Alzheimer's disease

Alzheimer's disease involves a measurable collapse in brain energy metabolism. AD brains show a reduced NAD+/NADH ratio and impaired cerebral energy production [1], which has made NAD+, a molecule central to mitochondrial function, an appealing target for researchers hoping to slow or reverse cognitive decline.

What the mouse data showed

In preclinical work, raising brain NAD+ reversed Alzheimer's-like pathology and memory deficits in mice [1]. That finding generated real excitement, because it offered a mechanism: restore cellular energy currency, restore neuronal function. The problem is that mice are not people, and the translation from rodent to human has, so far, failed to materialize.

What happened in human trials

NAD-precursor supplements, nicotinamide riboside (NR), nicotinamide, and NMN, do not improve cognition in people with Alzheimer's disease or mild cognitive impairment based on current human trial data [2]. The most rigorous test of this to date is a 12-week double-blind randomized controlled trial in 42 adults with amnestic MCI (Martens 2026): NR successfully doubled blood NAD+ levels, confirming that the supplement was working biochemically. Cognitive outcomes, cerebral blood flow, and blood pressure were all null [3]. Target engagement was confirmed; the cognitive benefit was not. The preclinical promise has not translated.

Where MCTs fit in

Medium-chain triglycerides (MCTs) take a different route. Rather than targeting NAD+, MCTs raise circulating ketones, which neurons can use as an alternative fuel when glucose metabolism falters, exactly the metabolic problem AD brains face. A meta-analysis of MCT and ketone interventions found modest cognitive benefits in AD patients [4]. The effect is small and appears more consistent in people who do not carry the APOE4 genetic variant; APOE4 carriers show less benefit [4]. "Modest" is the operative word here: MCTs are not a treatment, but the evidence is meaningfully more encouraging than what exists for NAD precursors in this context.

How these two strategies compare

The contrast is instructive. NAD-precursor supplements produce solid biochemical changes in the blood, NAD+ doubles, yet those changes do not appear to reach the cognitive endpoints that matter [3]. MCT supplementation produces smaller, harder-to-standardize metabolic shifts, yet the cognitive signal, though small, is detectable [4]. One explanation is that blood NAD+ may not reliably reflect brain NAD+; another is that the energy-metabolism deficits in AD are too downstream of NAD+ to be corrected by precursor loading alone. Neither explanation is settled.

Where the evidence is contested

The central tension is between the mouse data and the human data. Raising brain NAD+ clearly reverses AD-related pathology in animal models [1], and the biochemical rationale is sound. Human trials, however, including the highest-quality NR cognition RCT available, find no cognitive benefit despite confirmed NAD+ elevation in the blood [2] [3]. Whether this reflects a fundamental species difference, an inadequate dose reaching the brain, a trial duration too short to detect slow-moving effects, or a genuine dead end for this mechanism in humans is not yet resolved. The current human evidence does not support "reversal" language, but it also cannot rule out that a better-designed intervention (longer duration, higher dose, earlier disease stage, direct brain delivery) might show a different result. For MCTs, the modest benefit seen in meta-analysis [4] is qualified by the APOE4 interaction, inconsistent trial designs, and small effect sizes, enough to take seriously, not enough to treat as established.

References

1. Hou/Fang 2018, PNAS — NAD+ normalizes AD (mouse)
2. Nicotinamide riboside in MCI — RCT (null cognition)
3. Martens CR et al. 2026 (Alz & Dementia) — NR in aMCI pilot (n=42, 12 wk, DB-RCT); NAD+ doubled (target engagement confirmed); cognitive, CBF, BP… · PubMed 42478598
4. MCT/ketones & AD cognition — meta-analysis · PubMed 31870908