LITERATURE REVIEW

ALZHEIMER DISEASE AND TREATMENT UPDATE

Pembimbing :

dr. Noer Saelan Tadjudin, Sp. KJ

Disusun oleh :

Syarifah Soraya /406181005

FAKULTAS KEDOKTERAN
UNIVERSITAS TARUMANAGARA
 SECTION 1
INTRODUCTION

Dementia is a clinical syndrome characterized by progressive decline in two or more

cognitive domains, including memory, language, executive and visuospatial function,
personality, and behavior, which causes loss of abilities to perform instrumental and/or basic
activities of daily living. Alzheimer's disease (AD) is multifactorial neurodegenerative
disorder which has poor prognosis. It is the most common cause of dementia in the world. It
is progressive and irreversible disease and leads to severe impairment of memory. It is one of
the primary causes of cognitive dysfunction in elderly. AD is a highly prevalent
neurodegenerative disorder of old age. Alzheimer's association report’s 13% prevalence in
people older than 65 years in the developed countries. It is the fifth largest cause of death in
this age group. According to world health organization the prevalence is expected to
quadruple in the next decade reaching 114 million patients by 2050. The estimated number of
patient needing treatment is 24 million worldwide.1,2
The cholinesterase inhibitors (ChEI) and Memantine (MEM) are the approved drugs
for AD which temporarily improve symptoms. Presently there is no effective treatment in
terms of cure and prevention of AD. Considering the rise of AD in the population there is
urgent need to develop disease modifying agents. These agents need to reduce the
progression of neurodegeneration by inhibiting critical events that happen in the
pathophysiology of the disease. 1
 SECTION 2
LITERATURE REVIEW

2.1 Epidemiology
Alzheimer is the one of the leading cause of dementia cases globally. In the US alone,
approximately 5.3 million Americans have AD, of which 5.1 million are aged 65 years or
older and 200,000 have younger-onset AD.3 AD dementia accounted for 70% of the
dementia cases in US. Gender modulates the prevalence of AD. Nearly two-thirds of
all patients diagnosed with AD are women. Although age is the greatest risk factor for the
development of AD, in and of itself, old age is not sufficient to cause AD. Other major risk
factors include the presence of one or more apolipoprotein gene E4 alleles (APOE4), low
educational and occupational attainment, family history of AD, moderate or severe traumatic
brain injuries, and cardiovascular risk factors.4
Racial disparities in AD prevalence have also been reported. Older African Americans
and Hispanics have a higher prevalence of AD relative to older Caucasians in part because of
lower education levels and higher prevalence of cardiovascular comorbidities, although other
genetic and societal factors likely play a role as well.4

2.2 Etiopathophysiology
According to amyloid cascade hypothesis, cleavage of APP occurs by non-
amyloidogenic and amyloidogenic pathway. Nonamyloidogenic pathway, the APP cleavage
is done by alpha (α)- secretase and subsequently by gamma (γ) secretase which produce
soluble nontoxic peptides. Amyloidogenic pathway, the cleavage occurs by beta (β) secretase
and subsequently by γ-secretase. The product of this include two forms Aβ 40 amino acid
peptides and the other Aβ 42 amino acid peptide which are toxic and prone to form fibrils. 1
In AD there is genetic abnormality in APP hence it is mostly cleaved by β-secretase
of amyloidogenic pathway as a result of this, excessive Aβ peptides are produced which
accumulate into soluble oligomers that clump together to form insoluble fibrils called
plaques which are deposited extracellularly. These plaques create inflammatory response
that activate microglia and astrocytes which produce chemicals such as cytokines and free
radicals. 1
Aβ42 oligomers and the chemical events stimulate kinases which causes
hyperphosphorylation of tau converting microtubules into tangles within neuron called
NFTs. Phosphorylation of τ is regulated by several kinases, including Glycogen Synthase
kinase 3 (GSK3β) and cyclin-dependent kinase 5 (CDK5) activated by extra- cellular Aβ.3
The buildup of NFTs in the neuron ultimately leads to neuronal death. The synaptic
dysfunction and oxidative stress due to amyloid oligomers and neuronal death due to
hyperphosphorylation of tau relentlessly progress leading to shrinkage of brain. Clearance of
Aβ42 oligomers occurs by several pathways. Firstly, by the degradation caused by enzymes
such as proteases and insulin degrading enzyme (IDE). Secondly, they are removed through
the uptake by astrocyte and microglia. Thirdly, by passive flow into cerebrospinal fluid
(CSF). In AD there is excessive production and inefficient removal of Aβ peptide due to less
activity of the degradation enzymes. This imbalance between production and clearance leads
to accumulation of amyloid plaques1
Non-amyloidogenic pathway- the APP is cut via α- secretase into two forms α-APP which
is soluble and C-83 (83 amino acid peptide of carboxy terminal). γ secretase further cuts C-
83 into smaller peptides p3 and amyloid precursor protein intracellular domain (APPICD).
Amyloidogenic pathway- the APP is cut by β-secretase into β- APPs (soluble) and C99APP
which is further broken down by γ-secretase into Aβ peptides which form Aβ oligomers. The
oligomers cause hyperphosphorylation of tau, loss of synapse, cerebrovascular damage and
microglia activation leading to cognitive dysfunction. 1

Figure 2.1 Amyloid Hipotesis In Alzheimer Pathophysiology1

APP is cleaved differently in the diseased state. Aβ is released from APP through sequential
cleavages by BACE-1, a membrane-spanning aspartyl protease with its active site situated in
lumen, and γ- secretase, an intramembrane aspartyl protease that is made up of four proteins:
presenilin, nicastrin, anterior pharynx- defective 1 (Aph1), and Psen2 complexed together.
This complex contributes to the activity of γ-secretase, which produces insoluble and
neurotoxic Aβ fragments. β- secretase cleavage is the first and rate-limiting step, making a
cut at the N-terminus of Aβ. It removes the majority of the extracellular portion of the
protein, leaving the C-terminal of APP,22 which is further cleaved at the C-terminus of Aβ,
resulting in formation of the Aβ oligomers that further poly- merize, forming aggregated
plaques.3

Figure 2.2 Alternative splicing of APP in amyloidogenic and non-

amyloidogenic pathways3

Aβ plaques develop initially in basal, temporal, and orbitofrontal neocortex regions of the
brain and in later stages progress throughout the neocortex, hippocampus, amygdala,
diencephalon, and basal ganglia. In critical cases, Aβ is found throughout the mesencephalon,
lower brain stem, and cerebellar cortex as well. This concentration of Aβ triggers τ-tangle
formation, which is found in the locus coeruleus and transentorhinal and entorhinal areas of
the brain. In the critical stage, it spreads to the hippocampus and neocortex.3

2.3 Staging
a. Stage 1 preclinical stage or asymptomatic stage
Biomarkers play an important role in the identification of preclinical stages of AD and
aid in early diagnosis. Biomarker is a measurable parameter which reflects the presence and
severity of the disease. The biomarkers for AD are found by CSF analysis and imaging of
brain by magnetic resonance imaging (MRI) and positron emission tomography (PET). CSF
biomarkers are high phosphorylated tau (p,tau), high total tau (t tau), decreased concentration
of the Aβ42 peptide and increased tau amyloid ratio. MRI shows reduced volume of medial
temporal lobe and medial parietal cortex. Flurodeoxyglucose Positron Emission Tomography
(FDG –PET) is used to see brain glucose metabolism. Flurodeoxyglucose (FDG) is most
commonly used PET tracer which gives quantitative measure of glucose metabolism by
neurons. In AD there is progressive decline in the glucose metabolism reflecting neuronal
injury. Pittsburg compound B (PiB) PET is used to image amyloid in living brain. 1,5,6
Preclinical stage is further subdivided into 3 stages which are: Stage 1, it is
asymptomatic with PiB PET (Pittsburg compound B Positron Emission Tomography)
showing cerebral amyloidosis and low CSF amyloid Aβ 42 which are the markers of
amyloidosis. Stage 2, show features of stage 1 with an evidence of neurodegeneration as
shown by increase in CSF tau, abnormal volumetric loss on MRI and reduced glucose
metabolism with FDG-PET and finally stage 3, which includes all features of stage 2 and
subtle cognitive decline as evidenced clinically. Stage 3 is more likely to progress to MCI
when compared to stage 1 and 2. 1,5,6

Figure 2.3 Preclinical Stage of Alzheimer Disease according to

Biomarker1

b. Stage 2 mild cognitive impairment (MCI)

According to NIA-AA, MCI is defined as subjective and objective evidence for cognitive
decline without functional decline. The NIA-AA (National Institue ot Aging and Alzheimer
Association) criteria for MCI due to AD is, having cognitive impairment in one domain, with
positive biomarkers for amyloid accumulation and neurodegeneration (eg abnormal
radioactive tracer retention on amyloid PET scan, low CSF amyloid level of Aβ42, elevated
tau on CSF, decreased FDG uptake). MCI clinically presents as difficulty remembering
names, word finding difficulty and difficulty in concentrating. 1,6
Figure 2.4 Temporal (thick arrow) and parietal (thin arrow) hypometabolism on. FDG-
PET is often seen in patient with AD4

Figure 2.5 PET imaging of negative scan of amyloid plaque deposition (A), and positive
scan show significant updake in multiple cortical area, indicate the presence of moderate to
severe amyloid pathology4

c. Stage 3 Dementia
Dementia sets in with the development of cognitive decline in at least two cognitive domains
and behavioral symptoms which effect their daily functioning. Dementia of AD is diagnosed
when there is a proof of pathophysiologic process of AD as evidenced by clearly positive
biomarkers for brain amyloidosis and neurodegeneration. 1,6
 Figure 2.6 Timing of Major AD Clinical Course6

2.4 Clinical Feature and Diagnosis

Dementia is loss of mental function in two or more areas such as memory language,
or executive functions severe enough to interfere with daily activities and abilities to function
at work. Probable AD dementia is diagnosed when the onset is insidious with progressive
worsening of cognition with time. The initial and most prominent cognitive deficit of AD
dementia as evident on history. and examination are categorized into two types of
presentations amnestic and non-amnestic. Amnestic presentation is inability remembering
new things. Non- amnestic presentation includes language impairment, visuospatial
impairment and executive dysfunction. Changes in personality and behavioral symptoms
include fluctuations in mood, agitation and socially unacceptable behavior. 1 Mild to
moderate depressive symptoms are also frequently present early on. Disturbances of appetite
and sleep, disinhibition, and alterations in perception (hallucinations) or thought (delusions)
commonly occur in the later stages of dementia. In addition to the classic neuropsychiatric
behaviors, anosognosia (ie, lack of insight) often manifests early on and poses another
difficult management problem.4

Outside of the mental status examination, findings on the neurologic examination are
often normal in patients with AD. Parkinsonian symptoms can emerge in the later stages, but
if these symptoms are present early in the course of the disease (eg, within 1 year of onset of
cognitive problems) and especially when accompanied by cognitive fluctuations and early-
onset psychosis, a diagnosis of dementia with Lewy bodies should be considered. Later in the
disease course, pathologic reflexes such as grasp, root, and suck reflexes may be found.
Patients become increasingly impaired in the moderate and severe stages and are ultimately
mute, incontinent, and bedridden at the end stages of disease. At this stage, multiple
complications arise such as risk of aspiration with unsafe swallowing, malnutrition, im-
mobility with associated risks for bed- sores, deep venous thrombosis, and infections. Often,
these complications are the direct cause of death in patients with AD.4
The diagnosis of AD dementia relies on good clinical workup and
neuropsychological testing. Dementia is categorized into mild, moderate a severe using a
scale called Mini Mental Status Examination (MMSE). Score of 21-26 is mild, 10-20
moderate, 10-14 moderate severe and less than 10 is severe dementia. Guidelines by NIA-
AA suggest the use of biomarkers and imaging only for research application. Moreover, the
diagnosis of AD is only confirmed by brain autopsy with 80% accuracy. PET Scan has
sensitivity 96% dan 100% specifity to detect deposition of amyloid-β In brain. A more-
invasive but less-costly evaluation involves examination of CSF for Aβ42,
hyperphosphorylated tau peptide (p-tau), and total tau protein content has slightly less
diagnostic accuracy (85–90%) 1-3
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
re- classified delirium, dementia, amnestic and other geriatric cognitive disorders into the
more encompassing neurocognitive disorders. This change was made to better discriminate
between different neurodegenerative diseases, such as AD, dementia with Lewy bodies, and
frontotemporal dementia, as well as to include both major neurocognitive disorder
(equivalent to dementia) and mild neurocognitive disorder (equivalent to MCI)2

2.5 Treatment
a. Recent Treatment
 Acetylcholinesterase inhibitors
According to cholinergic hypothesis the cognitive dysfunction is due to loss of cholinergic
neurons. Therefore, blocking cholinesterase enzyme which metabolizes acetylcholine (Ach)
may help increase Ach levels which improves the cognition. AChEIs attempt at reducing the
breakdown of acetylcholine levels in the brain of the patients with AD by inhibiting the
responsible enzyme acetylcholinesterase in the synaptic cleft. Thus, AChEIs enhance central
cholinergic neurotrans- mission and finally tend to mitigate decline in cognition at least
during the first year of treatment. Further decline occurs, but even temporary discontinuation
of these drugs results in rapid decline and is associated with greater risk of nursing home
placement.6 The Food and Drug Administration (FDA) has approved Donepezil,
Rivastigmine and Galantamine for treatment of mild to moderate Dementia due to AD. ChEI
have significant efficacy in improving cognitive symptoms but not neuropsychiatric
symptoms in mild to moderate Dementia due to AD. Initiation of AChEI treatment as soon as
possible after the diagnosis is preferred as patients who started the AChEI 6 months later
showed more rapid cognitive decline than those who started the drug immediately.1,6,7
Pharmacokinetic characteristics differ among AChEIs: the primary route of elimination
for donepezil and galantamine is hepatic metabolism, whereas for rivastigmine is liver and
intestine metabolism. Donepezil and galantamine inhibit selectively and reversibly the
acetylcholinesterase, whereas riv- astigmine is a “pseudo-irreversible” inhibitor of acetylcho-
linesterase and butyrylcholinesterase. Donepezil has a long elimination half-life of 70 hours
and galantamine of 6 to 8 hours. The elimination half-life of rivastigmine is very short (1-
2 hours for oral and 3-4 hours for transdermal administra- tion), but the duration of action is
longer as acetylcholinester- ase and butyrylcholinesterase are blocked for around 8.5 and 3.5
hours, respectively.7
The most common adverse effects are triggered by the cholinomimetic action of the
AChEIs on the gastrointestinal tract and often include diarrhea, nausea, and vomiting. Rapid
eye movement sleep behavior disorder has been also remarked in some individuals.
Administration of the drug after a meal in the morning can minimize all of these adverse
effects. The transdermal patch of rivastigmine can induce rash at the site of application.
Adverse effects affect usually a 5% to 20% of patients but are mostly transient and mild. The
AChEIs may also trigger bradycardia and increase the risk of syncope. Thus, AChEIs are
contraindicated in conditions including severe cardiac arrhythmias, especially bradycardia or
syncope. They are also contraindicated in active peptic ulcer or gastrointestinal bleeding
history and uncontrolled seizures. Slow titration over months to years to a maximal tolerated
of the indicated dose is important for the safety of the patients.7

 N-methyl-D-aspartate receptor antagonists

The Aβ42 oligomers stimulate N-methyl-D-aspartate (NMDA) receptors which lead to
excitotoxicity and free radical damage of neuron. Memantine is a noncompetitive low-affinity
NMDA- receptor open-channel blocker and affects glutamatergic transmission. It is approved
by FDA for moderate to severe AD. MEM monotherapy improves cognitive and behavioral
symptoms. Combination of ChEI and MEM is superior in moderate to severe Dementia than
only MEM or only ChEI. Although these drugs have been able to relief the symptoms they
are unable to cure Dementia due to AD. Memantine monotherapy has demonstrated short-
and long-term benefits for patients with moderate to severe AD as assessed by different scales
evaluat- ing activities of daily living, cognition, and behavioral and psy- chological symptoms
of dementia (BPSD).1,6,7

According to British Association of Psychopharmacology Guidelines 2017 the

recommendations for anti-dementia drugs in clinical practice are as follow. ChEI such as
Donepezil, Rivastigmine, Galantamine are useful in mild to moderate AD dementia. MEM is
effective in moderate to severe AD dementia. Combination therapy of MEM and ChEI is
better over monotherapy with either of them alone in moderate to severe cases. Neither ChEI
nor MEM is recommended for use in MCI. 1

 Medication for BPSD

Antipsychotics and antidepressants remain the main medications for BPSD. Selective
serotonin reuptake inhibitors are preferred for treating depression and anxiety. Drugs with
low anticholinergic effects and an accept- able tolerability, such as sertraline, citalopram, and
escitalopram, are more appropriate. Antipsychotics should be administered only when a
significant safety risk for the patient or for the caregivers by aggressive behaviours makes
them necessary. Controversial and limited evidence cannot adequately support the use of
benzodiazepines, anticonvulsants stimulants, or dextromethorphan/quinidine.
Pharmacological approaches to managing BPSD are highly individualized and changeable,
depending on patient’s comorbidities, stage of the disease, and symptoms’ severity6

b. Treatment Under Research

AD involves protein misfolding, which distorts cellular systems and neuronal death. Protein
misfolding results in either loss or toxic gain of function of a protein. This might occur due to
abnormal protein aggregation, upon which the protein no longer performs its normal role and fails
to be cleared by the cellular environment, leading to deleterious biological responses. There are
constant AD studies on inhibiting the production of mis- folding proteins and their aggregation
and spread to limit the toxicity caused by abnormal proteins. The majority of AD- therapeutic
approaches are focused on reducing levels of toxic forms of Aβ and τ, the broad scope of
neurodegenerative processes underlying both early- and late-stage AD. Several drugs have been
analyzed and have reached Phase I, II, and III clinical trials.3,5

 Drug targeting amyloid production1,2,6,7

- Gamma secretase inhibitor
Semagacestat is the most studied γ-secretase inhibitor which reduced Aβ peptide in the CSF
of healthy humans and in patients with mild and moderate AD but did not show improvement
in cognitive dysfunction. The clinical trials were stopped due to its detrimental effects on
cognition and reports of skin cancers

- Gamma secretase modulator

According to the amyloid hypoth- esis, amyloidogenic pathway is promoted after the
sequential cleavage of APP by BACE1 and gama-secretase. Consequently, the inhibition of
these enzymes has been considered as a major therapeutic target. Unluckily, concerning
gama-secretase, in addi- tion to APP, this particular enzyme acts on many other sub- stances
and cleaves different transmembrane proteins. Notch receptor 1, which is essential for control

of normal cell dif- ferentiation and communication, is among them. This fact is probably

responsible for recent failures in clinical trials with gama-secretase inhibitors: semagacestat
was associated with worsening of activities in daily leaving and increased rates of infections

and skin cancer, avagacestat was associated with higher rate of cognitive decline and adverse

dose-limiting effects (skin cancer) and tarenflurbil which showed low brain penetration.
Serious safety concerns for gama-secretase inhibitors remove gama-secretase from the role of

appropriate target for the treatment of AD until in depth studies on this key enzyme could

help to therapeutically target gama-secretase in a safe way. No gamasecretase modulators are

currently studied in phase 1-3 clinical trialsBeta secretase inhibitor

- BACE Inhibitor
β-site amyloid cleaving enzyme 1(BACE1) inhibition is the major target of newer disease
modifying agent as it is the key enzyme involved in production of Aβ peptides. The greatest
limitation faced by these BACE1 inhibitors is the dose adjustment, as any excessive decrease
may lead to synaptotoxicity. Aβ peptides is synaptotrophic and neuroprotective in
physiological dose and synaptotoxic and neurotoxic in excess, hence less than physiological
level may be synaptotoxic. Therefore, careful dosing is the key issue in this regard
Two BACE inhibitors are still elabo- rated: elenbecestat (E2609) in phase 2 and
umibecestat (CNP520) in phase 3. The later agent is studied in asymptomatic individuals at
risk of developing AD (APOE4 homozygotes or APOE4 heterozygotes with elevated
amyloid, detected by cerebrospinal fluid [CSF] biomarkers or amyloid PET). However, the
clinical trials with the BACE inhibitors lanabecestat, verubecestat, and atabecestat have been
recently discontinued due to unexpected difficulties. The phase 3 lana-becestat trial was
discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased
due to ineffectiveness, as well as safety reasons (rash, falls, liver toxicity, and
neuropsychiatric symptoms).-All agents showed significant and dose-dependent result of
reducing CSF A42, but without cognitive or functional benefit while many of them were
poorly tolerated and some of them failed in subjects with prodromal AD. These results might
support the suggestion that blocking the process of forming of amyloid beta may be not
capable of halting the disease progression
- Alfa-secretase modulator
According to the amyloid hypothesis, nonamyloidogenic pathway is promoted after the
cleavage of APP by alfa-secretase. Consequently, the modulation of the enzyme has been
considered as a major therapeutic target. However, little is known of the main signaling
pathways that could stimulate cleavage of APP by alfa-secretase. Restricted, nowadays,
knowledge assumes that alfa-secretase activation is promoted through the
phosphatidylinositol 3-kinase (PI3K)/Akt pathway and may be through -aminobutyric acid
(GABA) receptor signaling; thus, agents that activate the PI3K/Akt pathway or act as
selective GABA receptor modulators are suggested as potential therapeutic drugs for AD.
Etazolate (EHT0202) stimulates the nonamyloidogenic alfa- secretase pathway acting as a
selective modulator of GABA receptors. A previous, phase 2 trial has showed that the agent
was safe and well tolerated in patients with mild to moderate AD. However, further
evaluation of etazolate in phase 3 trials has not progressed. Etazolate is currently evaluated in
animal studies for its preventive effect in post-traumatic stress disorder. Two alfa-secretase
modulators that activate the PI3K/Akt pathway are studied in phase 2 clinical studies: APH-
1105 and ID1201. APH-1105 is delivered intranasally and is assessed in mild to moderate
AD. ID1201 is a fruit extract of melia toosendan and also induces alfa-secretase activation. It
is evaluated in mild AD.

 Drug targeting amyloid aggregation1,2,6,7

- Glycosaminoglycans (GAGs) : promotes Aβ aggregation and deposition.
Tramiprosate antagonize interaction of Aβ with endogenous GAGs thus, preventing
aggregation. However, the research on this drug was stopped due to lack of efficacy in
phase III clinical trial
- Colostrinin (CLN) : inhibits aggregation of Aβ and dissolve already formed fibrils.
CLN is a proline rich polypeptide complex which was isolated first from ovine and
bovine colostrum. This drug has shown improvement in mild AD, but the effect was
not maintained
 - Methylene blue : has shown to inhibit both tau and amyloid aggregation. The clinical
trials for the derivatives of methylene blue are underway to demonstrate its utility in
treating AD

 Drug targeting amyloid clearance

Immunotherapy aims at clearance of amyloid load. Antibodies inhibit amyloid fibril
formation by antigen antibody interaction. Both antigen administration via active
immunization and antibody administration by passive immunization show reduction in Aβ
accumulation. Active immunization using Aβ (1-6) peptide produces active Aβ specific
antibody response in 75% patients without causing adverse inflammatory reaction.1,2,6,7
CAD1016 is Aβ (1-6) peptide designed in the form of drug which is presently in phase II
clinical trial. Passive immunization includes administration of monoclonal antibodies against
Aβ peptide (1-6). Monoclonal antibodies like bapineuzumab has shown disappointing results
and was stopped in phase III clinical trials due to reports of meningoencephalitis. Although
this drug increase Aβ peptide clearance it has not shown to improve cognition in patients with
mild to moderate AD. Solanezumab and gantenerumab are other monoclonal antibodies
which are researched on patients in preclinical stage. These drugs are currently in phase III
clinical trial. 1,2,6,7

 Drug inhibiting tau phosphorylation

Lithium and valproate have inhibitory actions on Glycogen synthase kinase-3 (GSK-3)
which is one of the primary enzymes involved in phosphorylation of tau. Although these
drugs have shown to slow the progression of cognitive deficit further large scale clinical trials
are required to assess its benefit in treatment of AD. Tideglusib is an irreversible inhibitor of
GSK-3. The research was stopped in phase II clinical trials due to lack of efficacy. 1,2,6,7

Summary the drug specific to amyloid target show in table below3

Drug Trials Target Actio

n
Aducanumab Phase I Antiamyloid Monoclonal antibody
Albumin + immunoglobulin Phase I Antiamyloid Polyclonal antibody
 AZD3293 (LY3314814) Phase I Antiamyloid BACE1 inhibitor
CAD106 Phase I Antiamyloid Amyloid vaccine
CNP520 PhaseI Antiamyloid BACE inhibitor
E2609 PhaseI Antiamyloid BACE inhibitor
Gantenerumab PhaseI Antiamyloid Monoclonal antibody
Nilvadipine PhaseI Antiamyloid Calcium-channel blocker
Solanezumab PhaseI Antiamyloid Monoclonal antibody
ATP PhaseII Antiamyloid Amyloid misfolding and
toxicity
Atomoxetine PhaseII Antiamyloid Adrenergic uptake
inhibitor
AZD0530 (saracatinib) PhaseII Antiamyloid Kinase inhibitor
Crenezumab PhaseII Antiamyloid Monoclonal antibody
JNJ54, -861, -911 PhaseII Antiamyloid BACE inhibitor
Posiphen PhaseII Antiamyloid Selective inhibitor of APP
production
Sargramostim (GM-CSF) PhaseII Antiamyloid Amyloid removal
UB311 Phase II Antiamyloid Monoclonal antibody
Valacyclovir Phase II Antiamyloid Antiviral agent
Aducanumab PhaseIII Antiamyloid Monoclonal antibody
KHK6640 PhaseIII Antiamyloid Amyloid-aggregation
inhibitor
Lu AF20513 PhaseIII Antiamyloid Polyclonal antibody
LY2599666 + solanezumab PhaseIII Antiamyloid Monoclonal antibody
combination
NGP 555 PhaseIII Antiamyloid γ-secretase modulator
MK8931 (verubecestat) Phase III Antiamyloid BACE inhibitor
There are promising drugs against Aβ toxicity, but in order to explore their maximum
effect on CNS cells, there is a need of nanocarriers to be employed. Availability of drugs in
the CNS is the major issue faced in the field of therapeutics against AD. The main reason
is the presence of a fully functional semiperme- able BBB, which poses as an obstacle for
transmigration of neurotherapeutic molecules (like drugs, peptides, vectors, and molecules)
across it, into the CNS. The BBB and its selective transport of molecules into the brain
oppose efficacious delivery of therapeutic agents. In addition, the BBB also negatively
affects drug effi- cacy and tolerance, because large doses of drugs are needed to reach levels
above the minimum effective concentration in the brain.3
 Nanotechnology inclusive of nanoparticulate systems offer an opportunity to over- come
such problems and can be used as Trojan-horse systems for transporting active molecules
across the, thus reducing toxicity and improving therapeutic efficacy. The use of drugs in
nanoplatforms or nanodevices results in enhancement of their pharmacokinetics and
pharmacody- namics, as well as reduces the toxicity. An essential aspect in nanomedicine
development is the delivery of drugs and con- trolled release of drugs into disease sites.
Therefore, the effectiveness of a treatment can be increased by incorporat- ing nanotechnology-
based drug-delivery systems.3
The advantages of NPs over plain drugs or microdrug systems are many, including bigger
surface area (higher drug loading) and a diverse range of biomaterials, organic (natural or
synthetic polymers), and inorganic (metals) compounds for NP production. The interaction
between the drug moiety and NPs is diverse. It can be covalent binding, the presence of an
ionic surface charge (ionic binding), direct adsorption, or surface bind- ing, and entrapment
of the drug. NP surfaces can be modified as well to aid drug binding, such as with
PEGylation, which is the process of covalent/noncovalent amalgamation of polyethylene
glycol (PEG) to the surface.3
Targeted drug delivery with the aid of NPs 100 nm in size can effectively increase drug
bioavailability across the BBB into the CNS with minimal or no side effects. Furthermore,
these nano- materials are designed to be biocompatible, hence redu- cing toxicity, plus with
the advancement in their magnetic and optical properties, they may be efficient alternative
agents for an early diagnosis. The delivery of saxagliptin via dipeptidyl peptidase 4 enzyme–
inhibitor molecules is now being explored for its activity in the therapy of AD, with the aid of
a chitosan–L-valine conjugate used to prepare NPs encapsulating saxagliptin. These NPs are
stable and crossed the BBB efficiently.3
MENPs are one of the most effective NP types for noninvasive and image-guided
personalized therapy against CNS diseases. They have a unique magnetoelectric actuation
effect, which allows longitudinal noninvasive monitoring utilizing MRI. In addition,
liposomal NPs are also potent candidates in drug delivery, as they can be easily surface-
modified, facilitating loading of both the hydrophilic and hydrophobic drugs, and aid
sustained release across the BBB. They can also be tagged with fluorescent lipids, which can
help in image-guided therapy by being able to be observed under microscopy.3
 Nutritional theraphy
- Phytocemical
 Neurotrophins are substances in brain which are required for survival of neurons. They
are reduced in neurodegenerative disorders such as AD . Phytochemical is a plant extract
from fruits such as grapes and nuts. They have the capacity to increase the Ach by inhibiting
ChEI, increase neurotrophins which promote growth of neurons and their survival. They also
act as antioxidants, prevent neuronal damage by scavenging reactive oxygen species (ROS)
and neutralize the free radicals. Studies showed that polyphenols which are present in grape
seed extract plays an important role not only by reducing oxidative stress but also by
inhibiting Aβ aggregation, reducing Aβ oligomerization. They also reduce tau
hyperphosphorylation and aggregation. The metabolites are capable of passing the BBB.
Resveratrol is another naturally occurring polyphenol which has shown efficacy in animal
models of AD. The phytochemicals formulated as nanoparticles have more efficacy, as such
particles can easily pass through the BBB. Among phytochemicals curcumin and quercetin
are formulated into nanoparticles and thus, have good bioavailability.1

- Antioxidant
Vitamin D stimulates Aβ phagocytosis, promotes neuronal survival and has antioxidant
effect. Vitamin D deficiency is associated with cognitive dysfunction in elderly and AD
dementia. However, no large randomized controlled trials have yet demonstrated efficacy of
vitamin D in treatment and prevention of AD. Further studies are needed to establish its
effectiveness in treatment and prevention of AD dementia. Efficacy of omega 3 fatty acid and
vitamin E has not shown good efficacy. 1

- Diet
Recent systematic reviews found that people who adhere to the Mediterranean diet (meals
consisting of fresh produce, wholegrains, olive oil, legumes, and seafood while limiting dairy
and poultry products and avoid- ing red meat, sweets, and processed foods) have reduced
risk of developing cognitive decline and AD2

d. Physical activity
Physical activity (PA) can reduce the risk of AD by promoting the hippocampal
neurogenesis, reducing inflammation, increasing synaptic plasticity and reducing oxidative
stress. A meta-analysis of six prospective studies published from 1990 to 2007 had found
45% decreased risk of AD with PA. Non-demented older individuals walking more than 4000
steps each day has shown better cognitive function and thicker hippocampus than those older
people who walked less than 4000 steps per day. The current evidence is not enough to
formulate the exact frequency, type and duration of PA that may be protective against AD.1,2

SECTION 3
CONCLUSION
The approved treatment for AD is symptomatic. It mainly consists of ChEI and NMDA
antagonist which reduce the symptoms but do not modify the progression of illness. Disease
modifying agents like β and γ blockers and monoclonal antibodies solanezumab and
gantenerumab has shown good efficacy in reducing the amyloid load. Drugs preventing tau
hyperphosphorylation and tau- based vaccines has also shown to reduce tau tangles. Till date
no disease modifying agents have been licensed either because of their toxic effects or lack
of efficacy. The lack of efficacy can be explained by the fact that these drugs were used in a
population which already presented with clinical symptoms. There urges the need to start
treatment in the early stage of illness

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