Alzheimer's disease model explains Alzheimer’s disease incidences

Abstract

AD-model rationale:

The contributing factors of Alzheimer's disease are cerebral vessel disease, insulin resistance, hypometabolism, oxidative stress, abnormal-protein aggregation, and inflammation. Brain insulin resistance is influenced by inflammation, glycemia, and stress, and glucose uptake into the central nervous system is mediated by brain glucose transporter. Glucose hypometabolism leads to oxidative stress. During protein synthesis, DNA is vulnerable to being insulted by reactive oxygen species. If repair fails, the neuron undergoes apoptosis. If the repair is imperfect, it may synthesize an abnormal protein, which could induce an immune response. The resulting inflammation may initiate brain insulin resistance, leading to glucose hypometabolism. Integrating all these major factors forms an AD model. One factor impacts more other factors. This process becomes a vicious cycle, creating a positive feedback loop.

AD-model application:

The AD model should be able to explain the observable AD incidents. The amyloid-β (Aβ) is extracellular, which would induce an immune response. On the contrary, tau and α-synuclein are intracellular proteins, which only cause an immune response if they leak out of the neuron. This is the reason why 2/3 of dementia cases are AD. Besides living longer, women have more immune sensitivity compared to men, and postmenopausal women have higher insulin resistance and endothelial dysfunction due to a decline in estrogen production. This is the reason why women have twice the AD in comparison to men. Removing abnormal proteins or applying an anti-inflammatory agent could reduce inflammation; therefore, one-third of people remain cognitively normal despite the presence of Aβ buildup in the brain.

Introduction

In 1906, Alois Alzheimer reported a 50-year-old woman whom he had followed from her admission for paranoia, progressive sleep and memory disturbance, aggression, and confusion, until her death 5 years later. He noted distinctive plaques and neurofibrillary tangles in the brain histology. ¹ The hypotheses of Alzheimer's disease (AD) include the amyloid cascade hypothesis and tau hyperphosphorylation. ² AD is a progressive brain disorder that slowly destroys memory and thinking skills. Currently, about 55 million AD cases in the world, ³ and there is no curative treatment. ⁴ Many scientists hypothesize new AD hypotheses to elucidate the AD development.

Amyloid cascade hypothesis

The accumulation of amyloid-β (Aβ) plaques in the brain is the initiating event in the disease process. This accumulation is thought to trigger a cascade of events. ⁵ The pathology is characterized by the amyloid peptide deposits and neurofibrillary tangles in the brain. Increased inflammation and oxidative stress appear to be key features contributing to the pathology. ⁶ All point to the Aβ pathway as a hallmark of disease pathophysiology. ⁷ Lecanemab and donanemab are antibody drugs to lower levels of amyloid plaques and slow cognitive decline in individuals with early symptomatic AD. ⁸ Both drugs are anti-amyloid only, therefore ineffective for the onset of AD.

Tau hypothesis

Tau protein aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases, disrupting the structure and function of neurons and leading to neuronal death, which triggers the initiation and progression of neurological. ⁹ Abnormally phosphorylated tau can increase Aβ production. As Aβ oligomers increase abnormal phosphorylation of tau, this would drive vicious cycles leading to the sporadic form of AD. ¹⁰ The repetitive failures of anti-Aβ drugs. Therefore, targeting the neurotoxic, hyperphosphorylated tau appears to be a more feasible strategy for designing AD therapeutics. However, the clinical benefits of tau-centric AD drugs are yet to be realized. ¹¹

Synaptic dysfunction

Synapses are structurally specialized regions in neurons that facilitate the propagation of an electrical or chemical signal from one cell to another. ¹² Synaptic dysfunction is a common pathogenic trait of several brain disorders. ¹³ Basal forebrain cholinergic cell loss is a consistent feature of AD. ² A strong correlation between the extent of synapse loss and the severity of dementia. ¹⁴ Mitochondrial dysfunction and oxidative stress are the main drivers of synapse dysfunction. ¹² Aβ and tau act at neuronal synapses and exert their pathological roles during disease progression. ¹⁵ The cholinergic system is also implicated in cognitive functioning; approved treatments for AD are limited to three cholinesterase inhibitors, none of which are disease-modifying. ¹²

Vascular hypothesis

Vascular dementia is the second most common type of dementia, ¹⁶ and causes around 17–30% of cases. ¹⁷ Vascular cognitive impairment and dementia is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. ¹⁸ The earliest event in AD is a decrease in cerebral blood flow (CBF). Appear early in disease progression and correlate with the severity of cognitive impairment. ¹⁹ This is caused by the constriction of capillaries by contractile pericytes, ²⁰ resulting in a significant decrease in CBF in AD patients compared to normal age-related populations. ²¹ Cerebral microvascular pathology and cerebral hypoperfusion may trigger the cognitive and degenerative changes in AD. ² Arteriolosclerosis is the most common form of cerebral small vessel disease (CSVD). ¹⁸

All these hypotheses have merits; however, this proposed hypothesis expands further by incorporating upstream factors, such as vascular dysfunction, hypometabolism, and oxidative stress, as well as downstream factors, including neuroinflammation. This article presents a detailed discussion of the Alzheimer's disease model and also uses observable AD incidences to explain this AD model and vice versa.

Alzheimer's disease model

Mixed dementia

Mixed dementia is a type of dementia with concurrent vascular and neurodegenerative pathological changes. ¹⁸ Autopsy studies of the brain have shown that 80% of patients with AD have small vessel damage. ²² The earliest event in AD is a decrease in CBF, ²⁰ and a decrease in glucose uptake in the brain. ²³ Besides stroke, most AD could be considered a mixture of vascular and degenerative dementia. It could be degenerative dementia only if there is no atherosclerosis.

Alzheimer’s disease model construction

AD is a multifactorial disease; however, integrating the major factors together forms a model (Figure 1). It could expand to a multi-loop if needed, for example, to study the effect of neuroinflammation on various dementias by combining three dementia models—AD, Parkinson's disease (PD), and dopaminergic neuron—into one composite model, as shown in Figure 2. Figure 1 could be simplified by reducing the four decision boxes to two: oxidative stress and DNA repair (Figure 3).

Figure 1.

Schematic Flowchart Alzheimer’s disease model.

Figure 2.

Schematic Flowchart AD v non-AD model.

Figure 3.

Simplify Schematic Flowchart Alzheimer’s disease model.

Alzheimer’s disease model implication

The positive feedback loop is inherently unstable as it is a vicious cycle. To slow down neurodegeneration or dampen the positive feedback process, it is essential to reduce as many negative impact factors as possible simultaneously. For example, improving cerebral vessel health and enhancing brain insulin sensitivity can help reduce hypometabolism. Additionally, promoting autophagy can reduce oxidative stress through exercise and fasting. Removing or reducing abnormal proteins can further reduce inflammation. However, glucose hypometabolism is a major impacting factor among them. ²⁴

Research priority based on the Alzheimer’s disease model

Hypometabolism is the primary dementia driver. The glucose uptake into the brain requires overcoming these two restrictions: atherosclerosis and the brain glucose transporter. Improving CBF and reducing brain insulin resistance should be the priority in AD studies. Reactive oxygen species (ROS), oxidative stress, abnormal protein aggregation, and inflammation are the consequences of hypometabolism.

At the starting point of the positive feedback loop (Figure 1), if fuel uptake to the CNS is insufficient, it initiates ROS production. The result of inadequate fuel intake to the CNS is oxidative stress, abnormal protein aggregation, and neuroinflammation. Upon the return of the feedback loop, neuroinflammation has a significant proportional effect on central insulin resistance, leading to hypometabolism in the CNS. On the contrary, the impact of inflammation (if it happens) on the central glucose transporter would be much less with already adequate fuel intake to the CNS. Therefore, sufficient brain fuel uptake would minimize the effect of the positive feedback loop.

Alzheimer's disease model details

To integrate the major AD impacting factors and form an AD model (Figure 1), it is necessary to explore each relevant impacting factor in detail. All these discussions in this section are the background materials for the purpose of establishing an Alzheimer's Disease Model.

Atherosclerotic plaque

Cerebrovascular dysfunction resulting in ischemic episodes is an etiological factor of AD. ²² All fuels and nutrients are taken up into the brain through blood vessels. Insulin resistance leads to inflammation and the formation of atherosclerotic plaque, ²⁵ and hypertension is a significant risk factor for the development of atherosclerosis. ²⁶

Brain insulin resistance

Humans need glucose to live, either from their diet or by breaking down proteins; alternatively, fatty acids are metabolized into ketones as an energy source.^27,28 Insulin action induces glucose uptake in the CNS. ²⁴ The blood levels of peripheral insulin and glucose are locked together in a negative feedback loop to achieve euglycemia. ²⁹ If a human consumes excessive carbohydrates, the glucose levels spike due to overconsumption of carbohydrates. The insulin resistance develops in response to excessive glucose entering cells. ³⁰ Insulin resistance is supposed to stop glucose from overwhelming the cells. ³¹ CNS insulin resistance causes glucose hypometabolism, and the hypometabolism is the driver of neurodegeneration. ²⁴

CNS insulin resistance and peripheral insulin are linked but independent.^27,29 CNS insulin resistance is an early and common feature of AD. ³² A low-carb diet improves peripheral insulin sensitivity.^33–35 Similarly, low-carb diets could also improve brain insulin sensitivity.

A low-carb diet is a safe diet. ³³ The sensible approach to managing neurodegeneration is to restore insulin sensitivity, as central insulin resistance is linked to cognitive and behavioral deficits.^24,36 Low-carb diets also reduce the development of atherosclerotic plaques. ³⁷ More studies are needed for the low-carb diet regarding side effects.

Brain glucose transporter

AD is associated with altered expression of glucose transporters in the brain, and transporter-related energy deficiency in neurons may contribute to the pathogenesis of AD. ³⁸ The transporter is affected by several factors, including inflammation and glycemia, ³⁹ and stress would induce insulin resistance. ⁴⁰

Stress

Poor sleep quality and insufficient sleep duration have been linked to impaired glucose metabolism and insulin resistance. ⁴¹ Following sleep deprivation, poor sleep was associated with a significant increase in the Aβ burden in the hippocampus and thalamus. ⁴² One night of sleep deprivation impaired the clearance of the tracer substance from most brain regions. ⁴³

Reactive oxygen species

A driver of AD is the synergy of brain glucose hypometabolism and oxidative stress. ⁴⁴ Mitochondrial dysfunction and increased production of ROS contribute to the development of AD. ¹² Glucose hypometabolism in the AD brain implicates the involvement of mitochondrial dysfunction early in the course of AD. ⁴⁵ Glucose deprivation stimulates the production of ROS. ⁴⁶ Damaged mitochondria release higher levels of ROS. ⁴⁷ Mitochondria contribute approximately 90% of the cellular ROS. ⁴⁸ Glucose deprivation causes mitochondrial dysfunction, leading to a depletion of neuronal ATP and stimulating ROS production, inducing oxidative stress.^49–52 The overproduction of ROS has been implicated in the development of various degenerative diseases. ⁵³ Aβ induces oxidative stress and reduces glucose consumption in the mouse brain, ⁴⁴ possibly due to a positive feedback loop.

Autophagy

Autophagy is a highly conserved lysosomal degradation pathway active at basal levels in all cells. ⁵⁴ Autophagy is a lysosome-based degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and aggregate-prone proteins. Their postmitotic nature and extremely polarized morphologies make neurons particularly vulnerable to disruptions caused by autophagy–lysosomal defects. ⁵⁵ Autophagy plays a housekeeping role in removing misfolded or aggregated proteins and clearing damaged organelles, such as mitochondria. ⁵⁶ Mitophagy removes and recycles damaged mitochondria, maintaining the optimal number of mitochondria to balance intracellular homeostasis.^57,58

Impairment of autophagy aggravates the accumulation of misfolded proteins and damaged organelles in neurons. ⁵⁹ Among several stress stimuli inducers of autophagy, fasting is the most potent non-genetic stimulator.^60,61 Exercise reduces age-related oxidative damage and improves mitochondrial function. ⁶² The exercise enhanced brain insulin and strengthened hippocampal functional connectivity. ⁶³

DNA breaks

The binding of histones to DNA and their organization into higher-order chromatin structures dramatically protects the DNA against DNA strand breaks. ⁶⁴ The chromatin around the gene must be decondensed before transcription can occur. Transcription can create conditions for high levels of mutations and recombination by opening the DNA structure, making it more accessible to DNA insulting agents. ⁶⁵ The DNA double helix must unwind while being transcribed. The DNA is vulnerable to being insulted by ROS during protein synthesis.

Abnormal protein synthesis

Although the classical view is that Aβ is deposited extracellularly, emerging evidence from transgenic mice and human patients indicates that this peptide can also accumulate intraneuronally, which may contribute to disease progression. ⁶⁶ The intraneuronal accumulation of Aβ has been demonstrated and is reported to be involved in synaptic dysfunction, cognitive impairment, and the formation of amyloid plaques in AD. ⁶⁷ In Lee's study, ⁶⁸ Profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes, termed PANTHOS. These AV also contained earlier forms of amyloid beta. And autolysosome acidification declines in neurons well before extracellular amyloid deposition.

At least five major DNA repair pathways allow the cell to repair DNA damage. ⁶⁹ Defects in DNA repair frequently lead to neurodegenerative diseases, ⁷⁰ and the relationship between compromised DNA repair and neurodegeneration was first suggested by Cleaver.^71,72 Excessive ROS can lead to the destruction of cellular components, including proteins and DNA, and ultimately result in cell death via apoptosis. ⁷³ Oxidative stress can break DNA while proteins are being synthesized. If the repair fails, the neuron will undergo apoptosis. Alternatively, if the repair is imperfect, it can result in the synthesis of abnormal proteins, such as Aβ, tau, or α-synuclein. Aβ pathology is often detected concurrently with glucose hypometabolism. ⁴⁴ Abnormal cellular metabolism in turn could affect the production and accumulation of Aβ and hyperphosphorylated tau protein, which, independently, could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. ¹²

Neuroinflammation

Microglia and astrocytes, as well as neuroinflammation, play fundamental roles in various neurodegenerative diseases. ⁷⁴ Inflammation plays a crucial role in promoting the progression of neurodegenerative diseases, including AD and PD. ⁷⁵ Age-related cognitive decline is associated with metabolic, vascular, and inflammatory changes. ⁷⁶ The DNA damage triggers STING-mediated brain inflammation. ⁷⁷ The recognition of misfolded Aβ and tau proteins by immune cells can trigger complex immune responses in AD, leading to neuroinflammation. ⁷⁸ The cause of brain insulin resistance in AD appears to be amyloid-β-triggered microglial release of proinflammatory cytokines, which inhibit insulin signaling. ³² The inflammation increases brain insulin resistance. ⁷⁹

BBB permeability

The blood-brain barrier (BBB) is formed by microvascular endothelial cells that line the cerebral capillaries, which penetrate the brain and spinal cord of most mammals. It protects the CNS from pathogens and toxins in the blood. ⁸⁰ With increasing systemic inflammation, the vascular BBB becomes more permeable.^81–83

Pathogen and unwanted chemical

The BBB is both a structural and functional barrier that prevents microorganisms and unwanted chemicals from entering the CNS from the bloodstream.

Supplement

Mitochondria are susceptible to micronutrient deficiencies. ⁸⁴ Older individuals may require supplements as nutrient deficiencies develop. ⁸⁵ As antioxidants are substances that are efficient in trapping ROS and decreasing oxidative damage, and all compounds aiming to influence brain aging must be able to surpass the limitation represented by the BBB after systemic administration. ⁸⁶

Nitric oxide

For vascular dementia caused by decreased blood supply, Nitric oxide (NO) is known to dilate blood vessels and improve CBF. Similarly, Viagra is believed to improve AD.^87–90 A deficiency of endothelial-derived NO is believed to be the primary defect that links insulin resistance and endothelial dysfunction. ⁹¹ The link between cardiovascular and central nervous system degenerative processes in patients with different severities of AD is likely related to the depletion of NO. ⁹² Loss of NO production, termed endothelial dysfunction, is the earliest event in the development of hypertension. ⁹³ Hypertension is considered the most significant risk factor for the development of atherosclerosis. ⁹⁴ Hypertension is associated with cognitive impairment and an increased risk of dementia. ⁹⁵ Cognitive impairment was prevalent in Chinese patients with hypertension, with a prevalence of 37.6%. ⁹⁶ Therefore, nitric oxide can reduce hypertension and atherosclerotic plaques. Scientist thinks Nitric oxide has a dual role in AD, acting as both a neurotoxic and neuroprotective agent; The neurotoxic factor is neuroinflammation, and the neuroprotective roles are increasing blood flow, myelination, and synaptic plasticity.^97–99

Positive feedback loop

• Because of insufficient glucose uptake, the mitochondria could produce more ROS.

• Oxidative stress causes neuron apoptosis or the synthesis of sub-optimal proteins.

• The abnormal protein can induce an immune response, leading to inflammation.

• The inflammation could increase CNS insulin resistance.

• The CNS insulin resistance could reduce glucose uptake into the CNS by restricting the brain insulin glucose transporter, thereby further reducing glucose uptake into the CNS (red path in Figure 1).

• Combining the above, this constitutes a positive feedback loop that causes more neuron death or synthesis of abnormal proteins, and becomes a vicious cycle.

• Ultimately, neurodegeneration is characterized by the progressive loss of structure or function, ultimately leading to the death of neuronal cells. ¹⁰⁰

Ketones

Ketogenesis occurs primarily in the mitochondria of liver cells. ¹⁰¹ Fatty acids are brought into the mitochondria via carnitine palmitoyltransferase (CPT-1). ¹⁰² Beta-oxidation is the catabolic process in which fatty acids are broken down in the mitochondria to produce acetyl-CoA and energy. ¹⁰³ The enzyme thiolase catalyzes the conversion of two molecules of acetyl-CoA to form acetoacetyl-CoA. ¹⁰⁴ Acetoacetyl-CoA is converted to HMG-CoA via the enzyme HMG-CoA synthase. ¹⁰⁵ HMG-CoA lyase then converts HMG-CoA to acetoacetate. ¹⁰⁶ Acetoacetate can be converted to either acetone through non-enzymatic decarboxylation or to beta-hydroxybutyrate via beta-hydroxybutyrate dehydrogenase. ¹⁰⁷ Ketogenesis is hormonally regulated, with glucagon stimulating it and insulin inhibiting it. ¹⁰⁸ Insulin suppresses ketogenesis primarily by decreasing free fatty acid availability and inhibiting their beta-oxidation in the liver. ¹⁰⁹

Administering ketones can fuel neurons while bypassing insulin resistance. ⁷⁶ Besides atherosclerosis restriction in blood vessels, the supply of ketones to the brain depends on their concentration in blood via monocarboxylic acid transporters.^110,111 Physiological ketosis can reach a limit of 8 mmol/L without associated acidosis. ¹¹² The ketones rescue long-term-potentiation through beta-hydroxybutyrate's enhancement of synaptic plasticity in a mouse model. ¹¹³ Diabetic ketoacidosis is a form of hyperglycemic emergency mainly characterized by the triad of hyperglycemia, ketosis, and anion gap metabolic acidosis. Diabetic ketoacidosis most commonly occurs in type 1 diabetes but may occur in patients with type 2 diabetes.^114–116 The other side effects of the ketogenic diet include nutrient deficiencies of vitamins, minerals, and digestive issues, such as constipation, diarrhea, bloating, and kidney stones.^117,118

The attractions of ketones are bypassing the glucose transporter and avoiding the problematic positive feedback loop. More study is needed to alleviate the negative side effects of ketones.

The Alzheimer’s disease model is similar to the Dementia model

AD shares a similar trait of synthesizing abnormal proteins with other dementias; for example, AD produces Aβ and tau proteins, ¹ while PD produces α-synuclein protein. ¹¹⁹ Therefore, the AD model is similar to the PD model (Figure 1).

Alzheimer's disease incidents

A sensible AD model should be able to explain the observable phenotype of AD incidents; alternatively, a sound explanation of AD incidents by an AD model implies that the AD model has merit.

Why is two-thirds of dementia Alzheimer's disease?

AD is the most common form of dementia and may contribute to 60–80% of cases. ¹²⁰ In one 36-month study, the annualized rate of conversion from amnestic mild cognitive impairment (MCI) to AD dementia was higher in amyloid-positive versus amyloid-negative MCI subjects.^121,122 Aβ aggregates are mainly extracellular, spreading in the extracellular space between brain regions ¹²³ (Figure 2A). Conversely, α-synuclein, tau, and huntingtin are intracellular proteins. Their aggregates are located in the cytosol or nucleus of neurons ¹²³ (Figure 2B). Microglia display a diverse set of toll-like receptors (TLRs). ¹²⁴ TLRs are pattern recognition receptors that mediate an inflammatory response upon the detection of specific molecular patterns, and the α-synuclein (if in the extracellular space) activates TLRs found on microglia, ultimately leading to chronic neuroinflammation. ¹²⁵ Moreover, the release of large amounts of α-synuclein into the extracellular space occurs when the neuron is damaged or dies, ¹²⁶ which activates inflammatory responses in microglia through the α-synuclein molecule ¹²⁷ (Figure 2B).

The plausible explanation is that Aβ is an extracellular molecule constantly exposed to immune cells, which should induce a stronger inflammatory response. ¹²⁸ In AD progression, the abnormal Aβ protein initiates constant inflammation, thereby creating a continuous positive feedback loop and neurodegeneration. In contrast, in non-AD, inflammation only occurs if the abnormal non-Aβ protein leaks into the extracellular space.

Why did women suffer twice as much from AD as men?

Almost two-thirds of Americans with AD are women. ¹²⁹ Women's life expectancy is about 5 years longer than men's on average, ¹³⁰ and age is the most significant known risk factor for AD. ¹³¹ A plausible explanation is that, in addition to women living longer, another reason is that women have lower levels of sex hormones in post menopause and stronger immunity.

The reduction of estrogen in postmenopausal women accelerates the development of insulin resistance.^132,133 The brain's insulin resistance would reduce the glucose supply to the CNS via the brain's insulin transporter. Also, postmenopausal women may be at risk for endothelial dysfunction due to a decline in estrogen production, ¹³⁴ which causes a higher burden of Cerebral small-vessel disease. ¹³⁵ Moreover, Women who entered menopause before the age of 40 had worse cognitive outcomes than women who entered menopause after the age of 50. ¹³⁶

CSVD refers to a group of pathological processes with various etiologies affecting the small arteries, arterioles, venules, and capillaries. ¹³⁴ Women showed a much greater increase in cerebral microbleed counts than men. ¹³⁷ Small vessel damage was more prevalent in the female subgroup. CSVD is the most important cause of vascular dementia. ¹³⁵ One possible mechanism for the observed sex differences in the rate of cognitive decline with age is the incidence of CSVD.^135,138 Blood flow may be reduced by decreases in vessel diameter. ²⁰ One possible explanation is that women experience a higher burden of CSVD, which may be due to their smaller vessel diameter compared to men. Carotid arteries are smaller in women. ¹³⁹ Small-vessel disease has a higher prevalence in women, ¹³⁴ and males exhibited significantly larger vessel radius than females, independent of age. ¹⁴⁰

Sex-based immunological differences contribute to variations in the incidence of autoimmune diseases. ¹⁴¹ Sex differences in both innate and adaptive immunity contribute to the increased prevalence of autoimmunity in females. ¹⁴² Aβ deposition triggers pro-neuroinflammatory microglial activation. ¹⁴³ Hypometabolism induces the production of ROS, produces Aβ, and induces inflammation, thereby forming a positive feedback loop and neurodegeneration. The stronger immune response by women is a reason why women have a greater risk of developing dementia than men of the same age. ¹²⁹

Why do some aged individuals have normal cognition despite having amyloid plaques?

Many clinically normal older individuals demonstrate evidence of abnormal Aβ protein aggregation at post-mortem examination and in vivo using either CSF or PET imaging. ¹⁴⁴ The prolonged activation of microglia results in their enlargement. If the microglia cannot remove the abnormal protein, in contrast, their production of pro-inflammatory cytokines remains unaffected. ¹⁴⁵ A plausible explanation is that if an anti-inflammatory agent could reduce inflammation, the plaque would have less impact on the positive feedback loop.

Long-term non-steroidal anti-inflammatory drug (NSAID) use may reduce the risk of AD, provided such use occurs well before the onset of dementia. ¹⁴⁶ Observational studies support the use of NSAIDs for the prevention of AD. ¹⁴⁷ Current evidence suggests that NSAID exposure might be significantly associated with a reduced risk of AD. ¹⁴⁸ Long-term NSAID use, but not cumulative dose, was associated with decreased dementia risk. ¹⁴⁹

Removing the immune molecule STING (stimulator of interferon genes) in a mouse model dampened microglial activation around amyloid plaques, protecting nearby neurons from damage. ⁷⁷ By reducing inflammation, which in turn damps down positive feedback and Aβ plaque formation.

The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is pathologically elevated in human and mouse AD. Genetic inhibition of 15-PGDH protects the BBB, is anti-inflammatory without affecting amyloid pathology, and blocks production of ROS. ¹⁵⁰ Again, reducing inflammation would dampen the positive feedback and slow downstream neurodegeneration.

Non-AD dementia incident: depletion of dopamine in PD

A natural behavior, exploring a novel environment, causes DNA double-strand breaks (DSBs) in the neurons of young adult wild-type mice. DSBs occurred in multiple brain regions and were repaired within 24 h. ¹⁵¹

Developed a mouse model to chronically increase dopamine (DA) neuron activity, and this was followed by the eventual PD, which is characterized by the death of substantia nigra DA neurons. ¹⁵²

The defects in energy metabolism and the lysosomal autophagy in clearing oligomeric assemblies of α-synuclein may play a role in the development of PD. ¹⁵³ With the dopaminergic neuron in Figure 4, the dementia model (Figure 2B and Figure 4B) can easily explain the reduction in DA that occurs when oxidative stress breaks the DNA. If the dopaminergic neuron's DNA cannot be repaired, then apoptosis of dopamine neurons follows. The computer model could explain dementia incidents, either AD or non-AD dementia.

Figure 4.

Simplify Schematic Flowchart Parkinson’s disease model.

Discussion

The Alzheimer's Disease Model remains a hypothesis until further studies prove its merit. However, it derives two key deductions: one is that hypometabolism is the primary driver of AD,^24,44 which suggests that poor CBF and brain insulin resistance are the primary causes of AD, and the other is that AD progression forms a positive feedback loop; quality sleep and autophagy could slow down AD progression.

In the absence of therapeutic drugs to manage AD, lifestyle change is a sensible option to slow down the neurodegeneration. Any lifestyle change should be under the supervision of a healthcare provider. It is challenging for MCI or AD frail individuals, but it may be more effective if the lifestyle change starts early in the disease.