Alzheimer's Disease

Question 1

alzheimer is characterized by

Answer 1

development of amyloid plaques and neurofibrillary tangles.

Question 2

2/3 of Americans over age 65 with AD are

Answer 2

women

Question 3

early onset type AD is inherited as

Answer 3

autosomal dominant.

Individuals with an affected first degree relative have 10% chance of AD.

Question 4

stages of AD

Answer 4

mild (2-4 years)
moderate (2-10 years)
severe ( 1-3 years)

Question 5

amyloid precursor protein (APP)

Answer 5

helps cell attach to one another.

it directs the movement of nerve cells during early development.

Question 6

formationof beta amyloid plaques

Answer 6

it comes from APP (is cut off from APP and found outside neurons)
Plaques form when beta-amyloid clump together.

Question 7

enzymes involved in cleaving APP

Answer 7

secretases

Question 8

APP is cleaved by two different pathways

Answer 8

benign cleavage: peptide of 40 AA which does not aggregate.

toxic cleavage: peptide of 42 - 43 AA which aggregates.

Question 9

benign cleavage of APP

Answer 9

alpha secretase cleaves the APP molecules and forms a soluble protein. The cleavage eliminates the production of the beta amyloid peptide.

Question 10

harmful cleavage of APP

Answer 10

beta secretase cleaves APP at one end, releasing sAPP beta. Gama secretase cuts the resulting APP fragment.

Question 11

neurofibrillary tangles are composed mainly of

Answer 11

hyperphosphorylated tau protein

Question 12

function of normal tau

Answer 12

binds to microtubules and stabilizes them.

Question 13

MAPT

Answer 13

gene that alternatively splice tau proteins.

Question 14

tau in AD

Answer 14

has an abnormally large number of phosphate molecules attached to it. As a results, tau disengages from the microtubules, causing microtubules to disentigrate.

Question 15

amino acids hyperphosphorylated in microtubules

Answer 15

series and threonines

Question 16

cognitive decline in AD patients is caused by

Answer 16

progression of dysfunctional tau protein

Question 17

the gene for APP is located on

Answer 17

chromosome 21

Question 18

early onset familial AD is inherited as

Answer 18

autosomal dominant

Question 19

three disease genes in Alzheimer’s disease (early onset)

Answer 19

amyloid precursor protein 
presenilin-1 (PS1) gene
presenilin-2 (PS2) gene
ABO-E4 (susceptibility gene)
They explain only 5 - 10% of early onset patients

Question 20

more than _ different mutations in the APP gene cause early onset AD

Answer 20

50.

These are responsible for less than 10 percent of all early onset cases of AD.

Question 21

PSEN-1 gene

Answer 21

have been found in 40% of early onset families.
Most mutations are missense.
on chromosome 14

Question 22

PSEN-2 gene

Answer 22

gene on chromosome 1

Question 23

components of the gamma secretase

Answer 23

Presenilin-1 and 2 proteins.

Gamme secretase cleaves APP to generate alpha/beta.

Question 24

Results of WES and early onset AD

Answer 24

mutations in SORL1 (missense and nonsense)

Question 25

inheritance of early onset AD

Answer 25

autosomal dominant.

Question 26

inheritance of late onset AD

Answer 26

complex.

concordance rate is 60%

Question 27

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.

Answer 27

10

Question 28

Risk factors for late onset AD

Answer 28

age
family history
gender
APOE4
Ethnicity

Question 29

number of genes identified by GWA studies

Answer 29

20

Question 30

excluding APOE4, the discovered genes for LOAD account for _ percent of genetic risk for AD.

Answer 30

<35%

Question 31

Rare variants in the _ gene cause susceptibility to LOAD.

Answer 31

TREM2

Question 32

APOE

Answer 32

protein that regulates transport of cholesterol and lipids throughout the body.

Question 33

The strongest genetic risk factor for AD

Answer 33

APOe4

Question 34

effect of APOe4 on CNS

Answer 34

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

Question 35

the presnce of an APOe4 allele defines greater risk for AD but is __ to predict disease status for an asymptomatic individual

Answer 35

not sufficient

Question 36

gender who has a higher risk for developing LOAD

Answer 36

women

Question 37

• Early onset Alzheimer’s disease (EOAD): Mendelian inheritance involving 3 genes:

Answer 37

• 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

Question 38

LOAD: o Biggest factor:

Answer 38

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