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

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Aging often accompanies and contributes to chronic inflammation, thus giving rise to the term “inflammatory.” In a recent study Scientific report Discusses how intestinal inflammation is related to age and Alzheimer’s disease (AD).

Study: Intestinal inflammation associated with age and Alzheimer’s disease pathology: a human cohort study. Image credit: Dragana Gordic /


With age, the gut microbiome may change, thus making the gut lumen more inflammatory and increasing the risk of gut epithelial barrier breakdown. As a result, bacterial cell wall components such as lipopolysaccharides (LPS), which are powerful pro-inflammatory chemicals, can enter the bloodstream.

Although there is evidence linking this type of deterioration to aging, the current study determined the incidence of changes in intestinal permeability and inflammation in healthy older adults. The researchers sought to identify the relationship between abnormal gut microbiome composition and inflammation outside the brain in people with AD, including 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.

Although gut dysbiosis has been linked to inflammation, cognitive impairment, and AD, the pathways responsible for this association remain unclear.

What does the study show?

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

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

The mean age was 74 years for AD Aβ+ and 66 years and 69 years for cognitively impaired Aβ- and cognitively impaired Aβ+, respectively. About 30% of AD Aβ+ carry the homozygous gene for apolipoprotein E ε4 (APOE ε4).

Stool samples were used to determine levels of calprotectin, which is often elevated due to intestinal inflammation, as it is released from the damaged intestinal barrier. The presence of calprotectin in stool is associated with inflammatory bowel disease (IBD), a functional disorder of the bowel characterized by elevated intestinal permeability.

Study results

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

Intestinal inflammation increases with age independently of symptomatic AD

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

Calprotectin levels were also increased along with Aβ42/Aβ40 and pTau181/Aβ42 levels in CSF, both associated with the presence of Aβ and pTau. Neurofilament light (NfL), which is associated with axonal degeneration, was also elevated 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 function, which supports other studies on Crohn’s disease and IBD. These conditions were not present in any of the participants in the current study, yet the relationship was observed.

Interventions that alleviate gut inflammation may have beneficial effects on cognitive function in older adults

Although calprotectin was not associated with cognitive test performance, individuals with higher calprotectin levels were more likely to have lower verbal memory function, even if their overall cognitive performance was normal. These modest changes may predict future onset of AD and indicate that intestinal inflammation may be greater in healthy Aβ-treated 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 genes. Bifidobacterium.

What are the effects?

Inflammation is a chronic low-grade inflammation associated with advanced age. This phenomenon may be partly due to intestinal dysbiosis, whereby bacterial metabolic changes break down the protective epithelial intestinal barrier. Subsequently, inflammation can occur within the gut and at the systemic level, thus promoting multiple degeneration and other conditions.

Current research links aging, the presence of Aβ+ AD, amyloid burden in the cerebral cortex, and intestinal barrier deterioration with neurodegeneration and CSF markers of AD.

Taken together, these findings suggest that intestinal inflammation is associated with brain pathology even at early disease stages. Furthermore, intestinal inflammation may accelerate the progression towards AD

Further research in a larger and more diverse cohort is needed to validate and extend these findings. Once established, modifiable targets for aging and AD prevention can be identified.

Journal Reference:

  • Heston, MB, Hanslick, KL, Zerbock, KR, etc (2023). Intestinal inflammation associated with age and Alzheimer’s disease pathology: a human cohort study. Scientific report. doi:10.1038/s41598-023-45929-z.

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