Alzheimer’s Disease

Question 1

Alzheimer’s Disease (AD)

Answer 1

Alzheimer’s Disease (AD) is a chronic degenerative brain disorder related to aging. Thought to cause 60% - 70% of all dementia.

Question 2

AD Epidemiology

Answer 2

The only* true diagnosis of AD is post-mortem so it’s a bit difficult to get actual numbers of patients.
- TentativediagnosisofADisbasedoncharacteristicclinicalfeatures;
- Confirmedonlybydistinctivecellularpathologyevidentinpost-mortembraintissue.
Most AD patients die of unrelated complications (e.g. heart attack, cancer, etc.) so numbers may be suppressed.
Today, there are over 500,000 Canadians with AD and an additional 25,000 cases diagnosed every year.

Question 3

Clinical Symptoms of AD

Answer 3

Early symptoms:
- Short-term memory loss;
- Subtle problems with executive function;
- Apathy*;
- Often disregarded as “Old Timer’s” disease.
Later stages:
- Difficulty with language; - Disorientation;
- Mood swings;
Advanced:
- Loss of motivation;
- Loss of bodily functions;
- Dependent on caregivers.

Question 4

amyloid plaques and intracellular neurofibrillary tangles

Answer 4

AD is characterized by a loss of neurons and synapses in specific and predictable brain regions.
Both extracellular amyloid plaques and intracellular neurofibrillary tangles are clearly visible by microscopy in brains of AD patients. These remain as the stereotypical hallmarks of the disease.
Mass shrinking of cortical thickness can be observed in late stages of the disease.

Question 5

dendritic trees/branches

Answer 5

As disease progresses, AD patients experience degeneration of dendritic trees/branches, and general atrophy of neurons.
These physical changes are associated with worsening of symptoms.

Question 6

How does this happen?

Answer 6

There are many ways in which a person can develop AD:
- Genetic predisposition (~70% of risk);
- Exposure to environmental elements (e.g. aluminum); - Immune reactions;
- Slow viruses;
- Prions (abnormal, infectious forms of proteins).
Either way, there are two principle neuronal changes that occur in AD patients:
1. Loss of cholinergic cells in the basal forebrain;
2. Development of neuritic plaques and tangles in the cerebral cortex.

Question 7

Acetylcholine Neurotransmission

Answer 7

Acetylcholine (ACh) was amongst the first neurotransmitter ever discovered.
ACh is widely distributed throughout the brain, and plays a crucial role in both sympathetic and parasympathetic branches of the autonomic nervous system, as well as the CNS.

Question 8

neuromuscular junctions

Answer 8

ACh is responsible for muscle contractions, as its released at neuromuscular junctions.

• Manydrugs,cosmeticsandtoxinsacton the cholinergic system.
• BotulinToxin,forexample,inhibitsACh release.

Question 9

Basal forebrain

Answer 9

Basal forebrain: projects to the hippocampus & cortex

Question 10

Midbrain

Answer 10

project to the basal ganglia, thalamus, diencephalon, pons, cerebellum, cranial nerve nuclei and reticular formation.

Question 11

Acetylcholine Neurotransmission

basal forebrain

Answer 11

ACh neurons in the basal forebrain are involved in cognitive function, particularly learning and memory.
- Drugs that increase activity of ACh enhance memory;
- Disruptions to CNS ACh neurotransmission impair memory.
Cells in the basal forebrain are among the first to die in AD.
- Specifically in the entorhinal cortex;
- Neurodegeneration spreads outwards, and extends into the cerebral cortex, as disease progresses.

Question 12

Neuritic Plaques

Answer 12

As mentioned earlier, the main pathological features of AD are plaques and neurofibrillary tangles.
These plaques and tangles interfere with normal processing of action potentials and cellular function;
- Decreasedinter-neuronalassociations;
- Asneuronsbecomemoreandmore“chokedoff”from their circuits, they begin to die.
Neuritic plaques are composed of a central core of homogenous protein called b-amyloid
- b-amyloid is a product of the amyloid precursor protein (APP) gene;
- Normallyb-amyloidisinvolvedinactivationofkinases, protection against oxidative stress, regulation of cholesterol transport, etc.
- Misfoldedproteinsaggregatetoformdense,insoluble deposits.

Question 13

Neuritic Plaques temporal lobe

Answer 13

The plaques are not distributed evenly throughout the cortex, but are concentrated in the temporal lobe areas involved in memory.

Question 14

Neuritic Plaques neurofibrillary tangles

Answer 14

Plaques are also associated with neurofibrillary tangles, which are paired helical filaments found in cerebral cortex and hippocampus.

Question 15

Neurofibrillary Tangles

Answer 15

Neurons are 3-dimensional creatures that require structural support.
Cytoskeleton is the evolutionary solution to maintaining a neurons 3D structure (as well as guiding the transport of proteins and molecules across vast distances.)
- Cytoskeleton functions as both flexible scaffold and transportation system.

Question 16

three main components to the cytoskeleton

Answer 16

1. Neurofilaments–control&transport of membrane proteins;
2. Microtubules–control the transfer/movement of substances and organelles throughout the cytoplasm;
3. Microfilaments–provides structural support to axons & dendrites.

Question 17

Tau Proteins

Answer 17

Tau proteins are involved in the stabilization and flexibility of microtubules and microfilaments.

• Highly soluble protein;
• Activated through phosphorylation;
• Promote the assembly of microtubules.

Question 18

Hyperphosphorylated tau

Answer 18

Hyperphosphorylated tau proteins begin to accumulate, eventually forming aggregates – neurofibrillary tangles – inside cell bodies.

As a consequence, microtubules disintegrate and ultimately destroy the structure of the cytoskeleton.
- Major collapse to neurons transport system;

Malfunctions in biochemical pathways and communication between neurons;
- Eventually leads to cell death.

Question 19

genetic

Answer 19

There is a genetic component to AD, however, the heritability of AD ranges (and is disputed).

Twin studies suggest between 49% - 79% heritability.
Several genes are implicated in AD;

One of the genes most commonly implicated codes for the amyloid precursor protein (APP)
Involved in many neurons, concentrated at the synapse;
Implicated in synapse formation and synaptic plasticity;
Proteolysis product is the b-amyloid protein;

APP gene is located on Chromosome 21. Trisomy 21 patients universally exhibit early AD symptoms (around age 40).

Question 20

the environment

Answer 20

As always, the environment also plays a role.

Acute exposure to, and poisoning from, heavy metals and pesticides is a known risk for AD.
Recent evidence is beginning to show that chronic, low-level exposure to these toxins also leads to neurodegeneration.

Air pollution, especially in large, urban cities, is a cocktail of organic and non-organic compounds, metals and gases that can be toxic.
Growing evidence to suggest that polluted air is linked to neurodegeneration and AD;
Many people cannot control their exposure to polluted air.

Question 21

Management & Treatment of AD

Answer 21

There is no cure for AD.

However, there are some promising research avenues aimed at finding a treatment.

For example, drugs that increase acetylcholine neurotransmission have been shown to improve cognitive symptoms of AD.
Exelon is a cholinergic agonist that appears to provide temporary relief from the progression of AD;
Available orally or via transdermal patch.

Consuming more choline in the diet is theoretically sound, however has yet to yield positive empirical results.
There is a ceiling amount of ACh produced and stored by neurons  they do not produce superfluous amounts;
Eating a choline rich diet may protect/delay the onset of AD.

Question 22

Hormone therapy with Estrogen

Answer 22

Hormone therapy with Estrogen:
The female gonadal hormone reduces the production of acetylcholine esterase (AChE);
AChE is responsible for for the breakdown of Ach;
Reducing AChE activity has been shown to increase ACh neurotransmission and improve symptoms.

Question 23

Vaccinations against b-amyloid:

Answer 23

Vaccinations against b-amyloid:
Aids in the removal of b-amyloid;
Delays onset and reduces overall size of plaques;
Improves cognitive function in animal models of AD.

Question 24

Environmental enrichment:

Answer 24

Environmental enrichment:
Has also been shown to be protective against the development of AD later in life;
Cognitively active lifestyle (e.g. University education), coupled with low-risk behavior, leads to protection against neurodegeneration.

Question 25

AD & Caregivers

Answer 25

Did you know…

Caring for AD patients is stressful, and long-term stress is damaging and is actually a risk factor for the development of AD.

Glaser et al (2000) gave an influenza virus to 32 caregivers and matched controls:
Caregivers had poorer antibody response;
Less activation of T-cell responses;
Higher levels of antibody responses were seen in those who reported greater social support and lower levels of anxiety.