N-DOSE AD: A Dose Optimization Trial of Nicotinamide Riboside in Alzheimer's Disease

N-DOSE AD: A Dose Optimization Trial of Nicotinamide Riboside in Alzheimer's Disease

The goal of this double-blinded placebo-controlled randomized trial is to determine the optimal dose of nicotinamide riboside (NR), in individuals with Alzheimer's disease (AD).

The main questions the N-DOSE AD trial aims to answer are:

What dose of nicotinamide riboside (NR) is required to achieve maximal cerebral nicotinamide adenine dinucleotide (NAD) increase, measured by 31P-magnetic resonance spectroscopy (MRS) or cerebrospinal fluid (CSF) metabolomics)?

What dose of nicotinamide riboside (NR) is required to achieve maximal alteration in the cerebral metabolism patterns, measured by fluorodeoxyglucose-positron emission tomography (FDG-PET)?

What dose of nicotinamide riboside (NR) will have optimal effect in the absence of unacceptable toxicity?

Participants will be asked to do participate in:

Clinical examinations

Cognitive assessments

Lumbar puncture

Magnetic resonance imaging - positron emission tomography (MRI-PET) scannings

Biosampling

They'll be given placebo, 1000 mg NR or escalating doses of NR (1000 mg - 2000 mg - 3000 mg) over 12 weeks.

N-DOSE AD is a double-blinded placebo-controlled randomized trial aiming to determine the optimal biological dose (OBD) of nicotinamide riboside (NR), in individuals with Alzheimer's disease (AD).

Individuals with AD (n = 80) will be recruited starting November 2022. Participants will be randomized 1:1:2 to either placebo group (n = 20) or NR 1000mg daily (n = 20) for 12 weeks or to a dose-escalation group where NR 1000mg daily will be administered week 1-4, NR 2000mg daily week 5-8 and NR 3000mg daily week 9-12 (n =40). Both the participants and the investigators will be blinded.

• Primary Objective:

  -- To compare the effect of orally administered nicotinamide riboside (NR), escalated to 1500 mg twice per day (3000 mg/day) in the dose escalation group (DE-group) - versus stable dosing of 500 mg twice per day (1000 mg/day) in the dose-stable group (DS-group) on cerebral NAD levels, at week 12.

• Secondary Objectives:

  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in cerebral NAD levels from baseline to weeks 4, 8 and 12.
  • To compare the effectiveness of orally administered nicotinamide riboside (NR) 1500 mg twice per day versus 500 mg twice per day in augmenting the NAD-metabolome in the central nervous system (CNS) at week 12.

• Safety Objectives

  -- To determine the safety and tolerability of NR at a dose of 1000 mg, 2000 mg, and 3000 mg per day in AD.

• Exploratory Objectives:

  • Neuroimaging
  • To compare the effect of orally administered NR in the DE-group versus DS-group on the NR related metabolic pattern (NRRP) expression at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in NRRP expression from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR DE-group versus DS-group on the AD-related pattern (ADRP) expression at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in ADRP expression from baseline to weeks 4, 8 and 12.
  • Metabolism & molecular markers
  • To compare the effect of orally administered NR in the DE-group versus DS-group on the NAD metabolome* in the blood, urine and central nervous system (CNS) at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in the NAD metabolome* in blood and urine from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on serum and CSF inflammatory markers at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in serum inflammatory markers from baseline to weeks 4, 8 and 12.
  • Clinical - cognitive & non motor symptom severity, quality of life
  • To compare the effect of orally administered NR in the DE-group versus DS-group on clinical severity of AD symptoms at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and change in clinical severity of AD symptoms from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on ADL severity in AD at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and change in ADL scores in AD from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on depressive symptoms in AD at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and depressive symptoms in AD from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on neuropsychiatric symptoms in AD at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and change in neuropsychiatric symptoms in AD from baseline to weeks 4, 8 and 12.

• Hypothesis-generating or resource-dependent endpoints (may be reported in follow-up or secondary publications).

  • To compare the effect of orally administered NR in the DE-group versus DS-group on gene expression at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in gene expression from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on protein expression at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in protein expression from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on serum and CSF inflammatory markers at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in serum inflammatory markers from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on histone acetylation in AD at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in histone acetylation in AD from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on H3K27 and H4K16 histone acetylation in AD at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in on H3K27 and H4K16 histone acetylation in AD from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on the genomic distribution of H3K27 and H4K16 histone acetylation in AD at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in the genomic distribution of H3K27 and H4K16 histone acetylation in AD from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on folate and one-carbon metabolism in AD at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in folate and one-carbon metabolism in AD rom baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on methyl donors in AD at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in methyl-donors in AD from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on DNA methylation at week 12.
  • To assess the dose-response relationship between NR dose (1000 mg, 2000 mg, 3000 mg per day) and changes in methyl-donors in AD from baseline to weeks 4, 8 and 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on synthesis of neurotransmitters in AD at week 12.
  • Determine whether NR-therapy affects the gut microbiome in a dose-responsive manner at week 12.
  • To compare the effect of orally administered NR in the DE-group versus DS-group on the gut metabolome at week 12.

• Procedures:

All participants will attend study visits at Baseline, week 4, week 8 and week 12. The study visits will consist of the following:

Assessment by physician and study nurse involved in the study including The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Clinical Dementia Rating (CDR), Montreal Cognitive Assessment Test (MoCA), Trail Making Test (TMT), The Lawton Instrumental Activities of Daily Living Scale (IADL), The Physical Self-Maintenance Scale (PSMS), Montgomery-Asberg Depression Rating Scale (MADRS), the The Neuropsychiatric Inventory Questionnaire (NPI-Q)

A 31P-magnetic resonance spectroscopy (MRS), 1H-magnetic resonance spectroscopy (MRS) and fluorodeoxyglucose-positron emission tomography (FDG-PET) scan.

Physical examination and measurement of vital signs. Routine blood tests. Urine sample collection. Faecal sample collection at Baseline and week 12. Cerebrospinal fluid (CSF) collection will be performed at Baseline and week 12.

Inclusion Criteria:

• The following condition must apply to the prospective patient at screening prior to receiving study agent:

  • Diagnosis of probable Alzheimer Disease (AD) according to the core clinical criteria updated in the National Institute on Aging (NIA) and Alzheimer's Association guidelines.
  • Biomarker evidence consistent with AD neuropathologic change, defined by cerebrospinal fluid (CSF) markers.
  • Diagnosed with AD within two years from enrollment.
  • Clinical Dementia Rating (CDR) 0.5-1 (inclusive) at enrollment.
  • Age 50 to 85 years (inclusive) at the time of enrollment.
  • A study partner (i.e. a family member or a friend) able to provide study data and assist the participant in the study drug administration, i.e. contact ≥ 3 times weekly.
  • Capacity to provide written informed consent for study participation defined as Montreal Cognitive Assessment (MoCA) score ≥ 16 or Mini Mental State Evaluation (MMSE) score ≥ 20. MMSE or MoCA must have been performed within 6 months prior to baseline. If there is any doubt regarding the participants capacity to give informed consent we will ask for an independent evaluation by a consultant clinician who is not associated with the N-DOSE AD study.
  • Cholinesterase inhibitors and memantine can be used if stable for 8 weeks prior to baseline visit.
  • Able to undergo lumbar puncture.
  • Able to undergo magnetic resonance imaging (MRI)

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

• Diagnosis of dementia other than probable AD.
• Comorbidity that precludes study participation or data interpretation.
• Any psychiatric disorder that would interfere with compliance in the study.
• Any severe somatic illness that would interfere with compliance and participation in the study.
• Use of high dose vitamin B3 supplementation within 30 days of enrollment.
• Metabolic, neoplastic, or other physically or mentally debilitating disorder at baseline visit.
• Current treatment with Oral Anti-coagulation Therapies
• Implants that preclude MRI examinations, e.g. DBS, pacemaker