Alzheimer's Disease Flashcards
alzheimer is characterized by
development of amyloid plaques and neurofibrillary tangles.
2/3 of Americans over age 65 with AD are
women
early onset type AD is inherited as
autosomal dominant.
Individuals with an affected first degree relative have 10% chance of AD.
stages of AD
mild (2-4 years)
moderate (2-10 years)
severe ( 1-3 years)
amyloid precursor protein (APP)
helps cell attach to one another.
it directs the movement of nerve cells during early development.
formationof beta amyloid plaques
it comes from APP (is cut off from APP and found outside neurons)
Plaques form when beta-amyloid clump together.
enzymes involved in cleaving APP
secretases
APP is cleaved by two different pathways
benign cleavage: peptide of 40 AA which does not aggregate.
toxic cleavage: peptide of 42 - 43 AA which aggregates.
benign cleavage of APP
alpha secretase cleaves the APP molecules and forms a soluble protein. The cleavage eliminates the production of the beta amyloid peptide.
harmful cleavage of APP
beta secretase cleaves APP at one end, releasing sAPP beta. Gama secretase cuts the resulting APP fragment.
neurofibrillary tangles are composed mainly of
hyperphosphorylated tau protein
function of normal tau
binds to microtubules and stabilizes them.
MAPT
gene that alternatively splice tau proteins.
tau in AD
has an abnormally large number of phosphate molecules attached to it. As a results, tau disengages from the microtubules, causing microtubules to disentigrate.
amino acids hyperphosphorylated in microtubules
series and threonines
cognitive decline in AD patients is caused by
progression of dysfunctional tau protein
the gene for APP is located on
chromosome 21
early onset familial AD is inherited as
autosomal dominant
three disease genes in Alzheimer’s disease (early onset)
amyloid precursor protein presenilin-1 (PS1) gene presenilin-2 (PS2) gene ABO-E4 (susceptibility gene) They explain only 5 - 10% of early onset patients
more than _ different mutations in the APP gene cause early onset AD
50.
These are responsible for less than 10 percent of all early onset cases of AD.
PSEN-1 gene
have been found in 40% of early onset families.
Most mutations are missense.
on chromosome 14
PSEN-2 gene
gene on chromosome 1
components of the gamma secretase
Presenilin-1 and 2 proteins.
Gamme secretase cleaves APP to generate alpha/beta.
Results of WES and early onset AD
mutations in SORL1 (missense and nonsense)
inheritance of early onset AD
autosomal dominant.
inheritance of late onset AD
complex.
concordance rate is 60%
it is restimated that people who have first degree relatives with AD are _ times more likely to develop the deisease themselves compared to people with no family history.
10
Risk factors for late onset AD
age family history gender APOE4 Ethnicity
number of genes identified by GWA studies
20
excluding APOE4, the discovered genes for LOAD account for _ percent of genetic risk for AD.
<35%
Rare variants in the _ gene cause susceptibility to LOAD.
TREM2
APOE
protein that regulates transport of cholesterol and lipids throughout the body.
The strongest genetic risk factor for AD
APOe4
effect of APOe4 on CNS
APoE modulates alpha beta metabolism, aggregation and deposition.
direct toxic effects on neurons
reduced beta amyloid (alpha/beta) clearance from brain in AD
toxic effects on the cerebrovascular system
the presnce of an APOe4 allele defines greater risk for AD but is __ to predict disease status for an asymptomatic individual
not sufficient
gender who has a higher risk for developing LOAD
women
• Early onset Alzheimer’s disease (EOAD): Mendelian inheritance involving 3 genes:
• Early onset Alzheimer’s disease (EOAD): Mendelian inheritance involving 3 genes:
o Beta-amyloid precursor protein (APP) gene
o Presenilin-1 (PS1 or PSEN1) gene
o Presenilin-2 (PS2 or PSEN2) gene
LOAD: o Biggest factor:
o Biggest factor: which form of ApoE you have
Positions 112 and 158
ApoE4: arg, arg increased risk for developing Alzheimer’s but not ABSOLUTE risk, page 35
• Presence of E4 decreases the age of onset
E3/E3 most common form of population
