A combination of ketones and NAD⁺ precursor preserves white matter integrity in mild cognitive impairment

Brain glucose metabolism declines and myelin deteriorates as Alzheimer's disease (AD) develops. Adequate energy supply to white matter (WM) is critical to maintain myelin integrity and axonal function. An exogenous source of ketones bypasses the glucose‑specific brain energy deficit and improves cognitive outcomes in mild cognitive impairment (MCI). The BREAK-AD (BRain Energy Activation with Ketones in AD) trial tested a ketone salt and nicotinamide adenine dinucleotide (NAD⁺) precursor mixture to compensate for reduced brain glucose uptake in MCI.

Participants were randomized to a placebo (n = 15) or active supplement (β-hydroxybutyrate salts + nicotinamide riboside (NR); n = 15). Brain ketone and glucose metabolism (quantified by positron emission tomography [PET]), and cognitive performance were assessed before and at the end of the 6-month intervention. For WM analysis, seven tracts of interest were extracted using diffusion magnetic resonance imaging (MRI), and myelin density measures were derived from magnetization transfer (MT) imaging.

Total gray matter ketone uptake increased by 2.4-fold (p < 0.001) in the active group, with no change in gray matter glucose uptake in either group. In WM, ketone uptake increased in the active group by 3.1-3.6-fold across all seven tracts of interest (p < 0.001). In the placebo group, myelin density declined by up to 10% in specific regions of the fornix (p = 0.027), with no change in the active group. Improved processing speed was significantly associated with post-intervention change in myelin density (r = -0.39 to -0.59; p = 0.002-0.046) and ketone uptake (r = -0.40 to -0.52; p = 0.010-0.046) in WM tracts. Ketone uptake in specific WM tracts (fornix, uncinate and arcuate fasciculi), as well as in the composite of all tracts of interest was strongly associated with myelin density.

This study shows for the first time that improved myelin density may help explain the positive association between increased WM ketone uptake and improved processing speed in MCI after a ketone salt and NAD⁺ precursor supplementation.