The Basics

The Genetics Behind AD
Neurofibrillary Tangles (NFTs)

Amyloid Plaques

Anatomy and Physiology

Treatment

Risk Factors

Signs and Symptoms

References

The Basics:

• 60-80% of all dementia cases are due to Alzheimer's.
• In 1996, approximately 4 million people were clinically diagnosed with Alzheimer's Disease in the US. This number is expected to triple in the next 50 years.

The Genetics Behind AD:

• Four genes are recognized as being involved:
  • Amyloid precursor protein (APP)
  • Presenilin 1 (PSEN1)
  • Presenilin 2 (PSEN2)
  • Apolipoprotein E (APOE)
• Three of these genes are involved with Early Onset AD. These include: APP, PSEN1, and PSEN 2.
• These genes are autosomal dominant. This means only one copy of the mutation is needed in order for the disease to be expressed, and this gene is carried on a numbered (non-sex) chromosome.

• APOE is located on chromosome 19.
  • This gene may have a role in synaptic remodeling.
  • APOE is a susceptibility gene. This means the gene increases the risk of AD, but doesn't cause it.

Neurofibrillary Tangles (NFTs)

• Tau proteins are essential for axon growth and development in normal cells.
• In those with AD, these tau proteins are hyperphosphorylated and form tangles, which lead to cell death.
• These tangles are formed within neurons of the hypocampus, medial temporal lobe, parietotemporal region, and frontal association cortexes.

http://www.webmd.com/alzheimers/guide/understanding-alzheimers-disease-basics

Amyloid Plaques:

• The Beta-Amyloid protein is a 39-42 amino acid peptide that is formed by proteolytic cleavage of Beta-Amyloid precursor protein (APP). This means APP is broken down by an enzyme which forms the Beta-Amyloid protein.
• The Beta-Amyloid protein has a stimulating effect on the production of free radicals which can result in neuronal cell death.
• Amyloid plaques are formed by pieces of these Beta-Amyloid proteins clumping together.
• These plaques can lead to cell death and are believed to block cell-to-cell communication

http://www.healthinformer.net/alzheimer-disease-plaques-seen-with-conventional-mri-in-animal-model-for-the-first-time.html

Anatomy and Physiology:

• Nucleus basalis of Meynert
  • This nuclei is rich in acetylcholine (ACh) and choline acetyltransferase (which aids in the production of ACh).
  • ACh is a very important neurotransmitter.
  • It's suggested that the nucleus basalis of Meynert plays a role in learning and memory.
  • In those with AD, many of these cholinergic neurons die, which results in a ACh deficiency.
  • This leads to a loss in the transmission of signals from neurons to their target cells.

http://www.uams.edu/m2004/Behavioral%20Sciences/Biological%20Determinants/Neurotransmitters/Neurotransmitters%20amino%20acid%20derivatives.htm

• Locus Coeruleus
  • This nuclei is the primary cite for the production of another neurotransmitter, norepinephrine.
  • In those with AD, a loss of these adrenergic neurons lead to a deficiency in norepinephrine.
  • This again leads to a loss in the transmission of signals from neurons to their target cells.

• Median Raphe Nucleus
  • Although most of the serotonin in the human body is found in the digestive system, a small percentage is produced in the Central Nervous System (CNS). The median raphe nucleus is the site for this production.
  • Serotonin is important in the regulation of some cognitive functions such as memory and learning.
  • Those with AD have a loss in serotoninergic neurons, leading to a deficienct in serotonin.

• Summary

Treatment:

• Currently drugs are used to address the symptoms of AD, not the pathogenesis.
• Due to the deficiency in ACh, different drugs are used to prevent the breakdown of ACh.
  • Cholinesterase inhibitors
  • The effects of these drugs are not apparent in some, and for others there may only be a slight increase in the concentration of ACh.
• For more severe forms of AD, drugs that normalize the levels of glutamate are used.
  • Glutamate is a neurotransmitter involved in learning and memory. In excessive quantities it is thought to aid in neurodegeneration.

Risk Factors:

• Age is the main risk factor.
  • 1% risk at the age of 60. The risk doubles every 5 years.
  • By the age of 85, there is a 30-50% risk of developing AD
• Other possible risk factors:
  • Lower levels of intelligence and education
  • Small head size
  • Men with previous head injuries
• Women are more affected by AD, but many believe this is due to the fact that on average women live longer than men. The ration of women with AD compared to men is nearly 2:1.

Signs and Symptoms:

• Typically begins with:
  • Short term memory loss
  • Inability to communicate properly
• Progresses with:
  • Diffuculty carrying out simple tasks
  • Trouble with orientating oneself
  • Behavioral problems including depression, anxiety, or apathy.
• Late-stage includes:
  • Delusions, hallucinations, and psychosis
  • Possible seizures
• End-stage includes:

  • End of cognitive activity resulting in vegetative state

References:

Knopman, David. "Alzheimer's Disease and Other Dementias." Goldman: Goldman's Cecil Medicine. 24th ed. Saunders, 2011. 2274-279. MD Consult. Web. 26 Nov. 2011. .

Sweeney, Patrick. "Alzheimer's Disease." Cleveland Clinic: Current Clinical Medicine. By Jimmy Tavee. 2nd ed. Saunders, 2010. 893-96. MD Consult. Web. 26 Nov. 2011. http://www.mdconsult.com.

Wright, Christopher. Nhi-Ha Trinh. Et. Al. "Genetics of Alzheimer's Disease." Stern: Massachusetts General Hospital Comprehensive Clinical Psychiatry. 1st ed. Mosby, 2008. 234-38. MD Consult. Web. 26 Nov. 2011.

http://www.uams.edu/m2004/Behavioral%20Sciences/Biological%20Determinants/Neurotransmitters/

Neurotransmitters%20amino%20acid%20derivatives.htmhttp://www.mdconsult.com.