Investigating the link between gut inflammation, aging, and Alzheimer's disease

By Dr. Liji Thomas, MDNov 15 2023Reviewed by Benedette Cuffari, M.Sc.

Aging is often accompanied by and contributed to by chronic inflammation, thus giving rise to the term “inflammaging.” A recent study in Scientific Reports discusses how gut inflammation is associated with age and Alzheimer's disease (AD).

Study: Gut inflammation associated with age and Alzheimer’s disease pathology: a human cohort study. Image Credit: Dragana Gordic / Shutterstock.com

Introduction

With age, the gut microbiome may change, thus causing the intestinal lumen to become more inflammatory and increasing the risk of intestinal epithelial barrier breakdown. As a result, bacterial cell wall components like lipopolysaccharides (LPS), which are potent pro-inflammatory chemicals, may enter the bloodstream.

While there is evidence to link this type of degradation to aging, the current study determined the occurrence of changes in gut permeability and inflammation in healthy older adults. The researchers also sought to identify associations between abnormal gut microbiome composition and inflammation outside the brain of individuals with AD, in which there is neuroinflammation with activated immune cells within the central nervous system (CNS). Markers of AD include the accumulation of amyloid beta (Aβ) and phosphorylated tau (pTau) proteins in the brain.

While gut dysbiosis has been associated with inflammation, cognitive impairment, and AD, the pathways responsible for this association remain unclear.

What did the study show?

The current study included 125 participants from the Wisconsin Alzheimer’s Disease Research Center (ADRC) Clinical Core and Wisconsin Registry for Alzheimer’s Prevention (WRAP).

Within the study cohort, 79 individuals were Aβ- and the rest Aβ+. Among the Aβ+ group, 33 individuals were cognitively unimpaired and the rest had AD.

The mean ages were 74 years for AD Aβ+ and 66 years and 69 years for cognitively unimpaired Aβ- and cognitively unimpaired Aβ+, respectively. About 30% of the AD Aβ+ carried homozygous genes for apolipoprotein E ε4 (APOE ε4).

Fecal samples were used to assess the levels of calprotectin, which often rises due to gut inflammation, as it is released from the damaged gut barrier. The presence of calprotectin in feces differentiates inflammatory bowel disease (IBD), which is characterized by higher gut permeability, from functional disorders of the gut.

Study findings

Calprotectin in fecal samples were correlated with the individual’s diagnosis, age, markers of AD in the cerebrospinal fluid (CSF) such as Aβ and tau protein, amyloid burden obtained by positron emission tomography (PET), along with cognitive tests for areas associated with AD. An increase in calprotectin levels was observed with age, even among cognitively unimpaired participants.

Advancing age increases gut inflammation independently of symptomatic AD.”

Calprotectin levels also rose with AD dementia. The greater the amyloid burden on PET imaging, the higher the calprotectin levels were, even after compensating for the higher mean age in this subset.

Calprotectin levels also rose with Aβ42/Aβ40 and pTau181/Aβ42 levels in the CSF, both of which are associated with the presence of Aβ and pTau. Neurofilament light (NfL), which is associated with axonal degeneration, was also raised in association with calprotectin levels, thus suggesting that intestinal inflammation is also associated with neurodegeneration.

AD does not appear to worsen in the presence of gut dysbiosis; however, gut inflammation was associated with lower memory functioning, which corroborates other studies on Crohn’s disease and IBD. These conditions were not present in any participant in the current study, yet the relationship was observed.

Interventions that mitigate intestinal inflammation could have a beneficial impact on cognitive function in older adults.”

While calprotectin was not associated with cognitive testing performance, individuals with higher calprotectin levels were more likely to have lower verbal memory function, even if their overall cognitive performance was normal. These slight changes could predict the future onset of AD and indicate that gut inflammation may be higher among healthy Aβ- adults without cognitive impairment.

Adults with higher calprotectin levels were more likely to be prescribed proton pump inhibitors (PPIs), which reduce gut microbiota diversity, including levels of beneficial genera like Bifidobacterium.

What are the implications?

Inflammaging is a chronic low-grade state of inflammation linked to advancing age. This phenomenon may be partly due to gut dysbiosis, with the resulting changes in bacterial metabolites promoting the breakdown of the protective epithelial intestinal barrier. Subsequently, inflammation within the gut and at the systemic level may arise, thereby promoting multiple degenerative and other conditions.

The current study links gut barrier degradation to aging, the presence of Aβ+ AD, amyloid burden in the brain cortex, and to CSF markers of neurodegeneration and AD.

Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.”

Further research in a larger and diverse cohort is needed to validate and extend these findings. If established, modifiable targets could be identified for the prevention of aging and AD.