SAHIN MONDAL

27701921112
B.Pharm 7th semster
Practice School
PT 781

Genetics , Pathophysiology &

monoclonal antibody in Alzheimer's
Disease
 Alzheimer's Disease

• Alzheimer's disease is a progressive and irreversible

neurodegenerative disorder that primarily affects the
brain, leading to a gradual decline in cognitive functions
such as memory, thinking, and the ability to perform
everyday activities.

• The condition typically manifests in older adults, and its

early stages may involve subtle memory loss and cognitive
impairments that progress over time
 Genetics of Alzheimer's Disease
Amyloid precursor protein
Amyloid precursor protein is a transmembrane protein that plays a crucial role in the pathogenesis
of Alzheimer's disease. It is involved in the production of beta-amyloid, a peptide that forms toxic
plaques in the brains of individuals with Alzheimer's.
APP has 10 isoform
APP 304
• Neuronal Growth and
APP 639
Repair APP 677
APP 695(CNS)
• Cellular Adhesion APP 696
APP 714
• Neuroprotective action APP 733
by APP APP 751(Cell)
APP 752
APP 770(Cell)
 Genetics of Alzheimer's Disease
Apolipoprotein E (APOE)

Apolipoprotein E (APOE) is a protein crucial for lipid metabolism, and its role in Alzheimer's
disease is significant. The APOE gene exists in different forms, with APOE ε4 being a major
genetic risk factor for late-onset Alzheimer's.

• Apolipoprotein E
Consist of total 299 APOE has three
amino acid in it's isoforms
structure. • APOE ε2
• 90% of APOE derive • APOE ε3
from liver. • APOE ε4
 Genetics of Alzheimer's Disease
Presenilin
Presenilin are integral nine transmembrane domains proteins crucially involved in the
cleavage of the amyloid precursor protein (APP) and the subsequent production of amyloid-
beta (Aβ) peptides, which are central to the pathogenesis of Alzheimer's disease.

There are two main types known as presenilin 1 (PSEN1) and presenilin 2 (PSEN2).

PSEN1 PSEN2
Chromosome 14 Chromosome 1
6 isoform are
5 isoform are
PSEN 1 a 184
PSEN 2 a 448
PSEN 1 b 374
PSEN 2 b 384
PSEN 1 c 378
PSEN 2 c 358
PSEN 1 d 409
PSEN 2 d 244
PSEN 1 e 463
PSEN 2 e 170
PSEN 1 f 467
 Genetics of Alzheimer's Disease
TAU Protein
Tau protein is a key protein in the human body, particularly within nerve cells (neurons). Its
primary function is to provide structural support to microtubules, which are essential
components of the cytoskeleton.

In Alzheimer's disease, tau undergoes abnormal post-translational modifications,

Hyperphosphorylated tau loses its normal function and detaches from microtubules.
TAU protein has eight isoform, those are-
PNS 𝜏 757
Fetal 𝜏 315
𝜏A 351
𝜏B 380
𝜏C 409
𝜏D 382
𝜏E 411
𝜏F 440
 Pathophysiology
Amyloid-Beta (Aβ) Plaques:
• Amyloid precursor protein (APP) is
processed abnormally, leading to the
accumulation of Aβ peptides.
• Aβ peptides aggregate to form plaques
outside neurons.
• These plaques disrupt neuronal
communication and contribute to
neurotoxicity.
Tau Protein Pathology:
• Tau protein undergoes abnormal
phosphorylation.
• Hyperphosphorylated tau loses its
normal function, detaches from
microtubules, and forms
neurofibrillary tangles inside
neurons.
• Tau pathology disrupts the structural
integrity of neurons and contributes
to cell death.
Monoclonal antibody in Alzheimer's Disease
Aducanumab (Aduhelm): Mode of Action
Developed by Biogen and Eisai.
(opsonization.)
Lecanemab (Leqembi):
Targeting Beta-Amyloid
Under investigation by Biogen
Solanezumab: Enhancing Immune Recognition
Investigated by Eli Lilly. Immune-Mediated Clearance
Crenezumab: Phagocytosis and Clearance
A fully humanized monoclonal antibody
targeting beta-amyloid.
Donanemab (LY3002813):
Developed by Eli Lilly.
 REFERENCE
• SAHIN MONDAL 27701921112 PROJECT WORK 7th SEMSTER.docx
• https://www.researchgate.net/publication/7331198_Pathophysiology
_of_Alzheimer's_Disease
• https://www.researchgate.net/publication/374074074_Alzheimer's_
Disease_Novel_Targets_and_Investigational_Drugs_for_Disease_Mod
ification