Nicotinamide as an Early Alzheimer's Disease Treatment

Nicotinamide, the amide of nicotinic acid (vitamin B3/niacin), is an oral therapy with a
wealth of clinical data in a variety of therapeutic areas, including preliminary data
supporting its safety in Alzheimer's disease (AD). Preclinical work in a mouse model that
develops both plaques and tangles supports the hypothesis that nicotinamide can act as a
histone deacetylase (HDAC) inhibitor to reduce phosphorylation of tau.

The study will implement a group sequential design, incorporating a futility analysis with a
go/no-go decision conditional on cerebral spinal fluid CSF biomarker outcomes at 12-months.
The primary outcome for the trial is change in p-tau231.

This study timeline includes a screening phase of up to 60 days and treatment phase which is
expected to last about 48 weeks and will include 4 study visits.

An additional 12-month treatment and follow-up period is planned, contingent upon a "go"
decision based on the primary outcome (CSF p-tau231) or one planned secondary outcome (CSF
p-tau181)

Inclusion Criteria:

1. Mild Cognitive Impairment (MCI) or dementia due to Alzheimer's disease (AD)

2. Biomarker criteria:

Cerebral Spinal Fluid (CSF) Amyloid Beta 1-42 (Aβ42) <= 600 pg/mL, or A ratio of total
tau to Aβ42 ≥ 0.39.

3. Mini-Mental State Exam (MMSE) ≥ 20

4. Blood laboratories, urinalysis, and electrocardiogram are within normal limits or
deemed clinically not significant by the site investigator

5. Stable medications (including approved AD therapies) for at least 4 weeks

6. At least 6 years of education

7. Able to swallow oral tablets

8. Speaks English fluently

9. Available qualified study partner (≥3 times per week in-person communication with the
participant)

Exclusion Criteria:

1. Active neurological or psychiatric diagnosis other than AD that may affect cognition
and/or function. (Obstructive sleep apnea is permitted, if treated.)

2. Inability to undergo lumbar puncture, including use of Coumadin, novel oral
anticoagulants, clopidogrel, or dipyridamole. Use of aspirin <= 325mg daily is
permitted.

3. Hachinski ischemic scale > 4

4. Magnetic Resonance Imaging (MRI) incompatibility

5. MRI evidence of cortical stroke >1cm, superficial siderosis, or extensive white matter
hyperintensity (Cardiovascular Health Study score 7-8+)

6. Diagnosis of cancer in the previous 5 years (with the exception of basal or squamous
cell carcinoma)

7. Geriatric Depression Scale (GDS) score >6

8. History within the past 5 years of alcohol or substance use disorder

9. Laboratory evidence of a clinically significant abnormality that may interfere with
study assessments

10. Active partial or total malabsorptive disease (e.g., celiac disease)

11. Resides in a skilled nursing facility

12. Participation in a clinical trial of a potential disease-modifying therapy for AD in
previous 6-months (time between last investigational drug administration and baseline
for the current study)

13. Pregnant, lactating or of child bearing potential (that is, women must be 2 years
post-menopausal or surgically sterile to be considered not child bearing potential).

14. Unwillingness to abstain from over-the-counter nicotinamide for the duration of the
trial