Genetics of early onset Alzheimer's disease

Published on August 26, 2010 Updated on November 6, 2014   35 min

Other Talks in the Series: Alzheimer's Disease

0:00
EKATERINA ROGAEVA: Hello. My name is Ekaterina Rogaeva. And I will present the data about the genetics of early-onset form of Alzheimer's disease which is considered to be highly familial.
0:14
We will talk about contribution of APP, PSEN1, and PSEN2 in the early-onset form of the disorder. We will also try to understand why these mutations lead to Alzheimer's disease. We'll talk phenotypic variability in early-onset disease and also genetic testing for Alzheimer's disease in clinical practice.
0:40
But first, I have to make a few general points about Alzheimer's disease, which is the most common form of progressive dementia. The brain pathology is characterized by neuronal loss, eventually leading to severe brain atrophy. Accumulation of the protein called amyloid, beta-peptide, or A beta in the form of extracellular amyloid plaques is the earliest sign of the brain pathology related to Alzheimer's disease. And finally, the disease pathology also associated is the deposition of tau positive neurofibrillary tangles inside of neurons. Clearly the formation of tangles has neurotoxic consequences itself because mutations in this gene are responsible for frontotemporal dementia. However, currently there is no convincing data that tau is genetically involved in early-onset form of Alzheimer's disease.
1:39
Neurotoxic A. Beta peptides are generated by cleavage of amyloid precursor protein known as APP. It is a type 1 membrane protein, a fragment of which accumulates in Alzheimer's disease brain. Accumulation of amyloid plaques starts decaying prior to disease symptoms and precedes the tau pathologen.
2:05
APP can be processed by two separate pathways. One involves alpha-secretase cleavage within the a beta peptide sequence, so a beta peptide cannot be generated. The other pathway requires sequential proteolysis by beta-secretase and gamma-secretase to generate the A. Beta 40 or A. Beta 42 peptides. The longer more neurotoxic either form, A. Beta 42, appears to be elevated in the brains of individuals affected with either sporadic or familial Alzheimer's disease. There are several proteins known to be responsible for the uptake or degradation of A. Beta peptide. However, in the case of Alzheimer's disease, this clearance mechanisms might not be effective.
2:57
One of the strongest risk factor of Alzheimer's disease is increase in age. Up to 50% of people older than 85 suffer from Alzheimer's disease. Only a small number, up to 5% or 10%, are associated with the early-onset form of Alzheimer's disease, which begins before age 65. Another strong risk factor of Alzheimer's disease is family history. Early-onset disease is often transmitted a s a pure autosomal dominant trait. In this case, the effected individuals are expected to have one copy of a mutant gene and one copy of a normal gene, and therefore have a 50/50 chance of passing the mutant gene to each of their children. Genetic analysis of such families have found three Alzheimer's disease genes, which is the subject of this presentation.
3:58
The first key for Alzheimer's disease genetics came from Down Syndrome. Because patients with Down Syndrome over the age of 40 developed plaques and tangles in their brain similar to Alzheimer's disease patients. The fact that individuals with Down Syndrome have a trisomy of chromosome 21, and the fact that APP is mapped to chromosome 21 made APP a very obvious gene-candidates for Alzheimer's disease.
4:31
However, the first APP mutation was discovered not in Alzheimer's disease, but in patients with cerebral hemorrhage, which is a stroke related amyloid dependent pathologen. The APP mutation at codon 693 is responsible for autosomal dominant disorder, presents in this massive amyloid deposition in cerebral vessels, leading to hemorrhages and eventually to the deaths at age 50 or 60 years of age.
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Genetics of early onset Alzheimer's disease

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