Volume 167, 2022, Pages 101-139Author links open overlay panelAbstract

Alzheimer's disease (AD) is the most prevalent form of dementia and can be influenced by genetic and environmental factors. Recent studies suggest that the intestinal microbiota is altered in AD patients when compared to healthy individuals and may play a role in disease onset and progression. Aging is the greatest risk factor for AD, and age-related changes in the microbiota can affect processes that contribute to cognitive decline. The microbiota may affect AD by modulating peripheral and central immunity or by secreting factors that influence neurogenesis or neuronal cell death. Finally, probiotic and dietary interventions that target the microbiome may have therapeutic potential to prevent or treat AD.

Section snippetsAlzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of misfolded proteins, neuronal cell death, and cognitive impairment (Hebert, Weuve, Scherr, & Evans, 2013; Alzheimer's's, 2013; Masters et al., 2015). Mutations associated with familial AD provide evidence that Aβ and tau contribute to the disease, however, 90% of AD is sporadic (Alzheimer's's, 2013), suggesting that there may be important environmental drivers of the disease. While altered genetics can

The gut microbiota influence health and disease in aging

The intestinal microbiota encodes a metabolic capacity that can influence the host physiology (O'Hara & Shanahan, 2006). It is environmentally acquired, making it a modifiable therapeutic target. Its diverse functions may benefit the host, such as maintaining gastrointestinal health, producing vitamins, and promoting neuronal health (O'Hara & Shanahan, 2006), but disruption can result in disease (Cho et al., 2012). Altered microbiota, whether induced by diet (Turnbaugh, Backhed, Fulton, &

The gut microbiota of patients with Alzheimer's disease

Several studies have investigated the gut microbiome in patients with AD. It is important to note that the AD risk and the gut microbiota composition have a high degree of geographic variation, which may be shaped by the host genetics, lifestyle factors, diet, and indigenous microbes to that location (Gupta, Paul, & Dutta, 2017). Furthermore, lifestyle factors within a population, including mobility and living independently vs. living in a long-term care facility can affect microbiota

Antibiotics and Alzheimer's disease

Antibiotics can have a profound effect on the gut microbiota and may have beneficial effects when targeting pathogens in a setting of infectious diseases or may have detrimental off-target effects. Disruption of the gut microbiota with antibiotics can reduce colonization resistance and increase the risk of infection with gastrointestinal pathogens (Kim, Covington, & Pamer, 2017) and has been linked to several chronic conditions, including obesity and metabolic syndrome (Cox & Blaser, 2015). The

The gut microbiota of murine models of Alzheimer's disease

Microbiota differences have been reported in several animal models of AD. Many of these animal models carry transgenes coding for proteins involved in amyloid processing which lead to the overproduction of amyloid peptides and formation of Aβ plaques. Other models carry transgenes with mutated forms of tau leading to the formation of neurofibrillary tangles. Depending on the mutations and expression levels of the transgenes, the animal models may exhibit pathology at different time points. The

The gut microbiome modulates peripheral immunity

There is substantial evidence that both peripheral immune activation and immunosenescence can play a role in AD (Fig. 2). Studies have found that patients with AD have increased levels of circulating proinflammatory cytokines (Licastro et al., 2000). These proinflammatory cytokines may be produced by peripheral immune cells or microglia and may lead to disruptions in the blood-brain barrier, leading to reduced expression of tight junction proteins and increased permeability to serum proteins,

Interactions between the diet, the microbiota, and Alzheimer's disease

The intestinal microbiota is shaped by diet among other factors and in turn, these microbes and their metabolites significantly influence gut health. Dietary patterns have been shown to influence AD pathology. There is a plethora of evidence of the neurocognitive improving actions of various diets including ketogenic and Mediterranean, as well as the consumption of prebiotics such as polyphenols in individuals and mouse models. However, there is a need to investigate the effects of these

Prebiotics

Prebiotics are dietary compounds that are not fully digested by the host and serve as growth substrates for beneficial microbiota. These can be a relatively low-risk intervention to modulate the gut microbiota, but the efficacy depends on having beneficial microbes already present in the microbiota, albeit at low levels.

Microbial mediators associated with Alzheimer's disease

The gut microbiota is estimated to contain as many cells as the human body and is estimated to carry 100 times the number of genes as the human genome. Along with this, the species within the gut microbiota can secrete a wide variety of neuromodulatory and immunomodulatory substances, may influence AD by direct or indirect mechanisms (Fig. 2).

Probiotic interventions can improve memory in models of Alzheimer's disease

A formulation of lactic acid bacteria and Bifidobacterium species (SLAB51) was given to triple-transgenic mice (3xTg-AD) for 4 months starting at 2 months of age. Administration of SLAB51 increased the abundance of Bifidobacterium spp in the gut of the mice and a reduction in Campylobacterales, which led to reduced accumulation of Aβ aggregates, improved recognition memory, and reduced cortical degradation. The reduced plaques were associated with higher plasma concentrations of gut hormones

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