Trigger 8 - Alzheimer’s disease and amyloid targeting therapies

Question 1

Define Dementia

Answer 1

Dementia is the loss of cognitive functioning (e.g., thinking, remembering, and reasoning) to such an extent that it interferes with daily life and activities.

Question 2

True or False: Dementia is a normal part of aging.

Answer 2

False. Dementia is not a normal part of aging.

Question 3

Fill in the Gap: Dementia prevalence increases with advancing _________.

Answer 3

Age.

Question 4

What is the most common form of dementia?
a) Vascular dementia
b) Frontotemporal dementia
c) Alzheimer’s disease
d) Lewy body dementia

Answer 4

c) Alzheimer’s disease

Question 5

Describe Early Onset Alzheimer’s Disease (EOAD):

Answer 5

EOAD occurs in individuals under 65 years of age and often has a significant genetic component.

Question 6

Describe Late Onset Alzheimer’s Disease (LOAD):

Answer 6

LOAD occurs in individuals over 65 years of age and is generally sporadic in nature.

Question 7

True or False: Alzheimer’s disease is characterized by short-term memory loss as its first symptom.

Answer 7

True

Question 8

Fill in the Gap: Alzheimer’s disease develops to more severe memory problems, confusion, disorientation, personality changes, and problems with ________ and _________.

Answer 8

Language and speech.

Question 9

Which of the following is NOT a sign or symptom of Alzheimer’s disease?
a) Misplacing items
b) Difficulty in decision making
c) Heightened ability to understand visual images
d) Social withdrawal

Answer 9

c) Heightened ability to understand visual images

Question 10

Define Alzheimer’s Disease

Answer 10

Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive decline, leading to interference with daily functioning and activities.

Question 11

True or False: Alzheimer’s disease is more prevalent in men than in women.

Answer 11

False. More women have Alzheimer’s disease than men.

Question 12

Fill in the Gap: Globally, over ______ million people have some form of dementia.

Answer 12

55 million.

Question 13

Which of the following is a common early symptom of Alzheimer’s disease?
a) Difficulty in problem solving
b) Reduced ability to understand visual images
c) Mood swings
d) Misplacing items

Answer 13

d) Misplacing items

Question 14

Describe Dementia Prevalence in the UK

Answer 14

In the UK, over 1 million people are currently affected by dementia, which accounts for approximately 1 in 11 individuals over the age of 65.

Question 15

True or False: Dementia prevalence is expected to decrease by 2050.

Answer 15

False. Dementia prevalence is expected to increase, with cases in the UK projected to reach at least 1.6 million by 2050.

Question 16

Fill in the Gap: Age is the biggest risk factor for _________.

Answer 16

Dementia

Question 17

Which form of Alzheimer’s disease has a larger genetic component?
a) Early onset
b) Late onset
c) Both have equal genetic components
d) Neither has a genetic component

Answer 17

a) Early onset

Question 18

Define Neuropathology

Answer 18

Neuropathology refers to the study of diseases of the nervous system, including the structural and biochemical changes that occur in the brain and nervous tissue.

Question 19

True or False: Alzheimer’s disease primarily affects the peripheral nervous system.

Answer 19

False. Alzheimer’s disease primarily affects the central nervous system, particularly the brain.

Question 20

Fill in the Gap: One of the signs of Alzheimer’s disease is confusion with ______ and ______.

Answer 20

Time and place.

Question 21

True or False: Memory loss is a common sign of Alzheimer’s disease.

Answer 21

True

Question 22

Fill in the Gap: Alzheimer’s patients may have difficulty in ________ items.

Answer 22

Misplacing

Question 23

Which of the following is a symptom of Alzheimer’s disease?
a) Enhanced ability in problem solving
b) Increased ability to complete complex tasks
c) Mood swings
d) Improved understanding of visual images

Answer 23

c) Mood swings

Question 24

Define: Repetitive Speech and Writing Issues

Answer 24

Repetitive speech and writing issues refer to the tendency of individuals with Alzheimer’s disease to repeat the same words, phrases, or sentences and to have difficulties with written communication.

Question 25

True or False: Social withdrawal is not associated with Alzheimer’s disease.

Answer 25

False. Social withdrawal is a common symptom of Alzheimer’s disease.

Question 26

Which of the following is NOT a symptom of Alzheimer’s disease?
a) Difficulty in decision making
b) Enhanced ability to complete complex tasks
c) Inability to complete complex tasks
d) Reduced ability to understand visual images

Answer 26

b) Enhanced ability to complete complex tasks

Question 27

Define: Inability to Complete Complex Tasks

Answer 27

Inability to complete complex tasks refers to the difficulty individuals with Alzheimer’s disease may have in carrying out tasks that require multiple steps or intricate problem-solving skills.

Question 28

True or False: Alzheimer’s disease does not affect judgment and decision-making abilities.

Answer 28

False. Alzheimer’s disease can impair judgment and decision-making abilities.

Question 29

Define Mild Cognitive Impairment (MCI)

Answer 29

Mild cognitive impairment refers to cognitive decline that is abnormal for age and education but does not interfere with function and activities.

Question 30

True or False: MCI is considered a precursor to degenerative dementia

Answer 30

True

Question 31

Fill in the Gap: When memory loss predominates in MCI, it is termed ________ MCI.

Answer 31

Amnestic

Question 32

Describe the Cause of Dementia

Answer 32

Dementia is caused by pathological changes in the brain that lead to loss of synaptic function and neurodegeneration, resulting in progressive impairment of brain circuitry and loss of function.

Question 33

True or False: The pathological hallmarks of Alzheimer’s disease include extracellular senile plaques and intracellular neurofibrillary tangles.

Answer 33

True

Question 34

Fill in the Gap: The main component of senile plaques is ________ aggregates/oligomers.

Answer 34

Ab (beta-amyloid).

Question 35

Which brain region largely spares the development of neurofibrillary tangles in Alzheimer’s disease?
a) Neocortex
b) Cerebellum
c) Hippocampus
d) Entorhinal cortex

Answer 35

b) Cerebellum

Question 36

Describe Neurofibrillary Tangles (NFTs)

Answer 36

NFTs develop from pre-tangles to mature tangles and are primarily composed of tau aggregates as paired-helical filaments (PHF), with “ghost tangles” remaining after neuron death.

Question 37

True or False: The spread of plaques and tangles across the brain is associated with functional deficits, synapse loss, and neuron loss.

Answer 37

True

Question 38

Fill in the Gap: Plaques originate in the ________ and spread through most other cortical areas and then most of the rest of the brain.

Answer 38

Neocortex

Question 39

Define Prion-like Spread:

Answer 39

Prion-like spread refers to the process in which a native (soluble) protein is “converted” into a misfolded “seed” by a pathological protein that acts as a template.

Question 40

True or False: Tau and Abeta spread along axon tracts and trans-synaptically to connected brain regions.

Answer 40

True

Question 41

Fill in the Gap: The pathological protein propagates by ________ nucleation, recruiting endogenous protein into aggregates.

Answer 41

Seeded

Question 42

What is the term for the process by which tau and Abeta spread along axon tracts and trans-synaptically to connected brain regions?
a) Seeded propagation
b) Prion replication
c) Axonal transmission
d) Trans-synaptic spread

Answer 42

d) Trans-synaptic spread

Question 43

Describe the Prion-like Spread Mechanism

Answer 43

The prion-like spread mechanism involves the conversion of native soluble proteins into misfolded seeds by pathological proteins, which then propagate through seeded nucleation, recruiting endogenous proteins into aggregates and spreading along axon tracts and across synapses to connected brain regions.

Question 44

Describe CERAD Staging

Answer 44

CERAD staging assesses plaque abundance in the neocortex as a method to score disease severity in Alzheimer’s disease.

Question 45

True or False: CERAD staging primarily focuses on tangle location in the brain

Answer 45

False. CERAD staging focuses on plaque abundance in the neocortex.

Question 46

Fill in the Gap: Braak staging primarily focuses on the location of _________.

Answer 46

Tangles

Question 47

Which staging system assesses tangle location in Alzheimer’s disease?
a) CERAD staging
b) Braak staging
c) Amyloid imaging staging
d) CSF biomarker staging

Answer 47

b) Braak staging

Question 48

Describe the Diagnosis of Alzheimer’s Disease

Answer 48

Even with advances in biomarkers such as imaging, blood tests, and cerebrospinal fluid (CSF) analysis, Alzheimer’s disease is usually diagnosed at an advanced stage. Genetic testing, particularly in those with mild cognitive impairment (MCI), along with biomarkers, may allow earlier diagnosis

Question 49

True or False: AD blood tests are typically based on the levels of phospho-tau and/or Abeta species in the blood.

Answer 49

True

Question 50

l in the Gap: A blood test for Alzheimer’s disease may not be able to rule in or out the disease 100% of the time, but it might be a cheap and easy way to help doctors spot which patients have hidden physical signs of the disease, years before ________

Answer 50

Telltale

Question 51

What does CERAD staging assess in Alzheimer’s disease?
a) Tangle location
b) Amyloid plaque abundance
c) Synaptic dysfunction
d) Neuronal loss

Answer 51

b) Amyloid plaque abundance

Question 52

Describe Amyloidogenic Pathway

Answer 52

In the amyloidogenic pathway, Ab is generated following cleavage of amyloid precursor protein (APP) by β and γ secretases.

Question 53

Define Non-amyloidogenic Pathway

Answer 53

In the non-amyloidogenic pathway, cleavage of APP by α and γ secretases precludes Ab production.

Question 54

Fill in the Gap: Gamma secretase first cleaves the APP-C99 substrate into either Aβ48 or Aβ49 peptides via ______-cleavage.

Answer 54

ε-cleavage.

Question 55

Which Aβ peptides does the field generally focus on in Alzheimer’s disease?
a) Aβ36 and Aβ38
b) Aβ40 and Aβ42
c) Aβ44 and Aβ46
d) Aβ50 and Aβ52

Answer 55

b) Aβ40 and Aβ42

Question 56

Describe Ab42

Answer 56

Ab42 is pro-aggregatory and is generally believed to be damaging in Alzheimer’s disease.

Question 57

Ab42 is pro-aggregatory and is generally believed to be damaging in Alzheimer’s disease.

Answer 57

True

Question 58

l in the Gap: Oligomeric Ab forms a “halo” around plaques, with ______ at the core.

Answer 58

Fibrils.

Question 59

Where is synapse loss greatest in relation to Ab oligomers?
a) At the center of plaques
b) Away from plaques
c) At the periphery of plaques
d) At the highest concentrations of Ab oligomers

Answer 59

d) At the highest concentrations of Ab oligomers

Question 60

Tue or False: The tau protein is encoded by the MAPT gene located on chromosome 17.

Answer 60

True

Question 61

Fill in the Gap: There are ______ main isoforms of tau in the adult human CNS, as a result of alternative splicing of Exons 2, 3, and 10.

Answer 61

Six

Question 62

What is the ratio of 3R:4R tau isoforms in the healthy brain?
a) 2:1
b) 1:1
c) 1:2
d) 3:1

Answer 62

b) 1:1

Question 63

Describe Tau Modifications in AD

Answer 63

In Alzheimer’s disease, tau undergoes phosphorylation, C-terminal cleavage, further phosphorylation in the mid-region/C-term end, misfolding after changes in charge, and additional modifications such as acetylation and ubiquitination. These modifications lead to the stacking of tau into fibrils with the microtubule binding domain at the core.

Question 64

True or False: Tau changes in Alzheimer’s disease are unrelated to synapse loss and clinical features of the disease.

Answer 64

False

Question 65

Fill in the Gap: Familial forms of AD, which are almost always early-onset, are caused by rare autosomal dominant mutations in 1 of 3 genes, including ______, ______, and ______.

Answer 65

APP, PSEN1, and PSEN2.

Question 66

Which gene encodes the amyloid precursor protein (APP)?
a) PSEN1
b) PSEN2
c) APP
d) MAPT

Answer 66

c) APP

Question 67

Describe the Role of PSEN1 and PSEN2 in AD

Answer 67

Presenilin 1 and 2 are part of the gamma secretase complex that cleaves Ab. Mutations in PSEN1 and PSEN2 largely favor the production of the most aggregation-prone forms of Ab.

Question 68

True or False: Age is the greatest risk factor for Alzheimer’s disease.

Answer 68

True

Question 69

Fill in the Gap: Highly penetrant mutations in APP, PSEN1, and PSEN2 that segregate with autosomal dominant AD are _______ and have large effect sizes.

Answer 69

Extremely rare

Question 70

Which of the following genetic variants increase the risk of Alzheimer’s disease, particularly in pathways related to the immune system/inflammation, lipid processing, endosomal pathways, and synapses?
a) APOE ε4
b) APOE ε2
c) Variants discovered by genome-wide associations
d) Mutations in APP, PSEN1, and PSEN2

Answer 70

d) Mutations in APP, PSEN1, and PSEN2

Question 71

Describe APOE ε2

Answer 71

APOE ε2 may provide some protection against Alzheimer’s disease. If Alzheimer’s occurs in a person with this allele, it usually develops later in life than it would in someone with the APOE ε4 gene.

Question 72

True or False: APOE ε3 is believed to have a neutral effect on the risk of Alzheimer’s disease.

Answer 72

True

Question 73

Fill in the Gap: APOE ε4 increases the risk for Alzheimer’s and is associated with an earlier age of disease onset in certain populations. About ______ of people have this allele.

Answer 73

15% to 25%

Question 74

Which allele of APOE increases the risk of Alzheimer’s disease?
a) APOE ε2
b) APOE ε3
c) APOE ε4
d) APOE ε6

Answer 74

c) APOE ε4

Question 75

Describe the Role of Genetics in Alzheimer’s Disease Risk

Answer 75

Genetics play a major role in the risk of Alzheimer’s disease onset, with certain genes elevating a person’s risk and others decreasing it. These genetic risk factors can be split depending on the form of AD, with APOE being a risk gene for late-onset AD and mutations in APP, PSEN1, and PSEN2 impacting early-onset AD.

Question 76

ue or False: Environmental factors such as a healthy diet and exercise have no impact on the risk of Alzheimer’s disease.

Answer 76

False

Question 77

True or False: The number of patients with Alzheimer’s disease doubles every 5 years after the age of 65.

Answer 77

True

Question 78

Fill in the Gap: Genetics play a major role in the risk of Alzheimer’s disease onset, with certain genes elevating a person’s risk and others decreasing it. These genetic risk factors can also be split depending on the form of AD, including ______-onset and ______-onset.

Answer 78

Late; early.

Question 79

Which chromosome is the APOE gene located on?
a) Chromosome 17
b) Chromosome 19
c) Chromosome 21
d) Chromosome 14

Answer 79

b) Chromosome 19

Question 80

Describe the Role of Presenilin 1 and 2 in AD

Answer 80

Presenilin 1 and 2 are part of the gamma secretase complex that cleaves Ab. Mutations in PSEN1 and PSEN2 largely favor the production of the most aggregation-prone forms of Ab, contributing to the pathogenesis of Alzheimer’s disease.

Question 81

True or False: Inheriting two copies of the APOE ε4 allele is associated with a higher risk of Alzheimer’s disease than inheriting one copy.

Answer 81

True

Question 82

Fill in the Gap: Variants discovered by genome-wide associations are mostly ______ to ______ with small effect sizes.

Answer 82

Common; low-frequency.

Question 83

What is the main form of pathogenesis in Alzheimer’s disease?
a) Tau aggregate formation
b) Synapse loss
c) Neuroinflammation
d) Abeta plaque accumulation

Answer 83

d) Abeta plaque accumulation

Question 84

Describe the Role of Age in Alzheimer’s Disease Risk

Answer 84

Advancing age is the most influential risk factor for Alzheimer’s disease. This is due to age-related co-morbidities such as atrophy of key brain areas, inflammation, vascular damage, production of free radicals, and breakdown of cell energy production.

Question 85

True or False: APOE ε2 is associated with an increased risk of Alzheimer’s disease

Answer 85

False. APOE ε2 may provide some protection against the disease.

Question 86

Fill in the Gap: Each person inherits two APOE alleles, one from each biological parent, meaning people can have one of ______ possible combinations.

Answer 86

Six

Question 87

Describe Pre-tangles

Answer 87

Pre-tangles represent the initial stage of neurofibrillary tangles and are characterized by the perinuclear accumulation of tau protein within neurons.

Question 88

True or False: Granulovacuolar degeneration is a well-understood process in Alzheimer’s disease.

Answer 88

False

Question 89

Fill in the Gap: Eosinophilic Rodlike Inclusions are characterized by the presence of interweaving parallel fibers composed of actin, tropomyosin, and ________.

Answer 89

Viculin

Question 90

Which component primarily constitutes the central core of senile plaques?
- a) Tau protein
- b) Amyloid beta protein
- c) Ubiquitin
- d) Cholinesterase

Answer 90

b) Amyloid beta protein

Question 91

Describe Synaptic Loss in Alzheimer’s Disease:

Answer 91

Synaptic loss refers to a substantial reduction in synaptic profiles, which correlates strongly with the severity of functional impairment in Alzheimer’s disease.

Question 92

True or False: Neurofibrillary tangles are primarily composed of amyloid beta protein

Answer 92

False

Question 93

Fill in the Gap: Senile plaques originate in the neocortex and then spread to other cortical areas and ________.

Answer 93

The rest of the brain.

Question 94

Which region of the brain is most commonly affected by granulovacuolar degeneration?
- a) Cerebellum
- b) Hippocampus
- c) Basal ganglia
- d) Neocortex

Answer 94

b) Hippocampus.

Question 95

Describe Ghost Tangles

Answer 95

Ghost tangles are composed of loosely arranged bundles of fibers with no associated nucleus, indicating neuronal death in Alzheimer’s disease progression.

Question 96

True or False: Vascular amyloid deposition is a common feature in Alzheimer’s disease that primarily affects the white matter of the brain.

Answer 96

False

Question 97

Excitotoxicity Theory

Answer 97

The excitotoxicity theory suggests that prolonged elevation of calcium ions (Ca2+) leads to suppressed synaptic function, synaptotoxicity, atrophy, and loss of learning and memory functions in Alzheimer’s disease. This theory is supported by the observation that NMDA receptor antagonists slow AD progression.

Question 98

Fill in the Gap: Excitotoxicity theory proposes that prolonged elevation of _______ ions leads to suppressed synaptic function in Alzheimer’s disease.

Answer 98

Calcium (Ca2+).

Question 99

Which receptors mediate synaptic plasticity required for memory and learning in Alzheimer’s disease?
- a) AMPA receptors
- b) GABA receptors
- c) NMDA receptors
- d) Dopamine receptors

Answer 99

c) NMDA receptors

Question 100

Describe Tau Protein Dysfunction:

Answer 100

Tau protein dysfunction in Alzheimer’s disease involves hyperphosphorylation, leading to the dissociation of the protein from microtubules. This results in inefficient transport, starvation of neurons, and ultimately, cell death.

Question 101

True or False: Tau protein mediates the transfer of Fyn to the dendritic compartment, where it phosphorylates NMDA receptors.

Answer 101

True

Question 102

Fill in the Gap: In Alzheimer’s disease, Aβ accumulation leads to the formation of amyloid plaques through the _______ pathway.

Answer 102

Amyloidogenic

Question 103

Which peptide is released as a result of the amyloidogenic pathway in Alzheimer’s disease?
- a) Tau
- b) Amyloid beta (Aβ)
- c) Synaptophysin
- d) Neurofilament

Answer 103

b) Amyloid beta (Aβ)

Question 104

Describe Mitochondrial Dysfunction and ROS Generation

Answer 104

Mitochondrial dysfunction in Alzheimer’s disease results in the aggregation of Aβ peptides within mitochondria, leading to disrupted mitochondrial conformation, decreased ATP release, and increased generation of reactive oxygen species (ROS). This oxidative stress contributes to neuronal damage and apoptosis.

Question 105

True or False: Oxidative stress occurs later in Alzheimer’s disease progression.

Answer 105

False

Question 106

Fill in the Gap: Aβ-peptides contribute to mitochondrial dysfunction by increasing the release of _______ and apoptosis-inducing factor.

Answer 106

Cytochrome C.

Question 107

Which theory suggests that accumulation of oligomeric Aβ leads to neuroinflammation, neurofibrillary tangles, vascular injury, and cognitive deficits in Alzheimer’s disease?
- a) Excitotoxicity theory
- b) Tau protein dysfunction theory
- c) Aβ hypothesis
- d) Mitochondrial dysfunction theory

Answer 107

c) Aβ hypothesis

Question 108

Describe the Amyloid Cascade Hypothesis

Answer 108

The amyloid cascade hypothesis proposes that the accumulation of amyloid-beta (Aβ) peptides, resulting from mutations in APP, PSEN1, and PSEN2 genes, is the primary event leading to neurodegeneration in Alzheimer’s disease.

Question 109

True or False: Synapse loss is evenly distributed across all brain regions in Alzheimer’s disease.

Answer 109

False

Question 110

Fill in the Gap: Modified tau loses important physiological functions and gains ______ properties.

Answer 110

Toxic

Question 111

Which of the following pathways are implicated in Alzheimer’s disease, based on genetic and experimental data?
- a) Tau production
- b) Neuroinflammation
- c) Axonal transport deficits
- d) All of the above

Answer 111

• d) All of the above

Question 112

Describe Tau Tangles in Alzheimer’s Disease

Answer 112

Tau tangles are present in brain stem nuclei and the entorhinal cortex of many cognitively normal aged individuals. In Alzheimer’s disease, the presence of cortical plaques correlates with neuronal tau propagation from the entorhinal cortex into neocortical areas.

Question 113

True or False: The mechanisms underlying neurodegeneration in Alzheimer’s disease are fully understood.

Answer 113

False

Question 114

Fill in the Gap: The lack of certainty about which mechanism is the most important for disease pathogenesis is reflected in the various ______ being explored in current clinical trials.

Answer 114

Targets

Question 115

What is the primary event proposed by the amyloid cascade hypothesis that leads to neurodegeneration in Alzheimer’s disease?
- a) Accumulation of tau tangles
- b) Accumulation of amyloid-beta peptides
- c) Synapse loss
- d) Neuroinflammation

Answer 115

b) Accumulation of amyloid-beta peptides.

Question 116

Describe Approved AD Treatments in the UK

Answer 116

Approved treatments in the UK for Alzheimer’s disease address some symptoms but do not modify the disease course. These include anticholinesterase inhibitors (rivastigmine, galantamine, donepezil) to treat cognitive symptoms and memantine, an NMDA antagonist, to offset glutamatergic neuron toxicity.

Question 117

True or False: Aducanumab was approved by the European Medicines Agency (EMA) for the treatment of Alzheimer’s disease.

Answer 117

False

Question 118

Lecanemab targets amyloid protofibrils and binds to them with high ______.

Answer 118

Affinity

Question 119

What is the primary target of donanemab in Alzheimer’s disease?
- a) Tau protein
- b) Glutamate receptors
- c) Amyloid protofibrils
- d) NMDA receptors

Answer 119

c) Amyloid protofibrils

Question 120

Describe Aducanumab

Answer 120

Aducanumab is a drug that targets aggregated amyloid in Alzheimer’s disease. Despite initially halted trials, subsequent analyses showed promising results, leading to FDA approval in the United States in June 2021. However, there have been conflicting opinions on its efficacy and safety.

Question 121

True or False: Lecanemab has shown significant improvement in cognitive decline in a Phase 3 trial.

Answer 121

True

Question 122

Fill in the Gap: Donanemab slowed the clinical progression of Alzheimer’s disease by ______ weeks.

Answer 122

76

Question 123

What is the primary mechanism of action of the approved AD drugs, Aducanumab, Lecanemab, and Donanemab?
- a) Inhibition of tau hyperphosphorylation
- b) Enhancement of cholinergic neuron function
- c) Targeting aggregated amyloid
- d) Modulation of glutamatergic neurotransmission

Answer 123

c) Targeting aggregated amyloid

Question 124

Describe the Mechanism of Anticholinesterase Inhibitors in AD Treatment:

Answer 124

Anticholinesterase inhibitors, such as rivastigmine, galantamine, and donepezil, offset the effects of cholinergic neuron loss in Alzheimer’s disease by inhibiting the breakdown of acetylcholine, thereby improving cognitive symptoms.

Question 125

True or False: Memantine is a first-line treatment for Alzheimer’s disease in the UK.

Answer 125

True

Question 126

Fill in the Gap: Aducanumab targets aggregated amyloid in Alzheimer’s disease and was approved by the ______ in June 2021.

Answer 126

U.S. Food and Drug Administration (FDA).

Question 127

What is the primary target of Lecanemab in Alzheimer’s disease?
- a) Tau protein
- b) Glutamate receptors
- c) Amyloid protofibrils
- d) NMDA receptors

Answer 127

c) Amyloid protofibrils

Question 128

Describe the Trial Design of Donanemab

Answer 128

Donanemab underwent an 18-month Phase 3 double-blind multicenter randomized controlled trial (RCT) to assess its efficacy in early symptomatic Alzheimer’s disease. Participants received intravenous doses of the drug every 4 weeks.

Question 129

True or False: Aducanumab was initially removed from further trials due to its lack of efficacy.

Answer 129

True

Question 130

What was the primary outcome of the Phase 3 trial for Donanemab?
- a) Reduction in tau pathology
- b) Improvement in cognitive decline
- c) Clearance of amyloid plaques
- d) Slowed clinical progression of the disease

Answer 130

d) Slowed clinical progression of the disease.

Question 131

Describe the Safety Concerns Associated with Lecanemab

Answer 131

Despite its efficacy in improving cognitive decline, Lecanemab raised safety concerns, including adverse events such as amyloid-related imaging abnormalities (ARIA).

Question 132

True or False: Donanemab was associated with more treatment-related deaths compared to the control group in its Phase 3 trial.

Answer 132

True

Question 133

Define Active Vaccinations

Answer 133

Active vaccinations involve exposing an individual to an antigen to stimulate an adaptive immune response, resulting in the production of antibodies to combat the antigen.

Question 134

Define Passive Vaccinations

Answer 134

Passive vaccinations entail administering antibodies against specific target proteins, bypassing the need for the individual’s immune system to generate an immune response.

Question 135

Passive vaccinations entail administering antibodies against specific target proteins, bypassing the need for the individual’s immune system to generate an immune response.

Answer 135

Ab (amyloid-β).

Question 136

Proposed Mechanisms of Anti-Aβ Antibodies

Answer 136

Anti-Aβ antibodies may directly target Aβ assemblies to neutralize their toxicity, activate microglia for phagocytosis via Fc-receptor (FcR) mediation, or create a concentration gradient between the brain and blood, facilitating Aβ removal via a peripheral sink mechanism.

Question 137

Describe Astrocytes and Microglia:

Answer 137

Astrocytes and microglia are two types of neuronal cells with various physiological functions in the brain. Astrocytes provide metabolic support, regulate blood flow, and maintain synaptic health, while microglia, known as the “primary immune cells of the brain,” engage in synaptic pruning and debris phagocytosis. In neurodegenerative diseases, both cells become activated, leading to altered functions, including driving neuroinflammation, which contributes to the disease pathology.

Question 138

True or False: GFAP is commonly used as a marker of microglia reactivity and neuroinflammation in the brain.

Answer 138

False. GFAP is typically used as a marker of astrocyte reactivity and neuroinflammation in the brain.

Question 139

Fill in the Gap: Microglia are implicated in antibody-mediated ______ clearance.

Answer 139

Ab (amyloid-β).

Question 140

Which of the following is NOT a proposed mechanism of anti-Aβ antibodies?
- a) Direct targeting of Aβ assemblies
- b) Activation of astrocytes
- c) Fc-receptor-mediated phagocytosis
- d) Peripheral sink mechanism

Answer 140

b) Activation of astrocytes

Question 141

Describe the Elan AN-1792 Vaccine Trial

Answer 141

The Elan AN-1792 vaccine trial was a double-blind, placebo-controlled phase 2a clinical trial utilizing an active vaccination approach with human amyloid-β (Aβ) 1-42 peptide. However, the trial was discontinued due to reports of serious side effects, specifically meningoencephalitis.

Question 142

True or False: Antibody responders in the Elan AN-1792 trial showed improvements in cognition and reduced CSF tau levels.

Answer 142

True

Question 143

Fill in the Gap: Antibody responders in the Elan AN-1792 trial showed decreased whole brain volume and increased ______ volume.

Answer 143

Ventricular

Question 144

What was observed in the 4.5-year follow-up of the Elan AN-1792 trial responders?
- a) Increased MMSE scores
- b) Reduced brain volume loss
- c) Less decline on Disability Assessment for Dementia and Dependence scales
- d) Higher levels of CSF tau

Answer 144

c) Less decline on Disability Assessment for Dementia and Dependence scales.

Question 145

Describe the Findings of the 15-Year Postmortem Follow-Up of the Elan AN-1792 Trial

Answer 145

Despite considerable plaque removal in antibody responders, most patients had progressed to severe dementia, suggesting that extensive tau pathology remained, potentially contributing to disease progression.

Question 146

True or False: The Elan AN-1792 vaccine trial resulted in significant improvements in cognitive decline and brain volume loss compared to the placebo group.

Answer 146

False

Question 147

Fill in the Gap: The Elan AN-1792 trial utilized an active vaccination approach using human amyloid-β (Aβ) _____ peptide.

Answer 147

1-42.

Question 148

What was the primary reason for discontinuing the Elan AN-1792 trial?
- a) Lack of efficacy
- b) Serious side effects, including meningoencephalitis
- c) High cost of treatment
- d) Regulatory issues

Answer 148

• b) Serious side effects, including meningoencephalitis

Question 149

Describe the Aducanumab Trials

Answer 149

Aducanumab trials consisted of two randomized, global, double-blind, placebo-controlled phase 3 clinical trials. It utilized passive immunotherapy with an antibody against human Aβ oligomers.

Question 150

True or False: The Aducanumab trials were halted due to reports of significant improvement in cognitive functions.

Answer 150

False

Question 151

Fill in the Gap: A re-analysis of the Aducanumab trials showed some improvement at the highest dose in one trial (EMERGE) and ______ in the other (ENGAGE).

Answer 151

Decline

Question 152

What measure of cognition showed the most significant improvement in participants on the highest dose of Aducanumab in the ENGAGE trial?
- a) CDR-SB
- b) MMSE
- c) ADAS-Cog
- d) PET

Answer 152

• c) ADAS-Cog

Question 153

Describe the Relationship Between Aducanumab Treatment and Plasma pTau

Answer 153

Aducanumab treatment resulted in reduced plasma pTau levels in both EMERGE and ENGAGE trials, and this reduction correlated with improvements in cognition.

Question 154

True or False: Aducanumab treatment in the EMERGE and ENGAGE trials was associated with a decrease in ventricular volume as observed in structural MRI scans.

Answer 154

False

Question 155

Fill in the Gap: ARIA occurred in ______% of participants treated with Aducanumab, with a higher incidence observed in ApoE4 carriers.

Answer 155

26% (low dose) - 36% (high dose).

Question 156

What was the outcome of the FDA approval for Aducanumab?
- a) Full approval
- b) Conditional approval
- c) Withdrawn approval
- d) Approval pending

Answer 156

c) Withdrawn approval

Question 157

Describe the Lecanemab Trial

Answer 157

Lecanemab trial was a multicenter (US) double-blind placebo-controlled phase 3 clinical trial. It utilized passive immunotherapy with an antibody against human soluble Aβ protofibrils for a duration of 18 months.

Question 158

Fill in the Gap: Out of 5967 screened participants, ______ were selected for the Lecanemab trial.

Answer 158

1795

Question 159

True or False: The completion rates for the Lecanemab trial were higher in the placebo group compared to the lecanemab group.

Answer 159

False

Question 160

What was the primary endpoint measure used in the Lecanemab trial?
- a) ADAS-Cog
- b) ADCOMS
- c) MMSE
- d) CDR-SB

Answer 160

d) CDR-SB

Question 161

Describe the Relative Improvement in Cognitive Decline Observed in Participants Treated with Lecanemab

Answer 161

Participants treated with lecanemab showed a significant decline in CDR-SB score relative to placebo, with a difference of 0.45 points on an 18-point scale, equivalent to approximately 12% overall improvement.

Question 162

Fill in the Gap: Lecanemab treatment resulted in approximately ______% reduction in brain amyloid burden relative to controls as measured by PET scans.

Answer 162

50%

Question 163

True or False: Lecanemab treatment in the trial was associated with an increase in adverse events leading to discontinuation compared to the placebo group, most of which were ARIA-related.

Answer 163

False

Question 164

What was the outcome of the FDA approval for Lecanemab?
- a) Full approval
- b) Conditional approval
- c) Withdrawn approval
- d) Approval pending

Answer 164

b) Conditional approval

Question 165

Describe the Donanemab Trial

Answer 165

The Donanemab trial was a randomized, global, double-blind, placebo-controlled phase 3 clinical trial. It utilized passive immunotherapy with an antibody against human Aβ aggregates (N-term, insoluble) for a duration of 18 months.

Question 166

Fill in the Gap: Out of 1736 participants, ______ were allocated to the donanemab group in the trial.

Answer 166

860

Question 167

True or False: The completion rates for the Donanemab trial were higher in the placebo group compared to the donanemab group.

Answer 167

False

Question 168

What was the primary endpoint measure used in the Donanemab trial?
- a) ADAS-Cog13
- b) CDR-SB
- c) ADCS-iADL
- d) iADRS

Answer 168

d) iADRS.

Question 169

Describe the Relative Improvement in Cognitive Decline Observed in Participants Treated with Donanemab

Answer 169

Participants treated with Donanemab showed a significant improvement in cognitive decline, with a 35% improvement in the low-medium tau group and a 21% improvement in the combined group, as measured by iADRS.

Question 170

Fill in the Gap: Donanemab treatment resulted in approximately ______% reductions in cognitive decline on other scales relative to placebo.

Answer 170

20-30%

Question 171

True or False: Both low-medium tau and combined groups in the Donanemab trial showed decreased brain volume and increased ventricular volume compared to placebo.

Answer 171

True

Question 172

What was the outcome of the FDA approval for Donanemab?
- a) Full approval
- b) Conditional approval
- c) Withdrawn approval
- d) Approval pending

Answer 172

b) Conditional approval.

Question 173

What is ADAS-Cog

Answer 173

ADAS-Cog, or the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, is a rating scale developed to assess the severity of cognitive dysfunction in Alzheimer’s disease.

Question 174

What is the primary purpose of ADAS-Cog

Answer 174

ADAS-Cog is the gold standard for assessing the efficacy of antidementia treatments. It is specifically designed to measure cognitive impairment in Alzheimer’s disease.

Question 175

How is ADAS-Cog scored?

Answer 175

ADAS-Cog is scored from 0 to 150 by summing the number of errors made on each task. Higher scores indicate worse performance.

Question 176

What are the two subscales of ADAS?

Answer 176

The two subscales of ADAS are ADAS-Noncog (non-cognitive subscale) and ADAS-Cog (cognitive subscale).

Question 177

Describe the tasks included in ADAS-Cog.

Answer 177

ADAS-Cog includes tasks such as word recall, naming objects and fingers, following commands, constructional praxis, orientation, and word recognition.

Question 178

What is iADRS and how is it calculated?

Answer 178

iADRS, or Integrated Alzheimer’s Disease Rating Scale, combines scores from ADAS-Cog and ADCS-iADL. It is calculated by summing the transformed ADAS-Cog14 score and the ADCS-iADL score

Question 179

What is the purpose of iADRS in clinical trials?

Answer 179

iADRS allows detection of disease progression across a broad range of the symptomatic disease spectrum. It serves as a primary endpoint in clinical trials evaluating potential treatments for Alzheimer’s disease.

Question 180

How is iADRS scored and what does it indicate?

Answer 180

The iADRS score ranges from 0 to 146, with lower scores indicating worse performance. It captures changes in both cognitive and functional domains, enhancing sensitivity to treatment effects.

Question 181

What is ARIA?

Answer 181

ARIA stands for amyloid-related imaging abnormalities, which are brain abnormalities detected by MRI findings in patients participating in Ab vaccination/immunotherapy trials.

Question 182

What are the different types of ARIA?

Answer 182

ARIA-E (edema/sulcal effusion)
ARIA-H (haemosiderin deposits in brain parenchyma - microhaemorrhage)
ARIA-H (haemosiderin deposits on pial surface – superficial siderosis)

Question 183

How is ARIA severity classified?

Answer 183

ARIA severity is classified based on the number and size of abnormalities detected by MRI.

Question 184

Define: Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog)

Answer 184

The ADAS-Cog is a widely used test to assess cognitive dysfunction in Alzheimer’s disease. It evaluates various cognitive domains such as memory, language, and praxis through a series of tasks.

Question 185

The ADAS-Cog score is calculated by summing the number of errors made on each task, with higher scores indicating ______________.

Answer 185

greater cognitive impairment

Question 186

What is the primary endpoint used in the evaluation of lecanemab in clinical trials?
a) MMSE
b) CDR-SB
c) ADCS-iADL
d) ADAS-Cog

Answer 186

b) CDR-SB

Question 187

Define: Amyloid-related imaging abnormalities (ARIA)

Answer 187

ARIA refers to brain abnormalities detected by MRI findings in patients participating in AD vaccination/immunotherapy trials, including ARIA-E (edema), ARIA-H (microhaemorrhage), and ARIA-S (superficial siderosis).

Question 188

What is the primary function of microglia in the brain?
a) Metabolic support
b) Blood flow regulation
c) Synaptic pruning
d) Neuronal signaling

Answer 188

c) Synaptic pruning

Question 189

Describe: Aducanumab

Answer 189

Aducanumab is a passive immunotherapy that targets aggregated amyloid-beta (Aβ) oligomers. It was evaluated in global phase 3 clinical trials for the treatment of Alzheimer’s disease.

Question 190

The iADRS score ranges from 0 to __________, with lower scores indicating worse performance.

Answer 190

146

Question 191

What is the main purpose of the integrated Alzheimer’s Disease Rating Scale (iADRS)?
a) Assessing amyloid-beta levels
b) Evaluating functional independence
c) Measuring neuroinflammation
d) Detecting disease progression in Alzheimer’s disease

Answer 191

d) Detecting disease progression in Alzheimer’s disease

Question 192

Define: Clinical Dementia Rating–Sum of Boxes (CDR-SB)

Answer 192

The Clinical Dementia Rating–Sum of Boxes (CDR-SB) is a scale used to measure the severity of cognitive impairment in patients with dementia. Scores range from 0 to 18, with higher scores indicating greater impairment.

Question 193

Describe: Lecanemab

Answer 193

Lecanemab is a passive immunotherapy evaluated in clinical trials for the treatment of Alzheimer’s disease. Its primary endpoint was the change from baseline to 18 months in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) score, with minimal clinically relevant changes estimated to be 1 to 2 points.

Question 194

At 18 months, the CDR-SB score had increased from baseline by __________ points with lecanemab and by 1.66 points with placebo.

Answer 194

1.21

Question 195

What is one criticism raised about the results of the lecanemab trial?
a) Significant improvement in cognitive decline
b) Meaningful change in outcome measures for women
c) Minimal reduction in amyloid PET signal
d) Lack of correlation between ARIA incidence and cognitive outcomes

Answer 195

c) Minimal reduction in amyloid PET signal

Question 196

The minimal clinically relevant change in the CDR-SB score has been estimated to be __________ points.

Answer 196

1 to 2

Question 197

Describe: General criticisms raised about statistical analysis of trial data

Answer 197

One criticism is the potential unblinding of participants when amyloid-related imaging abnormalities (ARIA) are detected, as well as the subjectivity of some scores (e.g., caregiver-based assessments) and the additional stress caused by MRI surveillance in some cases.

Question 198

Benefit/risk analysis questions the ________ improvement over time and the sustained long-term ________ after treatments.

Answer 198

Continued; loss of brain volume

Question 199

What is a concern regarding the lack of diversity in trials for anti-amyloid immunotherapies?
a) Lack of correlation between ARIA incidence and cognitive outcomes
b) Continued improvement over time
c) Significant loss of brain volume after treatments
d) Limited population eligibility, particularly among women and ApoE4 carriers

Answer 199

d) Limited population eligibility, particularly among women and ApoE4 carriers

Question 200

Define: Anti-amyloid immunotherapies

Answer 200

Anti-amyloid immunotherapies are treatments designed to target and reduce amyloid-beta protein levels in the brain, with the goal of slowing or halting the progression of Alzheimer’s disease. These therapies typically involve the use of antibodies or vaccines to target amyloid-beta aggregates.