Background

Alzheimer’s disease (AD), constituting 60-70% of dementia cases, is the most prevalent cause of dementia, with global estimates surpassing 50 million patients, thereby imposing a substantial societal and familial burden [1]. Clinically, AD manifests with progressive memory loss, cognitive impairment, and behavioral changes. Neuropathologically, β-amyloid (Aβ) deposits extracellularly, forming neuroinflammatory plaques, while intracellularly, excessive phosphorylation of tau leading to the formation of neurofibrillary tangles (NFTs), accompanied by synaptic loss and neurodegeneration [2,3,4]. Moreover, abnormalities in lipid metabolism have been identified as the third pathological feature of AD, associated with disease onset and progression [5]. Lipids, constituting 50% of the brain’s weight, encompassing fatty acids, cholesterol, phospholipids, and sphingolipids, play a pivotal role in brain function [6]. For instance, fatty acid oxidation contributes 20% of the brain’s energy supply [7], and cholesterol and sphingolipids are major components of lipid rafts [8, 9], playing crucial roles in neurotransmitter transmission, signal transduction, and neural synaptic plasticity. Alterations in lipid homeostasis manifest in the early stages of AD [10], with studies indicating abnormal lipid deposition in the brains of AD patients and 3×Tg AD mice, signifying disrupted lipid metabolism [11,12,13,14]. Concurrently, a systematic review also encapsulated the prevalent occurrence of lipid dysregulation in AD mouse models such as 5×FAD, APP/PS1, among others [15]. Metabolic analysis of serum, plasma, and cerebrospinal fluid from AD patients reveals the dysregulation of lipid metabolism is closely linked to cognitive decline and neuronal dysfunction [16, 150]. Consequently, APOE4 is considered the most potent risk factor for late-onset Alzheimer’s disease (LOAD) [114, 151, 152].

In-depth analyses of the gut microbiota in AD mice with different APOE genotypes, utilizing 16S rRNA sequencing and fecal metabolomics, have revealed correlations between APOE genotypes and the abundance of gut microbiota. Specifically, APOE2 genotype mice displayed higher levels of Ruminococcaceae and Prevotellaceae, bacterial families involved in SCFAs production. This is thought to contribute to the protective effect of the APOE2 genotype against AD. In APOE4 genotype AD mice, an increase in Lachnospiraceae and Deferribacteraceae, and a decrease in Bacteroidaceae were observed, accompanied by reduced concentrations of SCFAs and their precursors [153]. These findings suggest that APOE genotypes influence the composition of the gut microbiota and the generation of metabolites in AD mice. Changes of microbiota and metabolites induced by different APOE genotypes may play an important role in the impact of APOE genes on AD. Carriers of the APOEε4 allele often experience disturbances in CNS cholesterol homeostasis, and APOE4 mice also exhibit abnormal cholesterol levels and lipid metabolism disruptions [153]. This suggests that the gut microbiota and SCFAs may influence CNS cholesterol levels by affecting APOE gene.

Moreover, the microbiota and its metabolites also influence APOE genes. For instance, the microbiota-produced secondary bile acid TUDCA reduce the expression of APOE in the hippocampus and frontal cortex, inhibiting the production and accumulation of Aβ [154]. In the presence of melatonin, APOE4’s characteristics shift from promoting amyloid fibril formation to inhibiting it [137]. Additionally, the gut microbiota reduces neuroinflammation, tau pathology, and neurodegeneration in an APOE genotype-specific manner [100]. These findings highlight the significant interplay between the microbiota, its metabolites, and APOE genes in AD.

TREM2

TREM2 is a transmembrane receptor of the immunoglobulin superfamily specifically expressed in microglial cells of the central nervous system. It plays a role in microglial proliferation, transportation, phagocytic functions, and inflammatory responses [155, 156]. When functional loss mutations, such as R47N, R62H, and D87N, occur in TREM2, the risk of develo** LOAD increases. These mutations result in reduced cholesterol clearance by microglial cells, decreased uptake of CLU, LDL, and Aβ, exacerbating cholesterol lipid accumulation, amyloid pathology, and neuronal damage [81, 157,158,159].

Research has reported a close association between bacterial anionic LPS and TREM2. LPS bind to TREM2 [160], promoting the transition of microglial cells from an anti-inflammatory phenotype to a pro-inflammatory phenotype [210]. SCFAs play a crucial role in regulating lipid peroxidation. For example, butyrate enhances fatty acid oxidation, electron transport chain, and oxidative stress gene expression, while propionate interacts with fatty acid receptors, upregulating lipoprotein lipase to promote lipid synthesis [211, 212]. Acetate is involved in regulating cholesterol metabolism and adipogenesis [213]. Thus, existing evidence supports the role of gut microbiota in mediating oxidative stress alterations in AD [208]. Propionate bind to the free fatty acid receptor GPR41 in brain endothelial cells, inhibiting the expression of LRP-1 through a CD14-dependent mechanism, and protecting the blood-brain barrier from oxidative stress through NRF2 signaling [95]. Butyrate act as ligands for GPR109A, and by activating GPR109A, they block the NF-κB signaling pathway [212], a crucial pathway in oxidative stress in AD [214, 215]. Additionally, cells uptake butyrate through the sodium-coupled monocarboxylate transporter 1 (SMCT1), leading to the generation of Sp1. This activation of Sp1 stimulates NRF2, thereby promoting the production of SOD1 and suppressing NOX2, preventing the excessive accumulation of reactive ROS in neurons [216]. Indole derivative IPA, an effective scavenger of hydroxyl radicals, protects central neurons from oxidative damage by reducing DNA damage and lipid peroxidation [212].

Mitochondrial dysfunction

Various pieces of evidence indicate that mitochondrial dysfunction is an early event in the pathogenesis of AD, including alterations in mitochondrial structure, respiratory dysfunction, reduced ATP generation, impaired dynamics, and elevated mitochondrial-associated oxidative stress [192, 217, 218]. Mitochondrial dysfunction leads to the release of cytochrome c, which activates Caspase-9-dependent neuronal apoptosis, disrupting Ca2+ homeostasis and triggering neuronal death. The association between the gut microbiota and mitochondria has been extensively documented over an extended period [219, 220]. Microbial metabolite N6-carboxymethyllysine (CML) mediates ROS burst, damaging mitochondrial activity and ATP storage in microglial cells [221]. Butyrate enhances mitochondrial biogenesis in astrocytes by upregulating the expression of PGC-1A, contributing to improved mitochondrial function and enhanced cognitive abilities in AD mice [222]. IPA and indole-3-propionamide (IPAM) exert neuroprotective effects by mitigating mitochondrial electron leakage and neutralizing hydroxyl radicals. Moreover, indole compounds, including IPA and IPAM, permeate the mitochondrial membrane, binding to the rate-limiting phosphorylation site on respiratory chain complex I. This action serves as an energy metabolism stabilizer, leading to a reduction in ROS production and contributing to neuroprotection [137].

Epigenetic regulation

Epigenetic regulation encompasses processes such as histone modification, DNA methylation, chromatin remodeling, and non-coding RNA regulation, all of which have been demonstrated to play a crucial role in neurodegenerative diseases [92, 93]. It is well-established that the expression levels of key proteins implicated in AD, including APP, BACE1, PS1, and APOE, are subject to epigenetic regulation. Therefore, the imbalance in epigenetic regulation may underlie the aberrant expression of genes associated with synaptic plasticity and memory in AD [223]. Histone modification is a common form of epigenetic regulation in AD, influencing the stability of nucleosomes, chromatin-mediated processes to participate in the regulation of gene expression. Histone modification encompasses acetylation, methylation, ubiquitination, among others, with acetylation playing a crucial role in AD [224]. Research has revealed a reduction in H4K12 histone acetylation levels in aged mice, leading to defects in the expression of learning and memory-related genes [225]. Histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). In AD mice and patients, the expression of HDAC2 increases with age [226]. HDAC2 overexpression reduces dendritic spine density, impairs neural plasticity and memory function, and suppressing or downregulating HDAC expression effectively restores cognitive function in AD animals [227].

Butyrate is described as a HDAC inhibitor, improving memory function in APP/PS1 mice by enhancing hippocampal histone acetylation [96]. Acetate enhances histone H3K18 over-acetylation and epigenetic regulation of BDNFPII and PIV promoter regions, leading to increased expression of BDNF and improvement in cognition [97]. Furthermore, acetate supplementation, as demonstrated in 5×FAD mice, enhances histone acetylation, restoring synaptic plasticity and cognitive function in an ACSS2-dependent manner [228]. Studies have reported that the immature phenotype of microglia in GF mice arises from epigenetic markings of key mitochondrial genes by H3K4me3 and H3K9ac, accompanied by intracellular fatty acid and lipid depletion. Acetate, driving microglial maturation and metabolic homeostasis, can rescue the impaired microglial function in GF mice. In the pathological context of AD, acetate exhibits inhibitory effects on microglial phagocytic function, leading to increased Aβ burden in 5×FAD mice [99].

Targeting gut microbiota and lipids for the treatment of AD

Given the evidence supporting the role of gut microbiota and lipid metabolism in the pathological progression of AD, it becomes crucial to understand how modulating the levels of microbiota and metabolites to improve AD pathology. Therefore, this section summarizes the primary preventive and therapeutic interventions aimed at regulating gut microbiota and lipid metabolism (Fig. 3).

Fig. 3
figure 3

Potential interventions in the gut microbiota to regulate lipid balance and mitigate pathological progression in Alzheimer’s disease. Current evidence suggests that interventions such as gut microbiota-based therapies (probiotics, prebiotics, fecal microbiota transplantation), pharmacological treatments (polyphenols, herbal remedies, statins), and lifestyle modifications (dietary patterns, exercise) can target the gut microbiome. These interventions promote gut microbiota and lipid homeostasis, ultimately enhancing cognitive function. These measures hold promise as potential strategies for preventing and treating the progression of Alzheimer’s disease

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Gut microbiota-based therapy

Probiotics

Probiotics, as live microbial supplements, have been shown to effectively improve gut microbiota balance and provide therapeutic benefits for patients with AD [229]. Studies have demonstrated the therapeutic effects of SLAB51 on AD, it improves glucose homeostasis, reduces tau phosphorylation [230], increases SCFAs such as acetate, propionate, and butyrate, while decreasing inflammation and Aβ deposition [231]. It activates a SIRT1-dependent mechanism, reducing oxidative stress in the brains of AD mice [232]. Another study found that SLAB51 inhibits cholesterol biosynthesis, lowers the ω-6/ ω-3 fatty acid ratio, improves neuroinflammation and oxidative stress, ultimately reducing Aβ and tau aggregation, and slowing down AD progression [46]. Candida rugosa lipase (CRL) has been reported to increase the abundance of Acetatifactor and Clostridiales vadin BB60 in the gut, enhancing lipid hydrolysis and maintaining unsaturated fatty acid homeostasis, leading to reduced neuroinflammation and cognitive deficits in APP/PS1 mic [233]. Lactobacillus plantarum DP189 regulates gut microbiota dysbiosis and inhibits tau hyperphosphorylation, as reported [195]. Additionally, it suppresses TMA production and TMAO synthesis, thereby reducing CLU expression and alleviating neuroinflammation and neuropathological defects in APP/PS1 mice [233]. The probiotic VSL#3 efficiently reduces serum prostaglandin and deoxycholic acid levels, ameliorating intestinal inflammation and permeability. Nonetheless, its influence on brain plaque deposition, cytokine levels, and gliosis appears to be relatively limited [234]. Synthesizing this evidence with findings from other studies implies that combining probiotics with exercise could represent a more promising therapeutic strategy for enhancing cognitive function [235, 236]. In summary, probiotics modulate gut microbiota composition and lipid metabolism homeostasis, exerting positive effects on brain inflammation, oxidative stress, Aβ pathology, and tau pathology. Therefore, by regulating the microbial composition through probiotics, new preventive and therapeutic options for AD are proposed.

Prebiotics

Prebiotics, composed of nondigestible oligosaccharides, human milk oligosaccharides, and soluble, fermentable fibers, serve as an alternative to probiotic supplements. They effectively enhance beneficial bacteria such as Bifidobacteria and Lactobacilli, improving cognitive impairment in APP/PS1 mice through the gut-brain axis [237, 238]. The neuroprotective effects of prebiotics make them a potential oral formulation for the prevention and treatment of AD [239]. Fructooligosaccharides (FOS) demonstrate beneficial effects in APP/PS1 mice [190], and prebiotic mannan oligosaccharide (MOS) reshapes the gut microbiota, maintains intestinal barrier integrity, increases SCFAs production, inhibits neuroinflammation and oxidative stress, effectively alleviating cognitive and behavioral deficits in 5×FAD mice [240]. In conclusion, supplementing prebiotics to modulate microbial composition and function holds promise for improving AD; however, further research is needed to explore the applicability of prebiotics in AD treatment.

Fecal microbiota transplantation

Fecal microbiota transplantation (FMT) involves transferring a sample of healthy donor fecal microbiota into the gut of a patient or diseased animal to restore gut microbial health and improve disease treatment. Studies have shown that transplanting fecal microbiota from wild-type mice to ADLPAPT mice effectively ameliorated Aβ plaques, neurofibrillary tangles, glial reactivity, and cognitive impairment, suggesting that restoring gut microbial homeostasis through FMT may have beneficial effects on AD treatment [40]. Another study confirmed that fecal transplantation from WT mice increased the abundance of Bacteroidetes, reduced Proteobacteria and Verrucomicrobia in the gut of APP/PS1 mice, increased butyrate levels, and significantly improved pathological features such as Aβ accumulation, synaptic dysfunction, neuroinflammation, and cognitive deficits [241]. Intervention with FMT from WT mice modulate glycerophospholipid metabolism in APP/PS1 mice, leading to an amelioration of Aβ pathology and neuroinflammation [43]. Conversely, transplanting gut microbiota from AD mice impaired memory function and neurogenesis in wild-type mice [242, 243]. Although the specific functions of the gut microbiota in these contexts are not yet fully elucidated, based on these results, healthy gut microbiota transplantation appears to exhibit a positive role in AD pathology. Table 1 summarizes current research on the gut microbiota-based therapy in improving AD lipid metabolism and pathological features.

Table 1 Current research on the gut microbiota-based therapy in improving AD lipid metabolism and pathological features
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Pharmaceutical formulation

Polyphenols

Polyphenols, natural compounds found in fruits and vegetables, possess antioxidant and anti-inflammatory properties. It has been demonstrated that they improve the pathological processes of AD by modulating microbiota homeostasis, mitochondrial function, oxidative stress, and inflammatory responses [250]. Oral administration of 200 mg/kg hawthorn flavonoid (HF) increased the proportion of Dubosiella and Alloprevotella, reversing gut microbiota and metabolic disturbances in AD mice. This led to elevated levels of docosapentaenoic acid (DPA), sphingolipids, and PC, significantly ameliorating cognitive deficits, Aβ accumulation, and abnormal activation of hippocampal astrocytes in AD mice [251]. Curcumin reduced the abundance of Prevotellaceae, Bacteroides, and Escherichia/Shigella in the gut of APP/PS1 mice. In BV2 microglial cells, it upregulated the expression of TREM2, alleviating neuroinflammation and amyloid plaque burden, thereby enhancing cognition [252, 253]. Bilberry anthocyanins (BA) lowered serum and brain LPS levels, increased SCFAs in feces, induced microglial phagocytosis of Aβ through the CD33/TREM2/TYROBP signaling pathway, alleviated hippocampal neuroinflammation, and reversed cognitive impairments in APP/PS1 mice [254]. In conclusion, the interaction of polyphenols with the gut-brain axis enables them to influence the central nervous system and exert neuroprotective activity. Further development of their therapeutic potential in AD is warranted.

Herbal medicines

Herbal medicines (HMs), also known as botanical medicines or phytomedicines, refer to plant-derived materials or preparations with therapeutic or other human health benefits. Studies have reported that the chemical substances in herbal medicines can be transformed by gut microbiota into metabolites, thereby improving the composition, functional impairments, and associated pathological progress of the gut microbiota. The regulatory effects of herbal medicines on the gut microbiota have also been applied in AD [255]. Patchouli alcohol (PA) has been demonstrated to effectively inhibit pro-inflammatory microbial groups such as Bacteroides, Klebsiella, Bilophila, Proteobacteria, and Enterobacteriaceae. It enhances the abundance of anti-inflammatory microbial groups, such as Firmicutes and Lactobacillus, suppresses the activation of the C/EBPβ/AEP pathway, alleviates Aβ plaque deposition, tau hyperphosphorylation, and neuroinflammation, ultimately improving cognitive deficits in TgCRND8 mice [256]. Schisandra chinensis (S. chinensis) improves learning and memory abilities in AD rats by increasing SCFAs levels and alleviating neuroinflammation [257]. Alpinae Oxyphyllae Fructus (AOF) has been proven to regulate TREM2 and mitigate LPS-induced neuroinflammation, promoting a beneficial M2 phenotype in microglial cells and ameliorating cognitive impairments in mice [258, 259]. Epimedii Folium and Curculiginis Rhizoma, extracts of Horny Goat Weed and **anmao, enhance TREM2 protein expression in the hippocampus by reducing TNF-α and IL-1β, regulating the transformation and activation of microglial cells, thus improving LPS-induced cognitive impairments [260]. In addition, Pyrolae herba (PH) regulates TREM2 expression, inhibits LPS-induced neuroinflammation, and alleviates cognitive impairments [261]. The therapeutic effects of herbal medicine on AD are highly complex, involving multiple aspects, with gut microbiota and lipid metabolism being just one facet. The precise therapeutic mechanisms remain to be elucidated.

Statins

Statins inhibit HMG CoA reductase in the cholesterol biosynthetic pathway, affecting intracellular cholesterol distribution, gene expression, and proteasome activity. This leads to a reduction in Aβ production, lowering the risk of AD and demonstrating positive effects on cognitive function. Beyond their well-known lipid-lowering effects, statins may also influence AD cognitive function through mechanisms involving the gut microbiota. For instance, atorvastatin has been shown to effectively increase the abundance of intestinal Lactobacillus while reducing Blautia and Ruminococcaceae. This modulation of the gut-brain axis alleviates neuroinflammation and improves cognition. Both atorvastatin and rosuvastatin increase the abundance of butyrate-producing bacteria, such as Butyricimonas, Bacteroides, and Mucispirillum, leading to reduced IL-1β levels and improved inflammation [262]. Oral administration of simvastatin has been demonstrated to enhance gut microbial activity, increase SCFAs levels in feces, strengthen intestinal cell connections, and reduce cell death and amyloid plaque deposition in the hippocampal tissue [263]. As showed in Table 2. Furthermore, the effects and influences of statins on AD are still under ongoing exploration, with the interaction with gut microbiota being a potential mechanism.

Table 2 Relevant studies on the current oral drug formulations affecting the gut microbiota and lipids in AD
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Lifestyle

Dietary patterns

Dietary patterns have been shown to play a role in AD pathology. The Western diet, characterized by high fat, high protein, and low fiber intake, has been associated with a reduced abundance of beneficial microbial strains, including Lactobacillus, Ruminococcaceae, Lachnospiraceae, and SCFA-producing bacteria such as Ruminococcus bromii, Faecalibacterium prausnitzii, Eubacterium rectale, Eubacterium hallii, and Anaerostipes coli SS2/1, correlating with an increased risk of AD [266]. In contrast, the Mediterranean diet (MeDi), representing a balanced nutritional pattern rich in unsaturated fatty acids, vegetables, fruits, and lean meat proteins, has demonstrated the ability to effectively modulate the abundance of beneficial bacteria, including Bifidobacterium and Lactobacillus, in the gut, thereby reducing the risk of AD onset [267]. The ketogenic diet emphasizes very low carbohydrate intake and high-fat foods, exhibiting therapeutic effects in AD patients by modulating gut homeostasis, reducing neuronal overexcitation, enhancing mitochondrial metabolism, and decreasing oxidative stress [268]. In a randomized, double-blind, single-center clinical study, the Modified Mediterranean-Ketogenic Diet (MMKD), which allows increased carbohydrate consumption compared to the ketogenic diet, involves higher intake of vegetables, fruits, olive oil, as well as fats and proteins from fish sources. The results demonstrated that MMKD increased the abundance of the Phylum Tenericutes and the family Enterobacteriaceae, both negatively correlated with the expression levels of Aβ42 in the cerebrospinal fluid. This dietary approach also increased butyrate levels, restricted LPS diffusion, promoted gut barrier stability, effectively restored gut microbiota composition, enhanced steroid biosynthesis, and improved AD pathology [267]. Therefore, the modulation of gut microbiota and lipid metabolism by dietary patterns holds significant importance in the prevention of AD and the attenuation of disease progression.

Exercise

Exercise can stimulate the proliferation of “beneficial” microbial communities, maintaining gut microbiota balance and subsequently improving health conditions [269]. Consequently, exercise is regarded as an effective and readily available therapeutic approach, possibly the single most important and accessible lifestyle component offering protection against a broad range of diseases [270, 271]. There is a close association between exercise and the gut-brain axis. Studies have found a negative correlation between physical activity and the risk of AD, indicating that regular exercise in the elderly can prevent AD and slow cognitive decline. Therefore, exercise serves as both a preventive strategy and an intervention measure in the treatment of AD [272, 273].

A 16-week running wheel exercise regimen has been demonstrated to increase the abundance of Firmicutes while decreasing the abundance of Bacteroidetes and Tenericutes, effectively improving gut microbiota composition and memory [274]. Running exercise has also been shown to increase the microbial content of Eubacteria, Roseburia, and Clostridia in the intestines of APP/PS1 mice, while decreasing the abundance of Prevotella, Bacteroides, Bacteroides fragilis, and L. johnsonii. This alteration inhibits the transfer of LPS to the brain, thereby alleviating LPS-induced neuroinflammation and improving cognitive function and pathological markers in AD mice [273, 275]. Moreover, voluntary wheel running (VWR) exercise has been found to upregulate the abundance of phylum Bacteroidetes and genus Prevotella while reducing the abundance of phylum Actinobacteria and TM7, as well as genus Oscillospira and Ruminococcus. This modulation mitigates cognitive dysfunction induced by TMAO [276]. These studies collectively indicate that exercise serves as an effective measure in regulating gut microbiota to improve the pathological progression of AD, presenting substantial potential in both the treatment and prevention of AD. However, it is imperative to recognize that as an intervention for AD, further research is needed to explore the specifics of exercise protocols, modes, and intensities.

Conclusions and perspectives

As emphasized in this review, the intricate interplay between gut microbiota and lipid metabolism in the pathogenesis of AD is a noteworthy research area. We summarize the current research evidence, highlighting the central role of gut microbiota-derived metabolites such as SCFAs, LPS, TMAO, BAs, and tryptophan indole derivatives in the lipid metabolism disruption of AD pathology. As the ultimate products of gut microbiota, microbial metabolites not only interact with key lipid metabolism genes such as APOE, TREM2, ABCA1, ABCA7, SREBP1, SREBP2, and CLU but also participate in AD lipid metabolism and pathological processes by regulating Aβ and tau pathologies, neuroinflammation, oxidative stress, mitochondrial dysfunction, and epigenetic regulation. These mechanisms are interconnected and mutually influential, and while we have only begun to elucidate their complex pathological associations, the exact underlying mechanisms warrant further in-depth exploration. In future research, the application of omics techniques such as metagenomics, meta transcriptomics, and metabolomics will aid in uncovering the intricate mechanisms governing the relationship between lipids, gut microbiota, and AD, providing a deeper understanding of their interconnections. Moreover, current therapeutic strategies and drugs for AD remain limited, and the close connection between gut microbiota and lipid metabolism provides new insights into treatment approaches. Supplementation with potential beneficial bacteria through probiotics, prebiotics, and fecal microbiota transplantation may impede or slow the pathological progression of AD. Additionally, the direct impact of diet on the production of microbial metabolites should not be overlooked, emphasizing the importance of dietary regulation. Exercise, as a beneficial lifestyle factor, also holds importance in the prevention of Alzheimer’s disease. Polyphenols, herbal medicines, and statin drugs demonstrate neuroprotective effects in the gut microbiota and lipid metabolism of AD, potentially holding translational value.