Gut-Brain Axis and a Systematic Approach to Alzheimer’s Disease Therapies

Abstract

Alzheimer’s disease (AD) is a critical issue that affects both the quality of life of families and public health. Despite years of research, single-target therapies for AD remain limited. This is primarily because of the complex and multifaceted pathological mechanisms underlying AD. Recent findings of the involvement of gut microbiome dysbiosis in AD pathogenesis have offered novel insights, emphasizing the need for holistic approaches. As AD progresses, gut microbiota alterations contribute to metabolic and immune imbalances, sparking peripheral inflammation. Consequently, there is heightened infiltration of immune cells into the brain, thus exacerbating neuroinflammation and cognitive decline. Notably, drug developments targeting this mechanism have witnessed substantial advancements, presenting novel systematic treatment approaches for AD patients. Furthermore, the gut microbiota plays a pivotal role in many other diseases and their associated cognitive impairments. The gut-brain axis, a bidirectional communication network, therefore holds significant promise for AD treatment as well as broader cognitive impairment solutions, beyond those based on the amyloid-beta and tau theories.

1 Background

In 2019, Meiyu Geng and her team at the Shanghai Institute of Materia Medica achieved a groundbreaking milestone in Alzheimer’s disease (AD) research with the discovery of sodium oligomannate (GV-971), a compound that targets the gut-brain axis to treat AD [1]. This work earned Geng a place on Nature’s “Ones to Watch 2020” list, underscoring its importance in the field [2]. GV-971 brought renewed hope to AD patients and healthcare providers by offering a novel approach that differed substantially from the traditional, single-target AD treatments that often focus on amyloid-beta (Aβ) clearance in the brain.

David Holtzman from Washington University in St. Louis has also emphasized that gut-targeted interventions may represent an innovative path forward in AD treatment [3]. Following the discovery of GV-971, the gut-brain axis has emerged as a promising focus in AD research, spurring further studies into how gut health may influence neurodegenerative processes.

To date, several novel, single-target drugs for AD have emerged onto the market; however, they have been accompanied by concerns and uncertainties [4-7]. Consequently, it is imperative to review the historical trajectory of AD drug development, summarize the advancements in pathogenesis research, and reassess the obstacles, prospects, and future trends within this domain.

2 Challenges in Alzheimer’s Disease Drug Development

AD is a neurodegenerative disorder that has become an urgent global health concern, especially with the aging population worldwide [8]. Since the approval of the first AD drugs in the 1990s and early 2000s—such as donepezil, galantamine, rivastigmine, and memantine—progress toward developing effective treatments has seemingly stalled [9, 10]. The recent approval of GV-971, in 2019, marked an important advance after decades of limited success [11]. A retrospective analysis estimated that private investments in AD drug development reached $42.5 billion from 1995, with phase 3 trials consuming 57% of costs ($24 billion) [12]. However, nearly 99% of all clinical trials have reported that their treatments lead to no significant improvements over placebo [13].

A large portion of these unsuccessful trials targeted plaques comprised of Αβ, which is one of the hallmark proteins associated with AD. Notably, the high failure rate suggests that the complex pathology of AD may not be adequately addressed by single-target therapies. Recently, three anti-Αβ monoclonal antibodies were approved, driven by regulatory updates and the development of diagnostic tools such as positron emission tomography tracers [14]. These tools better enable patient stratification and the assessment of Αβ reduction, thus supporting conditional approval for drugs showing Αβ clearance [15].

Nonetheless, anti-Αβ monoclonal antibodies have encountered challenges because Αβ clearance does not consistently yield clinical improvements. For example, in a phase 1b trial of aducanumab (the PRIME study), the drug significantly cleared Αβ plaques; however, in later trials (such as the phase 3 ENGAGE clinical trial), the drug failed to achieve key efficacy endpoints [16, 17]. Despite its early promise, the commercialization of aducanumab (ADUHELM®) was ultimately discontinued in 2024 [18] and there is still controversy surrounding its clinical benefit and safety concerns. Similarly, in the open-label extension of the Clarity AD phase 3 trial for lecanemab, participants who switched from placebo to lecanemab treatment for 18 months showed no significant changes in disease progression, in contrast to the expected disease modification that was anticipated from the delayed-start design [19-21].

Emerging research suggests that anti-Αβ therapy may be ineffective because treatment is started too late in the disease process, indicating that treatment might need to start even earlier [22]. The Dominantly Inherited Alzheimer Network Trials Unit tested this hypothesis by conducting a randomized, placebo-controlled, multi-arm trial of gantenerumab and solanezumab in individuals with dominantly inherited AD across both asymptomatic and symptomatic stages. Participants received preventive treatment for 4-7 years; however, neither drug showed cognitive benefits over placebo [22]. This disappointing outcome led to broader reflections on the state of AD therapy, which was captured by The New York Times headline, “We Don’t Have Anything Now” [23]. As researchers Adam Boxer and Reisa Sperling have highlighted, the major pathological processes in AD accumulate in the brain up to 15-20 years before clinical symptoms appear [24]. However, based on the findings of the Dominantly Inherited Alzheimer Network Trials Unit, the single-target approach as a secondary prevention strategy fails to yield satisfactory results.

3 Need for Systematic Therapy in Alzheimer’s Disease

AD pathology is highly complex, involving not only Aβ and tau proteins but also a wide range of other biological factors [25, 26]. The 2024 AD drug development pipeline reflects this diversity, with targets addressing multiple underlying mechanisms, including Aβ, tau, apolipoprotein E, lipids, neurotransmitter receptors, neurogenesis, inflammation, oxidative stress, cell death, protein homeostasis, metabolism, bioenergetics, vascular health, growth factors, hormones, synaptic plasticity, and the gut-brain axis [27]. Only approximately 10% of AD patients have “pure” AD; the other approximately 90% present with AD accompanied by other pathologies, which raises further questions about the effectiveness of single-target approaches [24].

Experts such as Boxer and Sperling have advocated for AD clinical trials that focus on combination therapies; they recommend trial designs such as umbrella trials, which test multiple drugs for the same condition [24]. Similarly, Amos Korczyn and Lea Grinberg have argued that AD treatment requires a multifaceted approach rather than relying on a single “silver bullet” [28]. These insights underscore the need for a comprehensive, systematic approach to treating AD.

4 Gut-Brain Axis

Over 2,000 years ago, Hippocrates noted that “all disease begins in the gut.” This idea was further developed in 1998, when Michael Gershon described the gut as “the second brain” [29]. The gut-brain axis is a bidirectional communication network between the central nervous and gastrointestinal systems, and involves the vagus nerve, immune system interactions, and bacterial metabolites [30]. Research by Meiyu Geng has demonstrated a link between the gut-brain axis and AD, noting that changes in gut microbiota during AD progression contribute to metabolic and immune dysregulation. This dysregulation can activate peripheral inflammation, leading to increased immune cell infiltration in the brain, which then exacerbates neuroinflammation and cognitive decline [1].

Studies by researchers such as David Holtzman and Sangram Sisodia support this idea, indicating that an imbalanced gut microbiota promotes tau-related neurodegeneration by generating bacterial metabolites that interact with immune cells. This interplay escalates inflammation in the central nervous system and worsens both tau aggregation and neurodegenerative processes [31].

The compound GV-971 targets the gut-brain axis as a treatment approach for AD. Derived from marine algae, GV-971 was approved in China in 2019 and added to the National Reimbursement Drug List in 2021 [11, 32]. In a phase 3 clinical trial, GV-971 demonstrated significant efficacy in improving cognition, and these benefits were sustained over the 36-week study period [33]. This continuous improvement sets GV-971 apart from traditional AD medications and anti-Aβ monoclonal antibodies because it indicates that GV-971 consistently provides cognitive benefits above baseline levels [17, 19, 33-36].

Ongoing post-market studies have aimed to further assess the long-term effectiveness and safety of GV-971 during the 2-year treatment period in a large cohort (3,300 patients). Interim results from these studies indicate that GV-971 monotherapy produces sustained cognitive improvements in treatment-naïve patients with mild to moderate AD (unpublished data), consistent with findings from the phase 3 trial. As an innovative drug, clinical evidence supporting GV-971 is steadily accumulating. Ongoing clinical trials are examining its efficacy compared with symptomatic treatments (ChiCTR2100047830) and by evaluating objective biomarkers such as cerebrospinal fluid Aβ and tau levels (NCT05908695).

The mechanism of action of GV-971 includes reconditioning the gut microbiota, normalizing altered metabolites, reducing peripheral immune cell infiltration into the brain, decreasing neuroinflammation, and lowering Aβ and tau pathology [1]. One study reported that GV-971 disrupts the adherence of Rib^high-L.m. (a Lactobacillus murinus strain that highly expresses a gene encoding a putative adhesin containing Rib repeats) to gut epithelia via direct binding to Rib, which then corrects the excess lactate, reduces serum amyloid A, and alleviates T-helper 1 -skewed inflammation [37]. Moreover, research by Holtzman and Sisodia has demonstrated that GV-971 impacts the microbiota-microglia-amyloid pathway, reducing plaque formation and inflammatory markers in a sex-specific manner [38]. Additionally, a study by Aura Ferreiro highlighted the distinct gut microbiota profiles in individuals with preclinical AD, suggesting that gut-centric treatments such as GV-971 might help to alter AD pathology [39]. The Lancet has since recognized GV-971 as a potential disease-modifying therapy for its mechanism against neuroinflammation by restoring normal gut bacterial composition, and decreasing peripheral inflammatory cells [40].

A recent interim analysis of post-market GV-971 studies included microbiota evaluations from a subset of patients using 16S rRNA sequencing. The findings revealed notable differences in baseline microbiota composition between treatment-naïve and -non-naïve patients. In treatment-naïve individuals, researchers observed an increase in beneficial bacteria that produce short-chain fatty acids and a decrease in opportunistic pathogens, which may reflect the ability of GV-971 to alter the course of AD (unpublished data, Figure 1). This finding aligns with recent studies by Liping Zhao and his team, who identified a core microbiome structure composed of two competing bacterial communities: one beneficial and the other potentially harmful. They reported that these stable microbial communities are resilient to disruptions from factors such as dietary changes and disease, suggesting that targeting these stable communities may be a novel approach for maintaining or restoring health [41].

Figure 1

Competition between beneficial and opportunistic pathogenic bacteria. A hypothesis suggesting that gut microbiota may exist in a dynamic state is shown; shifts toward increased beneficial bacteria may improve conditions, whereas shifts toward harmful bacteria may worsen conditions.

David Holtzman has introduced the concept of a healthy versus AD-associated gut-brain axis, and proposed that the maintenance of gut microbiota balance is essential for brain health [42]. Factors such as aging, lifestyle, substance use, and stress can disrupt this balance, leading to systemic disorders from both metabolic and immune aspects, which can then negatively impact brain health. Consequently, restoring balance in an imbalanced gut microbiota might help to mitigate these effects and reduce neuroinflammation, metabolic disturbances, and AD progression (Figure 2).

Figure 2

Healthy gut-brain axis versus AD gut-brain axis [42]. The dysbiosis of gut microbiota may affect peripheral metabolism and immune function, which in turn regulate the innate immunity of the brain and AD progression. The eubiosis of gut microbiota may therefore help to adjust the process towards a healthy state.

5 Gut-Brain Axis Beyond Alzheimer’s Disease

The influence of the gut-brain axis extends well beyond AD. In 2017, Patrice Cani proposed that the gut microbiota might be “at the intersection of everything” given its connections to numerous health conditions [43]. Research has since demonstrated close links between gut microbiota and various neurological and metabolic diseases, including Parkinson’s disease, depression, autism, multiple sclerosis, and diabetes [44-48]. As a result, many researchers have explored gut-brain axis-targeted interventions across these conditions, with GV-971 serving as a prominent example. Studies of these interventions have revealed promising results, including the potential of such treatments to prevent severe acute pancreatitis, slow the progression of neuromyelitis optica, and reduce α-synuclein aggregation and associated pathology [49-51]. For example, gut-brain axis dysfunction in AD and stroke can lead to the production of abnormal metabolites, which can then leak into the bloodstream and trigger neuroinflammation through peripheral immune abnormalities [52]. This shared pathway contributes to cognitive decline, indicating that gut-brain axis-targeted therapies may also benefit individuals with post-stroke cognitive impairment [52]. Additionally, conditions such as diabetes and hypertension have been associated with gut microbiota imbalances, which in turn are linked to cognitive impairment [53-56]. Given the critical role of the gut-brain axis in these processes, it may therefore be time to view the gut-brain axis as a central player in overall cognitive health and disease prevention (Figure 3).

Figure 3

Gut-brain axis—at the intersection of all cognition? Here, we have further extended Patrice Cani’s theory of “Gut microbiota—at the intersection of everything?” to include cognitive impairment. Numerous studies indicate that the gut microbiota is affected in a wide range of pathological conditions. Moreover, beyond disorders of the central nervous system, many other systemic diseases have been linked to cognitive impairment or its risk factors. Notably, the gut microbiota has been identified as a key player in the cognitive decline associated with these conditions. Targeting the gut-brain axis therefore presents a promising strategy for treating cognitive impairment across various diseases.

6 Conclusions and Perspectives

Although we have faced both considerable challenges and noteworthy progress in the journey of AD research and development, we remain steadfast in our efforts. Notably, these obstacles and breakthroughs have prompted us to reassess the underlying pathological mechanisms and treatment strategies for AD through a more comprehensive lens. The gut-brain axis may play a crucial role in AD, and further research is needed to explore this concept. First, it is imperative to assess the effectiveness of GV-971 for addressing subjective cognitive decline and mild cognitive impairment. Second, there has been a notable surge to target inflammation within the AD drug development pipeline [27]. Targeting the gut-brain axis holds promise for mitigating neuroinflammation and even systemic inflammation [37, 40, 42]. Thus, this approach will not only advance therapeutic strategies for AD, but will also open up avenues for exploration in other inflammatory-related diseases and/or cognitive disorders.