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Review

Reducing Neuroinflammation and Risk of Mild Cognitive Impairment and Alzheimer’s Disease by Reducing Dietary Lipopolysaccharides, Arachidonic Acid, and Advanced Glycation End Products

by
Steven Blake
1,2,*,
Luciana Baroni
3,
Panida Piboolnurak
2,
Thomas Harding
1,
Maile Harding
1 and
Catherine Blake
1,2
1
Maui Memory Clinic, Maui, HI 96793, USA
2
Neuroscience Nutrition Foundation, Maui, HI 96708, USA
3
Scientific Society for Vegetarian Nutrition, 30171 Venice, Italy
*
Author to whom correspondence should be addressed.
J. Dement. Alzheimer's Dis. 2025, 2(3), 27; https://doi.org/10.3390/jdad2030027
Submission received: 12 March 2025 / Revised: 30 May 2025 / Accepted: 11 July 2025 / Published: 11 August 2025
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Abstract

Background/Objectives: Levels of lipopolysaccharide (LPS), arachidonic acid (AA), and advanced glycation end products (AGEs) are higher in the brain of subjects affected by cognitive impairment and Alzheimer’s disease (AD), compared to a healthy brain. Methods: In this narrative review, articles were selected with data on these three key dietary compounds relevant to neuroinflammation and cognitive impairment in order to provide practical dietary advice to reduce the risk of diseases affecting cognition. Results: Triggered by LPS and AGEs in food, inflammatory cytokines can enter the brain and stimulate microglial activation, inflammation, and oxidative damage. AA can elicit neuroinflammation by increasing leukotriene-A4 and prostaglandin-E2 production. Increased levels of neuroinflammation are associated with poorer cognition in AD. Discussion: A dietary reduction of LPS, AA, and AGEs could slow progression and reduce the risk of cognitive impairment and AD by reducing neuroinflammation through several mechanisms. The avoidance of foods that are highest in LPS, AGEs, and AA (dairy products, pork, poultry, beef, and seafood) and the emphasis on foods lowest in LPS, AGEs, and AA (fruits, vegetables, boiled whole grains, beans, raw nuts, and seeds) can reduce neuroinflammation and risk of cognitive impairment and AD. Conclusions: Reduction of chronic neuroinflammation with dietary changes may represent a novel approach to the treatment of AD and cognitive decline.

Graphical Abstract

1. Introduction

Alzheimer’s disease (AD) is an increasingly common disorder among older adults, with over 57 million people experiencing dementia worldwide in 2025 [1]. Chronic neuroinflammation can lead to neuronal damage and neurodegenerative diseases [2]. Activated microglia and cytokines can be a normal central nervous system response to damage, but chronic microglial activation leads to a pro-inflammatory state. These inflammatory cytokines can be counteracted by the synthesis and release of the anti-inflammatory cytokines interleukin-4, and interleukin-10, as well as by prostacyclin [3]. Large prospective cohort studies show that serum levels of inflammatory cytokines are closely associated with dementia [4]. The levels of lipopolysaccharides (LPS), arachidonic acid (AA), and advanced glycation end products (AGEs) are elevated in the plasma of cognitively impaired and AD patients compared to normal controls [5]., These molecules can increase neuroinflammation in the brain with various mechanisms [6]. Therefore, a complementary approach to treating neuroinflammation can be reducing dietary sources of inflammation. Lower intakes of dietary LPS, AA, and AGEs could decrease neuroinflammation and neuronal damage in the brain, and they can be obtained by reducing foods containing the highest amounts of LPS, AA, and AGEs. Foods containing these compounds may also contain high levels of saturated fatty acids, which may, over time, impair blood flow in brain circulation.
This article discusses the mechanisms underlying the detrimental effects of LPS, AA, and AGEs and hypothesizes that a reduction in the dietary intake of these molecules can both reduce risk of and treat cognitive impairment and AD. The main limitation of this review is the small number of intervention trials with AGEs and AA.

2. LPS, Neuroinflammation, and Cognition

The sources of lipopolysaccharides (LPS) for humans are bacterial infection, colonic microbiota, and certain foods. For example, in a clinical trial, thin-crust cheese pizza was found to raise serum LPS 65 times in just a few hours [7]. LPS is made up of about eighty percent of the Gram-negative bacterial cell wall. The term endotoxin is also used to describe LPS.
When plasma LPS is high, this can trigger an inflammatory immune activation, and LPS-induced inflammation can initiate inflammatory degeneration in AD [8]. Consequently, LPS is implicated in increased progressive neurodegeneration in AD [9]. Recent data clearly show that the pathophysiology of AD can be increased by inflammatory immune activation [6].

2.1. How LPS Increases Neuroinflammation

LPS can increase the production of three inflammatory cytokines: interleukin-1-beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα). AD patients had higher levels of IL-1β, IL-6, and TNF-α than normal controls [10]. LPS can stimulate microglia and astrocytes in the central nervous system to secrete higher levels of cytokines such as IL-6, TNFα, and interferon-gamma. Microglial activation may contribute to neuronal degeneration [11]. When stimulated by LPS, systemic inflammation can raise microglial expression of IL-1β and increase apoptosis of brain neurons. In an intervention trial, both central and peripheral inflammation were found to increase neurodegeneration, brain inflammation, and neuronal death [12]. Microglia, activated by LPS, can damage neurons via cytokines, nitric oxide, and reactive oxygen species (ROS). This can lead to phagocytosis and the death of synapses and neurons [13]. In addition, LPS can be neurotoxic in the central nervous system by reducing both synaptic signaling proteins and neuron-specific neurofilaments, which may increase neurodegeneration [14].
Toll-like receptor-4 is a surveillance receptor, triggering inflammation when LPS is detected. Toll-like receptor-4 protein expression was increased two-fold (p < 0.05) with higher circulating LPS levels. Higher LPS levels were found to increase IL-6 secretion (from 2.7 ng/mL to 4.8 ng/mL) and TNFα (from 1 pg to 33 pg) [15]. Nuclear factor kappa-B (NFқB) inhibitors inhibited this increase in cytokines, especially IL-6.
LPS challenge has been shown to increase IL-1β. IL-1β can stimulate microglial expression of IL-6, induce microglial proliferation, and activate microglia. IL-1β may promote the generation of ROS such as peroxynitrite, and it appears to be a mediator of apoptosis and neurodegeneration. Additionally, IL-1β may exhibit neurotoxic properties through increased amyloid-β and blood-brain barrier damage [10].
LPS can promote early neuroinflammatory changes in AD by activating the receptor for advanced glycation end-products (RAGE). RAGE can promote chronic neuroinflammation and neurodegeneration to amplify pro-inflammatory signaling, particularly in the hippocampus [16].

2.2. LPS Is Increased in the AD Brain

In comparison to brains from participants free from dementia, higher LPS levels in white and grey matter were found in brains from patients with AD. Also, in a case–control human cohort trial, LPS was found to be located near amyloid-β in amyloid plaques in AD brains [17]. LPS is higher and correlated with white matter injury in AD [4]. In a study of four AD brains, it was reported that LPS levels in the hippocampus were three times as high when compared to age-matched control brains. The hippocampus exhibited an increase of up to 26 times more LPS in certain advanced AD patients. Also, it was reported that plasma LPS levels were three times as high in 18 AD participants (mean 61 pg/mL) compared to 18 healthy controls (mean 21 pg/mL). In a Norwegian study, higher hippocampal levels of LPS were found in patients with AD, compared to non-AD age-matched controls [4].
AD patients were found to have elevated LPS in their blood and brain [18,19]. Some patients with AD were found to have 3-fold higher plasma LPS levels, compared to controls [20]. In another study, participants with mild cognitive impairment (MCI) had serum LPS levels that were double the level found in normal aging controls. In patients with dementia, serum LPS almost doubled, compared to MCI patients. Serum LPS was 700 ng/mL in patients affected by dementia, 400 ng/mL in patients affected by MCI, 150 ng/mL in normal aged people, and near zero in young normal people (Figure 1) [21]. In patients with MCI and AD, higher levels of LPS were found in the serum and cerebrospinal fluid [22].

2.3. LPS Can Increase the Risk of AD and Cognitive Impairment

Cognitive decline and lower cognitive function have been correlated with higher plasma LPS. Higher plasma LPS concentration can double the risk of MCI in participants without dementia [22].
Inflammation induced by LPS may be a significant initiator of inflammatory degeneration in AD [4]. Systemic markers of inflammation are risk factors for late-onset AD. Microglial activation can be detected in about half of patients with MCI [23]. Neuronal cell loss may be induced by LPS, partly by greatly increasing levels of TNFα and IL-1β [8]. Higher serum levels of inflammatory markers may be able to predict dementia [23].
AD risk can be increased by LPS, creating neuroinflammatory reactions and neurodegenerative changes when LPS enters the brain from the periphery [6]. High levels of plasma LPS can trigger the pathophysiology of AD by activating the immune system via inflammation [24]. Working memory/short-term verbal memory and the Digit Span Test were negatively impacted by higher levels of lipopolysaccharide binding protein [25]. Even low doses of LPS can impair immediate and delayed recall in human trials [26].

2.4. LPS Can Work with Arachidonic Acid to Degrade Memory

Higher plasma LPS can work together with arachidonic acid (AA) eicosanoid production to degrade memory function. This degradation of memory function is partially reversible with COX (cyclooxygenase) inhibitors [27]. When microglia were treated with LPS, they produced fourteen times the proinflammatory prostaglandin-E2 (PGE2), compared with untreated microglia. PGE2 from AA increases IL-6 inflammation [28]. LPS can activate COX2, leading to an increase in the production of ROS, including superoxide and peroxide [29].

2.5. How LPS from Food Can Enter the Bloodstream

LPS is principally absorbed from certain foods after a meal, but, in a study in men, it was also found to enter the bloodstream from infection or chronic dysbiosis (imbalanced gut bacteria) [30]. Dietary LPS is absorbed and integrated into chylomicrons, which transport digested lipids into the bloodstream. When chylomicrons containing LPS are in the bloodstream, the LPS can be transported by the LPS-binding protein (LBP). LBP is then transferred to the receptor cluster of differentiation-14 (CD14). CD14 can bind the LPS-LBP complex, activating nuclear factor-kappa-B (NFқB) via toll-like receptor-4. This cascade can result in the release of TNFα, Interleukin IL-1β, and IL-6, which are pro-inflammatory cytokines (Figure 2) [30,31]. It has been reported that excesses of these inflammatory cytokines can damage cognition.
Pro-inflammatory LPS co-absorbs with dietary saturated fatty acids, and the saturated fatty acids can increase the absorption of LPS in the intestine. Then, LPS is incorporated into chylomicrons, which enter the lymph system and then the bloodstream, and can contribute to increased plasma levels of LPS and inflammation after meals. LPS levels in chylomicrons increased from near zero up to half of a nanogram per milliliter after a high milk fat (40 g) meal. Milk fat triggered a quick and marked increase in LPS-laden chylomicrons at one hour after ingestion in a randomized crossover trial [32]. High plasma LPS levels resulted in a strong cytokine response [33].
Meat consumption was found to be the most influential dietary risk factor for AD [9]. Pork, beef, and turkey contained the highest levels of LPS. An average serving of turkey contains 67,000 ng LPS [34].
A single processed food meal may contain an average of about 200,000 ng LPS [34]. Table 1 shows examples of processed food meals and their LPS levels. Intravenous injection of only 49 ng LPS can impair verbal and nonverbal declarative memory functions and decrease immediate and delayed recall [35]. Compared to injected LPS, the amount of LPS in a single processed food meal can be up to four thousand times higher than has been found to damage memory (Table 1) [36].
Common foods can contain LPS, and the greatest concentrations were present in meat-based and cheese products. Whole vegetables, grains, fresh fruit, and potatoes are very low in LPS [34].
Neuroinflammation and plasma LPS levels can be significantly reduced by restricting dietary LPS [35]. Higher intakes of fruit and legumes were associated with 34% and 20% less circulating LPS, respectively. In a prospective study including 912 participants, only legumes and fruit were significantly associated with reduced LPS levels. People eating the Mediterranean diet had lower circulating LPS when compared to those eating a Western diet [18,36].

3. AGEs, Neuroinflammation, and Impaired Cognition

Foods that are sourced from animals can develop high levels of advanced glycation end products (AGEs) when processed or cooked with high heat. In a human cohort trial, heating of proteins and lipids using methods such as frying, roasting, grilling, or baking stimulated AGE formation [38]. Recent evidence shows that AGEs can increase the risk and progression of neurodegenerative diseases such as AD [5]. AGEs may increase oxidation and the death of brain neurons. In a randomized clinical trial, it was found that cell death from oxidation of cellular membranes may be one of the neuropathological mechanisms of AD [39].

3.1. How AGEs Can Increase Neuroinflammation and Impair Cognition

Receptor for advanced glycation end products (RAGE) serves as a receptor for both amyloid-β and AGEs. RAGE is located on the surface of cerebral blood vessels, microglia, and neurons. RAGE can regulate amyloid-β transport into the brain across the blood–brain barrier, increasing its accumulation in the brain [40]. RAGE can activate NF-κB and increase the biosynthesis of proinflammatory cytokines. This is how RAGE can increase oxidative stress [41].
Part of memory impairment may be due to RAGE-mediated mechanisms. Those amyloid-β that are crosslinked to AGEs are more toxic to neurons than non-glycated amyloid-β [40]. When amyloid-β binds to AGEs, cognitive impairment and dementia may be increased. In this situation, ROS are increased, and can promote amyloid-β, senile plaques, and neurofibrillary tangles (tau tangles) [42]. When amyloid-β, tau, and AGEs interact, this may contribute to the pathogenesis of cognitive impairment and dementia [43].
When AGEs are transported across the blood–brain barrier by RAGE, they initiate a cascade of inflammation beginning with the activation of phosphatidylinositol-3 kinase, mitogen-activated protein kinase, and NF-κBs (Figure 3) [44,45]. This results in inflammation triggered by the cytokines IL-6, TNF-α, and also C-reactive protein. AGEs, by binding to RAGE, can increase the risk of stroke, neurodegeneration, and atherosclerosis [46]. RAGE can also increase the amount of circulating amyloid-β in the brain, and the interaction of AGE and amyloid-β can lead to reduced cerebral perfusion [47].

3.2. AGEs in Food and Neuroinflammation

Limiting AGE intake from food may reduce inflammation and limit the risk of chronic inflammatory diseases, such as AD. A reduction of dietary AGE intake can lead to a reduction of inflammatory markers. Circulating inflammatory indicators went down with a low-AGE diet, as shown by five studies [44]. Circulating AGEs decrease in response to dietary restriction of AGEs [47]. Effective suppression of inflammatory molecules has been demonstrated after a sustained reduction in dietary AGEs [48]. Reduced dietary AGE intake can lower inflammation [49].
When people consume foods with a high content of AGEs, the production of C-reactive protein and inflammatory cytokines such as TNF-α can be increased [41]. When serum AGE concentrations are reduced after a dietary reduction of AGEs, markers of inflammation are reduced [50]. Conversely, a diet high in AGEs increased many inflammatory markers. Cytokines are increased by AGEs via increased activation of NF-κB [46].
The level of TNF-α went down by twenty percent on a low AGE diet, while the level of TNF-α rose by 86% for those on a high AGE diet. The reduced AGE diet lowered C-reactive protein twenty percent, while the high AGE diet raised C-reactive protein by 35% (Figure 4) [48].

3.3. AGEs Are Increased in the AD Brain

In AD brains, AGE content has been consistently reported to be higher in amyloid-β plaques, when compared with normal brains [49]. The accumulation of AGE-modified amyloid-β in the brain may be increased with higher levels of dietary AGEs [46]. Compared to healthy controls, the brains of AD patients typically contain five to ten times as many amyloid plaques [51].
Glial cells and senile plaques in cortical areas can accumulate AGEs in the AD brain [45]. AGEs can enlarge amyloid-β deposits. In AD patients, higher numbers of AGE-damaged neurons and astroglia are associated with disease progression [52]. When amyloid-β was glycated by AGEs, it was found to be more toxic to synaptic proteins when compared to non-glycated amyloid-β [53]. Subjects with AD had increased levels of AGEs in cerebrospinal fluid. The decline in cognitive function in AD subjects has been correlated to the amount of protein glycation [54].

3.4. How AGEs from Food Can Enter the Bloodstream

About one-tenth of dietary AGEs enter the bloodstream. Two-thirds of these AGEs that enter the bloodstream are stored in the body [5]. Once cross-linked, AGEs are difficult to break down [55]. This is why they are called “advanced glycation end products.” A diet rich in AGEs raised serum AGEs by sixty-five percent while a low-AGE diet decreased serum AGEs by 30 percent, in a human study. The two diets were similar, other than their AGE content, for example, broiled chicken versus boiled chicken. The diet change altered circulating AGEs within 2 weeks [48].
AGEs can be formed inside the body under conditions of oxidation and excess glucose. The highest dietary sources of AGEs were found in beef, cheese, poultry, pork, fish, and eggs. Butter also contains high levels of AGEs. Normal adults from New York City were found to take in 14,700 AGE kU/day (kU = kilounits). A diet rich in roasted or grilled meats can increase dietary AGE intake higher than 20,000 kU/day [56]. Just meat alone can supply eighty percent of dietary AGEs. Bacon contains elevated levels of AGEs (11,905 kU/serving) [47]. Those who ate an Atkins diet experienced seven times the level of methylglyoxal (an AGE precursor). A large increase in AGEs was found on the 18th day of the Atkins diet [57].
Roasting, frying, grilling, or baking food increases AGE formation by Schiff-base adducts coupled with the Maillard reaction. High dietary intake of AGEs from these foods can contribute to the pathogenesis of AD and cognitive impairment [38]. Water and antioxidants in whole plant foods can inhibit the formation of AGEs. The foods lowest in AGEs (under 28 kU/serving) are grains, vegetables, and fruits. Amounts of AGEs in some common foods are shown in Figure 5 [58].

3.5. Dietary AGEs Increase Risk of AD and Cognitive Impairment

Reducing the intake of AGEs in food may be considered an effective technique to lower the risk of neurodegenerative diseases. High serum AGEs are associated with cognitive decline [59]. It has been widely reported that reduced AGEs in serum are associated with a less rapid rate of cognitive decline [60]. In a group of elderly subjects without cognitive impairment, lower serum levels of methylglyoxal, an AGE precursor, were associated with a reduced rate of cognitive decline [52]. Among 4041 elderly Japanese, those with lower levels of AGEs had better cognitive scores, while those with higher AGE levels had worse cognitive scores [61].
In one study, when AGE levels rose to only half of the highest AGE levels in healthy people, the incidence of MCI increased 640% (OR = 6.402). This study adjusted for age and brain atrophy. Patients with MCI had both a significantly higher rate of brain atrophy and higher AGE content [62]. In a large prospective study, higher levels of AGEs were associated with lower global cognitive function, and carriers of the apolipoprotein-ε4 allele experienced a stronger effect. Conversely, in 2890 individuals in a Dutch study, lower AGEs were associated with better cognition [42].
A recent 4-year study found that higher AGEs were found to be significantly associated with a worse clinical dementia rating, even after adjustment for age, sex, education level, and apolipoprotein ε4 status. Importantly, patients with lower AGEs exhibited a slower decline in cognition [63]. AD and dementia risk was raised 21–22% for each standard deviation increase in AGEs [64].

4. Arachidonic Acid, Neuroinflammation, and Cognitive Impairment

Arachidonic acid (AA) is an omega-6, 20-carbon chain with 4 points of desaturation (C20:4 ω-6). AA is the second most common fatty acid in the brain (after DHA), comprising about 20% of neuronal membrane fatty acids [65]. AA is needed in the brain for normal membrane plasticity, and humans can make sufficient AA from linoleic acid. However, dietary AA can increase the content of AA in the membrane phospholipids to increase neuroinflammation [66].

4.1. How Excess Dietary AA Creates Neuroinflammation in AD

AA is released from neuronal cell membrane phospholipids by the enzyme phospholipase-A2 (PL-A2) and then converted by cyclooxygenase enzymes (COX1 and COX2) into prostaglandin-E2 (PGE2), which can contribute to the occurrence and progression of neuroinflammation. COX-2 overexpression in the brain of AD patients has been reported and correlated with the progression of AD in several studies [67]. The finding of elevated levels of AA and PL-A2 in AD brains supports the hypothesis that there is an active inflammatory process occurring in AD. PL-A2 can contribute to the inflammatory effects of amyloid-β 1–42 peptide in astrocytes and microglial cells [68].
Microglia, when activated by LPS, can synthesize PGE2 when extra AA is available. PGE2 can lead to a rapid increase in the inflammatory cytokine IL-6 [28]. Excess dietary AA can increase levels of phospholipase-A2, releasing AA, activating COX-2 to convert AA into PGE2, and increase production of inflammatory leukotrienes by 5-lipoxygenase (5LOX). High levels of dietary AA can also increase gene expression levels of NF-κB. As a result, pro-inflammatory cytokines (TNF-α and Il-1β) were up-regulated by AA [69].
Leukotriene-A4, made from AA via 5LOX, is associated with reduced neuronal survival and reduced neurogenesis, increased formation of amyloid plaques, tau tangles, and more neuroinflammation [70].
AA is converted by 5LOX into the highly inflammatory leukotriene-A4. Leukotriene-A4 has a strong impact on increasing amyloid-β peptide production and tau phosphorylation in neuronal cells [65]. 5LOX has been found to be expressed in the brain and extremely high levels of 5LOX have been found in the hippocampus and other brain areas in those with AD. 5LOX levels are high in neurofibrillary structures and amyloid-beta-containing plaques. 5LOX is involved in pathological inflammatory cascades that could perpetuate neuronal degeneration and loss of synapses in AD [71]. Lower leukotriene-A4 and 5LOX levels were associated with a lower decline in psychomotor processing speed [72].
It has been reported that decreasing dietary AA can (1) reduce neuroinflammation, (2) reduce amyloid-beta oligomer production, (3) reduce the amyloid-beta oligomer-induced apoptotic neuronal death, and (4) reduce neurotoxicity. In addition, AA was found to compete with the incorporation of protective DHA in neuronal membrane phospholipids. Reducing dietary AA could be of interest in preventive and therapeutic strategies in AD (Figure 6) [73].

4.2. Excess Arachidonic Acid Is Found in AD Brains

AA incorporation in the AD brain is increased compared with control brains, both throughout the brain and in regional brain areas demonstrating inflammatory neuropathology on postmortem. Positron emission tomography imaging of AA incorporation may become a marker of AD neuroinflammation for early diagnosis and evaluation of disease progression. It has been reported that AD patients had a 23% increased content of brain AA [74]. Phospholipase-A2 was higher in AD brains compared to controls, indicating more release of AA and higher production of inflammatory PGE2 and leukotriene-A4. COX-2 was over-expressed in the brains of AD patients, and this over-expression has been reported to correlate with the progression of the disease [65].
An accumulation of AA was observed in both the periphery and the brain in patients with AD. Plasma AA was 37% higher in AD (7.38 µM in AD versus 5.40 µM in control patients) [75]. Blood lipid analyses show that higher AA in cell membrane phospholipids was able to identify patients at higher risk of AD [76]. Those with higher prostaglandin-F2-alpha, an eicosanoid made from AA, had a 45% increased risk of all-cause dementia [77].

4.3. Excess Dietary Arachidonic Acid Can Impair Cognition

LPS and AA can work synergistically to damage memory. Higher plasma LPS can affect memory functioning partly due to increased AA eicosanoid production, which is partially reversible with COX inhibitors [27]. When microglia were treated with LPS, 14 times the PGE2 was produced from AA, increasing IL-6 inflammation [28]. LPS can activate COX2 to process AA and increase production of ROS, including superoxide [29]. Leukotrienes made from AA can increase inflammation and programmed cell death in the brain [78]. Many studies show that COX-2 is over-expressed in the cortex and hippocampus of patients affected by AD. If excess AA is available, the resulting increase in PGE2 can increase neuroinflammation [66].
In a crossover study with controlled diets, a group of men ate a normal Western diet with 210 mg AA per day) or a normal Western diet supplemented with 1.5 g AA daily. A 41% increase in thromboxane was noted in the high AA group (prostacyclin partially offsets this effect) [79]. Also, dietary AA can amplify the amyloid-beta induced alteration of cognitive abilities and synaptotoxicity [66]. Thromboxane, when made from AA, is a powerful inducer of platelet aggregation and vasoconstriction that may contribute to thrombosis, vascular dementia, or stroke risk [79].

4.4. Sources of Arachidonic Acid in Food

Dietary AA is found only in animal-derived foods [80]. The highest dietary sources of AA are meat, poultry, pork, and eggs (Figure 5) [81]. On the contrary, fruits, vegetables, legumes, grains, nuts, and seeds contain no AA.
Humans can convert the plant-based omega-6 linoleic acid to AA in the amounts needed. Deficiency of linoleic acid is rare [82], and increasing dietary linoleic acid does not increase tissue AA content in adults consuming Western-type diets [83]. Excess AA from animal fats can increase neuroinflammation. AA amounts increased in the last 40 years in Western diets, and the influence of dietary AA on the occurrence of AD is an important issue for the prevention and reduced progression of the disease (Figure 7).
AA in the diet can be efficiently absorbed and incorporated into neuronal membranes, resulting in an increased production of inflammatory thromboxane-A2 by platelets [79]. Plasma AA has been shown to be stable even with a higher dietary intake of the plant-based linoleic acid (C18:2 ω-6). However, a meta-analysis of 36 studies showed an association between dietary AA and higher AA amounts in blood. Brain AA content variations likely depend on dietary AA intake. More than 80% of dietary AA is provided by meat and eggs, especially poultry [66]. In another study, a quarter gram of dietary AA (e.g., one egg) increased plasma AA by over 20% [83].
Although the concentration of AA in the visible fat portion of meats may be significant, AA can also be concentrated in the membrane phospholipids of lean meats. The visible fat of meat contained AA ranging from 20 to 180 mg/100 g fat, but the AA content of the lean portion of meat was lower, ranging from 30 to 99 mg/100 g lean meat. Pork fat had the highest concentration of AA in visible fats (180 mg/100 g), while the highest level of AA in lean meat was in duck (99 mg/100 g) [86], see Table 2.

5. Conclusions

Research supports the hypothesis that higher dietary sources of LPS, AA, and AGEs can increase inflammation in the body and in the brain, while a lower dietary intake can reduce neuroinflammation and slow cognitive impairment [5,6]. Therefore, neuroinflammation and the risk of cognitive impairment and AD can be counteracted by avoiding foods that are highest in LPS, AGEs, and AA, such as dairy products, pork, poultry, beef, and seafood, and emphasizing in the diet the foods lowest in LPS, AGEs, and AA, like fruits, vegetables, boiled whole grains, beans, raw nuts, and seeds. This approach may be useful for professionals and open the way to a comprehensive management of neurodegeneration, which should also include the quality of the diet. Future studies that reduce dietary sources of LPS, AA, and AGEs in AD are warranted to confirm the impact on neuroinflammation and the consequent reduction of the risk and progression of cognitive impairment.

Author Contributions

Conceptualization, S.B.; validation, C.B. and L.B.; writing—original draft preparation, S.B.; writing—review and editing, C.B., L.B., T.H., M.H. and P.P.; visualization, S.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

Glossary

(AD) Alzheimer’s disease, (AGEs) advanced glycation end products, (AA) arachidonic acid, (CD14) cluster of differentiation-14, (COX) cyclooxygenase, (IL-1β) interleukin-1-beta, (IL-6) interleukin-6, (LBP) LPS binding protein, (5LOX) 5-lipoxygenase, (LPS) lipopolysaccharide, (MCI) mild cognitive impairment, (NFқB) Nuclear factor kappa-B, (PGE2) prostaglandin-E2, (PL-A2) phospholipase-A2, (RAGE) receptor for advanced glycation end-products, (ROS) reactive oxygen species, (TNFα) tumor necrosis factor-alpha.

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Jdad 02 00027 g001
Figure 1. Serum LPS in normal, MCI, and dementia. Based on data from [21].
Figure 1. Serum LPS in normal, MCI, and dementia. Based on data from [21].
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Figure 2. How increased LPS can impair cognition.
Figure 2. How increased LPS can impair cognition.
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Figure 3. Mechanisms whereby AGEs induce cognitive impairment.
Figure 3. Mechanisms whereby AGEs induce cognitive impairment.
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Figure 4. High AGE diets increase two markers of inflammation. Used with permission [5].
Figure 4. High AGE diets increase two markers of inflammation. Used with permission [5].
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Figure 5. AGEs in one serving of selected foods. Used with permission [5].
Figure 5. AGEs in one serving of selected foods. Used with permission [5].
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Figure 6. How AA induces neuroinflammation and cognitive impairment.
Figure 6. How AA induces neuroinflammation and cognitive impairment.
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Figure 7. Dietary sources of arachidonic acid [84,85].
Figure 7. Dietary sources of arachidonic acid [84,85].
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Table 1. LPS per serving in food (used with permission) [37].
Table 1. LPS per serving in food (used with permission) [37].
Foodng/g of LPSServing Size gLPS per Serving in ng
Macaroni cheese6500 ng/g340 g2,200,000 ng
Minced turkey7800 ng/g230 g1,800,000 ng
Cheese and onion rolls17,000 ng/g74 g1,300,000 ng
Minced pork10,000 ng/g110 g1,100,000 ng
Minced beef7000 ng/g98 g690,000 ng
Pork sausage rolls4200 ng/g2 rolls 120 g520,000 ng
Turkey300 ng/g230 g510,000 ng
Hamburger patty3090 ng/g98 g300,000 ng
Infant formula milk powder2800 ng/g100 g280,000 ng
Lobster1200 ng/g145 g170,000 ng
Pork1100 ng/g110 g120,000 ng
Spaghetti bolognese220 ng/g400 g90,000 ng
Skim milk, one cup75 ng/mL240 g18,000 ng
Milk, one cup50 ng/g240 g12,000 ng
Table 2. Effects of LPS, AGEs, and AA on risk of AD and cognitive impairment.
Table 2. Effects of LPS, AGEs, and AA on risk of AD and cognitive impairment.
Effect on Risk of AD and Cognitive ImpairmentRef.
LPS
Increased levels of LPS in the hippocampus of patients with AD.[4]
High levels of plasma LPS can worsen inflammatory neurodegeneration in AD.
Neuronal cell loss may be induced by LPS via TNFα and IL-1β.		[8]
Increased microglial expression of IL-1β and neuronal apoptosis in the brain with higher levels of LPS.[12]
Higher LPS caused a significant doubling of IL-6 secretion and greatly increased TNFα in a human study.[15]
LPS co-localizes with amyloid-β in amyloid plaques in AD brains. In a nested case–control design, LPS was significantly associated with a thirty percent higher risk of developing AD (12-year trial).[17]
AD patients were found to have elevated LPS in their blood and brain.[19]
Some patients with AD were found to have three times higher plasma LPS levels, when compared to controls.[20]
Those with MCI had almost double the LPS serum levels and those with AD had 4× the LPS serum levels, compared to normal aging controls. [21]
Higher LPS in plasma doubled the incidence of MCI in those without dementia, in a cross-sectional prospective cohort study,[22]
Working memory/short-term verbal memory and the Digit Span Test were negatively impacted by higher levels of lipopolysaccharide binding protein.[25]
LPS treatment of microglia produced 14 times the proinflammatory prostaglandin-E2 (PGE2) and increased IL-6 inflammation, compared with untreated microglia.[28]
Milk fat triggered an early and sharp increase in LPS-laden chylomicrons at 60 min after ingestion in a randomized crossover trial.[32]
High plasma LPS levels resulted in a strong cytokine response.[33]
Higher intakes of fruit and legumes were associated with 34% and 20% less circulating LPS, respectively.[36]
AGEs
It was found that cell death from oxidation of cellular membranes due to AGEs may be one of the neuropathological mechanisms of AD.[39]
When amyloid-β is crosslinked to AGEs, the amyloid-β is more toxic to neurons.[40]
Higher levels of AGEs were associated with lower global cognitive function, while lower levels of AGEs were associated with better cognition.[42]
Dietary AGEs appear to be important risk factors for AD.
RAGE and AGE-amyloid-β can lead to reduced cerebral blood flow.		[47]
AGE content has been consistently reported higher in amyloid-β plaques in AD brains, compared to normal brains.[49]
AD brains were found to contain about 3-fold more AGE adducts and 5- to 10-fold more amyloid plaques than healthy brains.[51]
In elder subjects, those with less methylglyoxal, an AGE precursor, in serum exhibited a slower rate of cognitive decline.[52]
AGE-modified amyloid-β was found to be more toxic to synaptic proteins than amyloid-β without AGEs.[53]
AGEs were increased in subjects with Alzheimer’s disease. The decline in cognitive function in AD subjects has been correlated to the amount of protein glycation and AGEs.[54]
In a large study of elderly Japanese, those with the lowest cognitive scores had the highest levels of AGE, while those with the highest cognitive scores had the lowest levels of AGEs.[61]
Even half of the maximum levels of AGEs found in normal people resulted in a 640% greater risk of MCI, compared to the lowest AGE levels.[62]
Patients with lower AGEs declined more slowly in regard to cognition. Higher AGE levels were closely associated with a worse score in the clinical dementia rating. [63]
AA
AA is converted by 5LOX into the highly inflammatory leukotriene-A4, increasing amyloid-β production and tau phosphorylation in neuronal cells.[65]
Over-expression of COX-2 (which makes the inflammatory PGE2) in the brain of AD patients has been correlated with the progression of AD.[67]
Elevated levels of AA and phospholipid-A2 in AD brains increases inflammation of amyloid-β 1–42 peptide in the brain in AD.[68]
5LOX levels are high in amyloid-beta-containing plaques. AA processed by 5LOX into inflammatory leukotrienes is involved in both pathological inflammatory degeneration and loss of neurons and synapses in AD.[71]
Decreasing dietary AA can 1) reduce neuroinflammation, 2) reduce amyloid-beta oligomer production, 3) reduce the amyloid-beta oligomer-induced apoptotic neuronal death.[73]
AA is elevated in the AD brain, particularly in regions reported to have high densities of senile plaques and activated microglia. [74]
An accumulation of AA (37% higher) was observed in both the periphery and in the brain in patients with AD.[75]
Blood lipid analyses show that higher AA in cell membrane phospholipids is able to identify patients at higher risk of AD.[76]
Those with higher prostaglandin-F2-alpha, an eicosanoid made from AA, had a 45% increased risk of all-cause dementia.[77]
The high AA group had a 41% increase in thromboxane, which, when made from AA, is a powerful inducer of platelet aggregation and vasoconstriction that may contribute to thrombosis, vascular dementia, or stroke risk.[79]
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Blake, S.; Baroni, L.; Piboolnurak, P.; Harding, T.; Harding, M.; Blake, C. Reducing Neuroinflammation and Risk of Mild Cognitive Impairment and Alzheimer’s Disease by Reducing Dietary Lipopolysaccharides, Arachidonic Acid, and Advanced Glycation End Products. J. Dement. Alzheimer's Dis. 2025, 2, 27. https://doi.org/10.3390/jdad2030027

AMA Style

Blake S, Baroni L, Piboolnurak P, Harding T, Harding M, Blake C. Reducing Neuroinflammation and Risk of Mild Cognitive Impairment and Alzheimer’s Disease by Reducing Dietary Lipopolysaccharides, Arachidonic Acid, and Advanced Glycation End Products. Journal of Dementia and Alzheimer's Disease. 2025; 2(3):27. https://doi.org/10.3390/jdad2030027

Chicago/Turabian Style

Blake, Steven, Luciana Baroni, Panida Piboolnurak, Thomas Harding, Maile Harding, and Catherine Blake. 2025. "Reducing Neuroinflammation and Risk of Mild Cognitive Impairment and Alzheimer’s Disease by Reducing Dietary Lipopolysaccharides, Arachidonic Acid, and Advanced Glycation End Products" Journal of Dementia and Alzheimer's Disease 2, no. 3: 27. https://doi.org/10.3390/jdad2030027

APA Style

Blake, S., Baroni, L., Piboolnurak, P., Harding, T., Harding, M., & Blake, C. (2025). Reducing Neuroinflammation and Risk of Mild Cognitive Impairment and Alzheimer’s Disease by Reducing Dietary Lipopolysaccharides, Arachidonic Acid, and Advanced Glycation End Products. Journal of Dementia and Alzheimer's Disease, 2(3), 27. https://doi.org/10.3390/jdad2030027

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