What causes Alzheimer's diasese?

According to the New England Journal of Medicine review article in front of me, Alzheimer's disease is a progressive neurodegenerative disorder manifested by cognitive and memory deterioration, progressive impairment of activities of daily living, and a variety of neuropsychiatric and behavioural disturbances. It sounds nasty, and it is. It is by far the largest single cause of dementia.

When you look at the brains of Alzheimer's patients under the microscope, the major abnormalities are extracellular senile plaques, intraneuronal neurofibrillary tangles and amyloid angiopathy.

'Senile' plaques are composed of a central core of amyloid material that is su
rrounded by dystrophic neurites (axons and dendrites). The spherical things you can see on the right are plaques as seen by a light microscope.

Neurofibrillary tangles are intracellular bundles of filaments that displace or encircle the nucleus of neurones. They are composed of paired helical filaments largely composed of a hyperphosphorylated form of the microtubule-associated protein tau.

Amyloid angiopathy refers to the deposition of amyloid material within the blood vessel walls. It predisposes to haemorrhagic strokes.

Although there is controversy about the exact pathogenesis, the leading hypothesis at present centres around the role of amyloid formation in the brain. The specific type of amyloid found in patients with Alzheimer's disease is formed from β-amyloid peptide. This peptide is derived from a much larger transmembrane protein found in neurones, called amyloid precursor protein (APP) which, despite its name, has important normal roles to play in neurone growth and repair.



It is not entirely clear what causes β-amyloid to accumulate in Alzheimer's disease, but it involves aberrant intracellular processing of APP. Whatever the cause, the resultant β-amyloid peptides aggregate and form the amyloid that is found in the brains of people with Alzheimer's disease.

β-amyloid is toxic to neurones by a variety of methods, including altering glucose metabolism and mitochrondrial function and altering calcium homeostasis. The resulting damage induces apoptosis of the neurones, and this cell death is believed to cause the symptoms of Alzheimer's disease.

Sources:
1. Robbins Pathologic Basis of Disease (6th Edn.) - Cotran, Kumar, Collins
2. Pathophysiology of Disease (4th End.) - McPhee, Lingappa, Ganong
3. Wikipedia Commons for the pictures