Conference: Alzheimer's

Question 1

Diagnosis of AD

Answer 1

can only be made post-mortem

Requires extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles

Clinical diagnosis based on slow progressive dementia and cerebral cortical atrophy

Neuroimaging Biomarkers: PET and MRI – to detect plaques and tangles

Fluid Biomarkers = Proteins in cerebral spinal fluid such as Aβ42 and tau

Question 2

Genetics of EOAD (ealy onset)

Answer 2

 EOAD represents only 1-5% of all AD cases

 Autosomal dominant

60% of EOAD cases caused by mutations in one of 3 genes: APP (amyloid precursor protein), PSEN1 (presenelin 1), & PSEN2 (presenelin 2)

Question 3

What are APP and Amyloid-β (Aβ)?

Answer 3

Amyloid precursor protein (APP) is membrane protein that is cleaved into several physiologically active products by: α-secretase, β-secretase, γ-secretase - produces Aβ peptide.

Mutations in APP, PSEN1 and PSEN2 that cause AD involve: Overproduction of all Aβ species, Overproduction of Aβ42 vs Aβ40, & Enhanced aggregation/decreased clearance of Aβ.

Question 4

Discuss Calcium Dyshomeostasis in AD

Answer 4

EOAD mutations appear to affect Ca2+homeostasis by causing Ca2+overload

Cytoplasmic Ca2+overload stimulates APP processing toward Aβ production, which results in more Ca2+overload, leading to neuronal dysfunction

Question 5

Discuss Tau and Neurofibrillary Tangles in AD

Answer 5

 Tau binds to and stabilizes microtubules

 Phosphorylated tau disengages from microtubules thereby allowing cargo to move along axon

 Hyperphosphorylated tau aggregates to form neurofibrillary tangles (NFTs)

 NFTs are always associated with AD

Question 6

What are some drug therapies in AD?

Answer 6

 Disease is incurable

 Current therapies only slow progression

Question 7

What are Risk Factors for LOAD?

Answer 7

1) Genetic: ApoE e4 variant – major, Many other genes

2) Environmental: age - major, Inflammation, Stress, Hypertension, Dietary factors

Question 8

What is the role of ApoE in AD?

Answer 8

ApoE is a component of VLDL, chylomicrons and HDL, it is a major apolipoprotein in CNS – needed for lipid transport, it is used in CNS damage repair & synaptic remodeling, & e4 Variant does not bind to receptors as well as e3 or e2.

Neurons of e4 individuals may not take up enough cholesterol for membranes

Question 9

Discuss the ApoE Isoforms (e2, e3, e4)

Answer 9

Differ structurally/ functionally: e3 binds normally to receptor, & e2 and e4 moderately dysfunctional in receptor binding

Most common genotype = e3/e3 (#1) and e3/e4 (#2)

e4 isoform increases risk of LOAD

• e4/e4 – increase risk of AD ~12 fold
• e3/e4 or e2/e4 – increased risk of AD 2-3 fold
• e2 isoform decreases risk of LOAD slightly

ApoE-e4 does not promote efficient degradation and clearance of Aβ, like ApoE-e3 does

ApoE-e4 doesn’t mediate efficient uptake of cholesterol by neurons so neuronal membranes lack cholesterol and show decreased synaptic efficiency leading to dementia

Many people with LOAD do not have ApoE-e4 allele (involvement of other genes)

Question 10

LOAD vs EOAD

Answer 10

EOAD

 Develops before age 65

 Autosomal dominant inheritance

 Three genes cause disease: APP, PSEN1 and PSEN2

 All involved in formation of Aβ peptide

LOAD

 Develops after age 65

 Complex interaction of genes and environment lead to disease

 May develop through a variety of pathways likely involving Aβ

 ApoE-e4 is major genetic risk factor

 Aging is major environmental risk factor

Question 11

Discuss LOAD & Type III HLP (hyperlipoproteinemia)

Answer 11

 ApoE is required for lipid uptake by neurons in brain and by cells of other organs

 Reduced uptake by neurons in e4/e4 individuals leads to cholesterol deficits, poor synaptic function, and AD

 Reduced uptake by other cells in e2/e2 individuals leads to cholesterol build up in blood, atherosclerosis, and Type III HLP (hyperlipoproteinemia)