Alzheimer's disease and symbiotic microbiota: an evolutionary medicine perspective

Abstract

Microorganisms resident in our bodies participate in a variety of regulatory and pathogenic processes. Here, we describe how etiological pathways implicated in Alzheimer's disease (AD) may be regulated or disturbed by symbiotic microbial activity. Furthermore, the composition of symbiotic microbes has changed dramatically across human history alongside the rise of agriculturalism, industrialization, and globalization. We postulate that each of these lifestyle transitions engendered progressive depletion of microbial diversity and enhancement of virulence, thereby enhancing AD risk pathways. It is likely that the human life span extended into the eighth decade tens of thousands of years ago, yet little is known about premodern geriatric epidemiology. We propose that microbiota of the gut, oral cavity, nasal cavity, and brain may modulate AD pathogenesis, and that changes in the microbial composition of these body regions across history suggest escalation of AD risk. Dysbiosis may promote immunoregulatory dysfunction due to inadequate education of the immune system, chronic inflammation, and epithelial barrier permeability. Subsequently, proinflammatory agents-and occasionally microbes-may infiltrate the brain and promote AD pathogenic processes. APOE genotypes appear to moderate the effect of dysbiosis on AD risk. Elucidating the effect of symbiotic microbiota on AD pathogenesis could contribute to basic and translational research.

Keywords: Alzheimer's disease; dementia; evolutionary medicine; immunoregulation; microbiome.

Figure 1.

Over the past 15,000 years of human history, there have been a series of major lifestyle transitions that comprised changes in demography, environments, subsistence, and epidemiology. These transitions also likely brought about major changes in the composition of symbiotic microbiota, including generally reduced diversity and enhanced pathogenic virulence. Suppositions regarding pre-Agricultural Revolution gut flora are based on analyses comparing the gut microbial compositions of contemporary people who practice hunting–gathering subsistence strategies in nonindustrialized communities in Tanzania (Hadza), Peru (Matses), Malawi, and Venezuela, and fossil assemblages of Neanderthals (compilation from Spain, Croatia, Germany, and Russia), Denisovans (from Siberia), and other early hominins (from Spain) with those of contemporary industrialized populations in Europe, North America, Asia, and Oceania. We note that contemporary hunter–gatherers offer an imperfect proxy for premodern gut microbiomes.

Figure 2.

Biomechanisms by which symbiotic microbiota in various regions of the human body may affect Alzheimer’s disease pathogenic processes.