Alzheimers disease

Question 1

What is dementia

Answer 1

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

Question 2

Incidence of dementia

Answer 2

944,000 people are estimated to be living with dementia in the UK

Question 3

Different sub-types of dementia

Answer 3

Dementia is an umbrella term used to describe clinical syndromes that are characterised by cognitive deficits – there are a number of dementia sub-types

Question 4

What is Alzheimer’s disease

Answer 4

• 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

Question 5

What are amyloid plaques

Answer 5

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

Question 6

What are neurofibrillary tangles of tau

Answer 6

• 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

Question 7

Genetic basis of Alzheimer’s disease

Answer 7

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

Question 8

APP mutations

Answer 8

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

Question 9

PSEN mutation

Answer 9

• 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

Question 10

APOE4

Answer 10

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

Question 11

Amyloid hypothesis

Answer 11

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

Question 12

Evidence against the amyloid hypothesis?

Question 13

What is a biomarker

Answer 13

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

Question 14

Importance of biomarkers

Answer 14

Can be used for:

1. Clinical diagnosis
2. Predict and monitor disease progression
3. Monitoring effects of novel drug candidates in clinical trials (and ensuring inclusion of subjects with disease-specific pathologies)
4. 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.

Question 15

Biomarkers for Alzheimer’s disease

Answer 15

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

Question 16

Cerebrospinal fluid

Answer 16

• 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

Question 17

CSF biomarkers

Answer 17

• 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

Question 18

Synaptic CSF biomarkers

Answer 18

• 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

Question 19

Neurogranin as a CSF biomarker

Answer 19

• 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

Question 20

CSF biomarkers advantages

Answer 20

sensitive and specific
can cross BBB
Correlates with AD directly
can detect AD progression

Question 21

CSF biomarkers disadvantages

Answer 21

invasive and painful procedure

irreproducible diagnosis sue to sample storage and transportation

Question 22

Acetylcholinesterase inhibitors (mild to moderate) examples

Answer 22

Donepezil
rivastigmine
galantamine

Question 23

Acetylcholinesterase AChE inhibitors mechanism

Answer 23

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

Question 24

Memantine

Answer 24

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

Question 25

Promising therapeutic agents

Answer 25

• Although AChE inhibitors and NMDA receptor antagonists have appreciable benefits for patients, ultimately, clinical outcomes are limited
• However, until recently, attempts to develop therapeutic agents able to block the synthesis and aggregation of Aβ42 or the formation of neurofibrillary tangles of hyperphosphorylated tau protein with a clinical outcome have failed…

Question 26

Aducanumab

Answer 26

• Aducanumab is a human monoclonal antibody that selectively binds to amyloid β fibrils and soluble oligomers
• Aducanumab treatment has been shown to reduce amyloid plaques in a dose-dependent and time-dependent manner
• In March 2019, clinical trials were discontinued due to uncertainties of clinical benefit for patients
• However, in June 2021, Aducanumab obtained controversial FDA approval in the US
• An FDA Advisory Committee member described the decision as “probably the worst drug approval decision in recent US history”