Battling Alzheimer’s Disease

Karachi Grammar School

Deena Kamran
deenakamran2006@gmail.com

Abstract: Alzheimer’s is a major degenerative disease that leads to dementia

and gets progressively worse with time. It’s characterised by shrinkage of the
brain and the eventual death of brain cells. According to WHO, 60-70% of people
with dementia have Alzheimer’s disease and it is estimated that 36 million people
are living with Alzheimer’s at the moment. If the current rates persist, 66 million
people worldwide will have Alzheimer’s disease by 2030. Alzheimer’s interferes
with the daily lives of people, making simple tasks difficult and since dementia is
the 7th leading cause of death, a feasible cure or treatment for AD is of utmost
priority, be it via drugs or physical therapy. That is what this paper hopes to shed
light on.

Key: Alzheimer’s, drugs, physical therapy

Introduction: :Alzheimer’s disease is a type of dementia that affects memory,

thinking and behaviour. It is the most prevalent form of dementia in individuals
over the age of 65. Symptoms eventually grow severe enough to interfere with
daily tasks. Alzheimer’s is not the same as dementia, but Alzheimer’s is one of
the leading causes of dementia, a general term for memory loss and other
cognitive abilities serious enough to interfere with daily life.

AD drugs at the moment are all symptomatic, meaning that they lessen the
symptoms of AD instead of preventing its progression. [1]

There are several hypotheses postulating the pathogenesis of AD, including the
cholinergic, amyloid cascade, tau hyperphosphorylation, and neuroinflammation
hypotheses. [2]

Acetylcholine(ACh) is a neurotransmitter, a chemical that carries messages from

your brain to your body through nerve cells. It’s an excitatory neurotransmitter. An
enzyme called choline acetyltransferase causes a reaction between choline and the
acetyl group to create acetylcholine. Its normal production and functioning is critical in
maintaining working memory, synaptic plasticity, learning and attention. The cholinergic
hypothesis postulates that damages and dysfunction in the cholinergic neurons found
in the basal forebrain, along with decreased cholinergic neurotransmission in the
cerebral cortex are the contributing factors to the memory impairment and other
cognitive symptoms seen in AD.[2]

Amyloid-β (Aβ) accumulation is a pathological hallmark of AD. Aβ peptides can

aggregate into various structures, including soluble Aβ oligomers, insoluble Aβ fibrils
and large Aβ plaques. While early theories postulate that Aβ plaque formation leads to
neurotoxicity, synapse loss, neurodegeneration, and consequently dementia, later
studies have found Aβ oligomers to have much greater toxicity compared to Aβ plaques
[3]. Aβ deposition and oligomerization can develop due to elevated Aβ production
combined with insufficient Aβ clearance from the brain, resulting in pathology
associated with AD[4]. Aβ deposition could trigger astrocyte and microglial activation,
leading to reactive oxygen species (ROS) generation through the pro-inflammatory ERK
(extracellular signal regulated kinase) signalling pathway activation, resulting in
neuronal damage [5]. Tau is a protein involved in the stabilisation of axonal
microtubules. In AD, tau can undergo hyperphosphorylation, leading to reduced affinities
and detachment from the microtubules along with conformational change that
promotes aggregation [6].
Hyperphosphorylated tau can aggregate into insoluble neurofibrillary tangles (NFTs).
Tau is considered as a key biomarker in AD, as tau hyperphosphorylation and NFT
accumulation can lead to structural damages to the microtubules in the axons, which
can result in compromised axonal transport and synaptic function [2].

Here’s a brief passage about one of the first and most popular cases of Alzheimer’s.

Alois Alzheimer and Auguste D

On November 3, 1906, a clinical psychiatrist and neuroanatomist, Alois
Alzheimer, reported “A peculiar severe disease process of the cerebral cortex” to
the 37th Meeting of South-West German Psychiatrists in Tubingen.
He described a 50-year-old woman(Auguste D) whom he had followed from her
admission for paranoia, progressive sleep and memory disturbance, aggression,
and confusion, until her death 5 years later [7].
Figure 1-Alois Alzheimer (1864-1915)[8]

Figure 2- Alzheimer’s first interviews with Auguste D.

Alzheimer recorded many conversations with his patients, including some with his most famous patient, Auguste D. The following
excerpt is from an interview conducted with Auguste D. on November 26th 1901, one day after her admission to the clinic. This
interview marks the beginning of scientific investigation into what has become known as Alzheimer’s disease. (Alzheimer’s
questions in italics, Auguste D.’s replies in normal font.) [She sits on the bed with a helpless expression.] What is your name?
Auguste. Surname? Auguste. What is your husband’s name? I believe Auguste. Your husband? I see, my husband… [She looks as
if not having understood the question.] Are you married? To Auguste. Mrs. D.? Yes, to Auguste D. How long have you been here?
[She appears to be trying to remember.] Three weeks. [At lunch she eats pork and cauliflower. When asked what she is eating, she
replies spinach. When chewing meat and asked what it was, she answers potatoes and then horseradish…] November 29th 1901:
How are you? It is always one as the other. Who carried me here? Where are you? At the moment, I have temporarily, as I said, I
have no means. One simply has to… I don’t know myself… I really don’t know… dear me, what is to then? What is your name? Frau
Auguste D. When were you born? Eighteen hundred and… In which year were you born? This year, no, last year. When were you
born? Eighteen hundred — I don’t know. What did I ask you? Ah, D. Auguste. […] What is your husband called? I don’t know. What
is your husband’s name? [She answers quickly and as if suddenly awoken.] August Wilhelm Karl; I don’t know if I can state it like
this. What is your husband’s profession? Clerk — I am so confused, so confused, I can not. […] What year is it? Eighteen hundred…
Which month? The 2nd. […] If you buy 6 eggs, at 7 pfennig each, how much is it? To poach. What street do you live on here? I can
tell you, I just have to wait a bit. What did I ask you? Well, this is Frankfurt am Main. On what street do you live? I can tell you,
Waldemarstraße, not, no… When did you marry? I don’t know at present. The woman lives on the same floor. Which woman? The
woman where we are living. [The patient calls out] Mrs Hensler, Mrs Hensler… here one step below, she lives. [Alzheimer shows her
different objects; she names them correctly.] What did I show you? I don’t know… I don’t know… so anxious, so anxious. [Alzheimer
shows her three fingers.] How many fingers? Three. Are you still anxious? Yes. How many fingers did I show you? Well, it is
Frankfurt am Main[8]

Diagnosis
The current diagnosis of AD mostly relies on the exclusion of other possible
conditions that can present with similar symptoms. Neuropsychological
evaluations can be conducted to assess the cognitive functions, including
memory, language ability, executive functions, visual spatial abilities and
everyday function [9].The diagnosis of AD can be aided by imaging techniques
such as computerised tomography (CT) and magnetic resonance imaging (MRI).
Structural changes of the brain can be visualised using MRI, where hippocampal
atrophy has been linked to neuronal degradation [10]. Additionally, visualisation
of the cortical thickness may aid in the diagnosis of AD, as studies have found
that cortical thinning can indicate neuronal loss, in particular, the cortical
thickness of the media temporal lobes is most severely reduced in AD brains [11].
However, some of the aforementioned characteristics are not AD-specific. For
instance, hippocampal and cortical volume loss can also be observed in other
neurodegenerative diseases, such as Parkinson’s Disease. [12]. Only
post-mortem histopathological examinations of the brain can provide a definitive
diagnosis, where the presence of NFTs and Aβ can be confirmed. In 2020, the
U.S. Food and Drug Administration (FDA) approved of flortaucipir, a radioactive
probe that can bind to tau fibrils to be used in the identification of NFTs. Studies
have revealed the ability to visualise the density and distribution of tau pathology
with increased specificity and sensitivity when flortaucipir is used in positron
emission tomography (PET) imaging[13].

Types of Therapy

1)Drug Therapy
1a) Diabetes and AD
Previous studies related to epidemiology, mechanisms of disease
and clinical manifestations revealed links between AD and diabetes[14].
Metabolic pathways leading to energy production are essential for normal
neuronal function and the brain of AD was related to decreased glucose
metabolism [15]. Although the underlying molecular mechanisms between
diabetes and AD are not yet obvious [16], anti-diabetic drugs are reviewed for
clinical benefit in AD.

1b) Targeting at mitochondrial function

Mitophagy plays a key role in inhibiting the accumulation of Aβ. UMI-77, a
small molecule inhibitor of Myeloid cell leukaemia-1(Mcl-1), was discovered to
safely and effectively induce mitophagy by using a sensitive quantitative
detection from the FDA-approved drug candidate. It doesn’t damage
mitochondria. It has the ability to degrade damaged mitochondria selectively.
Mitophagy was successfully induced in mouse brain tissue after
intraperitoneal injection of UMI-77 at a dose of 10mg/kg. The mechanism is
that UMI-77 releases MCL-1 from Bax/Bak, which then combines with LC3A
located on the outer membrane of the autophagy lysosome. The memory and
cognitive abilities of AD mice improved after the treatment with UMI-77, and
the area of Aβ plaques in the hippocampus was also reduced [17]

1c)Targeting Tau protein

Tau protein has been found to mediate some of the toxic effects of
Aβleading to dendritic simplification, synapse loss, and cell death in AD[18]
Protein Degradation Targeting Consortium (PROTAC) and Active Peptide
Vaccine AADvac1 are two new therapies that target Tau protein and
eliminate Tau aggregation. PROTAC makes two kinds of protein close to
each other, allowing for targeted protein degradation. It is composed of a
ligand for binding target protein, a ligand for recruiting E3 ligase and a
linker. PROTAC efficiently eliminated Tau aggregation in the 3xTg-AD
mouse model, improving cognition and synaptic functions[19] AADvac1 is
a Tau protein-targeted active peptide vaccination. A phase Ⅱ clinical trial
for this vaccine has been completed. It demonstrated that AADvac1 is
relatively safe and tolerable. AADvac1 significantly reduced the
accumulation of neurofilament light chain protein (NFL) by 58%, a key
marker of neurodegenerative diseases. Furthermore, tau and phospho-tau
are reduced in cerebrospinal fluid (CSF) . However, there was no
statistically significant benefit from this vaccine in terms of cognition[20]

1d) Targeting at Aβ
β-amyloid is a substance that can be cleared away from the brain in a
healthy state. However, during the ageing process of the human brain,
because of neuron’s intaking disorder, these amyloid plaques become
insoluble amyloid fibrils. Deposition of insoluble amyloid fibrils leads to the
death of nervous cells, resulting in impaired cognition. Because the cells in
the brain generally don’t regenerate, excessive damage can be
irreversible. Donanemab is an antibody that targets the Aβ epitope of
N-terminal pyroglutamate, which reached a breakthrough in phase Ⅱ of
clinical trials. Using an integrated Alzheimer’s disease scale(iADRS),
researchers discovered that individuals who got donanemab medication for
76 weeks had a 32% lower in iADRS score than that in the placebo group
(p＜0.05). It meant that patients who received domanemab had a lower
rate of cognitive loss. Meanwhile, PET imaging technology revealed a
rapid clearance of Aβ in patients’ brains after donanemab treatment, but
there was no improvement of Tau position. Around 68% of patients had a
PET-negative result after 18 months of treatment[21,22]

2) Non-drug therapy
2a) Plasma exchange with albumin replacement
Plasma exchange with albumin replacement (PE) is a novel treatment for
AD that has passed phase Ⅱb/Ⅲ trail. Plasma from AD patients contains
Aβ as well as highly oxidised albumin, which impairs the albumin’s
antioxidant activity. This therapy can improve the antioxidant activity of
plasma. Some symptoms in patients with mild-AD such as processing
capacity and speaking fluency got improved after PE treatment. The
short-term memory in moderate-AD patients also got enhanced. Patients
who had PE treatment had a higher quality of life in general [23]

2b) Multi sensory gamma stimulation

Giving 40HZ light-sound stimulation to Hippocampus and prefrontal cortex
has a profound impact on reducing the deposition of Aβ plaque and Tau
protein. Long Term exposure to 40HZ light improves not only the function of
synapsis and microglia acting through phagocytosis, but also alleviates
immunological inflammation [24]. In mild and moderate patients, this
innovative therapy has achieved Ⅱ-stage clinical findings. The results
showed that after 6-months treatment, the sleep and cognition of AD patients
improved noticeably, and the loss of brain volume decreased by 65 percent
[25].

2c) Deep brain stimulation

Deep brain stimulation (DBS) has been shown to help with Parkinson’s
disease, memory and other conditions. DBS may work in memory circuits by
reducing synaptic loss, boosting neurogenesis and improving glucose
metabolism. DBS aims to improve memory by coordinating activity across
many brain regions. Furthermore, it has potential to lower Aβ plaque load
DBS is a revolutionary treatment for AD that targets at entorhinal cortex and
hippocampus directly [26]

2d) Mesenchymal stem cell therapy

Lomecel-B, a novel mesenchymal stem cell treatment, promotes tissue healing
while also regulating the immune system. This approach reduces brain
inflammation and enhances the function of blood vessels. Anti-inflammatory
molecules such as IL-4, IL-6, IL-10 were significantly increased in patients with
different doses of Lpmecel-B in the phase Ⅰ of clinical trials as compared to
placebo. Furthermore, the volume of the left hippocampus was larger than that in
both low-dose group and placebo. Patients given low-dose Lomecel-B saw an
obvious improvement in their quality of life after 26-weeks of treatment [27].

2e)Hyperbaric oxygen therapy

Patients who receive hyperbaric oxygen therapy (HBOT) breathe 100% oxygen
in a controlled setting. Eliminating cerebral edema to reduce intracranial pressure
and reducing oxygen deficiency to the brain are two probable methods of HBOT.
Patients with AD improved in numerous areas after receiving HBOT treatment,
including memory, blood flow in the brain, attention and their information
processing ability [28]. However, this therapy is currently in the preclinical stage.
3)Others
3a) Nanotechnology
Most of the currently approved drugs are administered via the oral route in the
form of tablets, which may have drawbacks such as poor absorption and
degradation in the digestive tract, difficulties in blood-brain barrier (BBB)
permeation and poor control over the dosage that reaches the brain.
Nanoparticles present unique opportunities in crossing the BBB owing to the
flexibility in the modifications of their sizes, shapes, surfaces and
physicochemical properties based on different synthesis and functionalization
processes. They show size dependent permeation across the BBB[2].
The incorporation of nanotechnology in treatment of AD could be particularly
promising owing to the increased specificity and unique physicochemical
properties of nanoparticles. In recent decades, many nanoparticle-based
therapeutic agents have been proposed to target different aspects of AD,
including targeted drug delivery, delivery of antioxidant and anti-inflammatory
agents, Aβ fibrillisation and aggregation inhibitors, and Aβ removal from the
blood. However, extensive animal and human trials need to be conducted before
the implementation of clinical treatment, and the long-term toxicity needs to be
studied, since current research mainly focuses on examining the short-term
cytotoxicity[2].

Name of potential drugs for Characteristics Effects in AD

AD treatment

UMI-77 Releases MCL-1 Selectively degrade

damaged mitochondria

PROTAC Targeting at Tau Clears Tau aggregation

degradation efficiently
Improves cognition and
synaptic functions

AADvac1 An active peptide vaccine Reduces NFL

targeting at Tau protein Reduces Tau and Phospho
Tau in cerebrospinal fluid

Donanemab An Aβ antibody targeting Clear the deposition of

Lecanemab Aβ plaque Aβ
(BAN2401)
Aducanumab

Multi sensory gamma Physical therapy Improves patient’s sleep

stimulation and cognition
Deep brain stimulation Physical therapy Decreases loss of brain
volume,Improves
memory

Mesenchymal stem cell Non drug therapy Reduces brain

therapy inflammation Improves
the function of blood
vessels

Hyperbaric oxygen Physical therapy Reduce intracranial

therapy pressure Improving
oxygen deprivation to
the brain

Nanotechnology other targeted drug delivery,

delivery of antioxidant
and anti-inflammatory
agents, Aβ fibrillisation
and aggregation
inhibitors, and Aβ
removal from the

Conclusion:
Alzheimer’s is the most common cause of dementia, which is the 7th
leading cause of death in the world. Despite the multiple therapies present,
accurate diagnosis and effective treatments of AD are yet to be developed
since the pathogenesis and disease mechanism of AD are not yet
completely understood. Further development in nanotechnology and drugs
that target specific molecular sites could be a promising route in the
treatment of AD. Thorough and complete understanding of the
pathogenesis of AD is vital to prepare a drug that is not symptomatic.
Perhaps stem cell therapy is another avenue to explore for treating AD.
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Battling Alzheimer’s Disease- Research paper outline

1)Introduction:
Abstract: Alzheimer’s is a major degenerative disease that leads to
dementia and gets progressively worse with time. It’s characterized by
shrinkage of the brain and the eventual death of brain cells. According to
WHO, 60-70% of people with dementia have Alzheimer’s disease and it is
estimated that 36 million people are living with Alzheimer’s at the moment.
If the current rates persist, 66 million people worldwide will have
Alzheimer’s disease by 2030. Alzheimer’s interferes with the daily lives of
people, making simple tasks difficult and since dementia is the 7th leading
cause of death, a feasible cure or treatment for AD is of utmost priority, be
it via drugs or physical therapy. That is what this paper hopes to shed light
on.

a) General information:Alzheimer’s disease is a type of dementia that affects

memory, thinking and behavior. It is the most prevalent form of dementia in
individuals over the age of 65. Symptoms eventually grow severe enough to
interfere with daily tasks. Alzheimer’s is not the same as dementia, but
Alzheimer’s is one of the leading causes of dementia, a general term for memory
loss and other cognitive abilities serious enough to interfere with daily life. [K It,
WDOWE KNOW - N Engl] Med, 1986]

b) Acetylcholine, Amyloid-ꞵ, Tau

c) brief history:
-On November 3, 1906, a clinical psychiatrist and neuroanatomist, Alois
Alzheimer, reported “A peculiar severe disease process of the cerebral cortex” to
the 37th Meeting of South-West German Psychiatrists in Tubingen.
-He described a 50-year-old woman(Auguste D) whom he had followed from her
admission for paranoia, progressive sleep and memory disturbance, aggression,
and confusion, until her death 5 years later.
- Alzheimer’s first interviews with Auguste D [R Dahm - Current Biology, 2006]

2) Types of therapy
a) Drug therapy
- Diabetes and AD
- Targeting at mitochondrial function
- Targeting Tau protein
- Targeting Amyloid-ꞵ
--

b) Non drug therapy

- Plasma exchange with albumin replacement
- Multi sensory gamma stimulation
- Deep brain stimulation
- Hyperbaric oxygen therapy
- Mesenchymal stem cell therapy

c) Others
- Nanotechnology

3) Conclusion
Alzheimer’s is the most common cause of dementia, which is the 7th
leading cause of death in the world. Despite the multiple therapies present,
accurate diagnosis and effective treatments of AD are yet to be developed
since the pathogenesis and disease mechanism of AD are not yet
completely understood. Further development in nanotechnology and drugs
that target specific molecular sites could be a promising route in the
treatment of AD. Thorough and complete understanding of the
pathogenesis of AD is vital to prepare a drug that is not symptomatic.
Perhaps stem cell therapy is another avenue to explore for treating AD.