Biomarker-based Trial of NPC-1 for Alzheimer's Pathology

Inclusion criteria

• Age 55 and older, male and female;
• Subjective Cognitive Impairment or MCI or AD dementia per NIA-AA 2011 criteria;
• Clinical Dementia Rating \< or = to 2 and Mini Mental Status Exam \> or = to 16;
• Modified Hachinski Ischemic Score \< or = to 4
• Geriatric Depression Scale - 15 \< 6 documenting absence from significant depressive syndromes
• Other medications including non-disease modifying for MCI and AD (e.g., acetylcholine esterase inhibitor, N-methyl D-aspartate receptor antagonist) stable \> or = to 3-months ;
• Biomarker evidence of AD pathology: Plasma abeta42/40 ratio \< or = to 0.12 AND Plasma p-tau217 \> or = to 0.25 OR Amyloid PET positive (centiloid \> or = to 20) as part of routine clinical care.
• Sufficient vision and hearing to complete all tests
• 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
• 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

• CDR \> 2 MMSE \< 16;
• Significant CNS disease within the last 2 years (i.e., brain tumor, seizure disorder, subdural hematoma, cranial arteritis, cortical stroke);
• Alcohol or substance abuse according to DSM-IV criteria within the last 2 years
• Major depressive disorder or anxiety within the last year; Schizophrenia, bipolar disorder or other major psychiatric disorder defined by DSM-IV criteria
• Abnormal labs indicating potential reversible causes of dementing illness such as vitamin B12 deficiency, thyroid disease, or UTI (documented bacterial colonization is acceptable)
• Unstable or significantly symptomatic CVD (e.g. CAD with frequent angina, CHF with dyspnea at rest)
• Hypertension: defined as uncontrolled BP \> 160/100
• Clinical symptomatic orthostatic hypotension
• Diabetes mellitus that requires insulin injections
• Hachinski ischemic score \> or = to 4
• Cancer within the last 5 years, apart from localized prostate cancer (Gleason Grade \< 3) and non-metastatic skin cancers (melanoma).
• Illness that requires \>1 visit /month to a clinician
• Medications and dietary supplements:
• a. AD disease modifying monoclonal antibody treatment e.g., aducanumab or lecanemab
• b. Dietary supplements containing parthenolide or ipriflavone (1-month wash out period prior to enrollment is permitted)
• c. CNS active meds that have not been on stable doses for at least 2 months 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 discounted for a period of five half-lives prior to baseline 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
• Participation in any Alzheimer's Disease interventional trial. Participation in other non-AD related trials will be evaluated at the discretion of the investigator
• 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:
• 12-months post-menopausal
• 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).