An Updated Review on the Approved and Potential Drugs for

the treatment of Alzheimer’s Disease

By
Rifah Nanjiba
20146056

A thesis submitted to the School of Pharmacy in partial fulfillment of the requirements for the degree of
Bachelor of Pharmacy (B. Pharm.)

School of Pharmacy
BRAC University
October, 2024

© 2024. BRAC University

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Declaration

It is hereby declared that

1. The thesis submitted is my/our own original work while completing degree at Brac

University.

2. The thesis does not contain material previously published or written by a third party,

except where this is appropriately cited through full and accurate referencing.

3. The thesis does not contain material which has been accepted, or submitted, for any other

degree or diploma at a university or other institution.

4. I/We have acknowledged all main sources of help.

Student’s Full Name & Signature:

Rifah Nanjiba
20146056

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Approval

The thesis titled “An Updated Review on the Approved and Potential Drugs for Alzheimer’s
Disease” submitted by Rifah Nanjiba (20146056) of Spring, 2020 has been accepted as
satisfactory in partial fulfillment of the requirement for the degree of Bachelor of Pharmacy.

Supervised By: _______________________________

Approved By:

Dean: _______________________________
A.F.M. Yusuf Haider, PhD
Acting Dean, School of Pharmacy
Professor, Department of Mathematics and
Natural Sciences
Brac University

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Ethics Statement

This project does not involve any kind of animal and human trial.

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Abstract:
Alzheimer's disease (AD) is one of the most complex and prevalent neurodegenerative

disease, and over 55 million people around the world are suffering from it. There are only

three groups of drugs such as acetylcholinesterase inhibitors, NMDA antagonist, and anti-

amyloid antibodies that are clinically approved for the treatment of AD. Among these three

groups of drugs only anti-amyloid antibodies are disease modifying medicines and the rest

two groups of drugs only treat the symptoms of AD. Hence, there is a dire need of sufficiently

potent drugs and treatment strategies to manage this disease. Although the exact etiology of

this progressive neurodegenerative disease is still unknown, factors like genetic,

environmental, and lifestyle, might play a significant role. Meanwhile, extensive research is

continuously being performed for developing potential/novel drugs for AD such as beta-

secretase enzyme inhibitor, tau protein targeted inhibitors, genetic factors like ApoE4 gene

and immunotherapies, emphasizing the multifaceted pathophysiology of the disease. Despite

of certain challenges in novel drug development for AD, results obtained from recent clinical

trials and preclinical studies, suggest that a large number of compounds has the potential to

be used in the future therapeutic strategies for AD.

Keywords: Alzheimer's disease, neurodegenerative pathways, neuroinflammation, approved

drugs, disease-modifying therapies, novel therapeutics.

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Dedication
I want to dedicate this work to my parents and friends stood by me and showed their support

and encouragement throughout my entire journey.

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Acknowledgement
First and foremost, I would like to express my utmost gratitude to the Most Merciful Allah

for blessing me with strength and ability to complete this journey. I would like to express

my deepest gratitude to my supervisor, Assistant Professor Dr. Nishat Zareen Khair, for her

invaluable guidance, insightful feedback and expertise throughout the course of this thesis.

Her directions have been instrumental in shaping my ideas and enhancing the quality of

this work.

Finally, I would also like to extend my love and appreciation to my family and friends who

had belief in me and helped me to stay focused and dedicated towards my work.

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Table of Contents
Declaration....................................................................................................................................

Approval......................................................................................................................................

Ethics Statement..........................................................................................................................

Abstract.........................................................................................................................................

Dedication.....................................................................................................................................

Acknowledgement........................................................................................................................

Table of Contents..........................................................................................................................

List of Tables...............................................................................................................................

List of Figures.............................................................................................................................

List of Acronyms.........................................................................................................................

Chapter 1 Introduction................................................................................................................

1.1 What is Alzheimer’s Disease........................................................................................

1.2 Prevalence....................................................................................................................

1.3 Causes and Risk Factors...............................................................................................

1.4 Signs and Symotoms............................................................................………………5

1.5 Pathogenesis.................................................................................................................

1.5.1 Amyloid Aggregation..........................................................................................

1.5.2 Oxidative Stress................................................................................................

1.5.3 Metal ion imbalance..........................................................................................

1.5.4 Neurofibrillary Degeneration/Tau aggregation.................................................

1.5.5 Secretases..........................................................................................................

1.5.6 Excitotoxicity....................................................................................................

1.5.7 Cholinergic enzymes.........................................................................................

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 1.6 Rational of the Review...............................................................................................

1.7 Objective....................................................................................................................

Chapter 2 Methodology.............................................................................................................

Chapter 3 Approved and Potential Drugs for the treatment of Alzheimer’s Disease.........

3.1 Approved Drugs for the treatment of Alzheimer’s Disease.......................................

3.1.1 Acetylcholinesterase Inhibitors.........................................................................

3.1.2 NMDAR Antagonist..........................................................................................

3.1.3 Anti-amyloid Antibodies...................................................................................

3.2 Potential Drugs for the treatment of Alzheimer’s Disease.........................................

3.2.1 BACE1 Inhibitors..............................................................................................

3.2.2 TNF-α Inhibitors...............................................................................................

3.2.3 Tau Protein-Targeted Therapies........................................................................

3.2.4 ApoE4 Modulation............................................................................................

Chapter 4 Conclusion and Future Prospect............................................................................

References...................................................................................................................................

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 List of Tables
Table 1: Approved acetylcholinesterase inhibitor drugs for Alzheimer’s disease....................
18

Table 2: List of FDA approved Anti-amyloid antibodies for the treatment of

Table 3: List of compounds that can be developed into BACE1 inhibitor drugs for the
treatment of
AD..........................................................................................................................................31

Table 4: An overview of studies on using TNFIs to inhibit brain TNF-α in AD

Table 5: List of potential compounds that can be developed as anti-tau drugs for
AD...............35

Table 6: List of ApoE4 modulating drug candidates for potential therapeutic strategy for
AD……………………………………………………………………………………………....
38

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List of Figures
Figure 1: The formation of Beta Amyloid
Plaque..........................................................................2

Figure 2: Percentage of different age-group affected by Alzheimer’s

disease..............................3

Figure 3: The risk factors for Alzheimer’s

disease .......................................................................5

Figure 4: Pathogenesis of Alzheimer’s

disease............................................................................8

Figure 5: The role of Amyloid Plaque in the pathogenesis of

AD................................................9

Figure 6: The disruption of neurotransmission by the formation of Amyloid

Plaque..................9

Figure 7: The function of secretase enzyme in the breakdown of the Amyloid Precursor

Protein

(APP) ...........................................................................................................................................

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Figure 8: Schematic diagram indicating the sequential steps following which ACh is

synthesized and metabolized and the action of AChE

inhibitor.......................................................................17

Figure 9: AChE inhibition, nAChR modulation and correction of the cholinergic deficit by

galantamine. .................................................................................................................................

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Figure 10: Structure of

Memantine...............................................................................................23

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Figure 11: The mechanism of action of

Memantine.....................................................................24

Figure 12: Mechanism of action of LEQMBI (lecanemab) by activating

microgilia..................26

Figure 13: Different composition of the Amyloid

Plaque............................................................27

Figure 14: Mechanism of action of all the Anti-amyloid

antibodies............................................28

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List of Acronyms

AD: Alzheimer’s disease

APP: Amyloid precursor protein

Aβ: Amyloid beta

NFT: Neurofibrillary tangles

MAP: Microtubule associated protein

ApoE: Apolipoprotein E

ROS: Reactive oxygen species

IL‐1β: Interleukin-1β

TNF-α: Tumor necrosis factor-alpha

GSK-3: Glycogen synthase kinase-3

CDK5: Cyclin-dependent protein kinase 5

BACE1: Beta-site APP cleaving enzyme

NMDA: N-methyl-D-aspartate

NMDAR: N-methyl-D-aspartate receptor

ACh: Acetylcholine

AChE: Acetylcholinesterase enzyme

BuChE: Butyrylcholinesterase enzyme

IC50: 50% Inhibitory Concentration

nAChR: Nicotinic acetylcholinesterase receptor

mABs: Monoclonal antibodies

ARIA: Amyloid related imaging abnormalities

CFT: Carboxyl terminal fragment

AICD: APP intracellular domain

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