The goal of this clinical trial is to learn if orally administered nicotinamide riboside works to slow the progression of early Alzheimer disease in adults. It will also learn about the safety of drug nicotinamide riboside. The main questions it aims to answer are:
* Does drug nicotinamide riboside slow the progression of Alzheimer disease as measured by the Clinical Dementia Rating scale. * What medical problems do participants have when taking drug nicotinamide riboside? Researchers will compare drug nicotinamide riboside to a placebo (a look-alike substance that contains no drug) to see if nicotinamide riboside works to treat early Alzheimer disease.
Participants will:
* Take drug nicotinamide ribosie or a placebo every day for 24 months * Visit the clinic once every 26 weeks for checkups and tests
Diagnosis Early clinical AD, e.g. Stage 3 MCI or Stage 4 (mild AD dementia), as defined by the FDA, 2024.
Biomarker evidence consistent with AD neuropathologic change, defined by CSF markers, i.e. Aβ42 < 1030 ng/L and P-tau181/Aβ42 > 0,023 ng/L and/or T-tau/Aβ42 > 0,28 ng/L* or AD amyloid biomarker (as determined either by visual reading of amyloid PET scans using an approved ligand
Diagnosed with AD within 2 years from baseline.
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, this will be determined by an evaluation by a consultant clinician who is not associated with the N-AD study.
Diagnosis of dementia other than probable AD.
Abundant vascular pathology, i.e. Fazekas >2. or >3 lacunar infarcts, stroke involving a major vascular territory, severe small vessel, or white matter disease
More than 1 core feature of dementia with Lewy bodies, i.e; recurrent visual hallucination, cognitive fluctuations, REM sleep behaviour disorder, one or more spontaneous cardinal features of parkinsonism (tremor, rigidity and bradykinesia).
Comorbidity that precludes study participation or data interpretation.
Parallel
Nicotinamide Riboside (NR)
Dietary supplementNicotinamide Riboside 1000mg administered two times a day. Given as capsules. Duration of the trial; 104 weeks.
Palacebo
Other interventionPlacebo drug, administered two times a day. Given as capsules. Duration of the trial; 104 weeks.
Disease severity assessed by the Clinical Dementia Rating scale (CDR) sum of boxes.
CDR is a scale assessing clinical impairment in AD. CDR integrates assessments from 3 domains of cognition (memory, orientation, judgment/problem-solving) and 3 domains of function (community affairs, home/hobbies, personal care). Following semi-structured caregiver interview and systematic participant examination, the rater assigns a score describing the participant's current performance level in each of these domains of life functioning. The "Sum of boxes" scoring methodology (CDR-SB) sums the score for each of the 6 domains and provides a value ranging from 0 to 18 with higher scores indicating greater impairment. Positive change from baseline indicates greater impairment.
Change from baseline in the MoCA score at Week 104.
MoCA is a validated global measure of cognitive ability. The MoCA scale ranges from 0 - 30. Lower scores indicate cognitive impairment.
Change from baseline in Amsterdam ADL scale short version (A-IADL-Q-SV) at Week 104.
The Amsterdam ADL scale short version (A-IADL-Q-SV) is a 30-item, proxy-completed, psychometrically validated instrument designed to measure functional decline in instrumental activities of daily living (IADL). Lower scores reflect greater impairment.
Change from baseline in delayed recall performance on the CERAD 10-Word List at Week 104
CERAD 10-Word List Test evaluates memory. Higher scores reflect better performance.
Change from baseline in executive functioning as measured by Trail-Making Test Part B completion time at Week 104
Trail-Making Test B (TMT-B) measures executive function. Score = Time to Completion. Maximumt time in this trial is 360 sekunds. Longer time reflects greater impairment.
Change from baseline in plasma p-tau217 levels at 104 weeks
Plasma phosphorylated tau at threonine 217 (p-tau217) is a blood-based biomarker of Alzheimer's disease pathology. Plasma p-tau217 concentration will be measured using a validated analytical assay. Changes in p-tau217 levels from baseline to Week 104 will be assessed as an exploratory biomarker outcome to evaluate potential treatment effects on Alzheimer's disease-related tau pathology.
Change from baseline in plasma MTBR-tau243 levels at 104 weeks
Plasma microtubule-binding region tau fragment 243 (MTBR-tau243) concentration will be measured using a validated analytical assay. MTBR-tau243 is a biomarker associated with tau neurofibrillary tangle pathology in Alzheimer's disease. Change from baseline to Week 104 will be assessed as an exploratory biomarker outcome.
Frequency and severity of adverse events
The between-visit difference in incidence of treatment-associated mild/moderate/severe adverse events (AEs)
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