Air Pollution

Air pollution can be described as the modification of the natural environment by the introduction of
biological, chemical, and physical pollutants. It has been linked to cardiovascular and respiratory diseases
and was recently associated with AD. The National Ambient Air Quality Standards in the USA have
identified six air pollutants as a threat to human health. These include ozone (O 3), nitrogen dioxides (NO
x), CO, particulate matter (PM), sulfur dioxide (2), and lead (SO 2 ), among others. Research on animals
and cell models has shown that high levels of pollution can cause damage to the bulb and olfactory
mucosa, as well as the frontal cortex, much like AD. There is a link between neurodegeneration,
neuroinflammation, and oxidative stress in people who are exposed to air pollutants. This can be caused
by the presence of hyper-phosphorylated tau or Ab plaques within the frontal cortex. Air pollution can
lead to an increase in Ab 42 formation, accumulation, and impaired cognitive function.
Diet
Recent years have seen an increasing number of research on nutrition and AD. Many dietary supplements,
such as vitamins, antioxidants, and fish, were found to reduce the risk of AD. However, high-calorie
intake and saturated fatty acid were linked with an increase in the risk. Food processing can cause the
degradation of heat-sensitive micronutrients like vitamin C and folates, as well as loss of large quantities
of water and toxic secondary products (advanced glycation end products, or AGEs) due to non-enzymatic
Glycation of amino groups in proteins, nucleic acid, and lipids. The toxic effects of AGEs are defined as
their ability to induce oxidative stress, and inflammation and modify the structure and function of cell
surface receptors and protein bodies. Studies have shown that high serum levels of AGEs are associated
with cognitive decline and the progression of AD. The AGE receptor (RAGE), which is found in various
parts of the body, and includes microglia and astrocytes were shown to be highly expressed in AD
patients. It also serves as a transporter for Ab. Malnutrition is another risk factor in AD. A decrease in
cognitive function may be caused by a deficiency in vitamins B12, folate, and vitamin D. Patients with
AD may also have problems eating and swallowing which could increase the likelihood of malnutrition.
Metals
Metals can be found in nature and biological systems. They can be broken down into bio-metals with a
physiological function within living organisms (e.g., copper, zinc, and iron) and toxicological metals that
do not have any biological function (e.g., aluminum and lead). Aluminum is widely used in industries like
cosmetics, medicine, and processed foods. Aluminum is bound to plasma transportation and citrate
molecules in the body. These can facilitate the transfer of aluminum into the brain. Al is found in the
cortex, cerebellum, and hippocampus. It interacts with proteins and causes misfolding, aggregate, and
phosphorylation. This is a characteristic of AD. Lead can compete with bio-metals such as calcium for the
binding site and cross the blood-brain barrier (BBB). It can cause serious damage to the brain and alter
neural differentiation, synaptogenesis, and other functions. Acute exposure to lead was linked to AD,
causing an increase in Ab accumulation and b-secretase expression. Cadmium, a water-soluble and
carcinogenic metal, can cross the BBB to cause neurological diseases such as AD. Research has shown
that Cadmium ions play a role in the formation of Ab plaques as well as the self-aggregation and
accumulation of tau in the AD brain. Data accumulated about metals supports the idea that they are one of
the risk factors for the development of AD.
Infections
Chronic infections of the central nervous system (CNS) can lead to an accumulation of Ab plaques and
NFT. These are risk factors for AD. Itzhaki's studies showed that patients who were carriers of the ApoE-
4 allele had DNA from herpes simplex virus 1 (HSV-1). This explains why they are at high risk for
developing AD. HSV-1 can spread to the brain and activate the inflammatory response, leading to an
increase in Ab deposits and damage to neurons. This can lead to the gradual development of AD.
However, Miklossy's and Balin's research has shown the importance of chronic bacterial infections in
AD. The study results by Miklossy and Balin have shown that chronic bacterial infections can lead to
severe neurodegenerative diseases. Chlamydia pneumonia bacteria can also trigger late-onset AD. It
activates astrocytes and cytotoxic microglia, disrupts calcium regulation, and increases the risk of AD.

1.5.3 Medical Factors

Many risk factors can lead to Alzheimer's disease. Add to that, AD patients over 65 often have conditions
such as diabetes, heart disease, obesity, and other medical problems. These conditions all increase the risk
of AD.
Cardiovascular Diseases (CVDs).
CVDs are a risk factor for AD. Also, embolisms can occur due to atrial fibrillation. This can lead to
stroke and decreases cognitive function and memory. Heart failure also affects the pumping function and
causes insufficient blood supply to the body. This leads to hypoxia and can cause neural damage. Hypo-
perfusion, atherosclerosis, peripheral arterial disease, emboli, and emboli all contribute to an increased
risk of AD. Hypertension can lead to thickening and narrowing vessel walls, which decreases cerebral
blood flow. In chronic cases, cerebral edema may occur. All these risk factors are associated with AD and
CVD. CVD can be prevented and delayed by focusing on the relationship between AD and CVD.
Obesity, Diabetes
Obesity refers to excessive body fat. It is caused by consuming more calories than you burn. This can be
measured using your body mass index (BMI). An increase in body fat can lead to a decrease in brain
blood supply, which can cause brain ischemia, memory impairment, and vascular dementia. Obesity, poor
diet, and other factors can lead to impaired glucose tolerance (IGT), or diabetes. This is characterized by
hyperglycemia, which affects blood vessels and peripheral tissues. Chronic hyperglycemia can cause
cognitive impairment due to increased amyloid beta accumulation, oxidative stress, mitochondrial
dysfunction, and neuroinflammation. Obesity can be characterized by increased pro-inflammatory
cytokines from adipose tissues, which stimulate macrophages & lymphocytes and ultimately lead to
systemic and local inflammation. This inflammation can lead to insulin resistance and hyperinsulinemia.
Type 2 diabetes, CVDs, and cancer are all well-known risk factors. Obesity has been identified as a risk
factor for AD and type 2. Microglia are more active in brain inflammation, which results in decreased
synaptic plasticity as well as impaired neurogenesis. Brain inflammation can cause microglia to alter
insulin receptor substrate 1(IRS-1) or block intracellular insulin signaling. This is important for neural
health. Altering insulin action can lead to Ab accumulation and decrease tau protein degradation
associated with AD.
Treatment
The current number of Alzheimer's cases in the world is around 24 million. In 2050, it is expected that
there will be 4x more people living with dementia. Although AD is a serious public health problem, only
two types of drugs are currently approved for treatment. These include antagonists to N-methyl d-
aspartate and inhibitors of the cholinesterase enzyme. Many physiological processes involved in AD
damage Ach-producing cells, which decreases cholinergic transmission throughout the brain.
Acetylcholinesterase inhibitors (AChEIs), which are classified as reversible, irreversible, and pseudo-
reversible, act by blocking cholinesterase enzymes (AChE and butyrylcholinesterase (BChE)) from
breaking down ACh, which results in increasing ACh levels in the synaptic cleft. Over-activating
NMDAR can lead to increased levels of Ca 2+ which causes cell death and synaptic dysfunction.
NMDAR antagonist stops overactivation and Ca 2+ inflow. It also restores normal activity. These two
classes are only effective in the treatment of AD symptoms. Unfortunately, there have been very few
clinical trials of AD in the past decade. Several mechanisms can be used to study AD pathology and to
develop effective treatments. These include abnormal tau protein metabolism, beta-amyloid,
inflammation response, and cholinergic or free radical damage. However, most AD-modifiable risk
factors like lifestyle and cardiovascular habits can be avoided without medical intervention. Research has
shown that physical activity can increase brain health and decrease AD. It activates brain vascularization
and plasticity, neurogenesis, reduces inflammation, and lowers Ab production. All these factors
contribute to improving cognitive function in seniors. The Mediterranean diet (MD), intellectual
activities, and higher education may all help to reduce AD progression and memory loss, as well as
increase brain capacity and cognitive functions. Multi-domain intervention, which includes lifestyle
changes (diet, exercise, and cognitive training), and prevention of AD symptoms in older adults [ 101] has
been shown to increase cognitive function or prevent the onset of AD. We summarize the current drugs
and theories that are available for developing new treatments for AD.

1.6. AD Symptomatic Treatment

1.6.1. Cholinesterase Inhibitors
According to the cholinergic hypothesis, AD can be explained by a decrease in acetylcholine
biosynthesis. One of the most effective therapeutic strategies to increase cognitive and neural cell
function is increasing cholinergic levels through the inhibition of acetylcholinesterase. AChEIs can be
used to block acetylcholine degradation in synapses. This results in continuous accumulation and
activation of the cholinergic receptors. Tacrine (tetrahydroaminoacridine) was the first FDA (Food and
Drug Administration)-approved cholinesterase inhibitor drug for the treatment of AD, which acts by
increasing ACh in muscarinic neurons, but it exited the market immediately after its introduction due to a
high incidence of side effects like hepatotoxicity and a lack of benefits, which was observed in several
trials. Galantamine and rivastigmine were later introduced as AChEIs. They are currently being used for
the treatment of AD symptoms. An alternative strategy to treat AD is to increase choline uptake, which
may lead to an increase in acetylcholine synthase at the presynaptic terminus. You can do this by
targeting the CHT1 choline transporter, which is responsible to supply choline for ACh synthesis. The
future treatment for AD may be drugs that increase CHT1 in the plasma membrane.