WK10 - Alzheimer's

Question 1

What does the term dementia mean?

Answer 1

Umbrella term for a group of symptoms
* Can be caused by many diseases (AD ~70% cases)

Question 2

Early stage AD

Answer 2

1. Short-term memory loss
2. Communication problems
3. Confusion
4. Poor judgement
5. Behavioural changes

Question 3

Later stage AD

Answer 3

Difficulty:
1. Walking
2. Speaking
3. Swallowing

Question 4

AD progression

Answer 4

1. None
2. Preclinical (some pathology, no impairment)
3. MCI
4. Advanced AD (abundant pathology + impairment)

Question 5

Prevalence of Dementia in Australia

Answer 5

#1 cause of death for aus women
* 5% early onset (< 65)
* ~400k living with dementia AUS
* ~57m living with dementia WORLD

Question 6

What is the ratio of sporadic EOAD and “familial” EOAD?

Answer 6

~90% - sporadic
~10% - mutations
* APP, PSEN1, PSEN2
* “familial Alzheimer’s disease”

Question 7

Sporadic AD

Answer 7

~95% (< 65)
* Genes increase risk but none causative
* greatest influence: APOE, TREM2

Question 8

AD Macropathology

Answer 8

1. ↓ brain weight (grey)
2. narrowed gyri, widened sulci
3. Dilated ventricles
4. Atrophy of temporal structures (hippocampus, entorhinal cx., amygdala)

Question 9

AD Neuropathology

Answer 9

1. Amyloid plaques
2. Neurofibrillary tangle (Tau)
3. Cerebral Amyloid Angiopathy (80-90% of cases)

Question 10

How do tau tangles form?

Answer 10

Tau is hyperphosphorylated and forms tangle
* Fills up cell body and little bits of processors
* Neuron wont function, will die -> ghost tangles

Question 11

Cerebral Amyloid Angiopathy

Answer 11

Aggregates of beta-amyloid in a wall of BV

Question 12

Neuroinflammatory response to plaques

Answer 12

1. Astrocyte try to wall off a-beta (scar)
2. Microglia recruited (phagocytosis)

Question 13

How is Aβ produced?

Answer 13

Cleaved from amyloid precursor protein (APP). This cleaving is either:
1. NON-AMYLOIDOGENIC
2. AMYLOIDOGENIC

Question 14

NON-AMYLOIDOGENIC cleaving

Answer 14

a-secretase
* cuts in-between a-beta sequence, so none is produced

Question 15

AMYLOIDOGENIC cleavage

Answer 15

1. β-secretase: cleaves off at the top of Aβ portion, leaving behind C99 protein
2. 𝛄-secretase: combination of 4 proteins, cleave the remaining C99 in various places, you end up with Aβ of different sizes (Aβ40, Aβ42)

Question 16

Aβ40

Answer 16

Primarily found in cerebral amyloid angiopathy

Question 17

Aβ42

Answer 17

“Bad guy” in AD
* High propensity for aggregation
* More toxic to cells

Question 18

How are Aβ plaques formed?

Answer 18

Aβ monomers aggregate to form oligomers and then plaques
* we need conc. and proximity

Question 19

Previous attitudes to oligomers

Answer 19

Soluble, swim around and cause problems
* BUT based on fraudulent data

Question 20

Diverse physiological functions of Aβ

Answer 20

1. Help synaptic function
2. Protective

Question 21

Multiple pathological roles of Aβ

Answer 21

1. Prompt Tau phosphorylation
2. Synaptic dysfunction
3. Oxidative stress
4. Widespread neuroinflammation
5. Neuronal death

Question 22

Phosphorylated tau (pTau)

Answer 22

Main protein in tangles
* pTau aggregates present >20 diseases (e.g. AD, PSP etc.)
* Becomes hyperphosphorylated > keeps adding
* Change function and cause aggregation

Question 23

Diverse physiological functions of tau

Answer 23

1. Structure
2. Axonal Transport
3. Mitochondrial function
4. Interacts with RNA

Question 24

Pathological functions of tau

Answer 24

1. Synaptic dysfunction
2. Axonal + Mitochondrial disruption
3. Loss of n. excitability
4. Enhanced neuroinflammation

Question 25

Which pathological function of tau is strongly correlated with cognitive decline?

Answer 25

**Synaptic dysfunction** * *less* synapse > ***memory loss*** * correlates *better* than **Aβ**

Question 26

Prion-like seeding of amyloid and tau

Answer 26

*Pathological* Aβ/tau from a diseased neuron can “***infect***” a healthy neuron * Hypothesised way that they ***spread*** through **connected** neurons

Question 27

Hypothesized timing of AD pathology

Answer 27

* **Aβ** accumulation ***1st*** * Then **synaptic** *dysfunction* * **Tau** impact * **Cognitive** and **clinical** symptoms happen ***later***

Question 28

How do we diagnose AD?

Answer 28

1. Clinical **symptoms** (*tests*) 2. **Pathology** (*accelerated* in past 10y, ***PET***, mostly used in clinical ***trials***, **biomarkers** of *CSF* and *blood*)

Question 29

Treatment for AD

Answer 29

Approved ***immunotherapies*** *Not in Australia* * **Lecamemab** * **Donanemab**

Question 30

Limitations of immunotherapy in AD

Answer 30

1. **Remove** large amounts of ***amyloid*** but **did not** improve *cognition* much 2. **Cost** 3. Severe **side effects**

Question 31

Amyloid Hypothesis

Answer 31

**Dominant** hypothesis in the field * **Aβ-targeting** drug ***failures*** have *decreased* popularity * Still very *polarizing*...

Question 32

Critical Considerations for developing effective AD therapies

Answer 32

1. **Context** matters (why is your **target** *better*) 2. **Disease model** matters (*human*) 3. **Patient** cohort matters (how well does *cohort* reflect ***all AD*** patients?)