Can Alzheimer's be detected in the gut microbiome before cognitive impairment appears?

An altered gut microbiome may precede the clinical signs of Alzheimer's disease. Can the gut microbiome be used as an early biomarker?

Gut microbiome appears to change early in the disease process

The gastrointestinal tract harbours approximately 500 million enteric neurons, 70% of the body's immune cells and over 100 trillion microbes.4 Although the profile of each person's microbiota is different, the relative abundance and distribution of gut bacterial phylotypes are similar in healthy individuals. The two most important are Firmicutes and Bacteroides, which make up at least three quarters of the microbiome. This microbial community has important metabolic and physiological functions for the host and contributes to its homeostasis during life.5

A recent cross-sectional study published in Science Translational Medicine investigated the composition and function of the gut microbiome in a cohort of 164 cognitively normal individuals aged 68 to 94 years, 49 of whom had biomarkers for preclinical Alzheimer's disease. Clinical factors and diet were also taken into account.

The microbiomes of the individuals with evidence of preclinical Alzheimer's disease on cerebral imaging differed from the rest of the participants in many of the bacterial species present. This indicated that their microbiomes were also likely to function differently at a metabolic level. Altered gut microbiome composition correlated with amyloid-β plaques and tau accumulation in the brain, but not with biomarkers of neurodegeneration, suggesting that the gut microbiome changes early in the disease process.

Potential use of the gut microbiome as an early biomarker and therapeutic target

The inclusion of these microbiome features improved the accuracy, sensitivity and specificity of a model for predicting preclinical Alzheimer's disease status. Surprisingly, it is the first study to date to analyse the gut microbiome of people in the earliest stages of the disease.

"Science still has a long way to go before we know whether specific dietary changes can alter the gut microbiome and modify its impact on the brain in the right way," says the Director's Blog of the US National Institutes of Health (NIH), which funded the study.6 The exciting thing about this finding is the possibility of one day being able to use a stool sample to test whether a patient's gut microbiome correlates with an increased risk of Alzheimer's dementia. Such a test could help to recognise Alzheimer's earlier and intervene earlier to stop the disease.

The gut-brain axis is bidirectional

The team is now conducting a longitudinal study over 5 years to find out more precisely whether the differences observed in the gut microbiome are a cause or a consequence of the neuropathologies observed in Alzheimer's disease. This is because the gut-brain axis connects emotional and cognitive centres of the brain bidirectionally with peripheral gut functions: The microorganisms in the gut and their metabolites send neural, endocrine, immunological and humoral signals to the brain, but impulses also flow from the brain to the enteric nervous system and microbiome. The central nervous system and in particular the hypothalamic-pituitary-adrenal (HPA) axis can be activated in response to environmental factors such as emotions or stress. Via afferent and efferent autonomic pathways, these signals are transmitted to various targets in the gut, such as the enteric nervous system, muscle layers and intestinal mucosa, modulating motility, immunity, permeability and mucus secretion.5

The role of these interactions is also increasingly becoming the focus of research in other neurological diseases. For example, dysbiosis has already been linked to Parkinson's disease, autism, anxiety, depression and irritable bowel syndrome.5 A better understanding of these changes could enable new targeted therapies. If altered gut flora is a cause of Alzheimer's disease, a promising therapeutic target could be dietary interventions and specially formulated probiotics or faecal transplants that promote the growth of "good" bacteria over "bad" bacteria in the gut.6

Sources
  1. 2020 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia 16, 391–460 (2020).
  2. Vogt, N. M. et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep 7, 13537 (2017).
  3. Ferreiro, A. L. et al. Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease. Science Translational Medicine 15, eabo2984 (2023).
  4. Yu, C. D., Xu, Q. J. & Chang, R. B. Vagal sensory neurons and gut-brain signaling. Curr Opin Neurobiol 62, 133–140 (2020).
  5. Carabotti, M., Scirocco, A., Maselli, M. A. & Severi, C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 28, 203–209 (2015).
  6. Ph.D, L. T., D. D. S. Changes in Human Microbiome Precede Alzheimer’s Cognitive Declines. NIH Director’s Blog https://directorsblog.nih.gov/2023/06/27/changes-in-human-microbiome-precede-alzheimers-cognitive-declines/ (2023).