Miscellaneous:

Alzheimer's disease (AD), a brain disorder that causes the degeneration of cells, is the most common
cause of dementia. It is characterized by declines in thinking and independence in daily living activities.
AD is a multifactorial disorder. Two main hypotheses have been proposed to explain AD: the cholinergic
hypothesis and the amyloid hypothesis. The disease is also affected by many risk factors including
increasing age, genetic factors, head injuries, vascular diseases, infections, as well as environmental
factors like increased age and genetic factors. There are currently only two approved treatments for AD:
antagonists to -methyl-d-aspartate and inhibitors of cholinesterase enzyme. These drugs are effective in
managing symptoms but not the cure. The research now focuses on understanding AD pathology,
including abnormal tau protein metabolism, inflammation response, b-amyloid, and cholinergic/free
radical damage. This is in the hope of developing successful treatments that can stop or modify the
progression of AD. This review will discuss current and future therapies and theories to develop new
treatments for AD.

Introduction:
Alzheimer's disease (AD), named after German psychiatrist Alois Alzheimer, is the most common form
of dementia. It's characterized by neurofibrillary and neurotic plaques ( Figure1) and progressive
neurodegenerative diseases. This happens due to amyloid-beta protein's (Ab), accumulation in the most
affected areas of the brain, which includes the medial temporal and neocortical structure. Alois Alzheimer
observed amyloid plaques in the brain of his first patient who had suffered from memory loss, and
personality changes and died. He also described the condition as a severe disease of the cerebral cortex.
This medical condition was first named by Emil Kraepelin in his 8th edition of the psychiatry manual.
Alzheimer's disease (PD) can cause progressive loss of cognitive function.

There are currently approximately 50 million AD patients in the world. This number will double every
five years and increase to 152 million by 2050. The AD burden is a significant problem for individuals,
families, and the economy. It has an estimated global cost of US$1 trillion per year. There is currently no
cure for Alzheimer's, but there are treatments that improve symptoms. This review will provide a quick
overview of AD pathology, causes, and treatments. It will also highlight recent developments in
compounds that could treat or prevent AD.

Diagnostic Criteria for Alzheimer's Disease:

An AD patient should have several tests performed, including a neurological exam, magnetic resonance
imaging (MRI for neurons), laboratory examinations like vitamin B12, and other tests. These tests are in
addition to the family and medical history Vitamin (vit.) Some studies have shown that B12 deficiencies
are associated with an increased risk of AD and neurologic problems. Vit. A B12 deficiency can be
caused by high homocysteine levels. This can lead to brain damage through oxidative stress, increased
calcium influx, and apoptosis. Vit. By measuring serum vitamins, you can diagnose it. Complete blood
count, serum homocysteine levels, and B12 level can be checked 1984 saw the formation of a work group
by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's
Disease and Related Disorders Association. This was to create clinical diagnostic criteria for Alzheimer's
disease. These criteria include (1) Possible Alzheimer's disease (which can be confirmed by
neuropsychological testing), progressive memory loss, impaired daily life activity, and other symptoms
such as aphasia, motor skills disorder, and agnosia. These symptoms may appear between the ages of 40
and 90, provided there are no systemic or neurological disorders. (2) Possible Alzheimer's disease may be
applied even if there is no evidence of other neurologic or psychiatric conditions. (3) Definitive
Alzheimer's Disease can only be confirmed by histopathologic confirmation from a biopsy. 2011 saw
several changes by the National Institute on Aging-Alzheimer's Association. They updated the 1984
NINCDS ADRDA criteria to increase specificity and sensitivity when diagnosing Alzheimer's disease.
These new criteria include probable and possibly AD dementia to be used in clinical settings, and
probable or potential AD dementia with pathophysiological proof for research purposes. There are two
types of Alzheimer's disease biomarkers. (a) Markers of brain amyloid-like cerebrospinal liquid (CSF)
and positron emission (PET), and (b). These markers can be used to detect metabolic activity and
magnetic resonance imaging (MRI).

Alzheimer's Disease's Neuropathology:

Two types of neuropathological changes that are present in AD include (1) positive lesions (due to
accumulation). These are characterized by neurofibrillary plaques, neurofibrillary knots, amyloid plaques,
and dystrophic neurites. There are also (2) negative lesions that result from losses. These include large
atrophy caused by neuropil or neural loss. Other factors that can lead to neurodegeneration include
neuroinflammation and oxidative stress as well as injury to cholinergic neurons

1.1. Senile Plaques (SP)

Extracellular deposits of beta-amyloid protein (Ab), called senile plaques, can take many forms including
dense-cored, neurotic, classic, and compact types. The biosynthesis of Ab deposits is done by proteolytic
cleavage enzymes like b-secretase or g-secretase from the transmembrane amyloid precursor protein
(APP). These enzymes cleave APP into several amino acid fragments: 43-45, 46, 49, 49, 49, and 51,
which then reach the final form of Ab40 and Ab42. There are many types of Ab monomers. These
include large, insoluble amyloid fibrils that can build up to form amyloid plaques. They can also create
soluble oligomers which can spread throughout the brain. Ab plays an important role in neurotoxicity, and
neural function and the accumulation of dense plaques in the amygdala, hippocampus, and cerebral cortex
can cause stimulation and damage to astrocytes, microglia, and synapses.

1.2. Neurofibrillary Tangles (NFTs).

NFTs are abnormal filaments made of hyperphosphorylated tau proteins that can be twisted around to
form paired-helical filaments (PHF). These filaments accumulate in the neural cell, axons, and dendrites
and cause loss of cytoskeletal microtubules as well as tubulin-associated protein. Hyperphosphorylated
tau protein is the main component of NFTs found in AD patients' brains. Its evolution can be reflected in
NFTs morphological phases, which include (1) the pre-tangle phase where phosphorylated Tau proteins
accumulate in the somato dendritic cavity without the formation of PFHF; (2) mature NFTs which are
characterized by filament aggregation and displacement of the nucleus part of the soma and (3)
extracellular tangles (or the ghost NFTs) stage that results in neuronal loss from large amounts of tau
protein with partial resistance to proteolysis

1.3. Synaptic Loss

Memory impairment is caused by synaptic damage to the limbic and neocortex. This usually occurs in the
early stages. The synaptic loss mechanisms include defects in axonal transportation, mitochondrial
damage, and oxidative stress. Other processes can lead to small fractions such as the accumulation of Ab
or tau at the synaptic locations. These events eventually result in a loss of pre-synaptic terminals and
axonal dysfunction For the detection of synapse damage and severity, synaptic proteins are used as
biomarkers. These include neurogranin (a postsynaptic neuronal Protein), vision-like protein-1(VILIP-1),
synaptosome-

1.4. The Stages of Alzheimer's Disease

Pre-clinical and pre-symptomatic stages of Alzheimer's disease are different. These can last several years.
This stage is characterized by mild memory loss, early pathological changes to the cortex and
hippocampus, and no clinical signs or symptoms. (2) This is the mildest or earliest stage of AD. Patients
experience problems in daily living, including memory loss, disorientation, mood changes, and
depression (3) Moderate AD is when the disease has spread to the cerebral cortex. This causes memory
loss, difficulty in reading, writing, and speaking, as well as trouble recognizing family members and
friends. Severe AD, or late-stage, is when the disease spreads to the entire cortex with severe
neurofibrillary and neurotic plaque accumulations. This can lead to cognitive and functional impairments
that cause the patient to lose their ability to recognize family members and eventually to death.

Causes and Risk factors:

AD is a multifactorial disorder that has been linked to several risk factors, such as aging, genetic factors
and head injuries, vascular diseases and infections, and heavy metals and trace metals, among others. It is
not known what causes the pathological changes seen in Alzheimer's disease (Ab and NFTs) or synaptic
loss. There were many theories that could explain AD. However, two are the most likely to be true. Some
believe that AD is caused by impairments in cholinergic function. Others suggest that amyloid b protein
production and processing have been altered. There is currently no consensus on this mechanism.
Hypotheses about Alzheimer's Disease
The enzyme choline-acetyltransferase, which is responsible for the synthesis and regulation of
acetylcholine (ACh), was identified as the cause of neocortical cholinergic deficiencies in the 1970s. A
cholinergic hypothesis of AD was suggested due to ACh's essential role in cognitive function. ACh is
made in the cytoplasmic of cholinergic neurons from choline and Acetyl-coenzyme A. It is transported to
synaptic vessels by the vesicular acetylcholine transporter, ACh plays a critical role in many
physiological processes, including memory, attention, learning, and sensory information. AD is
characterized by the degeneration of cholinergic neuronal cells. This causes an alteration in cognitive
function, memory loss, and memory loss. amyloid is thought to alter cholinergic neurotransmission,
causing a decrease in choline uptake, and an increase in ACh release. Research has shown that amyloid
fibril and cholinergic synaptic losses are linked to Ab oligomers' neurotoxicity as well as interactions
between AChE peptide and AChE. Other factors contribute to the development of AD. These include a
decrease in nicotinic (M2) Ach and muscarinic(M2) Ach receptors and a deficit in excitatory amino acid
(EAA), neurotransmission. This is where glutamate concentrations and D-aspartate are significantly lower
in AD brains. Additionally, scopolamine, which is a cholinergic receptor antagonist, can cause amnesia.
You can reverse this effect by using compounds that activate Acetylcholine The pathway that allows for
the transport and synthesis of acetylcholine from presynaptic to postsynaptic nerve terminals. The
cholinergic hypothesis is therefore based on three concepts. It includes reduced presynaptic markers of
cholinergic in the cerebral cortex, severe neurodegeneration in the nucleus basalis Meynert in the basal
brain, which is the source for cortical cholinergic innervation, and the role of antagonists in memory loss
compared.
It has been known for decades that dementia is strongly linked to abnormal depositions of b-sheets within
the central nervous system. This led to the creation of the amyloid hypothesis. It was discovered that
amyloid plaques (AP), which are found in healthy brains, can also be found in older people, raising the
question of whether AP deposition may be responsible for AD onset. Although there have been other
hypotheses for non-inherited AD (NIAD) in recent years, the amyloid hypothesis is still the most widely
accepted pathological mechanism of inherited AD (IAD). According to the amyloid hypothesis, Ab is
reduced by APP by b and g secretase, and this leads to the accumulation of Ab peptides (Ab40/Ab42). An
increase in the ratio Ab42/Ab40 causes Ab fibril formation and, consequently, neurotoxicity and
induction of tau pathology. AD risk factors, mutations in several genes, such as APP, PSEN1, and
PSEN2, were shown to influence Ab catabolism. This causes rapid accumulation of Ab and rapid
progression of neurodegeneration