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.

Keywords

Alzheimer’s disease dementia insulin resistance ketones neuroinflammation oxidative stress positive feedback

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 regions¹²³ (Figure 2A). Conversely, α-synuclein, tau, and huntingtin are intracellular proteins. Their aggregates are located in the cytosol or nucleus of neurons¹²³ (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 molecule¹²⁷ (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.

Footnotes

Acknowledgements

The author has no acknowledgments to report.

ORCID iD

John Cheung-Yuen Chan

Author contribution(s)

John Cheung-Yuen Chan: Conceptualization; Formal analysis; Formal analysis; Investigation; Resources; Visualization; Writing – original draft; Writing – review & editing.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Hippius

Neundörfer

. The discovery of Alzheimer's disease. Dialogues Clin Neurosci 2003; 5: 101–108.

Mohandas

Rajmohan

Raghunath

. Neurobiology of Alzheimer's disease. Indian J Psychiatry 2009; 51: 55–61.

Alzheimer’s Disease International, https://www.alzint.org/about/dementia-facts-figures/ (accessed 24 July 2025).

Passeri

Elkhoury

Morsink

, et al. Alzheimer's disease: treatment strategies and their limitations. Int J Mol Sci 2022; 23: 13954.

Hardy

Higgins

. Alzheimer's disease: the amyloid cascade hypothesis. Science 1992; 256: 184–185.

Dyall

. Amyloid-beta peptide, oxidative stress and inflammation in Alzheimer's disease: potential neuroprotective effects of omega-3 polyunsaturated fatty acids. Int J Alzheimers Dis 2010; 2010: 274128.

Hampel

Hardy

Blennow

, et al. The amyloid-β pathway in Alzheimer's disease. Mol Psychiatry 2021; 26: 5481–5503.

Paczynski

Hofmann

Posey

, et al. Lecanemab treatment in a specialty memory clinic. JAMA Neurol 2025; 82: 655–665.

Yang

Zhi

Wang

. Role of tau protein in neurodegenerative diseases and development of its targeted drugs: a literature review. Molecules 2024; 29: 2812.

10.

Arnsten

AFT

Datta

Del Tredici

, et al. Hypothesis: tau pathology is an initiating factor in sporadic Alzheimer's disease. Alzheimers Dement 2021; 17: 115–124.

11.

Hagar

Fernandez-Vega

Wang

, et al. Hyperphosphorylated tau-based Alzheimer’s disease drug discovery: identification of inhibitors of tau aggregation and cytotoxicity. SLAS Discov 2025; 33: 100235.

12.

Tönnies

Trushina

. Oxidative stress, synaptic dysfunction, and Alzheimer's disease. J Alzheimers Dis 2017; 57: 1105–1121.

13.

Pelucchi

Gardoni

Di Luca

, et al. Synaptic dysfunction in early phases of Alzheimer's disease. Handb Clin Neurol 2022; 184: 417–438.

14.

Shankar

Walsh

. Alzheimer's disease: synaptic dysfunction and Abeta. Mol Neurodegener 2009; 4: 48.

15.

Chen

AKY

. Synaptic dysfunction in Alzheimer's disease: mechanisms and therapeutic strategies. Pharmacol Ther 2019; 195: 186–198.

16.

Morgan

McAuley

. Vascular dementia: from pathobiology to emerging perspectives. Ageing Res Rev 2024; 96: 102278.

17.

Alzheimer’s Disease International, https://www.alzint.org/about/dementia-facts-figures/types-of-dementia/vascular-dementia/ (accessed 24 July 2025).

18.

Inoue

Shue

, et al. Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer’s disease. Mol Neurodegeneration 2023; 18: 46.

19.

Bracko

Cruz Hernández

Park

, et al. Causes and consequences of baseline cerebral blood flow reductions in Alzheimer's disease. J Cereb Blood Flow Metab 2021; 41: 1501–1516.

20.

Korte

Nortley

Attwell

. Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease. Acta Neuropathol 2020; 140: 793–810.

21.

Goldsmith

. Alzheimer's disease: a decreased cerebral blood flow to critical intraneuronal elements is the cause. J Alzheimers Dis 2022; 85: 1419–1422.

22.

Pluta

. Gender-dependent modulation of Alzheimer’s disease by brain ischemia. Comment on Lohkamp et al. sex-specific adaptations in Alzheimer’s disease and ischemic stroke: a longitudinal study in male and female APPswe/PS1dE9 Mice. Life 2025; 15: 1146.

23.

Kumar

Kim

Bishayee

. Dysfunctional glucose metabolism in Alzheimer's disease onset and potential pharmacological interventions. Int J Mol Sci 2022; 23: 9540.

24.

Blázquez

Hurtado-Carneiro

LeBaut-Ayuso

, et al. Significance of brain glucose hypometabolism, altered insulin signal transduction, and insulin resistance in several neurological diseases. Front Endocrinol (Lausanne) 2022; 13: 873301.

25.

Brie

Christodorescu

Popescu

, et al.

Atherosclerosis and insulin resistance: is there a link between them?

Biomedicines 2025; 13: 1291.

26.

Ning

Chen

Waqar

, et al. Hypertension enhances advanced atherosclerosis and induces cardiac death in Watanabe heritable hyperlipidemic rabbits. Am J Pathol 2018; 188: 2936–2947.

27.

Abdalla

MMI

. Insulin resistance as the molecular link between diabetes and Alzheimer's disease. World J Diabetes 2024; 15: 1430–1447.

28.

Nakrani

Wineland

Anjum

. Physiology, glucose metabolism. Treasure Island, FL: StatPearls Publishing, 2025.

29.

Rhea

Banks

Raber

. Insulin resistance in peripheral tissues and the brain: a tale of two sites. Biomedicines 2022; 10: 1582.

30.

Rossetti

Giaccari

DeFronzo

. Glucose toxicity. Diabetes Care 1990; 13: 610–630.

31.

Kawahito

Kitahata

Oshita

. Problems associated with glucose toxicity: role of hyperglycemia-induced oxidative stress. World J Gastroenterol 2009; 15: 4137–4142.

32.

Talbot

. Brain insulin resistance in Alzheimer's disease and its potential treatment with GLP-1 analogs. Neurodegener Dis Manag 2014; 4: 31–40.

33.

Foley

. Effect of low carbohydrate diets on insulin resistance and the metabolic syndrome. Curr Opin Endocrinol Diabetes Obes 2021; 28: 463–468.

34.

Unwin

Khalid

Unwin

, et al. Insights from a general practice service evaluation supporting a lower carbohydrate diet in patients with type 2 diabetes HbA1c, weight and prescribing over 6 years. BMJ Nutr Prev Health 2020; 3: 285–294.

35.

Jooste

Kolivas

Brukner

, et al. Effectiveness of technology-enabled, low carbohydrate dietary interventions, in the prevention or treatment of type 2 diabetes mellitus in adults: a systematic literature review of randomised controlled and non-randomised trials. Nutrients 2023; 15: 4362.

36.

Lannert

Hoyer

. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 1998; 112: 1199–1208.

37.

Jacobs

Bazzano

, et al. Low-carbohydrate diets and prevalence, incidence and progression of coronary artery calcium in the multi-ethnic study of atherosclerosis (MESA). Br J Nutr 2019; 121: 461–468.

38.

Koepsell

. Glucose transporters in brain in health and disease. Pflugers Arch 2020; 472: 1299–1343.

39.

Arnold

Arvanitakis

Macauley-Rambach

, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol 2018; 14: 168–181.

40.

Vedantam

Poman

Motwani

, et al. Stress-induced hyperglycemia: consequences and management. Cureus 2022; 14: e26714.

41.

Lin

. The effects of sleep on glycemic control: understanding the connection. J Diabetes Med Care 2024; 7: 269–271.

42.

Shokri-Kojori

Wang

Wiers

, et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A 2018; 115: 4483–4488.

43.

Eide

Vinje

Pripp

, et al. Sleep deprivation impairs molecular clearance from the human brain. Brain 2021; 144: 863–874.

44.

Malkov

Popova

Ivanov

, et al. Aβ initiates brain hypometabolism, network dysfunction and behavioral abnormalities via NOX2-induced oxidative stress in mice. Commun Biol 2021; 4: 1054.

45.

Wang

Zhao

, et al. Mitochondria dysfunction in the pathogenesis of Alzheimer's disease: recent advances. Mol Neurodegener 2020; 15: 30.

46.

Marambio

Toro

Sanhueza

, et al. Glucose deprivation causes oxidative stress and stimulates aggresome formation and autophagy in cultured cardiac myocytes. Biochim Biophys Acta 2010; 1802: 509–518.

47.

Guo

Sun

Chen

, et al. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res 2013; 8: 2003–2014.

48.

Balaban

Nemoto

Finkel

. Mitochondria, oxidants, and aging. Cell 2005; 120: 483–495.

49.

Chang

Garcia

Melendez

, et al. Haem oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain. Biochem J 2003; 371: 877–885.

50.

Sarre

Gabrielli

Vial

, et al. Reactive oxygen species are produced at low glucose and contribute to the activation of AMPK in insulin-secreting cells. Free Radic Biol Med 2012; 52: 142–150.

51.

Sergi

Naumovski

Heilbronn

, et al. Mitochondrial (dys)function and insulin resistance: from pathophysiological molecular mechanisms to the impact of diet. Front Physiol 2019; 10: 532.

52.

Yan

Wang

Zhu

. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med 2013; 62: 90–101.

53.

Liu

Ren

Zhang

, et al. Role of ROS and nutritional antioxidants in human diseases. Front Physiol 2018; 9: 477.

54.

Gómez-Virgilio

Silva-Lucero

Flores-Morelos

, et al. Autophagy: a key regulator of homeostasis and disease: an overview of molecular mechanisms and modulators. Cells 2022; 11: 2262.

55.

Nixon

Rubinsztein

. Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases. Nat Rev Mol Cell Biol 2024; 25: 926–946.

56.

Glick

Barth

Macleod

. Autophagy: cellular and molecular mechanisms. J Pathol 2010; 221: 3–12.

57.

Wang

Yang

Liao

, et al. Effects of intermittent fasting diets on plasma concentrations of inflammatory biomarkers: a systematic review and meta-analysis of randomized controlled trials. Nutrition 2020; 79-80: 110974.

58.

Picca

Faitg

Auwerx

. Mitophagy in human health, ageing and disease. Nat Metab 2023; 5: 2047–2061.

59.

Cui

Yoshimori

Nakamura

. Autophagy system as a potential therapeutic target for neurodegenerative diseases. Neurochem Int 2022; 155: 105308.

60.

Bagherniya

Butler

Barreto

, et al. The effect of fasting or calorie restriction on autophagy induction: a review of the literature. Ageing Res Rev 2018; 47: 183–197.

61.

Mehrabani

Bagherniya

Askari

, et al. The effect of fasting or calorie restriction on mitophagy induction: a literature review. J Cachexia Sarcopenia Muscle 2020; 11: 1447–1458.

62.

Angulo

El Assar

Álvarez-Bustos

, et al. Physical activity and exercise: strategies to manage frailty. Redox Biol 2020; 35: 101513.

63.

Kullmann

Goj

Veit

, et al. Exercise restores brain insulin sensitivity in sedentary adults who are overweight and obese. JCI Insight 2022; 7: e161498.

64.

Ljungman

Hanawalt

. Efficient protection against oxidative DNA damage in chromatin. Mol Carcinog 1992; 5: 264–269.

65.

Gaillard

Aguilera

. Transcription as a threat to genome integrity. Annu Rev Biochem 2016; 85: 291–317.

66.

LaFerla

Green

Oddo

. Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci 2007; 8: 499–509.

67.

Takahashi

Nagao

Gouras

. Plaque formation and the intraneuronal accumulation of β-amyloid in Alzheimer's disease. Pathol Int 2017; 67: 185–193.

68.

Lee

Yang

Goulbourne

, et al. Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci 2022; 25: 688–701.

69.

Chatterjee

Walker

. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen 2017; 58: 235–263.

70.

Kargbo-Hill

Nathan

, et al. Neuronal enhancers are hotspots for DNA single-strand break repair. Nature 2021; 593: 440–444.

71.

Cleaver

. Defective repair replication of DNA in xeroderma pigmentosum. DNA Repair (Amst) 2004; 3: 183–187.

72.

Hegde

Bohr

Mitra

. DNA Damage responses in central nervous system and age-associated neurodegeneration. Mech Ageing Dev 2017; 161: 1–3.

73.

Klein

Ackerman

. Oxidative stress, cell cycle, and neurodegeneration. J Clin Invest 2003; 111: 785–793.

74.

Lopez-Lee

Kodama

Gan

. Sex differences in neurodegeneration: the role of the immune system in humans. Biol Psychiatry 2022; 91: 72–80.

75.

Zhang

Xiao

Mao

, et al. Role of neuroinflammation in neurodegeneration development. Signal Transduct Target Ther 2023; 8: 267.

76.

Antal

van Nieuwenhuizen

Chesebro

, et al. Brain aging shows nonlinear transitions, suggesting a midlife “critical window” for metabolic intervention. Proc Natl Acad Sci U S A 2025; 122: e2416433122.

77.

Thanos

Campbell

Cowan

, et al. STING Deletion protects against amyloid β-induced Alzheimer's disease pathogenesis. Alzheimers Dement 2025; 21: e70305.

78.

Zhang

Huang

, et al. The role of the immune system in Alzheimer's disease. Ageing Res Rev 2021; 70: 101409.

79.

Vinuesa

Pomilio

Gregosa

, et al. Inflammation and insulin resistance as risk factors and potential therapeutic targets for Alzheimer's disease. Front Neurosci 2021; 15: 653651.

80.

Kadry

Noorani

Cucullo

. A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 2020; 17: 69.

81.

Galea

. The blood-brain barrier in systemic infection and inflammation. Cell Mol Immunol 2021; 18: 2489–2501.

82.

Chen

. The blood–brain barrier: structure, regulation and drug delivery. Sig Transduct Target Ther 2023; 8: 217.

83.

Dando

Mackay-Sim

Norton

, et al. Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion. Clin Microbiol Rev 2014; 27: 691–726.

84.

Atamna

Frey

. Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer's disease. Mitochondrion 2007; 7: 297–310.

85.

Schneyder

. Malnutrition and nutritional supplements. Aust Prescr 2014; 37: 120–123.

86.

Terracina

Petrella

Francati

, et al. Antioxidant intervention to improve cognition in the aging brain: the example of hydroxytyrosol and resveratrol. Int J Mol Sci 2022; 23: 15674.

87.

Sheng

Liu

, et al. Sildenafil improves vascular and metabolic function in patients with Alzheimer's disease. J Alzheimers Dis 2017; 60: 1351–1364.

88.

Paul

Ekambaram

. Involvement of nitric oxide in learning & memory processes. Indian J Med Res 2011; 133: 471–478.

89.

Garthwaite

Boulton

. Nitric oxide signaling in the nervous system. Ann Rev Physiol 1995; 57: 683–706.

90.

Webb

AJS

Birks

Feakins

, et al. Cerebrovascular effects of sildenafil in small vessel disease: the OxHARP trial. Circ Res 2024; 135: 320–331.

91.

Cersosimo

DeFronzo

. Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab Res Rev 2006; 22: 423–436.

92.

Venturelli

Pedrinolla

Boscolo

, et al. Impact of nitric oxide bioavailability on the progressive cerebral and peripheral circulatory impairments during aging and Alzheimer's disease. Front Physiol 2018; 9: 169.

93.

Bryan

. Nitric oxide deficiency is a primary driver of hypertension. Biochem Pharmacol 2022; 206: 115325.

94.

Poznyak

Sadykhov

Kartuesov

, et al. Hypertension as a risk factor for atherosclerosis: cardiovascular risk assessment. Front Cardiovasc Med 2022; 9: 959285.

95.

Gottesman

Egle

Groechel

, et al. Blood pressure and the brain: the conundrum of hypertension and dementia. Cardiovasc Res 2025; 120: 2360–2372.

96.

Xie

Zhong

Zhang

, et al. Prevalence and risk factors of cognitive impairment in Chinese patients with hypertension: a systematic review and meta-analysis. Front Neurol 2024; 14: 1271437.

97.

Azargoonjahromi

. Dual role of nitric oxide in Alzheimer's disease. Nitric Oxide 2023; 134-135: 23–37.

98.

Katusic

d'Uscio

. Emerging roles of endothelial nitric oxide in preservation of cognitive health. Stroke 2023; 54: 686–696.

99.

Zhang

Chen

Xiong

, et al. The emerging role of nitric oxide in the synaptic dysfunction of vascular dementia. Neural Regen Res 2025; 20: 402–415.

100.

Fymat

. Neuroradiology and its role in neurodegenerative diseases. J Neurol Neuromed 2020; 5: 42–55.

101.

Suresh

Sivaprakasam

Bhutia

, et al. Not just an alternative energy source: diverse biological functions of ketone bodies and relevance of HMGCS2 to health and disease. Biomolecules 2025; 15: 580.

102.

Choi

Smith

Scafidi

, et al. Carnitine palmitoyltransferase 1 facilitates fatty acid oxidation in a non-cell-autonomous manner. Cell Rep 2024; 43: 115006.

103.

Panov

Mayorov

Dikalov

. Role of fatty acids β-Oxidation in the metabolic interactions between organs. Int J Mol Sci 2024; 25: 12740.

104.

Fox

Soto

Mozzicafreddo

, et al. Understanding the function of bacterial and eukaryotic thiolases II by integrating evolutionary and functional approaches. Gene 2014; 533: 5–10.

105.

Theisen

Misra

Saadat

, et al. 3-hydroxy-3-methylglutaryl–CoA Synthase intermediate complex observed in “real-time”. Proc Natl Acad Sci U S A 2004; 101: 16442–16447.

106.

Arnedo

Latorre-Pellicer

Lucia-Campos

, et al. More than one HMG-CoA lyase: the classical mitochondrial enzyme plus the peroxisomal and the cytosolic ones. Int J Mol Sci 2019; 20: 6124.

107.

Costa

Linda

Hester

, et al. The janus face of ketone bodies in hypertension. J Hypertens 2022; 40: 2111–2119.

108.

Puchalska

. Unraveling the complex connection between ketone bodies and insulin resistance. Acta Physiol (Oxf) 2024; 240: e14077.

109.

Kolb

Kempf

Röhling

, et al. Ketone bodies: from enemy to friend and guardian angel. BMC Med 2021; 19: 313.

110.

Cunnane

Courchesne-Loyer

Vandenberghe

, et al. Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer's disease. Front Mol Neurosci 2016; 9: 53.

111.

Jensen

Wodschow

Nilsson

, et al. Effects of ketone bodies on brain metabolism and function in neurodegenerative diseases. Int J Mol Sci 2020; 21: 8767.

112.

Paoli

. Ketogenic diet for obesity: friend or foe? Int J Environ Res Public Health 2014; 11: 2092–2107.

113.

Di Lucente

Persico

Zhou

. Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer’s mouse model and stimulates synaptic plasticity pathway enzymes. Commun Biol 2024; 7: 195.

114.

Umpierrez

Davis

ElSayed

, et al. Hyperglycaemic crises in adults with diabetes: a consensus report. Diabetologia 2024; 67: 1455–1479.

115.

Aldhaeefi

Aldardeer

Alkhani

, et al. Updates in the management of hyperglycemic crisis. Front Clin Diabetes Healthc 2022; 2: 820728.

116.

Calimag

APP

Chlebek

Lerma

, et al. Diabetic ketoacidosis. Dis Mon 2023; 69: 101418.

117.

Muscogiuri

Barrea

Laudisio

, et al. The management of very low-calorie ketogenic diet in obesity outpatient clinic: a practical guide. J Transl Med 2019; 17: 356.

118.

Masood

Annamaraju

Khan Suheb

, et al. Ketogenic diet. Treasure Island, FL: StatPearls Publishing, 2025.

119.

Calabresi

Mechelli

Natale

, et al. Alpha-synuclein in Parkinson's disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis 2023; 14: 176.

120.

Alzheimer's Association. 2013 Alzheimer's disease facts and figures. Alzheimers Dement 2013; 9: 208–245.

121.

Gamberger

Lavrač

Srivatsa

, et al. Identification of clusters of rapid and slow decliners among subjects at risk for Alzheimer's disease. Sci Rep 2017; 7: 6763.

122.

Doraiswamy

Sperling

Johnson

, et al. AV45-A11 Study Group; AV45-A11 Study Group. Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study. Mol Psychiatry 2014; 19: 1044–1051.

123.

Moretto

Stuart

Surana

, et al. The role of extracellular matrix components in the spreading of pathological protein aggregates. Front Cell Neurosci 2022; 16: 844211.

124.

Gao

Jiang

Tan

, et al. Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduct Target Ther 2023; 8: 359.

125.

Kouli

Horne

Williams-Gray

. Toll-like receptors and their therapeutic potential in Parkinson's disease and α-synucleinopathies. Brain Behav Immun 2019; 81: 41–51.

126.

Lee

Suk

Patrick

, et al. Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 2010; 285: 9262–9272.

127.

Kim

Suk

, et al. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun 2013; 4: 1562.

128.

Shi

Kouadir

Yang

. NALP3 Inflammasome activation in protein misfolding diseases. Life Sci 2015; 135: 9–14.

129.

Beam

Kaneshiro

Jang

, et al. Differences between women and men in incidence rates of dementia and Alzheimer's disease. J Alzheimers Dis 2018; 64: 1077–1083.

130.

Our World in Data, https://ourworldindata.org/why-do-women-live-longer-than-men (accessed 24 July 2025).

131.

Hou

Dan

Babbar

, et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 2019; 15: 565–581.

132.

Yan

Yang

Zhou

, et al. Estrogen improves insulin sensitivity and suppresses gluconeogenesis via the transcription factor Foxo1. Diabetes 2019; 68: 291–304.

133.

Ciarambino

Crispino

Guarisco

, et al. Gender differences in insulin resistance: new knowledge and perspectives. Curr Issues Mol Biol 2023; 45: 7845–7861.

134.

Patel

Aggarwal

Rao

, et al. Microvascular disease and small-vessel disease: the nexus of multiple diseases of women. J Womens Health (Larchmt) 2020; 29: 770–779.

135.

Kaur

Fouad

Pozzebon

, et al. Sex differences in the association between vascular risk factors and cognitive decline: a UK biobank study. JACC Adv 2024; 3: 100930.

136.

Nakanishi

Yamasaki

Stanyon

, et al. Associations among age at menopause, depressive symptoms, and cognitive function. Alzheimers Dement 2025; 21: e70063.

137.

Yoon

Rha

Park

, et al. Sex differences in the progression of cerebral microbleeds in patients with concomitant cerebral small vessel disease. Front Neurol 2022; 13: 1054624.

138.

Cote

Perron

Baillargeon

, et al. Association of cumulative lifetime exposure to female hormones with cerebral small vessel disease in postmenopausal women in the UK biobank. Neurology 2023; 101: e1970–e1978.

139.

Krejza

Arkuszewski

Kasner

, et al. Carotid artery diameter in men and women and the relation to body and neck size. Stroke 2006; 37: 1103–1105.

140.

Bullitt

Zeng

Mortamet

, et al. The effects of healthy aging on intracerebral blood vessels visualized by magnetic resonance angiography. Neurobiol Aging 2010; 31: 290–300.

141.

Klein

Flanagan

. Sex differences in immune responses. Nat Rev Immunol 2016; 16: 626–638.

142.

Dunn

Perry

Klein

. Mechanisms and consequences of sex differences in immune responses. Nat Rev Nephrol 2024; 20: 37–55.

143.

Zhang

Griciuc

Hudry

, et al. Cromolyn reduces levels of the Alzheimer's disease-associated amyloid β-protein by Promoting Microglial Phagocytosis. Sci Rep 2018; 8: 1144.

144.

Mormino

Papp

. Amyloid accumulation and cognitive decline in clinically normal older individuals: implications for aging and early Alzheimer's disease. J Alzheimers Dis 2018; 64: S633–S646.

145.

Zhang

Chen

, et al. Amyloid β-based therapy for Alzheimer's disease: challenges, successes and future. Signal Transduct Target Ther 2023; 8: 248.

146.

Zandi

Anthony

Hayden

, et al. Cache county study investigators. Reduced incidence of AD with NSAID but not H2 receptor antagonists. Neurology 2002; 59: 880–886.

147.

Wang

Tan

Wang

, et al. Anti-inflammatory drugs and risk of Alzheimer's disease: an updated systematic review and meta-analysis. J Alzheimers Dis 2015; 44: 385–396.

148.

Zhang

Wang

, et al. NSAID Exposure and risk of Alzheimer's disease: an updated meta-analysis from cohort studies. Front Aging Neurosci 2018; 10: 83.

149.

Vom Hofe

Stricker

Ikram

, et al. Long-term exposure to non-steroidal anti-inflammatory medication in relation to dementia risk. J Am Geriatr Soc 2025; 73: 1484–1490.

150.

Koh

Vázquez-Rosa

Gao

, et al. Inhibiting 15-PGDH blocks blood-brain barrier deterioration and protects mice from Alzheimer's disease and traumatic brain injury. Proc Natl Acad Sci U S A 2025; 122: e2417224122.

151.

Suberbielle

Sanchez

Kravitz

, et al. Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nat Neurosci 2013; 16: 613–621.

152.

Rademacher

Doric

Haddad

, et al. Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration. Elife 2025; 13: RP98775.

153.

Ramesh

Arachchige

ASPM

. Depletion of dopamine in Parkinson's disease and relevant therapeutic options: a review of the literature. AIMS Neurosci 2023; 10: 200–231.