Alzheimers disease Flashcards
(26 cards)
What is dementia
Dementia is a clinical syndrome characterised by a significant decline in performance in one or more cognitive domains that interferes with activities of daily living
Incidence of dementia
944,000 people are estimated to be living with dementia in the UK
Different sub-types of dementia
Dementia is an umbrella term used to describe clinical syndromes that are characterised by cognitive deficits – there are a number of dementia sub-types
What is Alzheimer’s disease
- First reported by Alois Alzheimer in 1906 in patient who suffered impaired memory, disorientation, inability to use language and “psychosocial incompetence”
- Post-autopsy, Alzheimer described as “a peculiar severe disease process of the cerebral cortex” with plaques between neurons and tangles within neurons
What are amyloid plaques
Amyloid plaques are extracellular accumulations composed of abnormally folded amyloid-b protein (AB protein) with 40 or 42 amino acids (AB40 and AB42) – 2 by products of amyloid precursor protein (APP) metabolism
sequential cleavages by γ-secretase to generate amyloid-β peptides including Aβ40 and Aβ42. Increased ratios of Aβ42 over Aβ40 are thought to cause Alzheimer’s disease
What are neurofibrillary tangles of tau
- Tau is a microtubule-associated protein, with a role in microtubule stabilisation and axonal transport
- Tau‐microtubule binding maintained by co‐ordinated actions of kinases and phosphatases; phosphorylation of tau regulates binding to microtubules
- The hyperphosphorylation of tau results in the formation of neurofibrillary tangles, which are primarily composed of paired helical filaments (PHF) of tau
Genetic basis of Alzheimer’s disease
A vast majority of Alzheimer’s disease occurs sporadically, however mutations in 3 genes cause a rare familial form of Alzheimer’s disease
Early on-set Mutations in: • Amyloid precursor protein APP • Presenillin-1 • Presenillin-2
Late on-set
• Typically, attributable to complex interplay between genetic and environmental factors
• The APoE gene attributed as the strongest risk factor
APP mutations
Amyloid precursor protein can be cleaved by three secretases:
• A secretase
• B secretase
• Y secretase
APP is cleaved in a non-amyloidogenic pathway (a and y secretase) Amyloidogenic pathway (b and y secretase)
APP mutations lead to a shift in the amyloidogenic pathway which leads to AB40-42 production
PSEN mutation
- Presenilin 1 and 2 are subunits of y secretase
* PSEN1/2 mutations impair y secretase function and drive amyloidosis through damages in the AB42/40 ratio
APOE4
Apolipoprotein E (ApoE) is a secreted lipoprotein involved in cholesterol metabolism
ApoE gene has three alleles:
• ApoE2
• ApoE3
• ApoE4
ApoE4 is a strong risk factor for late-onset Alzheimer’s disease
ApoE4 has been proposed to decrease clearance of extracellular Aβ
Amyloid hypothesis
The amyloid hypothesis proposes that the accumulation and deposition of oligomeric or fibrillar amyloid-β (Aβ) peptide is the primary cause of Alzheimer’s disease
- Proteolytic cleavage of APP can produce Aβ42 – aggregation results in oligomers, fibrils and plaques
- Toxicity of amyloid oligomers and fibrils lead to the cascade of tau hyperphosphorylation
- Tau hyperphosphorylation leads to formation of neurofibrillary tangles, which lead to neuronal cell death
Evidence against the amyloid hypothesis?
What is a 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
Biomarkers measured/detected via:
• Physical examination
• Lab assays
• Medical imaging
Importance of biomarkers
Can be used for:
- Clinical diagnosis
- Predict and monitor disease progression
- Monitoring effects of novel drug candidates in clinical trials (and ensuring inclusion of subjects with disease-specific pathologies)
- Clinical research into the pathogenesis of the disease
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.
Biomarkers for Alzheimer’s disease
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
Cerebrospinal fluid
- Cerebrospinal fluid (CSF) occupies the ventricular system and the cranial and spinal subarachnoid spaces
- Although lumbar puncture is invasive and potentially painful for the patient, CSF is probably 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)
- As a result, 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
CSF biomarkers
• Phosphorylated tau
• Total tau
neurogranin
• AB42 and AB42/AB40 ratio – the reason ab42 might be low in CSF is because most of them are within plaques
Synaptic CSF biomarkers
- 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
Neurogranin as a CSF biomarker
- Neurogranin is a dendritic protein expressed in the cortex and hippocampus with an important role in long‐term potentiation (strengthening synapse)
- Neurogranin expression is markedly reduced in the hippocampus and the frontal cortex in Alzheimer’s disease, indicating loss of post-synaptic elements
- Thus, 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
CSF biomarkers advantages
sensitive and specific
can cross BBB
Correlates with AD directly
can detect AD progression
CSF biomarkers disadvantages
invasive and painful procedure
irreproducible diagnosis sue to sample storage and transportation
Acetylcholinesterase inhibitors (mild to moderate) examples
Donepezil
rivastigmine
galantamine
Acetylcholinesterase AChE inhibitors mechanism
The cholinergic hypothesis links a deficit in acetylcholine (ACh) signalling to the cognitive deficits seen in Alzheimer’s disease patients.
- ACh is involved in critical physiological processes including within attention, learning and memory
- Degeneration of cholinergic neurons has been observed in Alzheimer’s disease patients – cholinergic synapses particularly affected by neurotoxic Aβ oligomers and synaptic loss is a major correlate of cognitive impairment
- AChE inhibitors stop the enzyme acetylcholinesterase from breaking down acetylcholine
- AChE inhibitors therefore increase ACh levels in the synapse and can thus alleviate cognitive symptoms in Alzheimer’s disease patients
Memantine
In patients with moderate-to-severe Alzheimer’s disease (or if intolerant or have a contraindication to AChE inhibitors), the NMDA receptor antagonist memantine can be prescribed.
- Glutamate binds to NDMA receptors
- NMDA receptor overactivation and subsequent glutamate mediated neurotoxicity has been associated with several neurodegenerative disorders, including Alzheimer’s disease
- Memantine is a low-affinity NMDA receptor antagonist that blocks excessively open NMDA receptor ion channels to reduce glutamate mediated neurotoxicity
