Gut microbiome alterations in preclinical Alzheimer's disease

Abstract

Background: Although some human studies have reported gut microbiome changes in individuals with Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI), gut microbiome alterations in preclinical AD, i.e., cerebral amyloidosis without cognitive impairment, is largely unknown.

Objective: We aimed to identify gut microbial alterations associated with preclinical AD by comparing cognitively normal (CN) older adults with cerebral Aβ deposition (Aβ+ CN) and those without cerebral Aβ deposition (Aβ- CN).

Methods: Seventy-eight CN older participants (18 Aβ+ CN and 60 Aβ- CN) were included, and all participants underwent clinical assessment and Pittsburg compound B-positron emission tomography. The V3-V4 region of the 16S rRNA gene of genomic DNA extracted from feces was amplified and sequenced to establish the microbial community.

Results: Generalized linear model analysis revealed that the genera Megamonas (B = 3.399, q<0.001), Serratia (B = 3.044, q = 0.005), Leptotrichia (B = 5.862, q = 0.024) and Clostridium (family Clostridiaceae) (B = 0.788, q = 0.034) were more abundant in the Aβ+ CN group than the Aβ- CN group. In contrast, genera CF231 (B = -3.237, q< 0.001), Victivallis (B = -3.447, q = 0.004) Enterococcus (B = -2.044, q = 0.042), Mitsuokella (B = -2.119, q = 0.042) and Clostridium (family Erysipelotrichaceae) (B = -2.222, q = 0.043) were decreased in Aβ+ CN compared to Aβ- CN. Notably, the classification model including the differently abundant genera could effectively distinguish Aβ+ CN from Aβ- CN (AUC = 0.823).

Conclusion: Our findings suggest that specific alterations of gut bacterial taxa are related to preclinical AD, which means these changes may precede cognitive decline. Therefore, examining changes in the microbiome may be helpful in preclinical AD screening.

Fig 1. Log predicted counts of the genera associated with Aβ positivity.

Prediction was made using GLM analysis adjusted for age, gender, BMI, APOE4 positivity. Only genera with q <0.05 are shown. Abbreviation. Aβ: amyloid beta; GLM: generalized linear model; Aβ+ CN: cognitively normal participants with amyloid retention Aβ− CN: cognitively normal participants without amyloid retention; APOE4: apolipoprotein E ε4; BMI: body mass index.

Fig 2. Receiver operating characteristic (ROC) curve analysis of the multivariate logistic model to detect preclinical AD using microbiome.

The blue line represents the model with the presence or absence of nine genera revealed from the GLM analysis and covariates (i.e., age, sex, APOE4 positivity and BMI), while a green line represents the reference model including only the covariates. Abbreviation. AD: Alzheimer’s disease; APOE4: apolipoprotein E ε4; BMI: body mass index.

Fig 3. Relative differences in predicted gene contents in microbiome between Aβ− CN participants and Aβ+ CN participants.

Abbreviations. Aβ+ CN: cognitively normal participants with amyloid retention Aβ− CN: cognitively normal participants without amyloid retention.