Dementia: Alzheimer's disease

Question 1

How do we define dementia?

Answer 1

Impairment in any of these:

• memory
• language
• visual processing and orientation
• mood, personality, and social skills
• Frontal executive function, including planning and problem solving

Therefore affecting ability to function independedntly

Question 2

3 most common causes of degenerative dementia?

Answer 2

1. Alzheimer’s disease
2. Vascular dementia
3. Others: e.g. LBD, PDdementia, FT dementia

Question 3

What are the features of alzheimer’s disease?

Answer 3

• a progressive degenerative brain disorder and the most common cause of dementia
• > 65 years
• majority: late onset, slow gradual
• predominance of memory impairment

Question 4

How do we diagnose AD?

Answer 4

Definitive diagnosis by neuropathological examination

- presence of amyloid plaques and neurofibrillary pathology

Question 5

Risk factors for AD?

Answer 5

Age
FHx
Down's syndrome (due to increase copy number of chromosome 21 - where amyloid protein is coded for)
Head injury
Apo -E4
Vascular disease risk
Smoking
Female

Question 6

Clinical diagnosis of AD?

Answer 6

Development of multiple cognitive defects manifested by both = dementia:

1. Memory impairment
2. one or more of the following: Aphasia (language difficulties), Apraxia (inability to carry out motor function), Agnosia (failure to identify objects), Disturbance in executive functioning (planning, organising, sequencing, abstracting)

Unlikely AD: acute onset possible other neuro conditions
Possible AD: Dementia syndrome with atypical onset, exclude other conditions e.g. CVD, HIV, PD, HD, systemic disorders: decrease in Vit B2, folic acid, ca2+
Probable AD:established by clinical or neurophysiological exam
Definite AD: meets symptom criteria + Histopathologicical evidence with autopsy or biopsy

Question 7

AD vs VaD

1. vascular conditions and risk factors
2. onset and progression
3. neuro-imaging positive for cvd
4. psychiatric comorbidity
5. Executive dysfunction
6. Focal neurological signs and symptoms
7. Memory impairment
8. Gait
9. Emotional lability (exaggerated change in mood)

Answer 7

AD -VaD

1. little - A lot
2. gradual - abrupt
3. no - yes
4. may be present - frequent
5. none or mild - yes
6. none - yes
7. yes - may not be prominent
8. no - yes
9. no - yes

Question 8

What is the ADAS-cog test?

Answer 8

Type of neuropsychiatric screening
Tests several features of cognition:
- language ability and comprehension
- concentration
- memory
- Word: finding and difficulty 
Total scores range from 0–70, with higher scores (≥ 18) indicating greater cognitive impairment.

Question 9

What do we use CT, MRI and PET for in AD?

Answer 9

CT: temporal lobe thickness
MRI: brain volume and atrophy
PET: blood flow, glucose metabolism

Question 10

What are the different types of AD biomarkers and how do they correlate with disease progression?

Answer 10

Clinical manifestation is the last thing you see

See Amyloid beta -> Tau -> Brain structure -> Memory loss -> then finally clinical function deterioration

Question 11

Where does neuronal loss first take place?

Answer 11

Temporal area - hippocampal circuit - CA1 region

However 25% of cases have hippocampal sparing and limbic-predominant AD

Question 12

List the genetic product, chromosome causing early onset and late onset AD

Answer 12

Early onset:

• Amyloid Precursor Protein: Chr 21 (APP/Abeta)
• Presenilin 1 - PSEN1: Chr 14
• Presenilin 2 - PSEN2: Chr 1

Late onset:
- Apolipoprotein E - APOE-e4 allele, ApoE (Chr 19)

Question 13

What are the pathological hallmarks of AD?

How do we monitor them?

Answer 13

• Amyloid plaques AND neurofibrillary tangles (tau protein aggregates)
• Increased brain atrophy
• Cerebral amyloid angiopathy: accumulation of amyloid in vessels
• Synapse loss

Pitsburg compound B in PET scan - PiB can be used to track amyloid and shows that amyloid can start accumulating 15 years before AD onset.

Increase NFT in temporal lobe ( can be stained with silver to see NFT): BRAAC staging - Stage 1-4 is normal ageing, Stage 5-6 is pathological for AD

Question 14

Can we immunise patients with AD?

Answer 14

Target AB42 which removes plaques but there is no effect on cognition or neuro-degeneration

Question 15

What is amyloid beta and its relationship with amyloid precursor protein (APP)?

Summarise the pathology of AB

Answer 15

AB a peptide of 38-43 (normal = 40, pathogenic =42)
It is a product of APP by proteolytic cleavage .
AB pathology is due to gain of function and can group together to form oligomers and then AB plaques

AB oligomers appear to be the problem. Synaptic loss + cognitive degeneration occurs before plaque formation

Question 16

How is AB formed from APP?

Answer 16

Protease enzymes (seperatases) cleave APP. 
Cleavage can occur at 3 sites- alph, beta and gamma.
Cleavage at alpha = non-amyloid cleavage and no formation of AB

Cleavage at beta and gamma = forms 2 main type of AB: AB40 or AB42(which forms plaques)

Question 17

Is amyloid beta really pathogenic?

Answer 17

Everyone has it, just AD patients have more.
E.g. trisomy Down syndrome patients. Chromosome 21 codes for AB, therefore downs syndrome patients tend to be at risk of AD

Question 18

How do APP mutations affect pathology?

Answer 18

Depending on where the mutation is on APP, it affects alpha, beta or gamma secretase cleavage

Question 19

What mutations affect gamma secretase?

Answer 19

Presenilins 1 and 2

Question 20

Can we target the promotion of alpha secretase or inhibit beta and gamma secretase?

Answer 20

No. as the secretases have other functions other than APP cleavage.

Alpha: cleaves other proteins e.g. TNF alpha, TGF alpha etc.
Gamma: cleave N- & E-cadherin, ErbB4, notch etc..
Beta also only codes for sialyl-transferase (and studies show you can live without it) so could be a good target

Question 21

What are the properties of the secretases?

Answer 21

Alpha:
ADAM Zn2+ co-factor
activated by furin
non specific enzyme - can be problematic
APP cleavage - non-amyloidegenic

Beta:
Also activated by furins
located predominantly in Golgi/endosomes
only one known physiological substrate

Gamma:
cleaves single-pass transmembrane proteins at residues within the transmembrane domain
PS1 essential for activity cell fate and differentiation
composed of: PSEN 1 and 2, nicastrin, Aph1

Question 22

What is the function of AB?

Answer 22

? neuroprotective but not sure
It is normally found in the CSF AB40 of everyone throughout life
It is thought to be secreted from healthy neurons in response to activity by inhibiting fast excitatory synaptic transmission (AMPA, NMDA) which leads to a decrease in synaptic activity and therefore impairs long term potentiation

Question 23

How does AB cause AD?

Answer 23

See amyloid cascade hypothesis sheet

Question 24

What is the relationship between AB plaque and NFT?

Answer 24

Unclear but Tau mutations causes fronto-temporal dementia

Neurofibrillary tangles are formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate, or group, in an insoluble form. The precise mechanism of tangle formation is not completely understood, and it is still controversial whether tangles are a primary causative factor in disease or play a more peripheral role.

Question 25

What are the different therapies for AD?

Answer 25

• Anti-inflammatories: AD associated inflammation
  AB vaccination: immunotherapy that destroys plaques. RPCDB AB vaccination trial, shows little or no protection against dementia - trial failed
• Targets for secretases: agonists of alpha, inhibitors of beta (BACE trial) and gamma
• Prion protein PrpC: a receptor for AB ?if prion misfolfef proteins which aggregate is how AB might work?