Evidence for the Existence of a Bacterial Etiology for Alzheimer’s Disease and for a Temporal-Spatial Development of a Pathogenic Microbiome in the Brain

Abstract

Background: Over the last few decades, a growing body of evidence suggests a role for various infectious agents in Alzheimers Disease (AD) pathogenesis. Despite diverse pathogens (virus, bacteria, or fungi) being detected in AD subjects brains, most research has focused on individual pathogens and only a few studies investigated the hypothesis of a bacterial brain microbiome. We profiled the bacterial communities present in non-demented controls and AD subject' brains. Results: We obtained post-mortem samples from the brains of 32 individual subjects, comprising 16 AD and 16 control aged-matched subjects with a total of 130 samples from the frontal and temporal lobes and entorhinal cortex. We used full-length 16S rRNA gene amplification with Pacific Biosciences sequencing technology to identify the bacteria. We detected bacteria in the brains of both cohorts with the principal bacteria comprising Propionibacterium acnes (recently renamed Cutibacterium acnes) and two species each of Acinetobacter and Comamonas genera. We used a hierarchical Bayesian method to detect differences in relative abundance among AD and control groups. Because of large abundance variances we also employed an unconventional analysis approach that utilized Latent Dirichlet Allocation, often used in computational linguistics. This allowed us to identify 5 classes of samples, each revealing a different microbiome. Assuming that samples represented infections that potentially began at different times, we ordered these classes in time, finding that the last class exclusively explained the existence or non- existence of AD. Conclusions: The AD-related pathogenicity of the brain microbiome seems to be based on a complex polymicrobial dynamic. The time ordering revealed a rise and fall of the abundance of Propionibacterium acnes with pathogenicity occurring for an off-peak abundance level in association with at least one other bacterium from a set of genera that included: Methylobacterium, Bacillus, Caulobacter, Delftia, and Variovorax. P. acnes may also be involved with outcompeting the Comamonas species, which were strongly associated with non-demented brain microbiome, whose early destruction could be the first stage of the disease. The statistical results are also consistent with a leaky blood brain barrier or lymphatic network that allows bacteria, viruses, fungi, or other pathogens to enter the brain.

Establishment of a consensus protocol to explore the brain pathobiome in patients with mild cognitive impairment and Alzheimer's disease

“…Over recent decades multiple studies on post mortem AD brains have reported that diverse pathogens are present, ranging from bacteria to fungi to viruses. [45][46][47][48][49][50][51][52][53] Archaea, Chloroplastida, and Holozoa have also been reported in the brain. 54,55 There are multiple potential routes of entry to the brain (Figure 2).…”

“…However, two recent studies identified potential differences in the microbiota of AD and age-matched brains. 53,55 One possible explanation is that dementias such as AD can have diverse etiologies in the same way that pneumonia can be caused by a variety of organisms. For example, viruses (influenza, COVID-19, sometimes herpesviruses), bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and others), and fungi (Aspergillus spp., Mucor spp., Candida spp., Cryptococcus spp.)…”

Establishment of a consensus protocol to explore the brain pathobiome in patients with mild cognitive impairment and Alzheimer's disease: Research outline and call for collaboration

“…For example, a microbe can be present but asymptomatic: most HSV1-infected individuals do not develop coldsores or other lesions, and many people infected with Mycobacterium tuberculosis do not develop tuberculosis. However, two recent studies identified potential differences in the microbiota of AD and age-matched brains [53,55]. One possible explanation is that dementias such as AD can have diverse etiologies in the same way that pneumonia can be caused by a variety of organisms.…”

“…Diverse methods are available for rDNA amplification, all based on conserved sequences. Ehrlich and colleagues have devised a pandomain assay for specifically amplifying and sequencing rDNAs (16S for prokaryotes; and 18S/23S for eukaryotic microbes) and have demonstrated that the strategy is broadly inclusive, highly sensitive, and species-specific [53,114,124,125]. The general method for 16S pandomain analyses reported by Earl et al was able to accurately characterize highly complex polymicrobial specimens containing hundreds of different species present at molar input levels that vary by more than three orders of magnitude.…”

“…Over recent decades multiple studies on post-mortem AD brain have reported that diverse pathogens are present, ranging from bacteria to fungi to viruses [45][46][47][48][49][50][51][52][53]. Archaea, Chloroplastida, and Holozoa have also been reported in brain [54,55].…”