Alzheimer's Disease Flashcards
Define Dementia
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.
What is the pathophysiology of Alzheimer’s
Amyloid plaques
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)
Early onset AD mutations in:
Amyloid precursor protein (APP)
Presenilin-1 (PSEN1)
Presenilin-2 (PSEN2)
What can late-onset AD be attributable to?
Late-onset AD can be attributed to complex interplay between genetic and environmental factors (e.g. air pollution, smoking).
Which gene is associated with Late-onset AD?
ApoE gene is attributed as the strongest risk factor for late onset AD
What is APP
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.
How can mutations in APP contribute to the
pathological hallmarks of Alzheimer’s
disease?
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
What are the functions of PSEN1/2
Presenilin-1/2 (PSEN-1/2) are subunits of gamma-secretase, the aspartyl protease responsible for Abeta production.
How can mutations in PSEN-1/2 contribute
to the pathological hallmarks of Alzheimer’s
disease?
PSEN1/2 mutations impair γ-secretase function
and drive amyloidosis through changes in the
Aβ42/Aβ40 ratio
what is Apolipoprotein E (ApoE)
Apolipoprotein E (ApoE) is a secreted lipoprotein involved in cholesterol metabolism
How many alleles does ApoE gene have?
What are they
Three alleles
1- ApoE2
2- ApoE3
3- ApoE4
Which ApoE allele is a strong risk factor for late-onset AD?
What is the proposed pathophysiology/mechanism
ApoE4
It is proposed to decrease clearance of extracellular Abeta
Which area in the brain is important for memory and learning
Hippocampus
Where does amyloid deposition begin
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
where does amyloid deposition travel to as disease progresses
As the disease progresses, amyloid deposition spreads to other parts of the brain, including the temporal, parietal, and frontal cortices/lobes.
What/which is the most abundant amyloid found in plaques
Abeta42 is most abundant within plaques due to its higher rate of fibrillation and insolubility
Define biomarker
a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or
pharmacologic responses to a therapeutic intervention.
State the methods in which biomarkers are detectable and measurable
Physical examinations
Laboratory assays
Medical imaging
What/which biomarkers would be useful for AD?
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.
How have biomarkers supported AD?
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
What is tau?
Tau is the microtubule-associated protein involved in microtubule stabilisation
The phosphorylation of tau regulates binding in microtubules
What is the pathophysiology of Alzheimer’s
Neurofibrillary tangles of tau
Hyperphosphorylation of tau results in the formation of neurofibrillary tangles
Leads to the disruption of neuronal transport > leading to neuronal degeneration
Describe the amyloid hypothesis of Alzheimer’s
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.
Cerebrospinal fluid (CSF)
occupies the ventricular system and the cranial and spinal subarachnoid spaces.
Describe why CSF biomarkers may/can be useful
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
State the advantages of CSF biomarkers
- 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
State the disadvantages of CSF biomarkers
- Invasive and painful procedure via lumbar puncture
- Irreproducible diagnosis due to sample storage and transportation
What specific type of CSF biomarker could be valuable?
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
What is Neurogranin
Neurogranin is a dendritic protein expressed in the cortex and hippocampus with an important role in long‐term potentiation
Neurogranin as a CSF biomarker
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
Blood based biomarkers
Blood-based biomarkers for Alzheimer’s disease would enable earlier and faster diagnosis and aid in risk assessment, early detection, prognosis and management.
What are the current treatments for Alzheimer’s
acetylcholinesterase (AChE) inhibitors;
donepezil
NMDA receptor
antagonist; memantine
What is the current pharmacological treatment for mild-to-moderate Alzheimer’s disease
Give the MOA
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
What is the current pharmacological treatment for moderate-to-severe Alzheimer’s disease
Give the MOA
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
Anti-amyloid and anti-tau strategies
AChE inhibitors and NMDA receptor antagonists have benefits for patients but its clinical outcomes are limited
Aducanumab
Human monoclonal antibody that selectively binds to amyloid beta fibrils and soluble oligomers and reduces amyloid burden in a dose and time dependent manner.
Lecanemab
Lecanemab targets amyloid as it begins
to form amyloid fibrils
Donanemab
Donanemab targets amyloids once
amyloid fibres have formed amyloid
plaques
What are the differences between Lecanemab and Donanemab?
Lecanemab and donanemab are two alternate human monoclonal antibodies
that target amyloid protein – but target amyloid at different stages.
Synaptic CSF biomarkers
As a potential for synaptic dysfunction.
Biomarkers to monitor synaptic and dendritic function
Evidence for the amyloid hypothesis
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
Evidence against the amyloid hypothesis/For Tau
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)
