Term
| What percentage of people over 85 have Alzheimer's disease? (AD) |
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Definition
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Term
at what age does Late Onset Alzheimer's begin?
What percentage of elderly population has Alzheimer's? |
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Definition
65 yrs old or after
6.5% of elderly pop. has AD |
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Term
| At what age does Early Onset AD begin? |
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Definition
60 yrs old or before - usually in the 40s
usually autosomal dominant |
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Term
| What 3 gene mutations can cause autosomal dominant AD? |
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Definition
APP - codes for Amyloid precursor protein
PSEN1 - codes for Presenilin-1
PSEN2 - codes for Presenilin-2 |
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Term
| What is the function of APP (Amyloid precursor protein)? |
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Definition
| It is the Type 1 transmembrane protein from which A-beta is generated |
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Term
| What is the function of Presenilin-1 and Presenilin-2? |
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Definition
| Involved in making A-beta. This protein is one part (subunit) of a complex called gamma-secretase. Gamma- secretase helps cleave APP and releases A-beta |
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Term
| mutations in APP affects its cleavage process how? |
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Definition
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Term
Finish the sentence-
Mutations in PSEN make it tend to cut APP… |
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Definition
| in a place to get a 42 amino acid chain as opposed to a 40 amino acid chain (42 is more toxic) |
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Term
| A-beta molecules are (monomers/dimers/trimers) that will ___ and form ___ which are the main pathology of AD. |
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Definition
| A-beta molecules are monomers that will aggregate and form plaques which are the main pathology found in AD |
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Term
| The Dominantly Inherited Alzheimer's Network (DIAN) studies patients with mutations in which of the 3 primary genes associated with AD? |
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Definition
| all 3 (APP, PSEN1, PSEN2) |
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Term
| The Alzheimer's Prevention Initiative (API) studies a mutation in which of the 3 genes associated with AD? |
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Definition
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Term
| First memory symptoms of Alzheimer's happen generally around ___ years after onset of the disease |
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Definition
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Term
Progression of Alzheimer's - What is occurring in the brain:
- 20 yrs before 1st symptom?
- 15 yrs before 1st symptom?
- 10 years before 1st symptom?
- 5 years before 1st symptom? |
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Definition
20 yrs - High levels of A-beta (declining), activation on FDG-PET
15 yrs - Plaque deposition, hippocampal atrophy, increased levels of CSF Tau, CSF A-beta is decreasing but is around normal range
10 yrs - Low CSF A-beta, decreased FDG-PET activation, brain becomes hypometabolic
5 yrs - Multi-domain cognitive deficits on testing |
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Term
| What's the average survival (yrs) from the first symptom of Alzheimer's? |
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Definition
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Term
| almost all plaque deposition occurs during which years before the first symptom of Alzheimer's ? |
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Definition
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Term
| Dementia due to AD is insidious, which means? |
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Definition
| gradual - Must rule out stroke or trauma as a causative factor |
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Term
| What are three molecules associated in pathogenesis of AD? |
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Definition
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Term
| which molecule is the main component of the plaque build-up in AD? |
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Definition
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Term
| what molecule is the main component of tangles in AD? |
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Definition
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Term
| what gene is the main genetic risk factor for AD? |
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Definition
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Term
| do the amyloid plaques cause AD? |
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Definition
| No - could be healthy response to prevent AD |
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Term
| Tangles are made from which molecule in neurons? They fill up neurons, so when stained, take their shape |
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Definition
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Term
| Experiment with mouse - Transgenic mouse with high levels of A-beta could not remember where platform is in pool |
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Definition
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Term
| Tau is a protein that binds what type of cellular structural component? |
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Definition
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Term
| In an AD brian, Tau proteins are (hypophosphorylated/hyperphosphorylated) |
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Definition
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Term
| What is the function of Tau proteins on microtubules? |
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Definition
| regulates axonal transport, stabilizes microtubules |
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Term
| what effect does Tau on microtubules have on kinesin movement |
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Definition
| impedes kinesin movement down microtubules |
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Term
| Hyperphosphorylated tau (stays on/falls off) microtubules causing what? |
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Definition
| Tau falls off causing destabilization of microtubules and impaired axonal transport |
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Term
| when Tau hyperphosphorylates and falls off microtubules, it does what? |
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Definition
| aggregates into neurofibrillary tangles |
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Term
T or F
ApoE causes autosomal dominant early onset alzheimers |
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Definition
| False - ApoE is associated with Late onset and is only a risk factor |
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Term
| which is the "bad" form of ApoE? Why is it "bad"? |
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Definition
ApoE4 is bad. It affects the age of AD onset.
If you are homozygous ApoE4 onset is around 70
If you are heterozygous ApoE3/ApoE4 onset is around 75
If you are homozygous for ApoE3 onset is around 85 |
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Term
T or F
brain atrophy is random or homogenous is AD |
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Definition
| False - Atrophy targets the Default Mode Network involved in memory |
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Term
| what is a specific part of the Default Mode Network of the brain involved in AD? It is the most vulnerable part of the Default Mode Network |
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Definition
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Term
put these in order of AD progression
Cognitive impairment
Atrophy on MRI
Raised levels of CSF Tau protein
Raised levels of CSF A-beta protein
Functional Impairment |
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Definition
1. Raised levels of CSF A-beta protein
2. Raised levels of CSF Tau protein
3. Atrophy on MRI
4. Cognitive Impairment
5. Functional Impairment |
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Term
| 2 classes of current therapies for AD |
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Definition
Cholinesterase inhibitors
NMDA receptor agonist - Memantine |
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Term
| Name three cholinesterase inhibitors |
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Definition
Donepezil
Rivastigmine
Galantamine |
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Term
| Cholinesterase is an enzyme that converts ___ to __ and ___ |
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Definition
| converts Acetylcholine to acetate and choline |
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Term
| In alzheimer's you have a loss of ___ neurons, causing less release of Ach |
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Definition
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Term
| cholinesterase inhibitors allow which neurotransmitter to remain in the synapse for longer? |
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Definition
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Term
| donezepil (prevents decline of AD/reverses some pathology of AD) |
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Definition
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Term
| Newer diagnostic criteria for earlier diagnosis includes measuring what proteins in the CSF? |
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Definition
lowered A-beta42
raised Tau (total and phosphorylated) |
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Term
| Newer diagnostic criteria includes measuring what in the temporo-parietal cortex? |
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Definition
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Term
| Newer diagnostic criteria includes using MRI for measuring what area of brain atrophy |
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Definition
| hippocampal/medial parietal atrophy |
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Term
| the A-beta:Tau ratio is (higher/lower) in AD CSF |
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Definition
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Term
| what are 3 A-beta targeted therapies |
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Definition
1. Inhibit Beta-secretase – decrease A-beta production
2. Inhibit gamma-secretase – Inhibiting cleavage can cause GI side effects
3. A-beta Aggregation Inhibitors
4. Immunotherapy – speeding up clearance and degradation of A-beta. Give patients Antibodies at can get into brain and bind A-beta |
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Term
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Definition
| Mild Cognitive Impairment |
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