NPC-1 (parthenolide and ipriflavone) for Alzheimer's blood biomarkers

Inclusion Criteria:

1. Age 55 and older, male and female;
2. Subjective Cognitive Impairment or MCI or AD dementia per the Revised criteria for diagnosis and staging of Alzheimer's disease criteria;
3. Clinical Dementia Rating \< or = to 2 and Mini Mental Status Exam \> or = to 16;
4. Modified Hachinski Ischemic Score \< or = to 4
5. Geriatric Depression Scale - 15 \< 6 documenting absence from significant depressive syndromes
6. Other medications including non-disease modifying for MCI and AD (e.g., acetylcholine esterase inhibitor, N-methyl D-aspartate receptor antagonist) stable \> or = to 1-month prior to screening visit;
7. Biomarker evidence of AD pathology: Plasma abeta42/40 ratio \< or = to 0.12 AND Plasma p-tau217 \> or = to 2.1 pg/mL OR Amyloid PET positive (centiloid \> or = to 20) as part of routine clinical care.
8. Sufficient vision and hearing to complete all tests
9. Study partner available with frequent (at least 1 hour/day or 1 day/week) contact with participant to provide collateral information about cognition, daily functioning, adverse events reporting, and support for study drug intake
10. General health status that will not interfere with the ability to complete the prospective study (these conditions are listed below in the study exclusion list)

Exclusion Criteria:

1. CDR \> 2 MMSE \< 16;
2. Other significant CNS disease within the last 2 years (i.e., brain tumor, seizure disorder, subdural hematoma, cranial arteritis, cortical stroke) That would impact the participant's ability to complete the study;
3. Alcohol or substance abuse according to DSM-IV criteria within the last 2 years
4. Major depressive disorder or anxiety within the last year; Schizophrenia, bipolar disorder or other major psychiatric disorder defined by DSM-IV criteria
5. Abnormal labs indicating potential reversible causes of dementing illness such as vitamin B12 deficiency, thyroid disease, or UTI (documented bacterial colonization is acceptable) or INR \> 1.2 (1.3 or higher) or platelets \< 100 K/uL at screening
6. Unstable or significantly symptomatic CVD (e.g. CAD with frequent angina, CHF with dyspnea at rest)
7. Hypertension: defined as uncontrolled BP \> 160/100
8. Clinical symptomatic orthostatic hypotension
9. Diabetes mellitus that requires insulin injections
10. Hachinski ischemic score \> or = to 4
11. Cancer within the last 5 years, apart from localized prostate cancer (Gleason Grade \< 3) and non-metastatic skin cancers (melanoma).
12. Illness that requires \>1 visit /month to a clinician
13. Medications and dietary supplements:

    * a. AD disease modifying monoclonal antibody treatment e.g., donanemab (Kisunla) or lecanemab (Leqembi). Wash out period of five half-lives prior to screening visit is permitted e.g., \> or = 60 days since last dose of donanemab and \> or = 35 days since last dose of lecanemab)
    * b. Dietary supplements containing parthenolide or ipriflavone (1-month wash out period prior to screening is permitted)
    * c. CNS active meds that have not been on stable doses for at least 1 month prior to screening visit e.g., cimetidine, beta-blockers, and SSRIs
    * d. Neuroleptics, antiparkinsonian agents, systemic corticosteroids, and narcotic analgesics; in the case where these were used for a self-limited time they must have been discontinued for a period of five half-lives prior to screening visit
    * e. Over the counter supplements are not by themselves exclusionary, however, participants are asked not to change the dosing regimen over the course of the trial unless medically indicated; the presence and dose of these product are recorded
    * f. Anticoagulation therapy: Vitamin K antagonist: warfarin (Coumadin, jantoven)
14. Participation in any Alzheimer's Disease interventional trial. Participation in other non-AD related trials will be evaluated at the discretion of the investigator
15. Currently pregnant. Positive pregnancy tests during the course of the trial will be evaluated at the discretion of the investigator.

Women of Child Bearing Potential (WOCBP)

For the purposes of this study, women of childbearing potential are defined as all women who are capable of becoming pregnant, unless they meet one of the following criteria:

1. 12-months post-menopausal
2. Post-hysterectomy/surgically sterile

If a female Participant does not meet either of these criteria they will be considered of childbearing potential and will have a serum pregnancy test performed at Screening, Visit 3 (2 months), Visit 6 (5 months), and Visit 10 (8 months).