Lecture 17: Alzheimers

Question 1

Alzheimer’s vs Dementia?

What is the difference?

Answer 1

Alzheimer’s disease is the most common CAUSE of dementia (general intellectual deterioration)

Question 2

Alzheimer’s age ranges, common ages to develop etc

Answer 2

Appears in people as young as 40, but chances of development increase with age.

10% of people over 65 y/o suffer from it, 35% over 85.

Question 3

What is meant by alz as a progressive disease?

Answer 3

Progressive disease - gets worse with time.

• Early stages are characterised by selective memory decline
• Intermediate stages marked by confusion, irritability, anxiety, deterioration of speech etc
• In the advanced stages the patient deteriorates to the point where swallowing and bladder control become difficult.

The disease is terminal

Question 4

Problems diagnosing alz…

Answer 4

Because Alzheimer’s isn’t the only cause of dementia, it cannot be diagnosed based solely on behavioural symptoms, it is definitively diagnosed via autopsy

Question 5

Defining characteristics of the disease…

Answer 5

The two defining characteristics of the disease are neurofibrillary tangles and amyloid plaques. As well as substantial neuron loss.

Neurofibrillary tangles – thread-like tangles of protein in the neural cytoplasm

Amyloid plaques – clumps of scar tissue composed of degenerating neurons and a protein called amyloid (present in normal brains in very small amounts)

Question 6

Neurofibrillary tangles

Answer 6

thread-like tangles of protein in the neural cytoplasm

Question 7

Amyloid plaques

Answer 7

clumps of scar tissue composed of degenerating neurons and a protein called amyloid (present in normal brains in very small amounts)

Question 8

Distribution of amyloid plaques and neuro tangles

Answer 8

Although neuron loss, neurofibrillary tangles and amyloid plaques occur throughout the brains of alz. patients, they are more prevalent in certain areas e.g. prevalent in medial temporal lobe structures like the entorhinal cortex, amygdala and hippocampus (areas involved in memory).

Also prevalent in the inferior temporal cortex, posterior parietal cortex and prefrontal cortex – all areas that mediate complex cognitive functions.

Question 9

Genetic component of Alzheimer’s disease…

Answer 9

• Alz. disease has a major genetic component.
• People with a victim of it in their immediate family have a 50% chance of developing the disease if they survive into their 80s.
• Accordingly, lots of research has focused on early onset familial forms of the disease.
• Several gene mutations have been found to be associated with early onset alz.

Question 10

A cure?

Answer 10

There is currently no cure. The massive research effort into finding a cure is fuelled by two things: the severity of the problem and the fact that a major advance seems feasible (as the disease is a disease of old age, the number of cases could be halved by a treatment that would slow it’s progress by 5 years)

Question 11

What’s stopping the development of a cure?

Answer 11

The major problem affecting a breakthrough is the fact that it’s not clear which symptom is primary. The amyloid hypothesis holds that the amyloid plaques are the primary symptom, others believe it’s the neurofibrillary tangles and others support other contenders.

Question 12

Amyloid hypothesis

Answer 12

The amyloid hypothesis holds that the amyloid plaques are the primary symptom

The main support for the amyloid hypothesis is from genetic analysis of families with the early onset Alzheimer’s disease.

The studies have identified three different gene mutation that cause early onset alz. and all three influence the synthesis of amyloid. Amyloid is toxic to neurons that have been artificially maintained in tissue cultures.

Question 13

First efforts to develop a cure…

Answer 13

The first efforts to develop treatments focused on the perceived declines in acetylcholine levels, were among the earliest neurochemical changes appearing in patients.

Cholinergic agonists are still sometimes prescribed, except for a few minor benefits early on in the disorder, they have proved ineffective.

Question 14

Immunotherapeutic approach to a cure…

Answer 14

Arguably, the most promising of the current developing treatments is the immunotherapeutic approach.

This approach has used an amyloid vaccine to reduce plaque deposits and improve performance on memory tasks in a transgenetic mouse model of Alzheimer’s disease

One study of an anti-amyloid antibody in the mouse model found that the health of nearby neurons improved once amyloid plaques had been cleared from the area – supporting the amyloid hypothesis.

Human trials of immunotherapeutic agents have been mixed. Some therapeutic effects have been observed, but some patients have experienced dangerous brain inflammation.

Question 15

Transgenetic mouse model of Alzheimer’s disease

What are transgenetic animals?

Answer 15

Transgenetic animals are animals into which the genes of another species have been introduced.

Question 16

Transgenetic mouse model of Alzheimer’s disease

The forms of thetransgenetic mouse model…

Answer 16

There are several forms of the transgenetic mouse model.

• In one, genes that accelerate the synthesis of human amyloid are injected into newly fertilised mouse eggs, which are then injected into a foster mother to develop.
  When these mice mature, their brains contain many amyloid plaques - like human alz. patients.

What’s cool is that the plaques are dispersed in the brain in a similar pattern to human alz. patients, with the highest concentrations in the medial temporal lobe structures (amygdala, hippocampus, entorhinal cortex). The mice display neural loss and memory disturbances.

Question 17

Transgenetic mouse model of Alzheimer’s disease

Issues with using mice

Answer 17

Amongst ethical issues…

Mice don’t develop neurofibrillary tangles

Despite this the model is still useful, even if it doesn’t mimic the human disorder in every respect. Is still being used to develop amyloid vaccines for testing on human patients.

Question 18

Amnesia of Alzheimer’s disease

What is amnesia?

Answer 18

Alzheimer’s disease is a major cause of amnesia (any pathological loss of memory).

Question 19

Amnesia of Alzheimer’s disease

Alzheimer’s and amnesia

Answer 19

The first sign of alz. is a mild deterioration of memory.

However, the disorder is progressive so as it develops dementia arises, which is a general intellectual deterioration – to the point where patients are incapable of simple tasks such as speaking, eating, recognising people or bladder control.

Question 20

Amnesia of Alzheimer’s disease

Predementia Alzheimers patients

Answer 20

Efforts to understand the disease have focused on predementia alzheimer’s patients (those who have yet to develop dementia).

The memory deficits of these patients are more general than those associated with medial temporal lobe damage, medial diencephalic damage or Korsakoff’s syndrome.

In addition to anterograde and retrograde deficits in tests of explicit memory, predementia alzheimer’s also display deficits in short-term memory and in some types of implicit memory (implicit memory for verbal and perceptual material is often affected, whereas their implicit memory for sensorimotor learning is not).

Question 21

Amnesia of Alzheimer’s disease

Acetylcholine

Answer 21

Levels of acetylocholine are greatly reduced in alz. patients, due to a degeneration of the basal forebrain (midline area above the hypothalamus, looks like a peanut) – which is the brains main source of acetylcholine.

This finding, coupled with the knowledge that strokes in the basal forebrain can cause amnesia, led to the view that acetylcholine depletion is the cause of alzheimers.
–> we now know it’s not the only factor

Question 22

Amnesia of Alzheimer’s disease

Brain damage and alz.

Answer 22

• The brain damage associated with alz. is incredibly diffuse, involving many areas of the brain including the medial temporal lobe and the prefrontal cortex – both areas involved in memory.

Also, damage to some structures of the basal forebrain produces attentional deficits, which can be mistaken for memory problems.

Question 23

What makes studying alz difficult?

Answer 23

One of the difficulties in studying this disease is that it’s a disease of age, even healthy elderly people display substantial neural and memory loss – however, it is notes that patterns of brain degeneration in healthy vs alz. older people do differ.