Unfriendly dialogue of gut microbiota and lipid metabolism in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a major neurodegenerative disease in the aging global population. Exploring the underlying mechanism is helpful to develop the novel strategy. Lipid metabolism disorder is the core accelerator of the occurrence and development of AD. Lipid deposition exacerbates the aging of microglia and astrocytes, leading to neural dysfunction, and consequently, neurodegeneration. In recent years, the crosstalk of gut microbiota and lipid metabolism has gained increasing attention. The gut microbiota and its metabolic products interfere with brain lipid metabolism via the gut-brain axis. This review explores the detrimental interactions between the disorder of lipid metabolism and gut microbiota, discusses its implications in potential pathogenesis, and highlights how restoring the imbalance ameliorates AD progression.

Keywords

Alzheimer's disease gut-brain axis gut microbiota lipid metabolism unfriendly dialogue

Introduction

Alzheimer's disease (AD) is a major neurodegenerative disorder and a pressing global health issue that remains unresolved. It is estimated that over 50 million people worldwide are affected by AD, imposing significant social and familial burdens. Clinically, AD is characterized by progressive declines in memory and cognitive abilities, leading to the gradual loss of independence in daily activities.^1,2 The extracellular deposition of amyloid-β (Aβ) to form neuroinflammatory plaques and the intracellular aggregation of hyperphosphorylated tau protein resulting in neurofibrillary tangles are the two primary pathological hallmarks of AD.¹ Interestingly, A growing body of research suggests that abnormal lipid metabolism is an important event throughout AD (Figure 1).^3–6

Figure 1.

Key advances in lipid metabolic dysregulation in AD. In 1907, Alois Alzheimer first observed abnormal lipid deposition in AD brains. From the 1950s to the 1970s, lipids were recognized as key components of neuronal membranes and signaling pathways, with a focus on phospholipids and sphingolipids. The discovery of apolipoprotein E (APOE) in 1973 linked lipids to neurodegenerative processes. In the 1990s, the identification of APOE ε4 as a major genetic risk factor solidified the connection between lipid metabolism and AD risk. Concurrently, ceramide, a sphingolipid metabolite, was implicated in apoptosis and inflammation. The 2010s, fueled by omics technologies, revealed mechanistic insights, including TREM2's role in recognizing lipid patterns and modulating microglial responses to amyloid-beta. With the advancement of precision medicine, multilayer omics approaches are identifying protein networks in the progression of AD. Disrupted lipid metabolism has been shown to induce neuroinflammation drive neuronal lipid droplet deposition via the APOE4/ACSL1 axis, and accelerate AD progression. These findings underscore the critical role of lipid metabolism in AD pathogenesis, opening new avenues for targeted therapies.

Furthermore, two-way communication between gut microbiota and the brain via the gut-brain axis (GBA) is essential for neurogenesis and cognitive function.⁷ Studies have shown that gut microbiota dysbiosis is a significant contributor to AD⁸; however, the precise mechanisms remain incompletely understood. Evidence has indicated that gut microbiota negatively affects AD progression, possibly by mediating lipid metabolism disorders.⁹ This review discusses the recent advances in lipid metabolism abnormalities in AD pathogenesis, highlighting the regulatory role of the gut microbiota and its metabolites in these processes, and providing new insights for developing intervention strategies based on the dialogue of gut microbiota and lipid metabolism via the gut-brain axis.

Lipid metabolism dysfunction in AD

In a healthy human brain, lipids constitute over 50% of the brain's total weight, playing a crucial role in maintaining the structure and function of the nervous system.^10–12 Brain lipids primarily include cholesterol, phospholipids, and sphingolipids. Cholesterol in the brain is transported to neurons through the formation of cholesterol-rich lipoproteins, such as apolipoprotein E (APOE). Within neurons, cholesterol is essential for maintaining the connections of neurites and synapses.¹³ Glycerophospholipids, particularly phosphatidylcholine (PC) and phosphatidylethanolamine (PE), form the main structural phospholipids of the cell membrane; the composition of these phospholipids influences the stability, permeability, and fluidity of the neuronal membrane.¹⁴ A phospholipid imbalance can cause the release of neurotransmitters, the structure, function and distribution of neurotransmitter receptors on the postsynaptic membrane, as well as the disruption of intracellular signal transduction pathways, thereby affecting various aspects such as the amplification and transmission of neural signals.^15,16 For instance, phospholipid imbalance (such as a decrease in anionic phospholipids or an increase in neutral phospholipids) reduces the Ca²⁺ sensitivity of Syt1, impairs the Ca²⁺-dependent release of synaptic vesicles, leading to abnormal neurotransmitters.¹⁷ Further interference with the activation of postsynaptic receptors and the function of ion channels disrupts the plasticity and efficiency of synaptic transmission. Additionally, PC and PE within brain cells regulate the anchoring of proteins to the membrane.¹⁸ Through receptor-mediated actions of phospholipases A, C, and D, the breakdown of glycerophospholipids produces second messengers, including long-chain polyunsaturated fatty acids (LCPUFAs).¹⁹ LCPUFAs, the precursors of eicosanoids and docosanoids, have a critical role in neuroprotection and anti-inflammatory responses in the central nervous system.²⁰ For instance, DHA and EPA can prevent the reduction of neurogenesis induced by cytokines and the increase of cell apoptosis, exerting anti-inflammatory and neuroprotective effects.²¹ Also, DHA and its derivatives can regulate the activity of astrocytes and control the clearance of Aβ in the early stage of AD.²² In addition, DHA can promote the growth of nerve synapses, increase the synthesis of synaptic proteins and the expression of glutamate receptors.²³ TREM2 is A myeloid cell surface receptor, which is mainly expressed on macrophages and microglia. In the central nervous system, TREM2 participates in the activation of microglia and helps to clear Aβ from the brain of AD patients, thereby improving the disease.²⁴ When some of its functions are mutated, it results in decreased cholesterol clearance and decreased uptake of CLU, LDL, and Aβ by microglia, exacerbating cholesterol lipid accumulation, amyloid pathology, and neuronal damage (Figure 1).^25,26 γ-secretase is a membrane-bound protease that cleaves the amyloid-β protein precursor (AβPP) to produce Aβ. Research has demonstrated that inhibition of γ-secretase results in the loss of synaptic function due to reduced cholesterol levels, thereby facilitating the pathogenesis of AD (Figure 1).²⁷ As critical components of the cell membrane, sphingolipids, maintain brain function, particularly in neurogenesis and synapse formation.²⁸ They also interact with cholesterol in lipid rafts, which are closely related to the activity of transmembrane proteins.²⁹

Lipid metabolism disturbance refers to abnormalities in the content and composition of lipids and their metabolites in the blood and organs due to genetic or acquired factors. Early researchers noted a higher incidence of “fatty inclusions” or “lipid droplets” in the brains of AD patients, suggesting potential lipid metabolism abnormalities.³⁰ At present, lipid droplet deposition in the brain has been confirmed as an early event in AD progression.^6,31 Studies have reported that early alterations in lipid homeostasis, such as abnormal lipid deposition and disrupted metabolism, occur in the brains of AD patients.³² Animal models of AD frequently exhibit lipid metabolism disorders as well.³³ APOE is a lipid-related risk gene for AD.³⁴ APOE genotype exerts regulatory control over the pathological progression of Aβ in the brain, while the specific APOE subtype primarily impacts AD by modulating the clearance and synthetic aggregation of Aβ.³⁴ The differential effects of APOE subtypes (particularly APOE4) on AD pathogenesis are largely attributed to their distinct capacities in lipid transport and metabolism. Compared to APOE2/3, APOE4 exhibits impaired cholesterol efflux from astrocytes and defective transport to neurons,^35,36 leading to synaptic cholesterol depletion and subsequent dendritic spine instability.³⁷ This cholesterol dyshomeostasis disrupts membrane microdomain organization, impairing synaptic vesicle recycling and neurotransmitter receptor traffickin.³⁸ Furthermore, neuronal cholesterol deficiency in APOE4 carriers promotes amyloidogenic processing of AβPP by enhancing BACE1 activity in lipid rafts.³⁹ Recently, a population of microglia expressing acyl-CoA synthetase long-chain family member 1 (ACSL1, a key enzyme responsible for lipid droplet formation) has also been particularly identified in individuals with the APOE4/4 genotype (Figure 1).³ Other AD risk genes, including CLU (clusterin) and ABCA1/7 (ATP-binding cassette transporter A1/7), have also been implicated in lipid metabolism dysregulation.⁴⁰ Other studies also support that dysregulation of lipid metabolism is closely related to the decline of learning and cognitive ability and the impairment of nervous system function.⁴¹

Abnormalities in lipid metabolism, including cholesterol and sphingolipid dysregulation, can directly exacerbate AD by promoting Aβ deposition or tau protein tangles.^10,42 For example, in neurons, increased cholesterol levels heighten susceptibility to oxidative stress in mitochondria mediated by Aβ, and inhibit the fusion event of damaged mitochondria and lysosomes. Such processes lead to the accumulation of dysfunctional mitochondria, and then, trigger apoptotic pathways, and consequently, cause significant neuronal loss.⁴³ Moreover, elevated cholesterol can enhance γ-secretase activity, facilitating the co-localization of AβPP with γ-secretase and β-secretase, thereby promoting Aβ production and AD progression.⁴⁴ In normal conditions, sphingolipids can inhibit Aβ accumulation. However, when sphingomyelin (a type of sphingolipid) is abnormally degraded, ceramide produced by sphingomyelinase catalysis can promote Aβ formation and accumulation (Figure 1).⁴⁵ The concentration of Platelet-activating factor acetylhydrolase-modified phospholipids (PlsEtns), a subtype of phospholipids, is significantly reduced in AD patients. This phenomenon exhibits a significant correlation with both cognitive dysfunction and clinical progression in patients.⁴⁶ Disruptions in phosphatidylinositol levels and the integrity of lipid rafts may also lead to abnormal phosphorylation of tau protein at key sites through the PI3K-Akt signaling pathway, mediated by downstream activation of GSK3β and Cdk5.⁴⁷ Several studies have pointed out that lipid deposition can aggravate the aging of microglia and astroglia and damage nerve function, thus leading to neurodegenerative diseases.⁴⁸ Organelle lipid communication refers to the information transmission and interaction between different organelles through lipid molecules.⁴⁹ In neurodegenerative diseases, the dysfunction of lipid communication between different organelles inside cells may cause the imbalance of lipid metabolism and the function of mitochondria, which adversely affects the survival and normal function of nerve cells.⁵⁰

Lipid metabolism dysregulation can also indirectly influence AD. High cholesterol levels and lipid metabolism disorders increase the risk of atherosclerosis and hypertension, leading to plaque buildup in the arteries. Over time, this process may result in cerebrovascular damage, reducing blood supply to the brain and exacerbating AD pathology.⁵¹ Cholesterol plays a crucial role in maintaining synaptic structure, and deviations from optimal cholesterol levels can compromise synaptic stability. Prolonged synaptic damage can impair neuronal signaling, accelerating disease progression if not addressed promptly.⁵² Insulin resistance, closely linked to glucose metabolism disorders, is also associated with lipid metabolism imbalance.⁵³ When energy metabolism pathways are disrupted due to reduced insulin sensitivity, neuronal excitability may decrease, potentially interfering with neurotransmitter release and reuptake.⁵⁴ In the long run, this constant imbalance of excitation or inhibition may cause damage to nerve cells.

Gut microbiota dysbiosis in AD

The gut microorganism refers to the complex community of microorganisms residing in the gastrointestinal tract, including bacteria, fungi, viruses, bacteriophages, and other microbes, which play a critical role in maintaining gut homeostasis.^55,56 The gut microbiota encodes over 3 million genes and produces a variety of metabolites that are vital to normal physiological functions.⁵⁷ Research has shown that the composition and metabolites of the gut microbiota in AD patients and AD mouse models are significantly altered, with increases in Bacteroidetes, Verrucomicrobia, and Proteobacteria, and decreases in Firmicutes.^58–60 However, there are also studies indicating that the number of Firmicutes bacteria increases in AD.⁶¹ This change in the gut microbiota may be closely related to various factors that affect the diversity of the gut microbiota, such as age, diet, disease stage, and gender.^62–64 Moreover, Minter Myles’ team found that antibiotic treatment of AD model mice reduces amyloid plaque deposition in the brain, increases soluble Aβ levels, attenuates local glial responses, and induces significant morphological changes in microglia.⁶⁵ Additionally, a previous study has explored the interaction of chiral gold nanoparticles with the gut microbiota in AD model mice.⁶⁶ It is shown that nanoparticle intake modulates gut microbiota structure and promotes the production of indole-3-acetic acid, which helps restore cognitive function in AD mice, along with the reduction of Aβ deposition and tau hyperphosphorylation.⁶⁶ Surprisingly, nanoparticles can exert a persistent effect on the gut microbiota.⁶⁷ Importantly, comprehensive toxicity evaluations confirmed the absence of systemic adverse effects at therapeutic doses.⁶⁶ Collectively, these findings support nanoparticles as modulators for gut microbiota in AD. Furthermore, fecal transplantation from wild-type mice to AD mice increases the abundance of beneficial bacteria and significantly improves neuropathological features including Aβ accumulation, synaptic dysfunction, and neuroinflammation.⁶⁸ In contrast, transplanting gut microbiota from AD mice to wild-type mice impaired memory and neurogenesis.⁶⁹ Our previous study also reported that transplanting healthy mouse fecal microbiota into obesity-induced cognitive impairment mice improved cognitive deficits.⁷⁰ In another experiment, researchers transplanted the gut microbiota of AD patients into antibiotic-treated rats and conducted 16S sequencing, metabolomics, and behavioral experiments. They found that the AD patient-derived microbiota induced cognitive deficits in recipient rats, impairing their AHN-dependent memory performance while significantly altering their gut microbial composition and related metabolites.⁷¹ Studies have shown that the characteristics of gut microbiota in AD patients show regular changes: compared with healthy people, the abundance of Firmicutes and Actinobacteria in the intestine of AD patients is significantly reduced, while the abundance of Bacteroidetes is significantly increased.⁵⁸ Also, it is important to note that some patterns of gut microbiota change in AD varies by population.^58,72 Notably, such composition changes of gut microbiota were closely correlated with key AD biomarkers. For example, increased abundance of Bacteroidetes was negatively correlated with Aβ₁₋₄₂/Aβ₁₋₄₀ ratio in cerebrospinal fluid, but positively correlated with P-tau levels and P-tau/Aβ₁₋₄₂ ratio.⁵⁸ More interestingly, similar structural alterations in gut microbiota have been observed in patients with mild cognitive impairment (MCI), suggesting that gut microecological imbalance may be an early event in AD.⁷³ Meanwhile, a study on 476 Chinese population has reported that AD patients had an abnormal abundance of 71 microorganisms, including depletion of putative beneficial genera (Bifidobacterium, Lactobacillus) and enrichment of pathobionts (Escherichia coli, Klebsiella pneumoniae) These findings provide a basis for early diagnosis and treatment of AD.⁶²

The gut-brain axis, a bidirectional network of interactions between the gut microbiota and the brain,^74,75 has become an important focus for understanding the pathogenesis and intervention strategies for neurodegenerative diseases including AD.⁷⁶ Several gut bacteria produce a diverse range of neuroactive metabolites, including amino acids and monoamines, which can permeate the bloodstream and traverse the blood-brain barrier (BBB) before being assimilated by cells involved in the synthesis of corresponding neurotransmitters.⁷⁷ Notably, recent clinical studies have reported significant correlations between gut microbiota composition and neurotransmitter precursor levels in both cerebrospinal fluid and plasma of AD patients.⁵⁸ Particularly, several microbial metabolites are enzymatically converted by various host enzymes into functional neurotransmitters (e.g., dopamine, norepinephrine) that modulate central nervous system function and host behavior, suggesting a direct microbiota-mediated influence on AD-related neurotransmission alterations.⁷⁸ Additionally, gut microbiota-derived metabolites, such as isoamylamine (IAA), can promote microglial apoptosis, leading to cognitive impairment.⁷⁹ In detail, IAA can cross the BBB, and induce p53 recruitment to the S100A8 gene promoter (a key player in sensing cellular senescence), thereby activating S100A8 transcription and promoting microglial apoptosis.⁷⁹ Notably, this phenomenon has significant pathological relevance in neurodegenerative diseases.⁷⁹ When gut microbiota imbalance, gut mucosal barrier disruption, or immune system activation occurs, several dangerous molecules can trigger the release of pro-inflammatory cytokines in macrophages, disrupting the immune homeostasis in the gut environment. With increased bacterial translocation and endotoxin uptake, toxins and pathogens can cross the damaged gut barrier, enter the bloodstream, and eventually reach the brain, triggering microglial and astrocyte responses.^80,81 Prolonged activation of these glial cells releases large amounts of pro-inflammatory cytokines,⁸² potentially leading to neuronal death and synaptic dysfunction.⁸³ Furthermore, activated glial cells are responsible for engulfing and destroying the delicate structure of synapses.⁸⁴ These chain reactions collectively contribute to the process of cognitive impairment and neurodegeneration. Thus, gut microbiota dysbiosis is a key event in AD progression.

Crosstalk of gut microbiota and lipid metabolism in AD

The gut microbiota plays a crucial role in regulating lipid metabolism.⁹ Studies have shown that the composition of the gut microbiota in AD model mice is closely related to fatty acids and glycerophospholipids.⁸⁵ A previous study indicates that in AD mice, gut microbiota can promote AD pathology by activating the C/EBPβ/AEP pathway, upregulating pro-inflammatory polyunsaturated fatty acid metabolism, and increasing microglial activation and neuroinflammation.⁸⁶ Interestingly, multi-strain probiotic preparations have been shown to improve lipid metabolism disorders and enhance cognitive functions such as learning and memory by reducing total cholesterol levels.⁸⁷ Eucommia bark polysaccharides (EPS), as a type of prebiotic, can restore the homeostasis of gut microbiota and promote the growth of bacteria producing short-chain fatty acids.⁸⁸ Additionally, dietary fiber supplementation can restore gut microbiota balance, and inhibit lipid accumulation in AD model mice, thereby alleviating cognitive dysfunction.^89,90 For instance, hazelnut soluble dietary fiber could adjust gut short chain fatty acids, promote the composition and structure of gut microbiota, and significantly balance the abundance of Lactobacillus, Roseburia, Ruminococcaceae_UCG-005 and Ruminococcaceae_UCG-014.⁹⁰ Interestingly, a composite material containing resveratrol-coated selenium nanoparticles and chitosan nanoparticles (Res@SeNPs@Res-CS-NPs), effectively reduces the abundance of Firmicutes while increasing the relative abundance of Bacteroidetes in the gut, preventing fat accumulation and insulin resistance, and further improves AD symptoms through the JNK/AKT/GSK3β signaling pathway.⁹¹ Recently, gut microbiota has been reported to regulate lipid metabolism programming in mice by inhibiting the expression of the long non-coding RNA, lncRNA Snhg9, in small intestinal epithelial cells,⁹² which may provide a potential way for treating lipid metabolism disorders in AD.

Gut microbiota-derived metabolites also regulate lipid metabolism dysregulation (Figure 2). For example, short-chain fatty acids (SCFAs) produced by Firmicutes, including butyrate and propionate, can regulate cholesterol and lipid metabolism by binding to GPR43 and GPR109A receptors.^93,94 Propionate binds to GPR41 in brain endothelial cells, impeding low-density lipoprotein receptor-related protein-1 (LRP-1) expression through a CD14-dependent mechanism and protecting the BBB from oxidative stress via NRF2 signaling.⁹⁵ Interestingly, adding high levels of acetate and butyrate to the diet has been shown to alleviate cognitive decline in AD model mice,⁹⁶ suggesting a protective role for endogenous SCFAs against cognitive impairment. On the contrary, other gut microbial metabolites, such as lipopolysaccharide (LPS) and bile acids (BAs), promote AD development by affecting lipid metabolism.^97–99 However, taurine deoxycholic acid in BAs, exhibit important antiapoptotic and neuroprotective activities, and experimental and clinical evidence suggests that they may be used as therapeutic ameliorators in neurodegenerative diseases.⁹⁸ Moreover, metabolomic analyses reveal altered bile acid synthesis pathways in AD patients, particularly with more activation of alternative pathways, leading to increased concentrations of cytotoxic bile acids in the blood.¹⁰⁰ Emerging evidence indicates that both SCFAs and BAs are regulators of APOE's expression and function. For example, SCFAs can indirectly regulate APOE activity by suppressing lipid accumulation and attenuating inflammatory responses, whereas BAs influence APOE expression through cholesterol metabolic pathways.^101,102 Their synergistic interactions are essential for maintaining systemic metabolic homeostasis. It is also reported that LPS can bind to specific complexes on the membrane of brain endothelial cells (bECs) in BBB, be internalized, and be recognized by caspase-11 in the bEC cytoplasm. This recognition activates gasdermin D (GSDMD), causing cell membrane perforation and pyroptosis, ultimately disrupting the BBB.¹⁰³ LPS can also directly damage endothelial cells, affecting the structure of advanced glycation end-product receptors and disrupting BBB function.^104,105 Moreover, the stimulation of LPS enhances the proteolytic processing of the ectodomain of LRP1, leading to the release of the LRP1 intracellular domain (ICD) from the plasma membrane through a gamma-secretase-dependent mechanism and its subsequent translocation to the nucleus. In the nucleus, it binds to and represses the interferon-gamma promoter. Consequently, in the absence of LRP1, there is an increase in both basal transcription of LPS target genes and LPS-induced secretion of proinflammatory cytokines.¹⁰⁶ LPS can also further impair AD-associated Aβ clearance mechanisms.¹⁰⁷ Notably, LRP-1 acts as the primary metabolic receptor for APOE in the brain, participating in APOE-mediated lipid transport,¹⁰⁸ indicating that LPS may indirectly affect APOE function. Overall, these findings suggest that microbiota-derived metabolites can act as signaling molecules that affect brain lipid metabolism, and lipid-targeting interventions can be optimized by considering the composition of the microbiota.

Figure 2.

The crosstalk of gut microbiota and lipid metabolism in AD. Alterations in the gut microbiota, including Bacteroides, Firmicutes, Clostridia, Lactobacillus, and Ruminococcus, lead to variations in the types and concentrations of their metabolic products. These metabolites can compromise the intestinal barrier, allowing harmful substances to enter the bloodstream and subsequently reach the brain. Once in the brain, these metabolites can disrupt lipid metabolism, which in turn triggers neuroinflammation, oxidative stress, and the accumulation of Aβ and hyperphosphorylated tau proteins. These pathological processes ultimately result in neuronal damage and exacerbate the progression of AD. TRYCAT: tryptophan catabolite; SCFA: short-chain fatty acids; LPS: lipopolysaccharide; Bas: bile acids; GBA: microbiota-gut-brain axis; APP: amyloid precursor protein; Aβ: amyloid-β protein.

Intervention strategies for AD targeting gut microbiota and lipid metabolism dysregulation

In recent years, researchers have made progress in developing AD interventions in the view of targeting gut microbiota and lipid metabolism dysregulation. Fecal microbiota transplantation (FMT) involves transplanting gut microbiota from a healthy individual into a patient's gut to restore gut microbiota balance, optimize gut and systemic microecological environments, and consequently, improve AD. A study revealed that FMT in AD model mice decreases the abundance of Proteobacteria and Akkermansia while increasing Bacteroidetes levels.⁶⁸ Moreover, Proteobacteria are closely linked to inflammatory responses, while Bacteroidetes promote SCFA production, which serves as an important signaling molecule between the gut and brain.⁶⁸ Recently, with advancements in acid-resistant enteric capsule materials, oral-fecal microbiota capsules (containing bacterial liquid or freeze-dried powder) have emerged as a cost-effective and efficient method of microbiota transplantation. Currently, fecal capsules have demonstrated efficacy in treating C. difficile infection and preventing its recurrence.¹⁰⁹ Furthermore, they have shown promising results in managing anxiety and depression.¹¹⁰ Additionally, emerging evidence suggests that the gut microbiota may play a pivotal role in the pathogenesis of AD,⁸ highlighting its potential as a novel therapeutic avenue for this condition. Consequently, exploring fecal bacteria transplantation/capsules could offer a new direction for AD treatment. The incidence of adverse events associated with FMT was reported to be 28.5%, with the majority being mild to moderate in severity. Notably, serious post-FMT complications have been documented in clinical practice.¹¹¹ At present, there are no reports evaluating the long-term effectiveness, sustainability and feasibility of FMT in clinical AD treatment. Such investigations are warranted to refine the therapeutic protocols and mitigate potential risks. Probiotics, beneficial active microorganisms, have been shown to effectively improve gut ecological environments and regulate neurodegenerative diseases, including AD, through promoting neurotransmitter release or other beneficial metabolites.¹¹² In a three-month clinical trial, the supplementation of probiotic Lactobacillus rhamnosus GG (LGG) showed a certain degree of improvement in specific cognitive domains,¹¹³ indicating a potential therapeutic direction for treating cognitive impairment. However, it should be pointed out that this trial was not directly aimed at AD, and also had limitations (e.g., small sample size). Moreover, in AD mice, a 10-week intervention of Lactobacillus plantarum DP189 also ameliorates cognitive impairment, along with a notable increase in serum levels of serotonin (5-HT), dopamine, and gamma-aminobutyric acid (GABA).¹¹⁴ Notably, this intervention leads to reduced neuronal damage, decreased deposition of Aβ protein, and mitigated pathological damage to tau in the brains of AD mice.¹¹⁴ In addition, other studies have indicated that a composite probiotic consisting of Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium longum can effectively enhance spatial memory and cognitive function in AD model rats, significantly reduce Aβ deposition and regulate the balance between antioxidants and oxidants.¹¹⁵ These findings suggest that probiotics could be an important direction for AD treatment. However, prolonged administration of prebiotics may induce adverse effects, including gut dysbiosis, low-grade inflammation induction and glycemic fluctuations, underscoring the need for further safety evaluations through rigorous clinical trials.^116,117

Given the importance of lipid metabolism dysregulation in AD pathogenesis, researchers have explored the use of weight-loss drugs to treat AD in recent years. For example, in a longitudinal registry-based cohort study, statins have been shown to improve cognitive deficits effectively and may have therapeutic effects on AD.¹¹⁸ Research conducted by Rik van der Kant and Lawrence Goldstein has revealed that statins can reduce the amount of cholesterol esters in neurons, and decrease the levels of Aβ and phosphorylated Tau proteins through two independent pathways.¹¹⁹ Statins can reduce intracellular cholesterol levels, gene expression, and proteasome function by inhibiting hydroxymethylglutaryl-Coenzyme A (HMGCoA) reductase, a key enzyme in the cholesterol biosynthesis pathway. This action reduces Aβ production, lowering AD risk, and demonstrating protective effects on cognitive decline.¹²⁰ Given the established association between dysregulated lipid/glucose metabolism and AD progression, emerging studies are investigating cognitive improvement through modulation of glucose metabolic pathways. In AD mouse models, glucagon-like peptide-1 (GLP-1) may counteract Aβ-induced reductions in astrocyte glycolysis by activating the PI3 K/Akt signaling pathway, enhancing aerobic glycolysis and reducing oxidative phosphorylation, thus achieving neuroprotective and energy balance therapeutic effects.¹²¹ Also, the administration of GLP-1 receptor agonists liraglutide not only reduces inflammation in the liver, kidneys, and heart but also alleviates neuroinflammation in the brain.¹²² Notably, in individuals with obesity, liraglutide can improve memory and learning functions, increase neuronal numbers, reduce Aβ deposition, and prevent phosphorylated tau accumulation.¹²³ These studies suggest that targeting lipid or glucose metabolism offers therapeutic benefits for AD, and combining conventional pharmacological therapies with microbiota-targeted interventions may represent a novel therapeutic strategy with synergistic effects. However, evidence has indicated that gut microbiota can influence drug metabolism. It is reported that gut microbiota can enhance the metabolic clearance of statins.^124,125 Also, decreased abundance of Clostridium in the gut microbiota is reported to inhibit the conversion of chenodeoxycholic acid (CDCA) to ursodeoxycholic acid (UDCA), ultimately leading to reduced GLP-1 secretion.¹²⁶ These complex interaction networks uncover that current pharmacological interventions may be compromised by microbial interference, resulting in sub-optimal therapeutic outcomes. Consequently, it is imperative to conduct in-depth investigations into the precise regulatory relationships between gut microbiota and drug metabolism, in order to develop more effective and reliable therapeutic strategies for AD.

Conclusions

The latest research emphasizes the critical role of lipid metabolism disorders in the progression of AD (Figure 1). Emerging evidence suggests that the gut microbiota significantly influences this process through the gut-brain axis (Figure 2). This review primarily discusses how gut microbiota may contribute to AD by mediating lipid metabolism disorders. It highlights the current research advances on lipid metabolism disruptions in AD, focusing on the various regulatory roles of the gut microbiota and its metabolites. These insights pave the way for innovative therapeutic approaches targeting the gut-brain axis in AD treatment.

Building on this foundation, the review discusses the broader implications of existing research for understanding and preventing AD, while also evaluating present therapeutic strategies, including the use of fecal microbiota capsules and statins. Despite these advances, significant gaps remain in the research, and many potential mechanisms have yet to be fully elucidated. Future studies employing cutting-edge omics technologies, such as metagenomics and spatial metabolomics, are crucial for uncovering the complex relationships between lipid metabolism, gut microbiota, and AD. They may provide deeper insights into their interactions.

Current treatment options and drug development for AD continue to face considerable challenges; however, the close link between gut microbiota and lipid metabolism offers promising avenues for future therapies. Modulating the gut microbiota to restore lipid metabolism balance could be a viable strategy to slow or reverse AD progression. This perspective expands the therapeutic outlook for AD and introduces the potential for personalized medical approaches. It provides a new idea and direction for the treatment of neurodegenerative diseases such as Alzheimer's disease in the professional fields of microbiology, immunity, and metabolism.

Footnotes

Acknowledgements

The diagram is created with BioRender.com.

ORCID iD

Wei Pan

Author contribution(s)

Yuhan Cao: Conceptualization; Investigation; Writing – original draft.

Shuni Liu: Conceptualization; Visualization; Writing – review & editing.

Zhicheng He: Conceptualization; Visualization; Writing – review & editing.

Wei Pan: Conceptualization; Funding acquisition; Supervision; Writing – review & editing.

Dahui Wang: Conceptualization; Funding acquisition; Supervision; Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Project support was provided in part by the Natural Science Foundation of Jiangsu Province (grant number BK20201459), the 333 High-level Talent Training Project of Jiangsu Province, the Lishui Science and Technology Project (grant number 2024SJZC151), and Doctoral Projects of Lishui University (grant numbers QDZK112023003, QDZK112023014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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