Listen to Your Gut. It Might Signal Early Alzheimer’s Disease.

Some researchers have found that, compared to healthy older adults, people who have Alzheimer’s disease harbor unique flora in their guts. So too, do people with preclinical AD, say researchers led by Gautam Dantas and Beau Ances at Washington University in St. Louis. In the June 14 Science Translational Medicine, they reported that, among 164 cognitively normal older adults, certain gut bacteria correlated with markers of amyloid plaques and neurofibrillary tangles. When combined with demographics, biomarkers, and genetic risk scores, microbiome data even improved the identification of those who had preclinical AD. The work supports the idea that changes to the microbiome might accompany even the earliest AD pathology.

  • People who have preclinical AD have an altered gut microbiome.
  • Prevalence of certain microbes correlated with plaque and tangle load.
  • Measuring specific bacteria species improved diagnosis of preclinical AD.

“An association with preclinical disease minimizes concern for reverse causation, which plagues cross-sectional studies of the gut microbiome,” wrote Andrew Chan, Massachusetts General Hospital, Charlestown. Previous associations with AD might be because symptoms of the disease, or its management, affect the microbiome rather than the gut microbiome being a causal factor, he noted.

Scientists have reported that gut bacteria seem to influence AD pathology, at least in animals. Inoculating a mouse model of amyloidosis and tauopathy with microbes from wild-type mice reduced plaque and tangle load, calmed reactive glia, and improved cognition (Kim et al., 2020). Likewise, tauopathy mice raised in a germ-free environment had fewer tangles than their microbe-rich counterparts (Jan 2023 news). What about in humans? People with symptomatic AD carry more Bacteroidetes and fewer Firmicutes species than cognitively normal adults, and these changes correlate with CSF Aβ42/40 ratios and phosphotau-181 levels (Vogt et al., 2017).

To find out what the gut microbiome looks like in preclinical AD, first author Aura Ferreiro analyzed stool samples from 164 cognitively normal adults ages 68 to 94 from the Knight AD Research Center cohort. Of those, 49 had preclinical AD, as deemed by a CSF Aβ42/40 ratio below 0.0673 or amyloid PET Centiloid value above 16.4. Stool samples were collected an average of 2.5 years before or after lumbar puncture or PET scan. Because diet drastically influences the gut microbiome, the researchers compared 24-hour food diaries from all participants, finding no major differences in calorie intake or consumption of macronutrients, vitamins, or minerals between the preclinical AD and controls at a group level.

Genomic sequencing of stool samples detected more Bacteroidetes and fewer Firmicutes species in people with preclinical AD, just as in those with symptomatic disease. However, the difference was not statistically significant. Seven other bacteria species did make the cut, appearing more or less often in people with preclinical AD: Dorea formicigenerans, Oscillibacter sp. 57_20, Faecalibacterium prausnitzii, Coprococcus catus, Anaerostipes hadrus, Ruminococcus lactaris, and Methanosphaera stadtmanae.

The prevalence of these bacteria also correlated with AD pathology, associating with amyloid and tau PET load but not with markers of neurodegeneration, namely CSF total tau, cortical and hippocampal volume, or white-matter hyperintensities. To the authors, this means that changes in the gut microbiome happen early in AD before neurodegeneration begins.

Microbiota data even helped predict who had preclinical AD. A machine-learning algorithm more accurately identified people with the disease when accounting for the prevalence of the seven bacterial species than when only demographics, polygenic risk score, ApoE4 status, biomarkers of AD pathology, or any combination of those were used (see image below). For example, adding microbe data to all types of biomarkers nudged accuracy from 0.985 to 0.999, while adding it to clinical and genetic data bumped accuracy from 0.706 to 0.755. The authors believe analyzing stool samples could aid in screening people for AD, helping identify those who should go on to have a lumbar puncture or PET scan.

Others agreed. “This [work] suggests that the microbiome could be used as an additional biomarker that is less expensive and invasive than a lumbar puncture,” wrote Steve Estus and Diana Zajac, University of Kentucky, Lexington. Jacob Raber of Oregon Health and Science University in Portland thinks that these microbes may also be a substitute for PET scans when they are unavailable. “Gut microbiome analysis might especially help when there is reduced or unequal access to imaging technologies,” he wrote.

Improving Diagnostic Accuracy. Including the prevalence of certain gut bacteria (green) improved the accuracy of most models used to diagnose preclinical AD, including clinical variables only (CC), clinical information plus polygenic risk score and ApoE4 status (CC + G), those plus biomarkers of neurodegeneration, tau, and amyloid (All), or all the markers minus Ab (All – A). [Courtesy of Ferreiro et al., Science Translational Medicine 2023.]

Another group of bacteria caught the researchers’ attention. Some species of Bacteroides, a subset of the Bacteroidetes phylum, were depleted in people with preclinical AD yet enriched in the healthy. Recently, Weifei Luo and Shuai Wang of China’s Guangxi Academy of Sciences reported that centenarians carried an abundance of Bacteroides, some even being the same species enriched in the healthy from Ferreiro’s study (Pang et al., 2023). “[Both] findings suggest that Bacteroides play a central role in maintaining gut homeostasis, and its dysbiosis might be involved in aging-related disease processes, such as AD,” Wang wrote to Alzforum. However, others have found the opposite, that people 85 and older carrying high levels of Bacteroides died sooner than those with low levels of the bacteria (Mar 2021 news).

Ances told Alzforum they are currently analyzing samples taken over time from the preclinical AD participants, as well as the microbiomes of people with mild to moderate AD, to track longitudinal changes in gut bacteria as AD progresses. They are also seeing how the gut microbiome correlates with plasma AD markers.—Chelsea Weidman Burke

Comments

  1. Ferreiro et al. have evaluated the microbiome in a series of preclinical AD and non-AD individuals. They report significant differences in beta diversity and identify differential taxa that improve preclinical AD prediction. Overall, this suggests that the microbiome could be used as an additional biomarker that is less expensive and invasive than lumbar puncture. Hence, their suggestion to include gut health assessments as a risk factor for chronic diseases (at least those associated with chronic inflammation) has merit and may help move the field forward. We agree and urge research and clinicians to further explore gut health as a measure of disease risk.

    View all comments by Steven Estus View all comments by Diana Zajac

  2. In this study, Ferreiro et al. provide evidence that in cognitively healthy individuals (68-94 years old) there are gut microbiome correlates of preclinical AD neuropathology (Aβ and tau biomarkers, but not markers of neurodegeneration) and that inclusion of microbiome features associated with preclinical AD improves prediction of preclinical AD status. While the α-diversity (i.e., within-sample diversity) was not different between the two groups, a principle components analysis (PCA) revealed global differences in gut taxonomic profiles by preclinical status, and measures of PET imaging of Aβ plaques correlated with a principle component.

    Species most associated with preclinical AD status included Dorea formicigenerans, Oscillibacter sp. 57_20, Faecalibacterium prausnitzii, Coprococcus catus, Anaerostipes hadrus, and Ruminococcus lactaris, whereas Methanosphaera stadtmanae was associated with the cognitively healthy. These taxa were also identified as important features in Random Forest classifiers for preclinical AD status.

    The microbial pathways most strongly associated with preclinical AD status included that involved in arginine and ornithine degradation, a pathway involving succinate, which is associated with obesity and inflammatory bowel disease and is a precursor of the short-chain fatty acid (SCFA) propionate, which is elevated in symptomatic AD and in AD mouse models. The pathway most associated with healthy status was glutamate degradation, which involves the SCFA acetate, which protects against cognitive impairments in mice and inhibits Ab aggregation in vitro. However, acetate is also associated with an elevated Aβ standardized uptake value ratio in PET scans (Marizzoni et al., 2020). 

    When Aβ PET and CSF Aβ42/Aβ40 were omitted from the model, inclusion of the selected taxa offered significant improvements in specificity, suggesting that the gut microbiome analysis might especially help when there is reduced/unequal access to imaging technologies.

    A limitation of this study is that the mean interval between stool sampling and PET imaging or lumbar puncture for quantification of Aβ and tau was 2.4 and 2.8 years, respectively. Another limitation of this study is that participant nutritional profiles were limited to 24-hour diet logs. It is conceivable that gut microbiome signatures based on diet and lifestyle are not necessarily captured this way.

    The results of this study are consistent with the fact that the human gut microbiome diversifies with age, reflects healthy versus unhealthy aging, is associated with a healthy lipid profile, predicts survival (Wilmanski et al., 2021), and that alterations in microbiome composition link to AD and impact AD-associated behaviors and brain pathologies (Kundu et al., 2022; Kundu et al., 2021; Marizzoni et al., 2020). Together with others on  the role of the gut microbiome in AD and AD mouse models (Kundu et al., 2022; Kundu et al., 2021), this study also suggests that the gut microbiome might play a critical role in both AD and Parkinson’s disease (Santos et al., 2019; Elfil et al., 2020; Keshvarzian et al., 2020; Koutzoumis et al., 2020; Sampson et al., 2016; Torres et al., 2018). 

    Since beneficial interventions in AD will likely need to start relatively early and be safe and affordable, future studies are warranted to assess the role of the gut microbiome as an early biomarker and therapeutic target, and possibly even as an origin of AD.

    References:

    Marizzoni M, Cattaneo A, Mirabelli P, Festari C, Lopizzo N, Nicolosi V, Mombelli E, Mazzelli M, Luongo D, Naviglio D, Coppola L, Salvatore M, Frisoni GB. Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer's Disease. J Alzheimers Dis. 2020;78(2):683-697. PubMed.

    Wilmanski T, Diener C, Rappaport N, Patwardhan S, Wiedrick J, Lapidus J, Earls JC, Zimmer A, Glusman G, Robinson M, Yurkovich JT, Kado DM, Cauley JA, Zmuda J, Lane NE, Magis AT, Lovejoy JC, Hood L, Gibbons SM, Orwoll ES, Price ND. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab. 2021 Feb;3(2):274-286. Epub 2021 Feb 18 PubMed.

    Kundu P, Stagaman K, Kasschau K, Holden S, Shulzhenko N, Sharpton TJ, Raber J. Fecal Implants From App NL-G-F and App NL-G-F/E4 Donor Mice Sufficient to Induce Behavioral Phenotypes in Germ-Free Mice. Front Behav Neurosci. 2022;16:791128. Epub 2022 Feb 8 PubMed.

    Kundu P, Torres ER, Stagaman K, Kasschau K, Okhovat M, Holden S, Ward S, Nevonen KA, Davis BA, Saito T, Saido TC, Carbone L, Sharpton TJ, Raber J. Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice. Sci Rep. 2021 Feb 25;11(1):4678. PubMed.

    Santos SF, de Oliveira HL, Yamada ES, Neves BC, Pereira A Jr. The Gut and Parkinson's Disease-A Bidirectional Pathway. Front Neurol. 2019;10:574. Epub 2019 Jun 4 PubMed.

    Elfil M, Kamel S, Kandil M, Koo BB, Schaefer SM. Implications of the Gut Microbiome in Parkinson's Disease. Mov Disord. 2020 Jun;35(6):921-933. Epub 2020 Feb 24 PubMed.

    Keshavarzian A, Engen P, Bonvegna S, Cilia R. The gut microbiome in Parkinson's disease: A culprit or a bystander?. Prog Brain Res. 2020;252:357-450. Epub 2020 Mar 5 PubMed.

    Koutzoumis DN, Vergara M, Pino J, Buddendorff J, Khoshbouei H, Mandel RJ, Torres GE. Alterations of the gut microbiota with antibiotics protects dopamine neuron loss and improve motor deficits in a pharmacological rodent model of Parkinson's disease. Exp Neurol. 2020 Mar;325:113159. Epub 2019 Dec 13 PubMed.

    Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016 Dec 1;167(6):1469-1480.e12. PubMed.

    Torres ER, Akinyeke T, Stagaman K, Duvoisin RM, Meshul CK, Sharpton TJ, Raber J. Effects of Sub-Chronic MPTP Exposure on Behavioral and Cognitive Performance and the Microbiome of Wild-Type and mGlu8 Knockout Female and Male Mice. Front Behav Neurosci. 2018;12:140. Epub 2018 Jul 18 PubMed.

    View all comments by Jacob Raber

  3. In this paper by Aura et al., the authors report changes in the gut microbiome that correlated with pathological biomarkers, but not with biomarkers for neurodegeneration, and thus the result suggests that the gut microbiome may change early in the disease process.

    Specific bacterial taxa associated with preclinical AD were also identified in the study. Among these taxa that may be involved in the early disease process and may predict AD risk, the genus Bacteroides are markedly decreased in the preclinical group,is, B. vulgatus, B. caccae, and B. stercoris are highly associated with preclinical or health status (Fig. 3). This is interesting because this finding is in line with our previous observations reported in  Nature Aging (Pang et al., 2023). We also found that Bacteroides spp. differentiate long-lived individuals from other old individuals, and that they are enriched in the intestines of centenarians. All these findings suggest that Bacteroides play a central role in maintaining gut homeostasis and that its dysbiosis might be involved in aging-related disease processes, e.g., AD.

    References:

    Pang S, Chen X, Lu Z, Meng L, Huang Y, Yu X, Huang L, Ye P, Chen X, Liang J, Peng T, Luo W, Wang S. Longevity of centenarians is reflected by the gut microbiome with youth-associated signatures. Nat Aging. 2023 Apr;3(4):436-449. Epub 2023 Apr 6 PubMed.

    View all comments by Shuai Wang

  4. This study provides some very intriguing evidence about the potential influence of the gut microbiome in the development and progression of Alzheimer’s disease.

    One of the strengths of the study is the finding of an association between gut microbiome features and preclinical disease, which strengthens the potential that the association is truly causal. An association with preclinical disease minimizes concern for reverse causation, which plagues cross-sectional studies of the gut microbiome. In other words, previous studies that have shown associations between the gut microbiome and clinically diagnosed Alzheimer’s disease may be because symptoms of the disease, or its management, affect the gut microbiome, rather than the gut microbiome being a causal factor in disease development.

    This work also lays the groundwork for potential use of the gut microbiome as a biomarker of Alzheimer’s disease in the future.

    View all comments by Andrew Chan

  5. The centenarian study by Pang and colleagues essentially agrees with our prior results, even though this data comes from a population in a different part of the world (Mar 2021 news). They do indeed see a drop in Bacteroides in older people (up to ~80-90 years old). That's what we saw too. What's new is that they see a slight increasing trend in Bacteroides in centenarians, whom we didn’t have in our study. Even that, though, may not be such a difference, because they still see decreasing Bacteroides in healthy participants. Thus, the signal of increased Bacteroides is largely driven by less-than-healthy centenarians (which of course becomes the norm at that advanced age). In our study, we emphasized that this trend held up only for those deemed healthy by various criteria.

    The paper by Ferreiro and colleagues is very interesting, but again the differences in the Bacterioides trends seem explainable and make sense. However, it is important to consider that chronic constipation often precedes neurodegeneration. Sean Gibbons at ISB has recently analyzed bowel movement frequency and how it impacts the microbiome (Johnson et al., 2023). His group found that Bacteroides depletes with constipation. So, the aging signal we saw, which was itself independent of bowel movement frequency, could be confounded with an overlapping disease signal. In general, it is important to distinguish clearly between associations that are disease-related and those related to aging.

    View all comments by Nathan Price

  6. The centenarian study is completely consistent with our aging paper (Mar 2021 news). As for the AD paper, it's important not to conflate aging-related disease with signatures of healthy aging. It is too bad the authors did not measure transit time, bowel movement frequency, or Bristol stool scores, because these factors are known to influence the composition of the gut microbiome (Asnicar et al., 2021) and chronic constipation is a risk factor for neurodegenerative disorders (Stirpe et al., 2016). 

    Several papers have shown associations between chronic constipation and neurodegeneration, but I don't know if this has been shown in presymptomatic patients. I'm guessing that if Ferreiro and colleagues had measured it, they would have found that presymptomatic patients tended to suffer from constipation much more frequently than the background population. Constipation is associated with a switch from saccharolytic fermentation to protein fermentation by the gut microbiota, which can increase blood levels of toxic microbial metabolites, such as p-cresol or trimethylamine-N-oxide (Johnson et al., 2023). It’s possible that such a shift explains at least some of the associations between gut flora and with markers of AD pathology.

    References:

    Asnicar F, Leeming ER, Dimidi E, Mazidi M, Franks PW, Al Khatib H, Valdes AM, Davies R, Bakker E, Francis L, Chan A, Gibson R, Hadjigeorgiou G, Wolf J, Spector TD, Segata N, Berry SE. Blue poo: impact of gut transit time on the gut microbiome using a novel marker. Gut. 2021 Sep;70(9):1665-1674. Epub 2021 Mar 15 PubMed.

    Stirpe P, Hoffman M, Badiali D, Colosimo C. Constipation: an emerging risk factor for Parkinson's disease?. Eur J Neurol. 2016 Nov;23(11):1606-1613. Epub 2016 Jul 22 PubMed.

    Johnson JP, Diener C, Levine AE, Wilmanski T, Suskind DL, Ralevski A, Hadlock J, Magis AT, Hood L, Rappaport N, Gibbons SM. Generally-healthy individuals with aberrant bowel movement frequencies show enrichment for microbially-derived blood metabolites associated with impaired kidney function. bioRxiv. 2023 Mar 6; PubMed.

    View all comments by Sean Gibbons

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References

News Citations

  1. Meddling Microbiome Worsens Tauopathy and Neurodegeneration
  2. Shape Your Microbiome. You’ll Live Longer, Scientists Say

Paper Citations

  1. Kim MS, Kim Y, Choi H, Kim W, Park S, Lee D, Kim DK, Kim HJ, Choi H, Hyun DW, Lee JY, Choi EY, Lee DS, Bae JW, Mook-Jung I. Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model. Gut. 2020 Feb;69(2):283-294. Epub 2019 Aug 30 PubMed.
  2. Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S, Zetterberg H, Blennow K, Bendlin BB, Rey FE. Gut microbiome alterations in Alzheimer's disease. Sci Rep. 2017 Oct 19;7(1):13537. PubMed.
  3. Pang S, Chen X, Lu Z, Meng L, Huang Y, Yu X, Huang L, Ye P, Chen X, Liang J, Peng T, Luo W, Wang S. Longevity of centenarians is reflected by the gut microbiome with youth-associated signatures. Nat Aging. 2023 Apr;3(4):436-449. Epub 2023 Apr 6 PubMed.

Further Reading

Primary Papers

  1. Ferreiro AL, Choi J, Ryou J, Newcomer EP, Thompson R, Bollinger RM, Hall-Moore C, Ndao IM, Sax L, Benzinger TL, Stark SL, Holtzman DM, Fagan AM, Schindler SE, Cruchaga C, Butt OH, Morris JC, Tarr PI, Ances BM, Dantas G. Gut microbiome composition may be an indicator of preclinical Alzheimer's disease. Sci Transl Med. 2023 Jun 14;15(700):eabo2984. PubMed.

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