alzheimer's disease screening

6. Use of any investigational agents within 30 days prior to screening

7. Major surgery within eight weeks prior to the Baseline Visit

8. Severe unstable medical illnesses, including uncontrolled cardiac conditions or heart failure (New York Heart Association Class III or IV)

9. Blindness, deafness, or any other disability which may prevent the participant from participating or cooperating in the protocol.

Excluded Medications*

Participants are not eligible for participation in the study if they are taking:

1. Experimental drugs

2. Vasoactive nitrates such as isosorbide dinitrate

3. Drugs for erectile dysfunction such as sildenafil, vardenafil, and tadalafil among others

4. Sulfonylurea antidiabetic agents that may confound efficacy measures for the secondary efficacy outcome measures.