Malnutrition exacerbating neuropsychiatric symptoms on the Alzheimer's continuum is relevant to the cAMP signaling pathway: Human and mouse studies

INTRODUCTION: Malnutrition correlates with neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD); however, the potential mechanism underlying this association remains unclear. METHODS: Baseline and longitudinal associations of nutritional status with NPSs were analyzed in 374 patients on the AD continuum and 61 healthy controls. Serum biomarkers, behavioral tests, cerebral neurotransmitters, and differentially gene expression were evaluated in standard and malnourished diet-fed transgenic APPswe/PSEN1dE9 (APP/PS1) mice. RESULTS: Poor nutritional status and increased cerebral blood flow in the midbrain and striatum were associated with severe general NPSs and subtypes, especially depression, anxiety, and apathy. APP/PS1 mice fed a malnourished diet showed poor nutritional status, depression- and anxiety-like behaviors, altered neurotransmitter levels, and downregulated c-Fos expression in the midbrain and striatum; these were associated with suppressed cyclic adenosine monophosphate (cAMP) signaling pathway. DISCUSSION: Malnutrition exacerbating NPSs is relevant to suppressed cAMP pathway in the midbrain and striatum, suggesting the potential for targeted nutritional interventions to mitigate NPSs in the AD continuum. HIGHLIGHTS: Poor nutritional status linked to general and specific neuropsychiatric symptom (NPS) deterioration. Malnutrition affects NPSs, usually involving the midbrain and striatum. Malnourished diet induces depression- and anxiety-like behaviors in APP/PS1 mice. Malnutrition exacerbates NPSs associated with cAMP signaling pathway in the midbrain and striatum.