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

Although biological effects of fructose metabolism and its byproduct, intracellular uric acid, appear critical for the survival of many animals in nature, including our ancestors, in modern society, it appears to be overengaged, increasing the risk for metabolic syndrome, obesity, diabetes, and other conditions
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uric acid translocatess NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) to the mitochondria, leading to oxidative stress that blocks the citric acid cycle (via inhibition of aconitase) and fatty acid β-oxidation. As mitochondrial function slows, glycolysis takes over, while uric acid inhibits AMP-activated protein kinase, reducing the ability to recover ATP. The effect is a reduction in ATP in the cell, activating a survival switch that includes hunger, thirst, foraging, fat accumulation, and insulin resistance.
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Uric acid translocates NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) to the mitochondria, where it causes oxidative stress, reducing fatty acid oxidation (blocking enoyl CoA hydratase) while inhibiting aconitase in the citric acid cycle
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In nature, dietary fructose from excessive intake of fruit provides a major pathway to activate this survival response, much like what occurs in the autumn when bears prepare for hibernation. However, fructose is also produced in the body via the polyol pathway, in which glucose is converted to fructose. The rate-limiting enzyme in the polyol pathway is aldose reductase, and its activity is stimulated during times of stress, such as when nutrient delivery is impaired (hypoxia or ischemia), when water supplies are low (dehydration, hyperglycemia, and hyperosmolarity), or when uric acid levels are high (reflecting degradation of nucleotides and ATP, suggestive of an energy crisis)

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However, the studies that evaluated the differences between fructose and glucose in cerebral metabolism using BOLD MRI were performed early (∼15 min), thus making it more likely to reflect true differences between fructose and glucose. The striking finding from these studies was that fructose reduced blood flow to the posterior cingulate cortex, the hippocampus, the thalamus, and the occipital cortex; however, blood flow increased to the area of the visual cortex associated with food reward. Cortical blood flow also decreased. Fructose administration also stimulated hunger and desire for food. These responses are consistent with a stimulation of the foraging response. In contrast, glucose inhibited blood flow to the hypothalamus, thalamus, insula, anterior cingulate, and striatum while stimulating blood flow to the cortex. These responses are expected to inhibit not only the foraging response but also responses involving appetite and reward.
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The brain can generate and metabolize fructose
Our hypothesis suggests that local fructose generation and metabolism may be the critical factor for how fructose induces AD because under normal circumstances, only 1%–2% of ingested fructose reaches the brain. Indeed, the brain is capable of producing fructose. As mentioned earlier, simply raising blood glucose levels increases brain fructose levels in healthy humans. Raising serum osmolality in mice by dehydration or salty food also stimulates fructose production in the brain (hypothalamus). Dietary fructose may also increase fructose production in the brain, possibly by raising uric acid levels in the brain. For example, acutely raising serum uric acid increases uric acid in both the hypothalamus and the hippocampus in association with local inflammation. In turn, uric acid stimulates fructose production and metabolism.
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Fructose is elevated in the brain of patients with AD
Sorbitol and fructose levels (both components of the polyol pathway) were significantly elevated, averaging 3–5-fold higher in all regions of the brain studied, including the hippocampus, entorhinal cortex, middle temporal gyrus, cingulate cortex, sensory and motor cortex, and cerebellum.
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Numerous studies have reported that subjects with AD have low serum uric acid levels, suggesting that this might be important to the pathogenesis. However, although serum uric acid may reflect fructose metabolism, it also is a general marker of nutrition status. Clinical manifestations of AD are often preceded by significant weight loss. Which may account for the lower serum uric acid levels on presentation of AD. This may also explain why obesity predicts AD in midlife but actually protects from AD late in life
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https://www.sciencedirect.com/science/article/pii/S0002916523000047

@LucH Thanks for the link. I'm curious regarding the interpretation of Beta-Amyloid and Tau Proteins by various parties. The behaviour of the proteins seemed to have commonality with Uric Acid.

Metformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice
Abstract
Insulin deficiency or resistance can promote dementia and hallmarks of Alzheimer's disease (AD). The formation of neurofibrillary tangles of p-TAU protein, extracellular Aβ plaques, and neuronal loss is related to the switching off insulin signaling in cognition brain areas. Metformin is a biguanide antihyperglycemic drug used worldwide for the treatment of type 2 diabetes. Some studies have demonstrated that metformin exerts neuroprotective, anti-inflammatory, anti-oxidant, and nootropic effects. This study aimed to evaluate metformin's effects on long-term memory and p-Tau and amyloid β modulation, which are hallmarks of AD in diabetic mice. Swiss Webster mice were distributed in the following experimental groups: control; treated with streptozotocin (STZ) that is an agent toxic to the insulin-producing beta cells; STZ + metformin 200 mg/kg (M200). STZ mice showed significant augmentation of time spent to reach the target box in the Barnes maze, while M200 mice showed a significant time reduction. Moreover, the M200 group showed reduced GFAP immunoreactivity in hippocampal dentate gyrus and CA1 compared with the STZ group. STZ mice showed high p-Tau levels, reduced p-CREB, and accumulation of β-amyloid (Aβ) plaque in hippocampal areas and corpus callosum. In contrast, all these changes were reversed in the M200 group. Protein expressions of p-Tau, p-ERK, pGSK3, iNOS, nNOS, PARP, Cytochrome c, caspase 3, and GluN2A were increased in the parietal cortex of STZ mice and significantly counteracted in M200 mice. Moreover, M200 mice also showed significantly high levels of eNOS, AMPK, and p-AKT expression. In conclusion, metformin improved spatial memory in diabetic mice, which can be associated with reducing p-Tau and β-amyloid (Aβ) plaque load and inhibition of neuronal death.
https://pubmed.ncbi.nlm.nih.gov/34283253/

Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice
Abstract
Diabetes increases the risk of Alzheimer's disease (AD). The pathological hallmarks for AD brains are extracellular amyloid plaques formed by β-amyloid peptide (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. This study was designed to determine AD-like brain changes in mice modeling for type 2 diabetes. The effects of metformin on these changes also were studied. Seven-week old male db/db mice received intraperitoneal injection of 200 mg kg− 1 d− 1 metformin for 18 weeks. They were subjected to Barnes maze at an age of 21 weeks and fear conditioning at an age of 24 weeks to assess their cognitive functions. Hippocampus was harvested after these tests for biochemical evaluation. The db/db mice had more tau phosphorylated at S396 and total tau in their hippocampi than their non-diabetic control db + mice. Activated/phosphorylated c-jun N-terminal kinase (JNK), a tau kinase, was increased in the db/db mouse hippocampus. Metformin attenuated the increase of total tau, phospho-tau and activated JNK. The db/db mice had increased Aβ levels. Metformin attenuated the reduction of synaptophysin, a synaptic protein, in the db/db mouse hippocampus. Metformin did not attenuate the impairments of spatial learning and memory as well as long-term hyperglycemia in the db/db mice. Our results suggest that the db/db mice have multiple AD-like brain changes including impaired cognitive functions, increased phospho-tau and Aβ as well as decreased synaptic proteins. Activation of JNK may contribute to the increased phospho-tau in the db/db mice. Metformin attenuates AD-like biochemical changes in the brain of these mice.
https://www.sciencedirect.com/science/article/abs/pii/S0091305712000640

Gout risk in adults with pre-diabetes initiating metformin
Conclusions: Metformin use was associated with a reduced risk of gout among adults with pre-diabetes, suggesting that metformin may be important in lowering gout risk in individuals with pre-diabetes.
https://ard.bmj.com/content/early/2024/05/15/ard-2024-225652

Metformin Lowers Serum Urate Levels but Not Gout Risk
https://www.rheumatologyadvisor.com/news/metformin-lowers-serum-urate-but-not-gout-risk/

Effect of metformin use on clinical outcomes and serum urate in gout patients with diabetes mellitus: a retrospective cohort study
In conclusion we could not confirm a clinically relevant anti-inflammatory or urate lowering effect of metformin in patients starting ULT treatment and receiving usual care flare prophylaxis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9153141/

Metformin Initiation Cuts Gout Risk in Prediabetes
Metformin use lowers the risk for gout by 32% in individuals with prediabetes; however, the treatment doesn't change serum urate or C-reactive protein levels.
https://www.medscape.com/viewarticle/metformin-initiation-cuts-gout-risk-prediabetes-2024a1000a4j

Metformin ameliorates high uric acid-induced insulin resistance in skeletal muscle cells
https://www.sciencedirect.com/science/article/abs/pii/S0303720716305482

Metformin protects against insulin resistance induced by high uric acid in cardiomyocytes via AMPK signaling pathways in vitro and in vivo
https://www.biorxiv.org/content/10.1101/2021.01.29.428905v1

Fasting enhances extinction retention and prevents the return of fear in humans

Fear is prone to return following extinction that is the basis of exposure therapy for fear-related disorders. Manipulations that enhance the extinction process can be beneficial for treatment. Animal studies have shown that fasting or caloric restriction can enhance extinction and inhibit the return of fear. The present study examined the effects of fasting on fear acquisition, extinction, and the return of fear in humans. One hundred and twenty-five male participants were randomized into a fasting group and food group and exposed to a Pavlovian fear conditioning paradigm. Changes in plasma cortisol and ghrelin levels were examined using enzyme-linked immunosorbent assays. One-night fasting had no effect on fear acquisition but enhanced fear extinction retention and prevented the return of fear, and this effect persisted for at least 6 months. This procedure was also effective for remote fear memory. Plasma ghrelin levels were elevated after fasting and had a negative relationship with the fear response in spontaneous recovery test. However, overnight fasting did not affect cortisol levels. These findings indicate that fasting enhances extinction retention and prevents the return of fear, without influencing fear memory formation. We propose that this novel procedure may open new avenues for promoting extinction-based therapies for fear-related disorders.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177454/

The Association of Posttraumatic Stress Disorder with Fast Food and Soda Consumption and Unhealthy Weight Loss Behaviors Among Young Women
Results
PTSD symptoms were associated with an increased frequency of consumption of fast food and soda as well as unhealthy dieting behaviors but not with increased body mass index (BMI).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153863/

Youtube - Fighting cancer cells with Calcium Carbonate

Mind-body practices lower blood sugar levels in people with type 2 diabetes
All practices achieve significant reductions in blood sugar levels

The team analyzed data from randomized controlled trials conducted across the globe between 1993 and 2022. They found 28 trials in which people with type 2 diabetes began a mind-body practice in addition to receiving medication and compared their results with people who only received medication to reduce their blood sugar levels.

This study, the first to analyze a range of mind-body practices including meditation, qigong, yoga and mindfulness-based stress reduction and their effect on blood glucose levels, revealed that all mind-body practices led to significant reductions in blood sugar levels.

Taken as a whole, the mind-body practices averaged a .84% reduction in hemoglobin A1c, a measure of the average blood glucose level for the past 3 months. Yoga, the most-studied modality, provided the largest benefit, about a 1% reduction in hemoglobin A1c. The authors noted that a 1% reduction is particularly notable because metformin, the most prescribed diabetes drug, reduces hemoglobin A1c in people with type 2 diabetes by 1.1% on average.

“What is important about this study is that the effect is very strong and that it is on top of the standard of care,” said Richard M. Watanabe, PhD, professor of population and public health sciences and physiology and neuroscience at the Keck School of Medicine, noting that the research revealed that mind-body practices helped participants achieve reductions in blood glucose levels on top of the reductions they were getting from medication.
https://keck.usc.edu/news/mind-body-practices-lower-blood-sugar-levels-in-people-with-type-2-diabetes/

Effect of 6 Months of Meditation on Blood Sugar, Glycosylated Hemoglobin, and Insulin Levels in Patients of Coronary Artery Disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934947/

Effects of Buddhist walking meditation on glycemic control and vascular function in patients with type 2 diabetes
Results
After 12 weeks, maximal oxygen consumption increased and fasting blood glucose level decreased significantly in both groups (p < 0.05). Significant decrease in HbA1c and both systolic and diastolic blood pressure were observed only in the WM group. Flow-mediated dilatation increased significantly (p < 0.05) in both exercise groups but arterial stiffness was improved only in the WM group. Blood cortisol level was reduced (p < 0.05) only in the WM group.

Conclusion
Buddhist walking meditation exercise produced a multitude of favorable effects, often superior to traditional walking program, in patients with type 2 diabetes.
https://www.sciencedirect.com/science/article/abs/pii/S0965229916300346

Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
https://www.nature.com/articles/nature13270

The ‘Jekyll and Hyde’ of Gluconeogenesis: Early Life Adversity, Later Life Stress, and Metabolic Disturbances
The physiological response to a psychological stressor broadly impacts energy metabolism. Inversely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA), and sympathetic nervous system activation. Glucocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of energy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance, and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, and the most prominent are early life adversity, or exposure to traumatic stress. We hypothesise that when the HPA axis is so disturbed after early life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037741/

Association between Metformin Treatment and Improved Symptoms of Post-Traumatic Stress Disorder
https://diabetesjournals.org/diabetes/article/69/Supplement_1/174-LB/56254

Metformin Use Associated with Decreased PTSD Symptoms in Diabetic Veterans
https://www.hcplive.com/view/metformin-associated-with-decreased-ptsd-symptoms-in-diabetic-veterans

Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation
https://pubmed.ncbi.nlm.nih.gov/31521867/

To counteract possible lactic acidosis induced by metformin, simply add a teaspoon of calcium carbonate to your favourite beverage:
Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin
Abstract
Objective: Of patients who are prescribed metformin, 10-30% have evidence of reduced vitamin B12 absorption. B12-intrinsic factor complex uptake by ileal cell surface receptors is known to be a process dependent on calcium availability Metformin affects calcium-dependent membrane action. The objective of this study was to determine the magnitude and mechanism of the reduction in serum vitamin B12 after metformin administration.

Research design and methods: A comparative study design was employed using 2 groups (metformin and control). A total of 21 patients with type 2 diabetes received sulfonylurea therapy; 14 of these 21 patients were switched to metformin. Monthly serum total vitamin B12 measurements and holotranscobalamin (holoTCII) (B12-TCII) were performed. After 3 months of metformin therapy, oral calcium supplementation was administered.

Results: Serial serum vitamin B12 determinations revealed a similar decline in vitamin B12 and holoTCII. Oral calcium supplementation reversed the metformin-induced serum holoTCII depression.

Conclusions: Patients receiving metformin have diminished B12 absorption and low serum total vitamin B12 and TCII-B12 levels because of a calcium-dependent ileal membrane antagonism, an effect reversed with supplemental calcium.
https://pubmed.ncbi.nlm.nih.gov/10977010/

The successful application of honey in wound care management has been achieved due to honey’s potent antibacterial effects, characterised by its multifactorial action. Impressive clinical efficacy has ignited its further use in diverse clinical disciplines, including stomatology. Indeed, there is increasing usage of honey in dental medicine as a preventive or therapeutic remedy for some periodontal diseases mainly associated with bacteria, such as dental caries, gingivitis and mucositides. Dental caries is undoubtedly a major oral health problem worldwide, with an increasing tendency of incidence. The purpose of this perspective review is to describe the recent progress in the laboratory and clinical use of honey in the prevention of dental caries, with emphasis on the antibacterial and antibiofilm effects of honey. The role of honey in the cariogenic process is also discussed. In addition, the quality of honey and the urgent in vitro evaluation of its antibacterial/antibiofilm properties before clinical use are highlighted. Findings based on data extracted from laboratory studies demonstrate the pronounced antibacterial effect of different honeys against a number of periodontal pathogens, including Streptococcus mutans. Although the promising antibiofilm effects of honey have been reported mainly against S. mutans, these results are limited to very few studies. From a clinical point of view, honey significantly reduces dental plaque; however, it is not superior to the conventional agent. Despite the positive in vitro results, the clinical effectiveness of honey in the prevention of dental caries remains inconclusive since further robust clinical studies are needed.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9455747/

Abstract
Importance: Supporting healthy aging is a US public health priority, and gratitude is a potentially modifiable psychological factor that may enhance health and well-being in older adults. However, the association between gratitude and mortality has not been studied.

Objective: To examine the association of gratitude with all-cause and cause-specific mortality in later life.

Design, Setting, and Participants: This population-based prospective cohort study used data from self-reported questionnaires and medical records of 49 275 US older female registered nurses who participated in the Nurses’ Health Study (2016 questionnaire wave to December 2019). Cox proportional hazards regression models estimated the hazard ratio (HR) of deaths by self-reported levels of gratitude at baseline. These models adjusted for baseline sociodemographic characteristics, social participation, physical health, lifestyle factors, cognitive function, and mental health. Data analysis was conducted from December 2022 to April 2024.

Exposure: Gratitude was assessed with the 6-item Gratitude Questionnaire, a validated and widely used measure of one’s tendency to experience grateful affect.

Main Outcomes and Measures: Deaths were identified from the National Death Index, state statistics records, reports by next of kin, and the postal system. Causes of death were ascertained by physicians through reviewing death certificates and medical records.

Results: Among the 49 275 participants (all female; mean [SD] age at baseline, 79 [6.16] years), 4608 incident deaths were identified over 151 496 person-years of follow-up. Greater gratitude at baseline was associated with a lower hazard of mortality in a monotonic fashion. For instance, the highest tertile of gratitude, compared with the lowest tertile, was associated with a lower hazard of all-cause deaths (HR, 0.91; 95% CI, 0.84-0.99) after adjusting for baseline sociodemographic characteristics, social participation, religious involvement, physical health, lifestyle factors, cognitive function, and mental health. When considering cause-specific deaths, death from cardiovascular disease was inversely associated with gratitude (HR, 0.85; 95% CI, 0.73-0.995).

Conclusions and Relevance: This study provides the first empirical evidence suggesting that experiencing grateful affect is associated with increased longevity among older adults. The findings will need to be replicated in future studies with more representative samples.

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2820770

Abstract
Estrogens (estron: E1; estradiol: E2; estriol: E3) are major water pollutants. For the removal of estrogens, activated carbon (AC) and ozone treatments were employed, and the chemical oxygen demand (COD) and pH of a single solution and multiple solution systems were investigated. The removal of estrogens increased with the amount of AC. The percentage of removed estrogens by AC in the single solution system was greater than that in the ternary solution system. The estrogens were completely removed using ozone, which also reduced COD and pH. The removal of estrogens increased the water quality and decreased the amount of organic carbon.
https://pubmed.ncbi.nlm.nih.gov/22123241/

By Antony Reed on Quora
"Having studied vitamin C extensively for 4+ years now, as well as being someone who has been taking 25–35 grams of ascorbic acid daily for that same time period, I have only had improved health over all. The acidity is not an issue as once the C is metabolized, it has a net alkaline result due to its antioxidant nature.

Most arguments against taking high doses rely on a few studies on healthy subjects and do not take into account the fact that 99% of the animal kingdom makes it internally and we fall into the category of the very few species who lost the ability to make an enzyme necessary to do so ourselves, so we need to acquire it from food.

Most animals make a human equivalent of between 4–13 grams of per day. However, if they are sick, injured or stressed, they can produce upwards of 10-times this amount.

We are no different. When we are sick, say, with a bad cold, we can consume vastly more ascorbic acid before reaching a bowel tolerance level. This can reach more than 100 grams in a day in some cases, or more."
https://www.youtube.com/watch?v=YrTDl0e04_k