NAD<SUP>+</SUP> METABOLIC DEFICITS DRIVE THE MITOCHONDRIAL-CIRCADIAN AXIS DISRUPTION IN ALZHEIMER'S DISEASE

Objectives: Circadian rhythm disruption and mitochondrial dysfunction are increasingly recognized as important features of Alzheimer's disease (AD). Emerging evidence suggests that these two processes interact and jointly contribute to disease progression. However, molecular pathways linking circadian oscillator, mitochondrial homeostasis, and AD pathology remain poorly defined.
Methods: Human post-mortem brain datasets from AD patients and healthy donors were analyzed to identify unbiased alterations in circadian and metabolic pathways. In-vitro cellular models expressing APP695 Swedish mutation (K595N/M596L) or human tau P301L mutation were used to recapitulate Aβ- and tau- associated circadian dysfunction. These models spontaneously generated AD-related pathological products and exhibited endogenous circadian disruption, enabling assessment of circadian gene expression, protein oscillatory dynamics, and AD-related phenotypes. Mitochondrial biosensors were employed to monitor mitochondrial activity and metabolic parameters.
Results: Both Aβ and tau pathology induced pronounced dysregulation of circadian gene expression, including acrophase shifts, phase inversion, and bidirectional amplitude changes. Core circadian proteins exhibited accelerated degradation under AD-related conditions. Integrative bioinformatic and experimental analyses converged on mitochondrial dysfunction and reduced NAD⁺ availability as central drivers of these disruptions. Direct supplement or indirect enhancing NAD⁺ level partially restored mitochondrial function, improved circadian rhythmicity, and alleviated AD-related molecular impairments in vitro.
Conclusions: Our findings support a model in which NAD⁺ metabolic deficits drive mitochondrial-circadian axis dysfunction in AD. Restoring NAD⁺ metabolism improves mitochondrial function and re-establishes circadian homeostasis, ultimately mitigating AD-associated cellular dysfunction. These results highlight NAD⁺-centered metabolic restoration as a promising strategy to target the interconnected metabolic and circadian disturbances underlying AD pathology.