Alzheimer’s Disease - Passive Immunotherapy with Aducanumab Flashcards
What are the broad stages Alzheimer’s Disease progresses through?
- Preclinical AD: measurable brain changes but no developed symptoms
- Mild Cognitive Impairment due to AD: new but subtle symptoms (e.g., problems with memory, language and thinking)
- Dementia due to AD: noticeable memory, language, thinking or behavioral symptoms combined with biomarker evidence of Alzheimer’s-related brain changes (divided into Mild AD, Moderate AD and Severe AD)
Please shortly describe the typical biomarker dynamics found in Alzheimer’s Disease
- Amyloid-β load first to increase, followed by Tau
- initial increase in hippocampal activation > diminishes in later phases, leading to hippocampal hypoactivation
- increasing brain atrophy (=loss of brain volume) due to the die-off of neurons and their connections across the entire cortex, reflected by increasing functional and cognitive impairment
What does the Amyloid Cascade Hypothesis postulate?
main position in the whole debate
The neurodegenerative process in AD is due to the formation and aggregation of deposits of amyloid peptides
meaning these are the first steps in the pathogenesis of AD
Why are the longer Aβ peptides the neurotoxic ones? Long Aβ peptides are also produced in healthy brains - what is different in an Alzheimer’s brain?
- Longer Aβ peptides are more prone to aggregation
- Higher levels of long form > excessive accumulation of Aβ peptides that leads to formation of soluble, non-fibrillar Aβ oligomers and, eventually, amyloid plaques
Result: destruction and removal cannot be accomplished anymore > dyshomeostasis bw production and clearance of Aβ peptides
Amyloid Cascade: which abnormalities have been observed on the level of synapses and brain networks?
- Synapses: Aβ oligomers affect normal synaptic transmission and induce hyperexcitability in neurons (e.g. block glutamate reuptake)
Result: Impairment of STP and LTP, LTD faciliation, loss of dendritic spines
- Brain networks: Aβ differentially affects synaptic interactions bw excitatory and inhibitory cells > produces complex imbalances in circuit and network activity
Please name the characteristics of patients included in the Aducanumab Phase 3 Trials EMERGE and ENGAGE?
3 charcteristics asked
- age: 50-85 years
- Mild Cognitive Impairment or Mild Dementia due to AD
- Confirmed amyloid pathology (visual assessment of amyloid PET)
Based on which surrogate endpoint did Aducanumab received FDA-approval (using the accelerated approval pathway)?
Dose- and time-dependent reduction in amyloid PET in both Phase 3 Studies
Controversy!
Please name the most common adverse event in the Aducanumab Phase 3 Trials. Which patient groups were affected the most?
ARIA-E (Amyloid-related imaging abnormalities, manifestation as brain edema or sulcal effusion ) > 35.2% in high-dose group
Higher in: high-dose groups + in APOE ɛ4 allele carriers
Serious ARIA events uncommon; 98% could resolve during the study
What can the Accelerated Approval Pathway (FDA) be used for? How is the process designed?
- For drugs against life-threatening illnesses with meaningful therapeutic advantages over existing treatments
- Decision can be based on drug’s effect on a surrogate endpoint that is likely to predict a clinical benefit to patients
- Post-approval trial required to verify that the drug provides the expected clinical benefits
β-amyloid precursor protein (APP) can be cleaved in a non-amyloidogenic and amyloidogenic way. Please shortly describe the two pathways.question…
- Non-amyloidogenic pathway: cleavage of APP by α-secretases (producing, among others, an extracellular sAPPα fragment with important functions for synpatic plasticity and resistance of the neuron)
- Amyloidogenic pathway: APP first cleaved by β-secretase (generating the primary N-terminal cut); remaining segment then cleaved by γ-secretase > results in an Aβ peptide containing 40 or 42 amino acids (Aβ40 and Aβ42)
APP: single domain plasma membrane protein found in different types of neurons and glial cells
Was the primary endpoint (change on the Clinical Dementia Rating Sum of Boxes (CDR-SB)) met in both Aducanumab Phase 3 Trials?
NO
- EMERGE: positive study > statistically sign. slowing of clinical decline in the high-dose arm (for the CDR-SB and 3 secondary endpoints)
- ENGAGE: negative study
Pathological forgetting (and its subtypes)
- Forgetting is a normal process: improves performance by dissolving unused snaptic connections
- pathological forgetting: amnesia
anterograde = deficit of encoding new memories
retrograde = deficit of retrieving old memories - dementia
What is dementia? what is the most common subtype?
A chronic condition characterized by progressive dementia [sic! - Dereks slide - impairment of memory / forgetting?] and often change of personality
* impairment of memory function and attention, language skills, visual-spatial orientation, abstract thinking, judgement
most common: Alzheimer’s dementia (60-80% of all dementias)
What is the function of tau protein and how does it change in pathology?
tau protein stabilizes microtubules which are important for intracellular transport
tau pathology: hyperphosphorylated tau
- excessive attachment of phosphate ions –> change in molecular structure
- disrupts substance transport within the cell –> cell death –> neurofibrillary tangles (of protein filament)
What is an example of Anti-Aß Treatment? What are the two subtypes of this treatment approach?
Anti-Aß Immunotherapy: i.e. teatment via modulation of the immune system
- injection with Aß-based antigens: active immunization –> elicits produciton of anti-Aß antibodies
- or anti-Aß antibody infusion: passive immunotherapy –> interfere with amyloid cascade
