Knopman et al 2021

Question 1

Is AD usually the only cause in older adult dementia? What other pathologies could occur?

Answer 1

Cerebrovascular, alpha synuclein, TDP43 pathology
Usually has at least 1 infarct

Question 2

What is the trend of dementia cases up to now and in the future?

Answer 2

Increasing trend in the last few decades due to increase in life expectancy
Expected to double by 2050

Question 3

Why have some high income countries seen decrease in dementia incidence?

Answer 3

Improvement in healthcare and education (helps with cognitive reserve)

Question 4

How do the incidence rates of MCI and dementia compare?

Answer 4

Usually rate of MCI is double that of dementia at each age group

Question 5

How much does AD contribute to dementia?

Answer 5

~70%

Question 6

What are risk factors of AD? (4 broad categories)

Answer 6

Age, sex, genes, modifiable factors

Question 7

What are examples of genetic risk factors?

Answer 7

APP, PSEN1/2, ApoE4, Tau binding proteins (BIN1, CD2AP)

Question 8

What are examples of modifiable risk factors?

Answer 8

Hypertension, obesity, TBI, alcohol, smoking, physical activity, social isolation

Question 9

What overt phenomena are seen in AD?

Answer 9

NFT, Amyloid plaques, glial activation, enlarged endosomes

Question 10

What covert phenomena are seen in AD?

Answer 10

Synaptic dyshomeostasis and impaired network integrity

Question 11

Describe how APP is processed in amyloidogenic and nonamyloidogenic pathways, along with products.

Answer 11

Non amyloidogenic:
Uses alpha and gamma secretase
Alpha -> produce sAPPalpha and alphaCTF
Gamma -> p3 + AICD

Amyloidogenic:
Uses beta and gamma secretase
Beta -> produce sAPPbeta and betaCTF
Gamma -> Abeta (38-43 aa) + AICD

Question 12

Is Abeta produced in physiological conditions and by what cells under what condition?

Answer 12

Yes, highly in neurons and secreted during synaptic activity

Question 13

What are the different species of amyloid?

Answer 13

monomer, oligomer (soluble and toxic), protofibril, fibril, plaque (found in AD)

Question 14

What are examples of receptors that oligo Abeta interact with? (4)

Answer 14

NMDAR, Insulin receptors, a7 nicotinic Ach R, mGluRs

Question 15

What kind of changes do Abeta cause on neurons?

Answer 15

Causes dendritic spine retraction and reduces synaptic efficiency

Question 16

What are tau proteins?

Answer 16

Microtubule stabilizing proteins and has binding domains

Question 17

What does tau phosphorylation do to it?

Answer 17

Causes destabilization of microtubule

Question 18

When are pTau secreted?

Answer 18

Synaptic activity

Question 19

What are the 3 different types of tau aggregations? Describe what those are.

Answer 19

intracellular NFT, neuropil threads (tau fragments), dystrophic neurites (Abeta plaques surrounded by degenerated axons and dendrites with tau)

Question 20

Describe the differences in Abeta and tau pathological progression. How do they influence each other?

Answer 20

Abeta pathology is widespread in throughout cortex
Tau is initially restricted to MTL (HPC, parahippocampal regions) and spreads to cortical regions like temporal parietal frontal cortices when Abeta is also elevated

Tau seeding and spread is potentiated by Abeta, but unclear how because they are spatially distinct (but could be mediated by soluble species instead of plaques)

Question 21

How do Abeta and tau progression parallel cognitive deficits? Give years

Answer 21

Usually abeta depositions decade before cognitive decline. Tau is more proximal in years.
Tau progression parallels cognitive deficits better

Question 22

How do Apoe genotypes affect AD pathologies?

Answer 22

Apoe4 causes high Abeta seeding and low abeta clearance, and E2 lowest seeding and highest abeta clearance
E4 can shift the onset of Abeta accumulation but otherwise same progression

Question 23

Describe how synaptic loss can happen in Abeta presence.

Answer 23

Abeta plaque facilitates production of soluble oligo Abeta surrounding it, which causes synaptic loss

Question 24

Describe how synaptic dysfunction can happen by Abeta? By Tau?

Answer 24

Abeta: Increased Ca2+ flux and can cause excitotoxicity (calcium dyshomeostasis)
Tau: Changes basic ephys properties of firing pattern and rates
Can also decrease activity in parietal cortex

Question 25

How do synapse remodeling happen in early AD?

Answer 25

Microglial pruning

Question 26

What is the 1st intracellular organelle affected in AD?

Answer 26

Endosomes (enlarged and accumulate)

Question 27

What is the ELN and autophagy, and how does it relate to AD? It’s dysfunction to AD pathology?

Answer 27

Main network to breakdown and clear damaged or aggregated proteins (eg. Abeta and tau)
Autophagy is the process activated during stress to clear intracellular proteins and organelles, which helps combat AD pathology.

BetaCTF can hyperactivate Rab5 which causes increased endocytosis and therefore accumulation of endosomes and enlarged endosomes.
ELN is overburdened with autophagy too and eventually leads to failure and leakage of oxidized substrates. Activate cell death

Question 28

Describe how betaCTF is involved in Abeta, Tau, synaptic pathology

Answer 28

Can promote accumulation of endosomes and thus accumulation of toxic proteins that cannot be broken down
Can activate kinases to promote pTau
Can promote endocytosis of AMPARs -> dendritic spine retraction and loss

Question 29

How is microglia involved in AD?

Answer 29

Can release IL-1Beta in response to Abeta -> neuroinflammation and exacerbates neurodegeneration

Question 30

How are PSEN and its dysfunction involved in AD via ELN?

Answer 30

PSEN is required for the vATPase to pump protons into lysosomes
Without this, enzymes cannot function optimally and leads to decreased protein degradation