Alzheimer's disease

Question 1

Features of AD

Answer 1

Progressive loss of short-term memory
Aphasia (loss of speech)
Apraxia (loss of voluntary movement)
Agnosia (poor object recognition)
Changes in behaviour

Question 2

Non-modifiable risk factors

Answer 2

Age
Prevalence high in females than males
1-5% of cases due to mutations in genes encoding APP, PS1 and PS2
SNPs in 30 genes increase the risk of developing sporadic AD

Question 3

Modifiable risk factors

Answer 3

Diabetes, hypertension and obesity
Diet high in saturated fats and low in folic acid
Smoking
Alcohol consumption
Physical inactivity

Question 4

Plaques and tangles

Answer 4

Extracellular senile plaques form from aggregated beta amyloid
Intracellular neurofibrillary tangles from hyperphosphorylated tau
Microglia activated by neuronal stress. Causes chronic inflammation (release of cytokines)
Both plaques and tangles must be present for diagnosis

Question 5

Beta-amyloid

Answer 5

Made from 30 different proteins
Resistant to proteolysis
Form via amyloidogenic processing of APP (beta secretase)
Beta amyloid monomers oligomerise and form fibrils (oligomers may be most toxic form)

Question 6

Neurofibrillary tangles

Answer 6

Made from paired helical filaments
PHFs arise from hyperphosphorylation of microtubule associated protein tau (axonal microtubule assembly and stability)
Phosphorylated tau aggregates within axon. Hyperphosphorylation disturbs binding of tau to microtubule

Question 7

Tau isoforms

Answer 7

6 major isoforms derived by alternative mRNA splicing from single MAPT gene on chromosome 17

Question 8

MAPT mutations

Answer 8

Cause frontotemporal dementia but not AD
Mutations in exon 9, 12 and 13 affect all 6 tau isoforms
Mutations alter tau production and cause changes in microtubule assembly or aggregation

Question 9

Vascular damage in AD

Answer 9

Cerebral amyloid angiopathy. Deposition of beta-amyloid in walls of blood vessels and brain
Damage to blood brain barrier
Dysregulated cerebral blood flow

Question 10

Amyloid cascade hypothesis

Answer 10

Beta amyloid aggregation sets off downstream events leading to formation of PHFs and NTFs

Beta-amyloid can induce tau phosphorylation in vitro
Treatment with AB causes death of many different cell types

Question 11

Tau hypothesis

Answer 11

Tau pathology precedes beta-amyloid plaques
NTFs are main cause of neuronal dysfunction and death

Pathological studies have reported tau lesions early than AB in human brains
Animals that express human NTFs have neuronal death

Question 12

Cholinergic hypothesis

Answer 12

Ach important for memory and attenuation

Cholinergic neurons die early in AD

Question 13

AD treatment

Answer 13

AChE inhibitors (donepezil, galantamine)
NMDA uncompetitive antagonist (memantine)

Question 14

Immunotherapy

Answer 14

Injection of pre-aggregated beta-amyloid 42 causes antibodies to beta-amyloid
Antibodies cross BBB and attack senile plaques (removed via phagocytosis)

Question 15

Beta-secretase inhibitors

Answer 15

Difficult to develop as need large binding site and BBB penetration