Alzheimer's disease (AD) is a degenerative disorder of the central nervous system characterized by the deposition of amyloid-beta (Aβ) amyloid proteins and p-Tau, leading to chronic inflammation, oxidative stress, neuronal damage, and functional impairment. Circadian rhythm is a phenomenon where an organism's physiological, biochemical, and behavioral activities exhibit a rhythmic pattern of approximately 24 h. Study found that circadian disruption can occur in the early stages of AD, with sleep disturbances present in 25–40% of mild-to-moderate AD patients [1].

Lifestyle changes, such as time-restricted feeding (TRF), have been studied for their effectiveness in restoring circadian rhythms. TRF refers to limiting eating to a fixed time window while abstaining from food during other times. This eating pattern has been shown to reduce body weight and improve metabolism [2]. Studies have found that TRF can reduce cell apoptosis, rescue brain pathology in AD mice, and improve memory and other cognitive functions [3]. Existing studies have found that TRF can regulate the expression of both GCK and NPY [4,5].

Glucokinase (GCK), also known as hexokinase 4, belongs to the hexokinase family. In the human body, GCK is primarily concentrated in the pancreas, liver, brain, and gastrointestinal tract. Studies have shown that the expression of GCK is influenced by feeding and exhibits circadian rhythmic fluctuations. Typically, GCK activity increases postprandially but decreases during fasting periods, which helps in processing glucose absorbed from food [4]. In addition, GCK is a key component of the neuronal glucose-sensing mechanism and is expressed in brain regions that control a range of homeostatic processes. Although there is limited research on GCK in central nervous system degenerative diseases, studies have found that the activation of GCK is associated with neuronal apoptosis [6].

Neuropeptide Y (NPY) is a neuropeptide closely associated with the regulation of appetite, widely distributed in the central nervous system, where it plays a critical role in regulating various physiological processes, including appetite, stress response, and neuronal apoptosis. Research has shown that NPY can reduce neuronal damage by decreasing the accumulation of Aβ plaques and tau tangles. Additionally, NPY plays a crucial role in regulating synaptic plasticity and neuronal survival. It helps counteract neuronal loss by inhibiting apoptosis and promoting neurogenesis, ultimately improving the cognitive function associated with AD [7]. Interestingly, the expression of NPY is influenced by GCK. Inhibition of GCK can increase the expression of NPY in the brain [8].

We hypothesize that TRF improves AD-related cognitive deficits by modulating the GCK/NPY pathway and ameliorating neuronal apoptosis. Using an in vivo AD mouse model, we demonstrate that TRF reduces p-Tau levels and neuronal damage. Furthermore, we provide direct causal evidence by silencing GCK in HT22 cells.