06 Alzheimer's Disease Flashcards
What is forgetting and amnesia?
- forgetting is normal process to improve performance by dissolving of unused synaptic connections
- amnesia: pathological forgetting
- anterograde: deficit of encoding new memories
- retrograde: deficit of retrieving old memories
What is dementia and its most common form?
- chronic condition characterized by progressive amnesia and often change of personality
- most common: Alzheimer’s dementia (60-80% of all dementias)
- 5-10% of US population > 65, up to 45% of >85
Symptoms, Diagnosis and genetic contributions to Alzheimer’s
- impairment of recent memory function and attention, then language skills, visual-spatial orientation, abstract thinking, judgement
- definite diagnosis only post-mortem (amyloid plaques, neurofibrillary tangles)
- e.g. gene encoding for amyloid precursor protein (APP) on chromosome 21
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
- neurodegeneration begins in hippocampal-entorhinal cortex
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
- abnormal metabolism of β-APP leads to amyloidogenic pathway: cleavage of APP by β-secretase (non-amyloidogenic: alpha-s) generates primary N-terminal cut, cleavage of remaining segment by gamma-secretase
- result: Aβ-peptide containing 40-42 amino acids
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 (may precede symptoms by decades)
- AD: 40% long form (compared to 5-10% in healthy brains)
- 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
Tau pathology: Neurofibrillary tangles
- tau protein stabilizes microtubules (important for intracellular transport)
hyperphosphorylated tau: - attachment of excessive amounts of phosphate ions, change in molecular structure
disruption of substance transport within the cell leads to cell death and neurofibrillary tangles (of protein filament)
Anti-Aß Immunotherapy
- treatment via modulation of immune system
- aims at eliciting anti-Aβ immune response to reduce/eliminate Aβ aggregates via injections with aβ-based antigens (active immunization) or anti-Aβ antibody infusion (passive immunization)
Active Immunotherapy
- vaccination (antigen) with Aβ42 (or other Aβ types)
- aim: elicit production of anti-Aβ antibodies
- potential for long-term effects with short-term administration (lower cost)
- inconsistent immune response (interind. var.) and no succesful outcomes yet
Passive Immunotherapy
- based on administration of (preformed) antibodies against Aβ
- antibodies interfere with amyloid cascade
- antibody level can be controlled directly
- repeated application necessary
- promising direction of research
Anti-Aβ monoclonal antibodies (mAbs)
- antibodies derived from clones of a single parent B-cell (e.g. Aducanumab, Gantenerumab)
- differ in species and aggregation state of Aβ targeted
- different hypotheses about their mechanism, e.g. trigger cascade leading to microglia activation
Aducanumab - Development
- “fully human” IgG1 monoclonal antibody
- screening of libraries of B-memory cells in healthy elderly individuals without signs of cognitive impairment
- criteria: ability to stain Aβ plaques on brain tissue sections (patients with AD or APP transgenic mice)
- the B-cells that produced antibodies showing an anti-Aβ reaction were cloned to engineer Aducanumab
- resulting antibodies are thus selected to have anti-Aβ effects
Aducanumab - Effects on Aβ
- able to cross blood brain barrier (transgenic mice)
- significant decrease in brain Aβ-plaque levels (time- and dose-dependent)
- clinical benefit: stabilization of cognitive decline
- high affinity for Aβ42 oligomers but does not bind Aβ40
β-amyloid precursor protein (APP) can be cleaved in a non-amyloidogenic and amyloidogenic way. Please shortly describe the two pathways.
- 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
