Alzheimer's Disease

Question 1

Define Dementia

Answer 1

Clinical syndrome characterised by a significant decline in performance in one or more cognitive domains that interfere with activities of daily living

Dementia is an umbrella term used to describe clinical syndromes characterised by cognitive deficits.

Question 2

What is the pathophysiology of Alzheimer’s
Amyloid plaques

Answer 2

Amyloid plaques; an accumulation of abnormally folded amyloid B (AB) proteins 40 or 42 amino acid residues in length (these are by products of amyloid precursor protein (APP) metabolism)

Question 3

Early onset AD mutations in:

Answer 3

Amyloid precursor protein (APP)
Presenilin-1 (PSEN1)
Presenilin-2 (PSEN2)

Question 4

What can late-onset AD be attributable to?

Answer 4

Late-onset AD can be attributed to complex interplay between genetic and environmental factors (e.g. air pollution, smoking).

Question 5

Which gene is associated with Late-onset AD?

Answer 5

ApoE gene is attributed as the strongest risk factor for late onset AD

Question 6

What is APP

Answer 6

amyloid precursor protein (APP): is a transmembrane protein involved in neural proliferation, migration, differentiation, plasticity and synaptogenesis.

APP can be cleaved by three secretases: alpha-secretase, beta-secretease and gamma-secretase.

Question 7

How can mutations in APP contribute to the
pathological hallmarks of Alzheimer’s
disease?

Answer 7

APP can be cleaved by three secretases: alpha-secretase, beta-secretease and gamma-secretase.

Non-amyloidogenic pathway: APP is cleaved by alpha-secretase, gamma-secretease
Amyloidogenic pathway: APP is cleaved by beta-secretease and gamma-secretase.

APP mutations lead to a shift to the amyloidogenic pathway. This leads to Abeta40-42 production

Question 8

What are the functions of PSEN1/2

Answer 8

Presenilin-1/2 (PSEN-1/2) are subunits of gamma-secretase, the aspartyl protease responsible for Abeta production.

Question 9

How can mutations in PSEN-1/2 contribute
to the pathological hallmarks of Alzheimer’s
disease?

Answer 9

PSEN1/2 mutations impair γ-secretase function
and drive amyloidosis through changes in the
Aβ42/Aβ40 ratio

Question 10

what is Apolipoprotein E (ApoE)

Answer 10

Apolipoprotein E (ApoE) is a secreted lipoprotein involved in cholesterol metabolism

Question 11

How many alleles does ApoE gene have?
What are they

Answer 11

Three alleles

1- ApoE2
2- ApoE3
3- ApoE4

Question 12

Which ApoE allele is a strong risk factor for late-onset AD?
What is the proposed pathophysiology/mechanism

Answer 12

ApoE4
It is proposed to decrease clearance of extracellular Abeta

Question 13

Which area in the brain is important for memory and learning

Answer 13

Hippocampus

Question 14

Where does amyloid deposition begin

Answer 14

Amyloid deposition begins in the temporal lobe and hippocampus (hippocampus is an important region for learning and memory)
*hallmark of AD is impact on learning and memory

Question 15

where does amyloid deposition travel to as disease progresses

Answer 15

As the disease progresses, amyloid deposition spreads to other parts of the brain, including the temporal, parietal, and frontal cortices/lobes.

Question 16

What/which is the most abundant amyloid found in plaques

Answer 16

Abeta42 is most abundant within plaques due to its higher rate of fibrillation and insolubility

Question 17

Define biomarker

Answer 17

a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or
pharmacologic responses to a therapeutic intervention.

Question 18

State the methods in which biomarkers are detectable and measurable

Answer 18

Physical examinations
Laboratory assays
Medical imaging

Question 19

What/which biomarkers would be useful for AD?

Answer 19

Biomarkers that would allow for pre-symptomatic detection are particularly crucial as it would facilitate the development of an efficient and rapid treatment as early as possible.

Question 20

How have biomarkers supported AD?

Answer 20

Biomarkers for Alzheimer’s disease have provided supporting evidence for the amyloid hypothesis.
initiating event is the abnormal processing of β-amyloid peptide (Aβ), leading to formation of amyloid plaques
After a lag period, tau-mediated neuronal dysfunction and neurodegeneration become the dominant pathological processes

Subsequently, neuronal cell death leads to changes in brain structure and leads to deficits in cognitive function

Amyloid biomarkers are detected earlier than tau biomarkers. This is ‘evidence’ for the amyloid hypothesis. Amyloid triggers tau deposition to occur

Question 21

What is tau?

Answer 21

Tau is the microtubule-associated protein involved in microtubule stabilisation
The phosphorylation of tau regulates binding in microtubules

Question 22

What is the pathophysiology of Alzheimer’s
Neurofibrillary tangles of tau

Answer 22

Hyperphosphorylation of tau results in the formation of neurofibrillary tangles
Leads to the disruption of neuronal transport > leading to neuronal degeneration

Question 23

Describe the amyloid hypothesis of Alzheimer’s

Answer 23

Proposes the accumulation and deposition of oliogmeric or fibrillar amyloid-beta peptide is the primary cause of Alzheimer’s disease

Proteolytic cleavage of APP produced Abeta42

Toxicity of the amyloid oligomers and fibrils lead to the cascade of tau hyperphosphorylation

Tau hyperphosphorylation = formation of neurofibrillary tangles. leading to neuronal cell death

Occurs in the hippocampus first the becomes more widespread.

Question 24

Cerebrospinal fluid (CSF)

Answer 24

occupies the ventricular system and the cranial and spinal subarachnoid spaces.

Question 25

Describe why CSF biomarkers may/can be useful

Answer 25

Although lumbar puncture is invasive and potentially painful for the patient

CSF is the most informative fluid in biomarker discovery for neurodegenerative disorders

CSF has more physical contact with brain than any other fluid, as it is not separated from the brain by the blood brain barrier (BBB)

proteins or peptides that may be directly reflective of brain specific activities as well as disease pathology would most likely diffuse into CSF than into any other bodily fluid

Question 26

State the advantages of CSF biomarkers

Answer 26

• Highly sensitive and specific – not separated from the brain via the blood brain barrier (BBB)
• Can correlate with Alzheimer’s disease directly
• Can detect Alzheimer’s disease progression

Question 27

State the disadvantages of CSF biomarkers

Answer 27

• Invasive and painful procedure via lumbar puncture
• Irreproducible diagnosis due to sample storage and transportation

Question 28

What specific type of CSF biomarker could be valuable?

Answer 28

Synaptic CSF biomarker.

Core CSF biomarkers are well-validated for neurodegeneration as well as amyloid plaque and tau tangle pathology
However, there are no validated biomarkers for synaptic dysfunction – this is one of the best pathoanatomical correlates of cognitive deficits and predicts disease better than amyloid plaque load

It is clear that reliable biomarkers to monitor synaptic and dendritic function and loss directly would be a valuable addition to the Alzheimer’s disease diagnostic biomarker toolbox

Question 29

What is Neurogranin

Answer 29

Neurogranin is a dendritic protein expressed in the cortex and hippocampus with an important role in long‐term potentiation

Question 30

Neurogranin as a CSF biomarker

Answer 30

Neurogranin expression is markedly reduced in the hippocampus and the frontal cortex in Alzheimer’s disease, indicating loss of post-synaptic elements

measurement of neurogranin in CSF may serve as a biomarker for dendritic instability and synaptic degeneration

Studies have suggested that high CSF neurogranin may be specific for Alzheimer’s disease

Question 31

Blood based biomarkers

Answer 31

Blood-based biomarkers for Alzheimer’s disease would enable earlier and faster diagnosis and aid in risk assessment, early detection, prognosis and management.

Question 32

What are the current treatments for Alzheimer’s

Answer 32

acetylcholinesterase (AChE) inhibitors;
donepezil

NMDA receptor
antagonist; memantine

Question 33

What is the current pharmacological treatment for mild-to-moderate Alzheimer’s disease
Give the MOA

Answer 33

In patients with mild-to-moderate
Alzheimer’s disease, the
acetylcholinesterase (AChE) inhibitors;
donepezil

AChE inhibitors prevent the breakdown of ACh
by the enzyme acetylcholinesterase (AChE)
* AChE inhibitors therefore increase ACh levels and can thus alleviate cognitive symptoms in
Alzheimer’s disease patients

Question 34

What is the current pharmacological treatment for moderate-to-severe Alzheimer’s disease
Give the MOA

Answer 34

In patients with moderate-to-severe
Alzheimer’s disease, the NMDA receptor
antagonist; memantine

Memantine is a low-affinity NMDA receptor antagonist that blocks excessively open NMDA receptor ion
channels to reduce glutamate mediated neurotoxicity

• NMDA receptor overactivation and subsequent glutamate mediated neurotoxicity has been associated with Alzheimer’sdisease

Question 35

Anti-amyloid and anti-tau strategies

Answer 35

AChE inhibitors and NMDA receptor antagonists have benefits for patients but its clinical outcomes are limited

Question 36

Aducanumab

Answer 36

Human monoclonal antibody that selectively binds to amyloid beta fibrils and soluble oligomers and reduces amyloid burden in a dose and time dependent manner.

Question 37

Lecanemab

Answer 37

Lecanemab targets amyloid as it begins
to form amyloid fibrils

Question 38

Donanemab

Answer 38

Donanemab targets amyloids once
amyloid fibres have formed amyloid
plaques

Question 39

What are the differences between Lecanemab and Donanemab?

Answer 39

Lecanemab and donanemab are two alternate human monoclonal antibodies
that target amyloid protein – but target amyloid at different stages.

Question 40

Synaptic CSF biomarkers

Answer 40

As a potential for synaptic dysfunction.
Biomarkers to monitor synaptic and dendritic function

Question 41

Evidence for the amyloid hypothesis

Answer 41

Amyloid biomarkers are detected earlier than tau biomarkers.
(Suggesting than amyloid triggers tau deposition to occur)

Low Amyloidb42 is found in AD - reflects brain amyloid deposition

Low Ab42/40 ratio is found in AD

Question 42

Evidence against the amyloid hypothesis/For Tau

Answer 42

High t-tau is found in AD. This reflects the intensity of neurodegeneration (and potentially disease progression)

High P-tau is found in AD. High P-tau reflects phosphorylation state of tau and tau pathology in AD.

P-tau is more specific for AD than t-tau. (high csf levels have not been found in other neurodegenerative disorders)