**1. Introduction**

The original descriptions of cortical plaques in subjects with dementia was provided by several scientists, including Emil Redlich (1898), Koichi Miyake (1906), Alois Alzheimer (1906), Oskar Fischer (1907), and Soloman Carter Fuller (1907) [1]. However, the molecular analysis of the material in the plaque was not clarified until Glenner and Wong (1984) described the amino acid sequence of the amyloid which they found to have no homology to any known protein. Subsequently, it has been determined that the protein, now called amyloid Beta (Aβ), is a breakdown product of a larger molecule, the amyloid precursor protein (APP), coded by a gene on chromosome 21. Mutations in APP have been found to be a genetic cause of early-onset Alzheimer's disease (AD). This led to the "amyloid hypothesis", which posited that accumulation of the Aβ protein in the brain is responsible for the pathogenesis of AD [2,3].

There is now overwhelming evidence that Aβ buildup in the brain is certainly an important part of the AD pathogenic process. But it remains to be determined if it is the critical factor responsible. Furthermore, the amyloid hypothesis does not explain how the process starts. That is, what is the initiating factor responsible for Aβ accumulation, and why do some people get the disease and others remain unaffected? This is a critical question in the ~99% of cases of AD that are sporadic, and do not have a causative gene.

Prusiner has suggested that the key mechanism in Alzheimer's etiology is stochastic—an unfortunate misfolding of the Aβ protein causing a non-catalytic, prion-like self-replicating pathogenic process [4]. We find the stochastic explanation unsatisfactory and prefer to look for the opportunity for environmental factors to be involved. Our largest environmental exposure is to the myriad organisms (bacteria, viruses, archaea, yeasts, parasites, fungi) which reside on our body surfaces and in our body cavities. It has now been extensively documented that more than half of a person's cells are of microbial origin, and there are 100 times more nucleotide sequences in our bodies coding for bacterial, rather than human proteins [5]. In this commentary, we will examine the potential molecular mechanisms by which the microbiota may influence cortical Aβ deposition. The mechanisms noted below may operate independently, or more likely, work in unison (i.e, neuroinflammation triggers Aβ aggregation [6]).
