Alzheimer's Disease

Question 1

Hallmarks of AD pathology

Answer 1

• early loss of cholinergic neurons
• amyloid plaques (extracellular)
• neurofibrillary tangles (intracellular)

Question 2

Early-onset inherited cases of AD are caused by incredibly rare mutations in which 3 genes?

Answer 2

PSEN1, PSEN2, APP

Question 3

AD is the leading form of…

Answer 3

Dementias

Question 4

Having 2 copies of the __ gene makes you >8 times more likely to develop AD

Answer 4

APOE4

Question 5

Risk variant in __ makes a person 3 times more likely to develop AD

Answer 5

TREM2

Question 6

APOE4 gene carriers should consider…

Answer 6

dietary modifications to reduce lipid levels

Question 7

Biggest risk factor for AD

Answer 7

Advanced age

Question 8

What brain region does AD usually begin in

Answer 8

Temporal lobe

Question 9

Main neural networks that degenerate in AD

Answer 9

Cholinergic basal forebrain neurons
Glutamatergic neurons (medial temporal lobe)

Question 10

Additional neural networks that degenerate in late-stage AD

Answer 10

Noradrenergic neurons
Serotonergic neurons
Dopaminergic neurons

Question 11

Major component of amyloid plaques

Answer 11

An aggregated form of amyloid-β protein (Aβ)

Question 12

What is the Amyloid Cascade Hypothesis?

Answer 12

Aβ accumulation is a starting point in disease pathogenesis

Question 13

Evidence against the Amyloid Cascade Hypothesis

Answer 13

“The Nun study”
Cognitively normal elderly people with extensive amounts of amyloid plaques
Aβ vaccines that remove plaques from brain do not slow or halt cognitive decline in AD

Question 14

What are neurofibrillary tangles?

Answer 14

Paired helical filaments (PHFs) of hyperphosphorylated tau protein

Question 15

What does the presence of neurofibrillary tangles lead to?

Answer 15

Destabilisation of microtubules
Loss of dendritic & axonal transport ability
Damage to neuronal cytoskeleton → neurodegeneration

Question 16

Approved clinical therapies for AD

Answer 16

AChE inhibitors: Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne)
NMDA receptor antagonist Memantine (Namenda)
Amyloid vaccine: Aducanumab (Aduhelm)

Question 17

Disease-modifying therapy for AD

Answer 17

Aducanumab

Question 18

The first cholinesterase inhibitor (now rarely prescribed)

Answer 18

Tacrine (Cognex)

Question 19

Plasma half-life of Donepezil

Answer 19

70h

Question 20

Administration of Rivastigmine

Answer 20

Transdermal patch

Question 21

Rivastigmine MOA

Answer 21

Inhibits both AChE and butrylcholinesterase

Question 22

Plasma half-life of Rivastigmine

Answer 22

2h

Question 23

Galantamine MOA

Answer 23

• Competitive and reversible inhibitor of AChE
• Positive allosteric modulator of pre- and post-synaptic nACh receptors

Question 24

Memantine MOA

Answer 24

• Weak NMDA receptor antagonist
• Interacts with Mg²⁺ binding site
• Spares normal NMDA receptor function
• Used in combination with AChE inhibitors
• Reduces excitotoxicity

Question 25

Plasma half-life of Memantine

Answer 25

60-80h

Question 26

Mild to severe side effects of cholinergic drugs (uncommon)

Answer 26

Cardiac: bradycardia, dysrhythmias, hypotension

GI: increased output of gastric acid, nausea, vomiting, abdominal cramps, diarrhoea

Excessive salivation

Bronchoconstriction

Question 27

Experimental drugs in AD treatment

Answer 27

Amyloid reducing therapies e.g. vaccine, B or 𝛾 secretase inhibitors
Tau reducing therapies e.g. kinase inhibitors, vaccine
Antioxidants (Vit E, melatonin)
Nicotinic receptor agonist
PPAR𝛾 agonist

Question 28

Example of a 𝛾-secretase inhibitor

Answer 28

Semagacestat (Eli Lilly)

Question 29

How do high cholesterol diets affect Aβ pathology in animals

Answer 29

They increase Aβ pathology. Cholesterol has a direct effect on APP processing

Question 30

What metal ions is Aβ aggregation partly dependent on?

Answer 30

Cu²⁺ and Zn²⁺

Question 31

What is Clioquinol?

Answer 31

An anti-fungal/protozoan/viral agent that chelates Cu²⁺/Zn²⁺ → anti-amyloidogenic

Question 32

Therapies that address __ may be most effective in treating AD

Answer 32

Cellular aging