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 examinationsCognitive assessmentsLumbar punctureMagnetic resonance imaging - positron emission tomography (MRI-PET) scanningsBiosamplingThey'll be given placebo, 1000 mg NR or escalating doses of NR (1000 mg - 2000 mg - 3000 mg) over 12 weeks.

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 TherapiesImplants that preclude MRI examinations, e.g. DBS, pacemaker