Gut microbiome dysbiosis in early Alzheimer’s disease and mild cognitive impairment: a systematic review

Introduction

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide, affecting approximately 55 million people, projected to reach 139 million by 2050. Classical pathophysiology centres on amyloid-beta (Aβ) plaque deposition and tau-related neurofibrillary tangle formation; however, Aβ-clearing therapies slow progression by only approximately 35%, implicating peripheral mechanisms. Growing evidence links gut microbiome dysbiosis to AD pathogenesis via the microbiota-gut-brain axis. Whether these changes are detectable in early AD and mild cognitive impairment (MCI) remains unresolved.

Aims

To synthesise evidence from case-control studies examining gut microbiome composition in early AD and MCI versus age-matched healthy controls, characterising diversity indices, taxonomic shifts at phylum and genus level, and associated short-chain fatty acid (SCFA) metabolic changes.

Methods

A systematic search was conducted across PubMed, Embase, Scopus, and Cochrane Library using terms including Alzheimer’s disease, gut microbiome, 16S rRNA, and short-chain fatty acids. Twelve studies were included (case-control, cross-sectional, and meta-analytic designs). Inclusion required human adult participants with diagnosed AD or MCI; microbiome characterisation by 16S ribosomal RNA sequencing or shotgun metagenomics; and reporting of diversity or taxon abundance outcomes. Quality was assessed with the Newcastle-Ottawa Scale and AMSTAR-2. Owing to methodological heterogeneity, findings were synthesised narratively with reference to reported effect sizes.

Results

Across 12 studies representing 679 AD/MCI cases and 632 controls, alpha diversity was significantly reduced in AD in the majority of studies (Shannon index reduction in >70% of primary studies [1,2]). Beta diversity was consistently distinct between groups (p < 0.05 in all studies reporting permutational multivariate analysis of variance). Key taxonomic findings are summarised in Table 1.

Table 1. Key gut microbiome changes in early AD and MCI versus healthy controls

Phylum / genus	Direction in AD	Key metabolite link	Note
Firmicutes (Faecalibacterium, Lachnospiraceae, Ruminococcus)	Decreased	Butyrate ↓	Consistent across cohorts; correlates with MMSE decline
Proteobacteria (Escherichia / Shigella)	Increased	LPS ↑, ROS ↑	Associated with blood-brain barrier disruption
Bacteroidetes	Geography-dependent	Propionate ↓ (disease group)	Increased in US cohorts (SMD 0.75); decreased in Chinese cohorts (SMD −0.79) [1]
Phascolarctobacterium	Increased (MCI stage only)	—	Potential stage-specific early biomarker [1]

Faecalibacterium prausnitzii declined progressively with disease severity (p < 0.01) [2]. Elevated trimethylamine N-oxide was detected in cerebrospinal fluid of AD patients versus controls. MCI-stage dysbiosis, including elevation of Phascolarctobacterium, was identifiable prior to established dementia [1], and animal data suggest microbiome alterations precede amyloid deposition [3].

Conclusions

Gut microbiome dysbiosis is a consistent, early feature of AD, detectable in the MCI prodrome and characterised by reduced alpha diversity, depleted butyrate-producing Firmicutes, and enriched pro-inflammatory Proteobacteria. These changes are plausible mediators of neuroinflammation via lipopolysaccharide translocation, microglial activation, and blood-brain barrier disruption. Geographic heterogeneity and methodological variability across sequencing platforms and dietary controls currently preclude diagnostic application. Findings warrant cautious interpretation given cross-sectional designs and limited polypharmacy control. Longitudinal cohorts with standardised multi-omics methodology remain the priority before microbiome signatures can inform clinical practice.

References

References

1. Jemimah, S., Chabib, C.M.M., Hadjileontiadis, L., AlShehhi, A., 2023. Gut microbiome dysbiosis in Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis. PLoS ONE 18 (5), e0285346.
2. Hung, C.C., Chang, C.C., Huang, C.W., Nouchi, R., Cheng, C.H., 2022. Gut microbiota in patients with Alzheimer’s disease spectrum: a systematic review and meta-analysis. Aging (Albany NY) 14, 477–496.
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