Why is Dementia Called Type 3 Diabetes and is it Preventable?

We Know A Few Things About Alzheimer’s

Alzheimer’s disease has been studied extensively for decades. We know quite a lot! Alzheimer’s disease has been extensively studied, revealing significant insights into its pathology and potential triggers. Neuropathologically, Alzheimer’s is marked by the accumulation of amyloid-β plaques and tau protein neurofibrillary tangles, which contribute to synaptic loss and neuronal death, leading to cognitive dysfunction. While genetics account for approximately 70% of Alzheimer’s risk, with the APOE-E4 allele being a notable genetic factor, environmental and lifestyle factors also play a crucial role in its etiology. Having the APOE-E4 allele does not guarantee you will get the disease. Environmental contaminants, including toxic metals like aluminum and copper, pesticides, and industrial chemicals, have been implicated in neuroinflammation and neuropathology associated with Alzheimer’s. Additionally, factors such as diet, exercise, chronic inflammation, and vascular issues are believed to influence disease development. The concept of Alzheimer’s as “type 3 diabetes” suggests common pathophysiological mechanisms with type 2 diabetes, emphasizing the role of insulin resistance in the brain. Despite these findings, Alzheimer’s remains a complex and multifactorial disease, with ongoing research aiming to unravel its intricate causes and develop effective prevention and treatment strategies.

Functional Impairments of Alzheimer’s

Functional impairments in Alzheimer’s disease significantly affect patients’ quality of life, manifesting as a decline in the ability to perform activities of daily living (ADLs), such as self-care, managing finances, and engaging in social activities. These impairments progress alongside cognitive decline, particularly in memory and executive function, driven by neuroanatomical changes like hippocampal atrophy. In advanced stages, Alzheimer’s affects social interactions and hobbies, as individuals struggle with communication and recognizing familiar people and places. The resulting loss of independence increases caregiver burden and often necessitates institutional care.

Alzheimer’s Has Been Reversed in Mice

Researchers at the Okinawa Institute of Science and Technology (OIST) successfully reversed Alzheimer’s symptoms in mice using a synthetic peptide, PHDP5, which crosses the blood-brain barrier to target the memory center. PHDP5 prevents the interaction between dynamin and microtubules, ensuring dynamin is available for vesicle endocytosis, thereby restoring synaptic communication and rescuing learning and memory deficits in mice. These findings highlight the potential of innovative approaches targeting specific molecular interactions in the brain to treat Alzheimer’s disease[17].

In the Tg2576 transgenic mouse model, which overexpresses a mutant form of amyloid precursor protein, memory loss was fully reversed using BAM-10, a monoclonal antibody targeting the N terminus of amyloid-β (Aβ). This treatment neutralized Aβ assemblies that impair cognitive function, suggesting that targeting these assemblies could improve memory in Alzheimer’s patients[18].

Insulin Resistance and IGF Dysfunction

Insulin resistance occurs when cells in the body become less responsive to insulin, a hormone that regulates blood sugar, leading to higher blood glucose levels and potentially causing type 2 diabetes if left untreated.

Insulin resistance in the brain is thought to impair glucose metabolism, leading to oxidative stress and neurodegeneration, key features of Alzheimer’s pathology. Insulin resistance and insulin-like growth factor (IGF) dysfunction in the brain are increasingly recognized as critical factors in the pathogenesis of Alzheimer’s disease. Insulin is essential for neuronal survival, synaptic plasticity, and memory formation, while IGF plays a vital role in neuroprotection and cognitive function. When insulin signaling is impaired, as seen in insulin resistance, neurons cannot effectively utilize glucose, the brain’s primary energy source, leading to energy deficits and increased vulnerability to oxidative stress. This metabolic dysfunction contributes to the accumulation of amyloid-β plaques and tau protein hyperphosphorylation, exacerbating neurodegeneration. Additionally, impaired insulin signaling can lead to increased inflammation and mitochondrial dysfunction, further promoting neuronal damage. IGF dysfunction compounds these effects, as IGF is crucial for maintaining neuronal health and preventing apoptosis. Together, insulin resistance and IGF dysfunction create a cascade of pathological events that mirror those observed in Alzheimer’s disease, highlighting the potential for therapeutic strategies targeting these pathways to mitigate cognitive decline and neurodegeneration.

Amyloid-β (Aβ) Protein Pathology

Insulin resistance may contribute to the accumulation of amyloid-β proteins, exacerbating neurodegeneration by affecting their processing and clearance.

Amyloid-β (Aβ) protein pathology is a central feature in the pathogenesis of Alzheimer’s disease, contributing significantly to neurodegeneration. Insulin resistance in the brain is thought to exacerbate the accumulation of amyloid-β proteins by affecting their processing and clearance. Aβ proteins are derived from the amyloid precursor protein (APP) through sequential enzymatic actions involving β-secretase and γ-secretase. The accumulation of Aβ, particularly in its oligomeric form, is believed to initiate a cascade of pathological events. These oligomers are neurotoxic, impairing synaptic function and promoting neuronal death, which leads to cognitive decline and memory loss[9][10][11]. The oligomer cascade hypothesis emphasizes that Aβ oligomers, rather than fibrillar plaques, are the primary pathogenic agents in Alzheimer’s disease[9]. Additionally, environmental factors such as exposure to toxic metals and industrial chemicals may further influence Aβ pathology by inducing neuroinflammation and oxidative stress, which can alter Aβ metabolism and aggregation[10]. The interaction between Aβ and tau proteins also plays a crucial role, with toxic Aβ species modulating protein kinases and phosphatases that regulate tau phosphorylation, thereby promoting tau pathology and neurofibrillary tangle formation[13]. Despite extensive research, therapeutic strategies aimed at reducing Aβ levels “have yet to yield successful outcomes” in Alzheimer’s disease[12][13].

Tau Hyperphosphorylation

Tau protein, named as an abbreviation for “tubulin associated unit,” is a microtubule-associated protein that, when hyperphosphorylated (excessive phosphate groups are added), loses its ability to stabilize microtubules and instead aggregates into neurofibrillary tangles, a characteristic feature of Alzheimer’s disease and other tauopathies. Central insulin resistance could lead to tau protein hyperphosphorylation, disrupting neuronal function and contributing to cognitive decline.

Tau hyperphosphorylatio destabilizes microtubules and disrupts neuronal function. Central insulin resistance is believed to contribute to this process by impairing insulin signaling pathways that regulate tau phosphorylation. In a healthy brain, tau proteins stabilize microtubules, which are essential for maintaining neuronal structure and facilitating intracellular transport. However, when insulin signaling is disrupted, as seen in insulin resistance, there is an upregulation of kinases such as glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5), which phosphorylate tau beyond normal levels. This hyperphosphorylated tau detaches from microtubules, leading to their disassembly and the formation of neurofibrillary tangles, which are toxic to neurons. The accumulation of these tangles impairs synaptic function and neuronal communication, ultimately contributing to cognitive decline and memory loss. Additionally, tau hyperphosphorylation is exacerbated by oxidative stress and neuroinflammation, both of which are linked to insulin resistance. Understanding the mechanisms behind tau hyperphosphorylation and its relationship with insulin resistance offers potential therapeutic avenues for mitigating neurodegeneration and preserving cognitive function in Alzheimer’s patients.

Theories Involving Food Additives and Chemicals

Ultra-Processed Foods (UPFs)

Association with Alzheimer’s: Diets high in UPFs, which contain unhealthy fats, salt, sugars, and artificial additives, have been linked to an increased risk of dementia, including Alzheimer’s disease.
Mechanism: UPFs may promote chronic inflammation, oxidative stress, and gut microbiota alterations, indirectly contributing to cognitive decline through conditions like obesity and hypertension.

Toxic Metals

Aluminum: Found in processed foods and packaging, aluminum exposure is hypothesized to contribute to Alzheimer’s by inducing neuroinflammation and disrupting amyloid-β homeostasis.
Copper and Lead: These metals have been associated with neurotoxicity and Alzheimer’s-like symptoms in experimental models.

Pesticides and Industrial Chemicals

Pesticides: Organophosphate insecticides are linked to cognitive impairment and may contribute to Alzheimer’s disease through chronic exposure.
Flame Retardants and Plasticizers: Chemicals like bisphenol A are suspected to cause neurodevelopmental disturbances and behavioral changes, potentially impacting Alzheimer’s progression.

Claims of Cures and Mechanisms

Insulin Sensitizers

Drugs like metformin are being explored for their ability to enhance insulin signaling in the brain, potentially slowing cognitive decline by improving glucose metabolism. Recent studies have shown that metformin may also activate AMPK (AMP-activated protein kinase), which can promote neuronal survival and reduce tau phosphorylation.

Nutraceuticals and Antioxidants

Compounds such as polyphenols and omega-3 fatty acids, known for their antioxidant properties, may reduce oxidative stress and inflammation, offering a potential therapeutic avenue. For instance, resveratrol, a polyphenol found in red wine, has been shown to activate SIRT1, a protein that can protect against neurodegeneration by deacetylating tau.

Lifestyle Interventions

The Mediterranean diet, rich in vegetables, fruits, whole grains, olive oil, beans, and fish, is associated with a reduced risk of Alzheimer’s disease and cognitive decline[20][21]. It actually includes whole grains as a significant component, which are believed to contribute to its protective effects against Alzheimer’s[20][24]. Dr. David Perlmutter, in his book “Grain Brain,” argues that grains can negatively impact brain health and contribute to dementia, suggesting a different perspective on the role of grains in cognitive health. Perlmutter argues that carbohydrates, including whole grains, trigger inflammatory responses leading to neurological issues. However, the Mediterranean diet’s emphasis on whole grains, along with other plant-based foods, has been shown to reduce Alzheimer’s risk by lowering inflammation and supporting brain health[19][21]. Probably what ChatGPT and most doctors fail to understand is that compared to the Standard American Diet, whole grains are better than that, but even better would be cutting out the grains, as Perlmutter says. While whole grains are beneficial compared to refined grains, very low-carb or grain-free diets may offer even better blood sugar control, especially for individuals with type 2 (and/or type 3) diabetes. These grain-free diets have shown significant benefits in systematic reviews and randomized controlled trials[28]. We recommend belieivng your body, which means do a test: three weeks with whole grains and three weeks getting your carbs from healthy non-grain sources like sweet potatoes, mushrooms, fruits, legumes, and vegetables.

Multitargeted Drug Therapies

Research is ongoing into drugs that target multiple pathways involved in both diabetes and Alzheimer’s, aiming to improve insulin signaling and reduce neuroinflammation. One promising candidate is the drug pioglitazone, a PPARγ agonist, which has demonstrated potential in modulating glucose metabolism and reducing amyloid-beta deposition in preclinical models.

Preventing tau protein hyperphosphorylation

Preventing tau protein hyperphosphorylation is a key focus in Alzheimer’s disease research, as this process is linked to neurodegeneration and cognitive decline. Here are several strategies and theories on how tau hyperphosphorylation can be prevented, along with their molecular mechanisms:

Inhibition of Kinases

Glycogen Synthase Kinase-3β (GSK-3β) and Cyclin-Dependent Kinase 5 (CDK5)

– Mechanism: These kinases are heavily involved in the phosphorylation of tau. Inhibiting their activity can reduce tau hyperphosphorylation, potentially preventing the destabilization of microtubules and subsequent neurodegeneration[1][5].
– Therapeutic Development: Drugs targeting these kinases are being designed to prevent tau phosphorylation and aggregation, with some showing promise in preclinical studies[5].

Activation of Phosphatases

Protein Phosphatase 2A (PP2A)

– Mechanism: PP2A is a major phosphatase that dephosphorylates tau. Enhancing its activity can counteract hyperphosphorylation, restoring normal tau function[1].
– Therapeutic Strategy: Activators of PP2A are being explored as potential therapies to reduce tau pathology in Alzheimer’s disease[3].

Targeting Tau O-GlcNAcylation

– Mechanism: O-GlcNAcylation is a post-translational modification that can compete with phosphorylation on tau, potentially reducing hyperphosphorylation[1].
– Research Focus: Modulating O-GlcNAcylation levels could provide a novel approach to controlling tau phosphorylation and its pathological consequences.

Immunotherapy

– Mechanism: Immunotherapy aims to use antibodies to target and remove hyperphosphorylated tau species, thereby preventing aggregation and the formation of neurofibrillary tangles[4].
– Clinical Trials: Various immunotherapy strategies are in development, focusing on different tau epitopes to enhance clearance of pathological tau[4].

Small Molecule Inhibitors

– Mechanism: Small molecules designed to stabilize microtubules or prevent tau aggregation are being investigated. These compounds aim to maintain tau in its functional state and prevent the formation of toxic aggregates[3][5].
– Examples: Compounds like LiCl, MW181, and Fasudil have shown potential in reducing tau hyperphosphorylation and aggregation in preclinical models[3].

From a pharmceutical perspective, preventing tau hyperphosphorylation involves targeting the kinases and phosphatases that regulate tau phosphorylation, as well as exploring novel therapeutic avenues such as immunotherapy and small molecule inhibitors. While promising strategies are in development, further research is needed to establish effective treatments for Alzheimer’s disease and related tauopathies.

Triggers of Tau Hyperphosphorylation

Imbalance in Kinase and Phosphatase Activity

Tau phosphorylation is regulated by a balance between kinases and phosphatases. An imbalance, often due to increased kinase activity or decreased phosphatase activity, leads to hyperphosphorylation. Key kinases involved include glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5), and extracellular signal-regulated kinase 2 (ERK2).

Oxidative Stress

Oxidative stress is a significant factor contributing to tau hyperphosphorylation. It can alter kinase and phosphatase activities, promoting phosphorylation and subsequent tau aggregation. Additionally, oxidative stress can damage cellular components, exacerbating neurodegenerative processes.

Pollution: Exposure to air pollutants increases free radicals, leading to oxidative stress.
Cigarette Smoke: Smoking introduces free radicals and toxins, significantly raising oxidative stress.
Radiation: Non-ionizing (eg UV) and ionizing radiation increases reactive oxygen species.
Poor Diet: Diets high in fat, sugar, and processed foods elevate oxidative stress levels.
Obesity: Excess body fat is linked to increased oxidative stress from inflammation.
Alcohol Consumption: Alcohol can generate ROS, contributing to oxidative stress.
Pesticides and Industrial Chemicals: Many substances can raise ROS production .
Chronic Inflammation: Inflammatory processes produce free radicals, increasing oxidative stress.
Excessive Exercise: While moderate exercise is beneficial, excessive activity raises ROS levels.
Certain Medications: Some drugs can induce oxidative stress by increasing ROS production.

Lack of Exercise: While not a direct cause of oxidative stress, sitting around too much increases the damage from oxidative stress from other sources. This is because regular physical activity helps upregulate antioxidant defenses and improve ability to neutralize free radicals, while a sedentary lifestyle increases vulnerability to oxidative damage.

Chronic Inflammation

Chronic inflammation is hypothesized to play a role in triggering tau hyperphosphorylation. Inflammatory cytokines can modulate kinase activity, leading to increased phosphorylation. This persistent inflammatory state may also disrupt neuronal function and integrity over time.

Post-Translational Modifications

Tau undergoes various post-translational modifications, including glycation, nitration, and ubiquitination, which can influence its phosphorylation status and promote aggregation. These modifications can affect tau’s interaction with microtubules, impairing their stability and function.

Conclusion

While the concept of type 3 diabetes offers a framework for understanding the link between diabetes and Alzheimer’s, it remains a hypothesis. Further research is necessary to elucidate the exact mechanisms and validate this connection.