Microbiota and Alzheimer’s disease: toward new clinical approaches
Keywords:
Alzheimer’s Disease, APOE, Neuroinflammation, Microbiota, Short-chain fatty acide, Probiotics
Abstract
Alzheimer’s disease (AD) is now viewed as a systemic disorder in which genetics, the gut microbiome and immune dysregulation converge to accelerate amyloid-β (Aβ) and tau pathology. Genetic studies have identified 70 risk loci. APOE ε4 is the strongest AD risk loci, conferring dose-dependent risk through impaired cholesterol trafficking, reduced Aβ clearance and heightened neuroinflammation. Rare mutations in TREM2 and CD33 further illustrate the centrality of microglia-mediated innate immunity. Importantly, peripheral Th17 skewing, neutrophil hyper-activation and loss of regulatory myeloid cells amplify neuroinflammation. Growing evidence links gut dysbiosis to these genetic factors. APOE ε4 carriers show depletion of Short-Chain Fatty Acids (SCFA)-producing taxa (Gemmiger, Roseburia, Faecalibacterium) and enrichment of pro-inflammatory Proteobacteria (Escherichia/Shigella, Morganella). In mice, APOE4-dependent loss of butyrate-producing bacteria lowers colonic and serum SCFA levels and worsens tauopathy, whereas Germ-free housing, early antibiotics and SCFA supplementation rescue pathology. Large meta-analyses correlate Collinsella and Veillonella with higher AD risk, and Eubacterium nodatum and Prevotella 9 with protection. Metabolomic shifts mirror these compositional changes: acetate, propionate and butyrate, as well as trimethylamine N-oxide (TMAO) promote epigenetic regulation, blood–brain-barrier (BBB) integrity and microglial homeostasis, whereas secondary bile acids compromise cognition. The microbial amyloids and lipopolysaccharide can cross-seed Aβ, activate the NLRP3 inflammasome, and breach the blood-brain barrier. Intermittent fasting, ketogenic diets, specific probiotics (Bifidobacterium breve A1, Lacticaseibacillus rhamnosus CBT-LR5), sodium oligomannate (GV-971) or fecal microbiota transplantation can remodel gut ecology, raise beneficial SCFAs, dampen pro-inflammatory cytokines and improve cognition in patients with AD or mild cognitive impairment. Collectively, the data support a gut–immune system-brain axis in which host genotype shapes microbiota, and microbial metabolites or antigens contribute to neurodegeneration. Future work must define responder phenotypes, optimise next-generation probiotics and integrate multi-omics profiling with biomarker-driven clinical trials to translate microbiota modulation into disease-modifying therapy for AD.
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2. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2018 Apr;14(4):535–62.
3. Jack CR, Andrews JS, Beach TG, Buracchio T, Dunn B, Graf A, et al. Revised criteria for diagnosis and staging of Alzheimer’s disease: Alzheimer’s Association Workgroup. Alzheimers Dement J Alzheimers Assoc. 2024 Aug;20(8):5143–69.
4. Sherrington R, Froelich S, Sorbi S, Campion D, Chi H, Rogaeva EA, et al. Alzheimer’s Disease Associated with Mutations in Presenilin 2 is Rare and Variably Penetrant. Hum Mol Genet. 1996 Jul 1;5(7):985–8.
5. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991 Feb;349(6311):704–6.
6. Tcw J, Goate AM. Genetics of β-Amyloid Precursor Protein in Alzheimer’s Disease. Cold Spring Harb Perspect Med. 2017 Jun 1;7(6):a024539.
7. Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem. 2008 Oct 31;283(44):29615–9.
8. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977–81.
9. Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet. 2022 Apr;54(4):412–36.
10. Shore VG, Shore B. Heterogeneity of human plasma very low density lipoproteins. Separation of species differing in protein components. Biochemistry. 1973 Jan 30;12(3):502–7.
11. Huang Y, Weisgraber KH, Mucke L, Mahley RW. Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer’s disease. J Mol Neurosci MN. 2004;23(3):189–204.
12. Han X. The role of apolipoprotein E in lipid metabolism in the central nervous system. Cell Mol Life Sci CMLS. 2004 Aug;61(15):1896–906.
13. Xia Z, Prescott EE, Urbanek A, Wareing HE, King MC, Olerinyova A, et al. Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease. Nat Commun. 2024 Jun 1;15(1):4695.
14. Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med. 2015 Mar 9;212(3):287–95.
15. Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A, et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci. 2013 Jul;16(7):848–50.
16. Bhattacherjee A, Jung J, Zia S, Ho M, Eskandari-Sedighi G, St Laurent CD, et al. The CD33 short isoform is a gain-of-function variant that enhances Aβ1-42 phagocytosis in microglia. Mol Neurodegener. 2021 Mar 25;16(1):19.
17. Griciuc A, Patel S, Federico AN, Choi SH, Innes BJ, Oram MK, et al. TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer’s Disease. Neuron. 2019 Sep 4;103(5):820-835.e7.
18. Tran TTT, Corsini S, Kellingray L, Hegarty C, Le Gall G, Narbad A, et al. APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer’s disease pathophysiology. FASEB J Off Publ Fed Am Soc Exp Biol. 2019 Jul;33(7):8221–31.
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