Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism?

Johnson, Richard J.; Tolan, Dean R.; Bredesen, Dale E.; Nagel, Maria A.; Sánchez‐Lozada, Laura G.; Fini, Mehdi A.; Burtis, Scott; Lanaspa, Miguel A.; Perlmutter, David D.

doi:10.1016/j.ajcnut.2023.01.002

Cited by 15 publications

(12 citation statements)

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“…As antioxidants and free radical scavenger, uric acid also plays a neuroprotective role by alleviating oxidative stress damage induced by aging or inflammation (Tana et al., 2018). In addition, mitochondrial dysfunction has been confirmed as one of the pathogenesis of AD (Perez Ortiz & Swerdlow, 2019), while uric acid preserves mitochondrial function by inhibiting the cytotoxic effect of lactoperoxidase and repairing DNA damaged by oxygen radical (Johnson et al., 2023; Yu et al., 1998).…”

Section: Discussionmentioning

confidence: 99%

“…as one of the pathogenesis of AD (Perez Ortiz & Swerdlow, 2019), while uric acid preserves mitochondrial function by inhibiting the cytotoxic effect of lactoperoxidase and repairing DNA damaged by oxygen radical (Johnson et al, 2023;Yu et al, 1998).…”

Section: Countrymentioning

confidence: 99%

“…Some cohort studies have suggested that hyperuricemia is associated with better cognitive function (Chen et al, 2021;Tan et al, 2023). Yet, by contrary, several epidemiological studies have shown that elevated serum uric acid was associated with cognitive impairment (Alam et al, 2020;Huang et al, 2022), especially AD (Johnson et al, 2023). Therefore, it is unclear whether gout or hyperuricemia is prone to AD or prevent against AD.…”

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confidence: 99%

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Gout/hyperuricemia reduces the risk of Alzheimer's disease: A meta‐analysis based on latest evidence

Wang,

Tan,

Wang

et al. 2023

Brain and Behavior

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ObjectivePrevious studies have found the potential role of gout or hyperuricemia in subsequent development of Alzheimer's disease (AD) but reported inconsistent results. We conducted the current meta‐analysis to evaluate whether an association exists between gout/ hyperuricemia and AD.MethodsWe systematically searched PubMed and EMBASE for the published cohort studies that measured the risk of AD in subject with gout/ hyperuricemia up to May 20, 2023. Data extraction was employed by two authors independently. Rev Man 5.3 and Stata 15.0 software were used to calculate the relative ratio (RR) or hazard ratio (HR) for including studies. Subgroup analysis was performed to assess the sources of heterogeneity. A random‐effects model was adopted when heterogeneity was present. The funnel plot, Begg's test, and and Egger's test were used to assess publication bias.ResultsAfter rigorous screening, seven eligible studies were included in the final analyses. Pooled results indicated that gout or hyperuricemia decreases the risk of AD (RR: 0.69, 95% CI: 0.64∼0.72), with a high heterogeneity of 93%. Subgroup analyses showed that regional distribution was the source of heterogeneity. Egger's and Begg's tests as well as visual inspection of funnel plot suggested no publication bias in the studies.ConclusionThe findings suggested that gout or hyperuricemia might have a protective effect against AD. This negative correlation should be verified by more cohort studies due to the existence of substantial heterogeneity.

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Section: Discussionmentioning

confidence: 99%

Section: Countrymentioning

confidence: 99%

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confidence: 99%

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Gout/hyperuricemia reduces the risk of Alzheimer's disease: A meta‐analysis based on latest evidence

Wang,

Tan,

Wang

et al. 2023

Brain and Behavior

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“…The hypotheses also provide mechanistic pathways for how fructose-induced obesity can be associated with other features of metabolic syndrome. Indeed, the pathway can also explain the pathogenesis of other conditions, including obesityassociated cancers [71], behavioral disorders [72], and Alzheimer's disease [73], as well as the reason uric acid is so strongly linked with metabolic disorders [74]. The metabolism of fructose and generation of intracellular uric acid also induces oxidative stress due to the stimulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [25,75], which can cause oxidative stress that may have a role in cardiovascular disease.…”

Section: Other Hypothesesmentioning

confidence: 99%

“…In summary, our studies suggest that glucose and fructose have very distinct functions, with glucose meant to provide immediate energy while fructose assists in the storage of energy [13]. The consequences of chronically activating this switch are not simply to cause obesity but also to drive many noncommunicable diseases (Figure 3) [13, 46]. Although initially the effects of fructose are time‐limited, over a lifetime the repeated oxidative stress to the mitochondria causes mitochondrial fission and drop‐out, leading to more permanent changes that lock one into the obese state and drive the aging process.…”

Section: A Quick Overview Of the Fructose Survival Pathwaymentioning

confidence: 99%

The fructose survival hypothesis as a mechanism for unifying the various obesity hypotheses

Johnson,

Sánchez‐Lozada,

Lanaspa

2023

Obesity

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The pathogenesis of obesity remains contested. Although genetics is important, the rapid rise in obesity with Western culture and diet suggests an environmental component. Today, some of the major hypotheses for obesity include the energy balance hypothesis, the carbohydrate‐insulin model, the protein‐leverage hypothesis, and the seed oil hypothesis. Each hypothesis has its own support, creating controversy over their respective roles in driving obesity. Here we propose that all hypotheses are largely correct and can be unified by another dietary hypothesis, the fructose survival hypothesis. Fructose is unique in resetting ATP levels to a lower level in the cell as a consequence of suppressing mitochondrial function, while blocking the replacement of ATP from fat. The low intracellular ATP levels result in carbohydrate‐dependent hunger, impaired satiety (leptin resistance), and metabolic effects that result in the increased intake of energy‐dense fats. This hypothesis emphasizes the unique role of carbohydrates in stimulating intake while fat provides the main source of energy. Thus, obesity is a disorder of energy metabolism, in which there is low usable energy (ATP) in the setting of elevated total energy. This leads to metabolic effects independent of excess energy while the excess energy drives weight gain.

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Charnolosome and inflammasome in chronic MDR diseases

Sharma

2025

The Charnolosome as a Novel Nanothereranostic Biomarker

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Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism?

Cited by 15 publications

References 168 publications

Gout/hyperuricemia reduces the risk of Alzheimer's disease: A meta‐analysis based on latest evidence

Gout/hyperuricemia reduces the risk of Alzheimer's disease: A meta‐analysis based on latest evidence

The fructose survival hypothesis as a mechanism for unifying the various obesity hypotheses

Charnolosome and inflammasome in chronic MDR diseases

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