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Neurofibrillary tangles (NFT) is one of the hallmarks of Alzheimer’s disease (AD). Recent research suggests that pretangle tau, the soluble precursor of NFT, is an initiator for AD pathogenesis, thus targeting pretangle tau pathology may be a promising early intervention focus. The bidirectional communications between the gut and the brain play a crucial role in health. The compromised gut-brain axis is involved in various neurodegenerative diseases including AD. However, most research on the relationship between gut microbiome and AD have focused on amyloid-β. In this mini review, we propose to target preclinical pretangle tau stages with gut microbiota interventions such as probiotic supplementation. We discuss the importance of targeting pretangle tau that starts decades before the onset of clinical symptoms, and potential intervention focusing on probiotic regulation of tau hyperphosphorylation. A particular focus is on GSK-3β, a protein kinase that is at the interface between tau phosphorylation, AD and diabetes mellitus.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, characterized by the presence of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) formed from abnormally phosphorylated tau proteins (ptau). To date, there is no cure for AD. Earlier therapeutic efforts have focused on the clinical stages of AD. Despite paramount efforts and costs, pharmaceutical interventions including antibody therapies targeting Aβ have largely failed. This highlights the need to alternate treatment strategies and a shift of focus to early pre-clinical stages. Approximately 25–40% of AD cases can be attributed to environmental factors including chronic stress. Gut dysbiosis has been associated with stress and the pathogenesis of AD and can increase both Aβ and NFTs in animal models of the disease. Both stress and enrichment have been shown to alter AD progression and gut health. Targeting stress-induced gut dysbiosis through probiotic supplementation could provide a promising intervention to delay disease progression. In this review, we discuss the effects of stress, enrichment, and gut dysbiosis in AD models and the promising evidence from probiotic intervention studies.