Based on the findings extracted from this systematic review, it becomes evident that probiotic supplementation emerges as a viable intervention with the capacity to effectively ameliorate cognitive function in AD patients. Among the array of microbial strains harnessed within the five encompassed studies, Lactobacillus strains included L. acidophilus, L. casei, L. fermentum, L. plantarum, L. salivarius, and L. lactis. Complementing this, Bifidobacterium strains comprised B. bifidum, B. lactis, B. breve, and B. longum. The integration of these diverse Lactobacillus and Bifidobacterium strains in the probiotic interventions underpins the investigation’s therapeutic framework. A substantial body of research has extensively investigated the profound impact of probiotics, predominantly encompassing strains from the Lactobacillus and Bifidobacterium groups, on the reinforcement of intestinal barrier integrity. This effect is notably attributed to the augmentation of tight junction proteins' expression, thereby contributing to the preservation of the intestinal barrier's structural integrity [5]. The study conducted by Akbari et al. yielded findings of cognitive function improvements among patients subjected to probiotic intervention. Notably, the improvement in cognitive function was evidenced through the alteration in MMSE scores within the probiotic-treated cohort [3]. Microbiome is known to play an essential role in synaptic transmission [3]. Several studies have shown that gut microbiota could produce neuromodulators and neurotransmitters, including GABA, serotonin, dopamine, norepinephrine, and acetylcholine [3, 5]. GABA, the principal inhibitory neurotransmitter within the central nervous system (CNS), plays a pivotal role in modulating neural activity. Dysregulations in GABAergic signaling have been interlinked with a spectrum of neuropsychiatric implications including anxiety, depression, and cognitive deficits [3]. A study by Leblhuber et al. also showed improvements in cognitive function. Their research reported connections between discrete biomarkers indicative of immune activation and inflammation in individuals afflicted by cognitive impairment, and the intricate compositional makeup of the gut microbiome [4].

Hwang et al. administered DW2009 orally, which has been substantiated to yield enhancements in cognitive capabilities. The probiotic-treated group demonstrated substantial cognitive amelioration, particularly within the domain of attention [9]. Similarly, the study conducted by Xiao et al. unveiled cognitive enhancements as indicated by the RBANS score following a 16-week regimen of probiotic intervention. The findings accentuate the potential of RBANS as a valuable and responsive neuropsychological assessment tool, particularly for evaluating the primary impacts of probiotics on memory functions and the efficacy of specific probiotic strains in enhancing memory-related capacities [10].

A growing body of empirical evidence has underscored the notable impact of probiotics on cerebral functions, largely attributed to their regulatory role within the gut–brain axis, particularly discernible in individuals beset by cognitive impairments such as AD and mild cognitive impairment (MCI) [8]. In this context, the principal focus of this review resides in patients afflicted by AD, a population with inherent vulnerability to a spectrum of complications encompassing augmented oxidative stress, microvascular pathology, insulin resistance, dyslipidemia, and heightened mortality [3]. The discernments drawn from these studies collectively underscore the substantial impact of probiotics on the intricate interplay of the gut–brain axis within individuals afflicted by AD. Central to this phenomenon is the gut–brain axis, a bidirectional conduit facilitating unceasing communication between the central enteric nervous system (ENS), a neural network orchestrating gastrointestinal function, and the CNS. This intricate communication mechanism encompasses an array of processes, including endocrine and metabolic signaling, as well as immune and neural interactions [5]. The ENS holds the capacity to function autonomously or respond to CNS influences through the mediation of sympathetic signaling (via the prevertebral ganglia) and parasympathetic signaling (via the vagal nerve) [5].

Researches have indicated that numerous bacteria within the gut microbiota have the capability to generate substantial quantities of monomeric soluble lipopolysaccharide (LPS) and amyloid beta (Aβ), which could potentially modulate signaling pathways influencing the host immune and nervous systems [11, 12]. Should there be any compromise in intestinal barrier integrity, it could result in the activation of immune cells via the interaction between LPS derived from gut bacteria and the toll-like receptor 4 (TLR4) signaling pathway. Over time, the soluble form of Aβ may undergo polymerization, forming insoluble fibrous protein aggregates that could contribute to the pathogenic processes of AD [13]. The observed improvements in cognitive performance following probiotic supplementation underscore the multifaceted nature of the gut–brain axis and its role in modulating cognitive processes. Probiotics, through their influence on gut microbial composition and activity, have demonstrated the capacity to impact neurotransmitter systems, attenuate neuroinflammation, and enhance neuroplasticity [14]. Probiotic strains have been shown to produce neurotransmitters or precursor molecules, thereby influencing neurotransmitter synthesis and release within the central nervous system. Previously identified supplements consisting of a multispecies live mixture of bifidobacterium and lactobacillus were administered to aging rats, resulting in alterations in brain metabolites, specifically GABA and glutamate, within the cortex and hippocampus. These alterations were found to be conducive to enhancing neuronal signaling and memory function [15]. This intricate interplay extends to the modulation of neuroinflammatory pathways, wherein probiotics may serve to mitigate systemic inflammation and attenuate neuroinflammation, both of which are implicated in cognitive decline [16]. From memory consolidation and executive function to attentional processing and mood regulation, probiotics exhibit a broad spectrum of effects on cognitive performance. These effects are likely mediated through various pathways, including direct interactions with neural circuits, modulation of immune responses, and alterations in gut microbial metabolites [17]. The primary myeloid cell in the brain, microglia, is sustained by the host microbiota during normal conditions to prime for the innate immune response in the CNS. It is indicated by evidence that activated microglia form a defensive shield around amyloid deposits, impeding the addition of new Aβ onto established plaques [11]. Minter et al. demonstrated that antibiotic treatment leads to modifications in the composition of the gastrointestinal microbiome, which is associated with a decrease in Aβ deposition [18].

This review is not without limitations, notably in the heterogeneity of cognitive assessment tools employed across the five studies. Specifically, the cognitive evaluation methods encompassed MMSE in two studies, RBANS in one study, a computerized neurocognitive function test in another, and CERAD-K in the remaining study. Despite the diversity in assessment instruments, it is noteworthy that all included investigations arrived at a consistent conclusion, collectively substantiating the substantial potential of probiotics to positively impact cognitive function among individuals afflicted by AD. Another limitation of this review pertains to the inherent heterogeneity observed in the strains of probiotic microorganisms employed across the diverse studies. This variability in strains introduces the potential for divergent outcomes, as distinct strains may confer disparate effects on cognitive function. In the systematic review, four RCTs were included, where participants were randomly assigned to intervention and control groups. Additionally, one interventional study was incorporated, which might have utilized different design methodologies without strict randomization or control groups. This diversity in study design may affect the overall comparability and generalizability of the findings. Ultimately, these efforts stand to unravel the true therapeutic potential of probiotics and contribute to the refinement of treatment strategies for cognitive impairment in AD.