Families learn the shape of the day before they learn the biology. The waking at four in the morning. The afternoon that unravels. The way daylight and mealtimes, which used to anchor a person, stop working as anchors at all. In the review published this year in Alzheimer's & Dementia, the authors describe exactly that pattern in clinical language: in dementia, some patients show a progressive advance in the phase of their circadian rhythms, a reduced amplitude of core clock gene expression, and diminished responsiveness to external time cues such as light and feeding schedules. The clock does not just tell the wrong time. It tells it more quietly.
The paper, led by Shi-qi Zhang and Jiyeon Lee with senior authors including Erik S. Musiek at Washington University in St. Louis, Evandro Fei Fang at the University of Oslo and Akershus University Hospital, and Weidong Le at Dalian Medical University, is a synthesis rather than an experiment. It reports no new patients and no new trial. What it does is gather the existing evidence on one molecule, nicotinamide adenine dinucleotide, or NAD+, a coenzyme every cell uses to convert fuel into work, and argue that its decline and the failure of the circadian system are not two separate stories running in parallel but one loop feeding itself. The authors cover Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia, frontotemporal dementia, and vascular cognitive impairment.
The loop, as they lay it out, is almost elegantly circular. The core clock proteins CLOCK and BMAL1 switch on NAMPT, the enzyme that recycles NAD+ from its own breakdown product, so NAD+ rises and falls on a daily rhythm. That rhythmic NAD+ then fuels SIRT1, which strips acetyl groups from BMAL1 and the PER proteins and so reaches back to tune the clock that made it. Meanwhile two hungry enzymes, PARP1 and CD38, consume NAD+ from the other end, and CD38 is itself under the control of the clock-driven factor REV-ERB alpha. Damage the clock and NAD+ supply falters; drain NAD+ and the clock loses amplitude. It is a tidy diagram, and it should be read as one: much of the underlying work sits in mice, in cells, and in models, and the review's authors flag which of these links still need confirmation.
The honest test of any such map is what happens when people take the molecule. Two trials give a sense of the ground. In a phase 2a proof-of-concept study reported in Neurology in December 2024, 47 people with early Alzheimer's disease took 1,500 mg of nicotinamide twice daily or placebo for 48 weeks; the primary outcome, the level of tau phosphorylated at threonine 231 in cerebrospinal fluid, did not reach statistical significance. In a phase 2 randomized pilot published this year in Alzheimer's & Dementia by Martens and colleagues, 52 older adults with amnestic mild cognitive impairment were randomized and 42 completed 12 weeks of nicotinamide riboside at 500 mg twice daily or placebo. Blood NAD+ roughly doubled against placebo. Cognition, the primary outcome, did not improve. Neither did total cerebral blood flow or blood pressure. An exploratory analysis hinted at increased blood flow in the hippocampus, which is the kind of signal that generates the next trial rather than the kind that changes anyone's medicine cabinet.
That gap, between a molecule that clearly moves in the blood and an outcome that does not move in the person, is the whole story of NAD+ right now. It is also why the circadian framing matters. If NAD+ works in rhythm, then when you give it may be as consequential as how much, and none of the trials so far were built to answer that. The review points in a related direction with obstructive sleep apnea, which it treats as a modifiable risk factor for vascular cognitive impairment, one that may push the NAD+ and SIRT1 axis in the wrong direction through repeated overnight drops in oxygen, while stating plainly that it remains unclear whether targeting that pathway helps.
For a family reading this over breakfast, the practical content is thinner than the biology suggests and more interesting than nothing. The daily pattern you are watching, the early waking, the flattened day, is not incidental to the disease; researchers now treat it as part of the machinery. But NAD+ supplements sold on shelves have not been shown to slow dementia, and questions about supplements, sleep, and breathing at night belong in a conversation with the clinician who knows the whole chart.