Abstract
BackgroundPlasma amyloid-β (Aβ) may facilitate identification of individuals with brain amyloidosis. Gut microbial dysbiosis in Alzheimer’s disease (AD) is increasingly being recognized. However, knowledge about alterations of gut microbiota in preclinical AD, as well as whether the combination of plasma Aβ and gut microbiota could identify preclinical AD, remains largely unknown.MethodsThis study recruited 34 Aβ-negative cognitively normal (CN−) participants, 32 Aβ-positive cognitively normal (CN+) participants, and 22 patients with cognitive impairment (CI), including 11 patients with mild cognitive impairment (MCI) and 11 AD dementia patients. All participants underwent neuropsychological assessments and fecal microbiota analysis through 16S ribosomal RNA (rRNA) Illumina Miseq sequencing technique. Meso Scale Discovery (MSD) kits were used to quantify the plasma Aβ40, Aβ42, and Aβ42/Aβ40 in CN− and CN+ participants. Using Spearman’s correlation analysis, the associations of global standard uptake value rate (SUVR) with altered gut microbiota and plasma Aβ markers were separately evaluated. Furthermore, the discriminative power of the combination of gut microbiota and plasma Aβ markers for identifying CN+ individuals was investigated.ResultsCompared with the CN− group, the CN+ group showed significantly reduced plasma Aβ42 (p = 0.011) and Aβ42/Aβ40 (p = 0.003). The relative abundance of phylum Bacteroidetes was significantly enriched, whereas phylum Firmicutes and class Deltaproteobacteria were significantly decreased in CN+ individuals in comparison with that in CN− individuals. Particularly, the relative abundance of phylum Firmicutes and its corresponding SCFA-producing bacteria exhibited a progressive decline tendency from CN− to CN+ and CI. Besides, the global brain Aβ burden was negatively associated with the plasma Aβ42/Aβ40 (r = −0.298, p = 0.015), family Desulfovibrionaceae (r = −0.331, p = 0.007), genus Bilophila (r = −0.247, p = 0.046), and genus Faecalibacterium (r = −0.291, p = 0.018) for all CN participants. Finally, the combination of plasma Aβ markers, altered gut microbiota, and cognitive performance reached a relatively good discriminative power in identifying individuals with CN+ from CN− (AUC = 0.869, 95% CI 0.782 ~ 0.955).ConclusionsThis study provided the evidence that the gut microbial composition was altered in preclinical AD. The combination of plasma Aβ and gut microbiota may serve as a non-invasive, cost-effective diagnostic tool for early AD screening. Targeting the gut microbiota may be a novel therapeutic strategy for AD.Trial registrationThis study has been registered in ClinicalTrials.gov (NCT03370744, https://www.clinicaltrials.gov) in November 15, 2017.
Highlights
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder, causing globally heavy healthcare burden [1]
Participants were defined as Cognitively normal (CN)+ when they matched the criteria: (1) normal performance on standardized neuropsychological tests, (2) aggregated Aβ evidence derived from amyloid positron emission tomography (PET), and (3) failure to meet the criteria for mild cognitive impairment (MCI) and dementia
The results showed that the relative abundance of phylum Bacteroidetes, class Bacteroidia, and order Bacteroidales were significantly enriched, whereas phylum Firmicutes, class Clostridia, class Deltaproteobacteria, order Clostridiales, order Desulfovibrionales, family Lachnospiraceae, family Desulfovibrionaceae, family Ruminococcaceae, genus Bilophila, and genus Faecalibacterium were significantly reduced in the CN+ group (LDA score cutoff > 2.0, Fig. 3B)
Summary
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder, causing globally heavy healthcare burden [1]. Increasing evidence implicates that the pathophysiological process of AD begins 15–20 years before the emergence of clinical symptoms [2, 3]. Preclinical AD is defined by biomarker evidence of AD-related pathological changes in cognitively healthy individuals. Abnormal amyloid positron emission tomography (PET) scan or low cerebrospinal fluid (CSF) amyloid-β (Aβ) or Aβ42/Aβ40 ratio are considered as the evidence of Aβ deposition. It is noteworthy that amyloid PET is gaining attraction in clinical practice, expensive costs and radioactivity limit its wide application. Exploring novel and potentially alternative hallmarks for identifying preclinical AD are needed. Plasma amyloid-β (Aβ) may facilitate identification of individuals with brain amyloidosis. Knowledge about alterations of gut microbiota in preclinical AD, as well as whether the combination of plasma Aβ and gut microbiota could identify preclinical AD, remains largely unknown
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