Alzheimer's disease

Question 1

What is important to remember about the pathophysiology of Alzheimer’s

Answer 1

No absolute law- but many theories.

Question 2

Summarise the epidemiology of Alzheimer’s disease

Answer 2

Main risk factor – Age
Huge economic cost in the UK BUT low research investment
Nov 2016 – ONS announces AD & dementia are leading cause of death in UK
Genetics - APP, PSEN, ApoE (hereditary ~ 8%)

Question 3

Describe how age is a risk factor for Alzheimer’s disease

Answer 3

The main risk factor for Alzheimer’s disease (AD) is advancing age with prevalance increasing from around 2% for people below 75 to around 20% for people above 75.

Question 4

Describe the economic effects of Alzheimer’s disease

Answer 4

Due to people living increasing long lives the prevalance of AD is increasing and it is a huge economic cost in the UK BUT low research investment.

High costs- due to burden of treatment and carers who take time off work

Low research investment- risky as many drugs have failed.

Question 5

Describe the genetics associated with Alzheimer’s disease

Answer 5

The vast majority of AD cases are due to environmental factors (~90%) but individuals with mutations in certain genes (e.g. APP, PSEN, ApoE are known to have an increased risk of developing AD

APP= Amyloid precursor protein
PSEN- encodes for Presenillin protein
ApoE- Apolipoprotein E

Increase risk of early onset Alzheimer’s- different subset to that of elderly dementia.

Question 6

Describe the clinical symptoms of Alzheimer’s

Answer 6

Memory loss – especially recently acquired information
Disorientation/ confusion – forgetting where they are
Language problems – stopping in the middle of a conversation
Personality changes – becoming confused, fearful, anxious
Poor judgement – such as when dealing with money

Memory loss- most important- cardinal symptom
The other symptoms tend to vary between individuals.

Question 7

Outline the physiological processing of amyloid precursor protein

Answer 7

Amyloid Precursor protein is membrane bound
Alpha-secretase and gamma-secretase are membrane bound enzymes.

Amyloid precursor protein (APP) cleaved by -secretase
sAPP released - C83 fragment remains
C83  digested by -secretase
Products removed

The end products of this pathway are non-toxic.

Question 8

Outline the pathophysiological processing of APP thought to be involved in Alzheimer’s disease

Answer 8

APP cleaved by -secretase (at a different site to alpha-secretase)
sAPP released - C99 fragment remains (longer than CD83)
C99  digested by -secretase releasing -amyloid (A) protein
A forms toxic aggregates- monomer aggregates

Aβ is the major constituent of amyloid plaques, which form toxic aggregates on neurons and the microvasculature

Question 9

Why is beta-amyloid thought to be involved in the pathophysiology of Alzheimer’s disease

Answer 9

Beta amyloid plaques are found in the autopsy of brains of patients who have died from Alzheimer’s disease

Beta amyloid plaques build up isnide the neurones or outside the neurones (mostly) and cause neuronal cell death (neurodegeneration) either by:
Triggering an immune response- inflammation kills neurones
Releasing toxins which kill the neurones directly.

Question 10

What is the Tau protein

Answer 10

Soluble protein present in axons
Important for assembly & stability of microtubules

Microtubules needed in neurones for:
Stability, shape and integrity
Transport of proteins along the axon to pre-synpatic terminal.

Question 11

Describe the role of Tau proteins in the pathophysiology of Alzheimer’s disease

Answer 11

Hyperphosphorylated tau is insoluble  self-aggregates to form neurofibrillary tangles
These are neurotoxic
This also results in microtubule instability (less Tau available for microtubules) - tau dissociated from the microtubules.
Both of these are responsible for the neuronal cell death seen in Alzheimer’s

Question 12

Are the Tau hypothesis and Amyloid hypothesis mutually exclusive

Answer 12

No, both can occur in the same patient

Often, tau precedes amyloid plaque build up

Question 13

What are microglial cells

Answer 13

Specialised CNS immune cells - similar to macrophages

Involved in release of inflammatory mediators, neuroprotection and phaocytosis.

Question 14

Summarise the inflammation hypothesis for the pathophysiology of Alzheimer’s disease

Answer 14

Inappropriate activation of inflammatory pathways in the brain is known to be involved in the pathogenesis of AD but there is no consensus about exactly how the inflammatory pathways contribute to neurodegeneration.

Microglia are specialised CNS immune cells and astrocytes are also facultative macrophages. There is eveidence that these cells become activated in AD resulting in:

increased release of inflammatory mediators & cytotoxic proteins
increased phagocytosis
reduced levels of neuroprotective proteins

Question 15

In the inflammation hypothesis, what may activated the microglia

Answer 15

The Tau proteins and beta amyloid plaques
Or the individual just may be predisposed to having aberrantly activated microglia.

The inflammation process became relevant as retrospective studies have shown a reduced incidence of Alzheimer’s in patients who reguarly took NSAIDs- however NSAIDs can’t be given as treatment for patients once they get Alzheimer’s.

Question 16

What is important to remember about the treatments available for Alzheimer’s disease

Answer 16

The drugs are not related to the pathophysiology seen.
Therefore, they treat the symptoms but not the underlying condition
Hence they tend to be beneficial for around 2 years, but soon will be overcome by the ongoing neurodegeneration.

Question 17

Why may anticholinesterases be useful in treating alzheimer’s disease

Answer 17

Although changes in many transmitter systems have been observed, mainly from measurements on postmortem AD brain tissue, a relatively selective loss of cholinergic neurons in the basal forebrain nuclei (Ch. 40) is characteristic. This discovery, made in 1976, implied that pharmacological approaches to restoring cholinergic function might be feasible, leading to the use of cholinesterase inhibitors to treat AD (see later).

Choline acetyl transferase activity, acetylcholine content and acetylcholinesterase and choline transport in the cortex and hippocampus are all reduced considerably in AD but not in other disorders, such as depression or schizophrenia

Question 18

What are the three anticholinesterases used in A.D

Answer 18

Donepezil (first line therapy)
Rivastigmine
Galantamine

These are used for mild-moderate A.D

Question 19

Describe donepezil

Answer 19

Reversible cholinesterase inhibitor.

Long plasma half-life- important for A.D- only needs to be given orally once a day

Question 20

Describe Rivastigmine

Answer 20

Pseudo-reversible AChE & BChE inhibitor
8 hour half-life
Reformulated as transdermal patch
transdermal patch- makes it selective for AChE found in the CNS- minimising side effects in the Liver.

Question 21

Differentiate between AChE and BChE

Answer 21

AChE = acetylcholinesterase
BChE= Butyrylcholinesterase 

AChE- found primarily in CNS
BChE-found in liver (but small amount also found in the CNS)

Question 22

Describe Galantamine

Answer 22

Reversible cholinesterase inhibitor  
7-8 hour half-life
alpha7 nAChR agonist - nicotinic receptors found in the CNS- beneficial- increase ACh available- reverses symptoms of A.D
nAChR in CNS ( 5 alpha 7 subunits)
nAChR in NMJ (3 Alpha, beta, gamma)

Question 23

Where are Nicotinic receptors expressed

Answer 23

NMJ and CNS

Question 24

What severity of A.D are NMDA receptor blockers used to treat

Answer 24

Moderate- Severe

Question 25

Describe Memantine (NMDA receptor blocker)

Answer 25

Use-dependent non-competitive NMDA receptor blocker with low channel affinity
Only licensed for moderate-severe AD
Long plasma half-life

Use-dependent- more access to channel with greater activity of channel. Why only used in moderate-severe- more neurodegeneration hence more loss of inhibitory GABA neurones- greater excitotxicity of NMDA receptors
Non-competitive- binds to the NMDA receptor at a different site to glutamate.

its adverse effects include headache, dizziness, drowsiness, constipation, shortness of breath and hypertension as well as a raft of less common problems.

Question 26

List some cholinergic side effects

Answer 26

Increased salivation and sweating, lacrimation, increased urinary incontinence, G.,I cramps, diahhroea, blurred vision

Question 27

Describe how gamma-secretase failed

Answer 27

Targets both physiological and pathophysiological processing of APP
Tarenflurbil binds to amyloid precursor protein (APP) molecule - enantiomer of ibuprofen- failed in trials- not an NSAID but inhibits gamma secretase
Semagacestat is a small molecule -secretase inhibitor- inhibited the enzyme called notch, increasing the risk of skin cancer

Question 28

Describe how drugs that targeted B-amyloid failed

Answer 28

Bapineuzumab & Solanezumab
Humanised monoclonal antibodies
Aducanumab?- targets B-amyloid plaques- but targets of fibrils and monomers slightly differently- may be licences in U.S soon
Vaccines also in early stages of development

Can get drugs which target B-secretase but they failed- not even named
Beta-amyloid a better target.

Question 29

Describe how Tau inhibitors failed

Answer 29

Methylene blue
Licensed for the treatment of methaemoglobinaemia

Evidence of being effective at reducing Tau
But can make you blue, and no money in trialling it (already licenced).
Methylene blue is in phase III clinical trials

Question 30

What is a consequence of these drugs not working

Answer 30

Questions whether our understanding of the pathophysiology (Amyloid hypothesis) is correct.

Question 31

What may be more effective in terms of preventing and treating A.D than drugs

Answer 31

Diet and exercise.