Pathophysiology of Alzheimer's Disease

Question 1

Alzheimer’s is a

Answer 1

PROGRESSIVE
IRREVERSIBLE
NEURODEGERNATIVE disorder with INSIDIOUS onset

Question 2

Alzheimer’s shows as

Answer 2

Impairment of cognitive functions like memory, performance of simple task, language, and daily living

Question 3

Risk Factors for Alzheimer’s

Answer 3

Age
Genetics
Head Trauma
Female
Neuroinflammation
Lower level of education
Obesity and hypercholesterolemia
Trisomy 21

Question 4

Preclinical Phase of AD

Answer 4

No evidence of dementia or altered cognitive skills

- Some amyloid accumulation

Question 5

Mild Cognitive Impairment Phase of AD

Answer 5

Measurable memory problems but doesn’t compromise independent function

• Tau can be measured in CSF
• Not all will progress to AD

Question 6

AD phase

Answer 6

Clinical disease stage with signs/symptoms

• Early tend to be genetic
• Later tend to be sporadic

Question 7

Genetics types

Answer 7

Familial cause or sporadic cause (no genetics)
Early: Less than 60
Late: Greater than 60

Question 8

Genetic Factors in AD

Answer 8

Presenilin 1
Presenilin 2
Amyloid Precursor Protein
Mutated Paolipoprotein E4

Question 9

Preseniline 1 and 2 function

Answer 9

Involved in formation of beta amyloid (enhance the formation of beta amyloid)

Question 10

Mutated Apolipoprotein E4 function

Answer 10

Decreases age of onset and increases the number of plaques in the brain
Normal: ApoE and ApoJ bind beta amyloid and help clear it
There is actually a higher number of E4 in AD but they are mutated
- Risk factor not cause!!

Question 11

Define Amyloidosis

Answer 11

Normal protein misfold into beta secondary structure

Question 12

What happens after amyloidosis

Answer 12

• Multiple beta containing peptides aggregate and precipitate out of solution forming tissues deposits that damage tissue
• Primarily in the neocortex and hippocampus and primary amyloid beta peptide (BA4)

Question 13

Senile vs Diffuse plaques

Answer 13

• Senile plaques have a core of amyloid surrounded by a “halo” of dystrophic neurites and activated astrocytic and microglial cell
• Diffuse plaques lack a halo and appear with general aging

Question 14

Testing for amyloid plaques and neurofibrillary tangles?

Answer 14

• Accuracy in testing is 80% with histologically by silver-staining or by binding to Congo Red or thioflavine stain
• Imagining-based methods of detection: Amyvid and Vizamyl

Question 15

Define Neurofibrillary Tangles and what happens to them

Answer 15

Filamentous aggregations of microtubule-associated protein (TAU)
• Paired helical filaments
• Accumulate in and occupy the neuronal cell soma → lead to cell death and become extracellular

Question 16

Neuronal cell loss and gross brain atrophy occurs how?

Answer 16

• Selective neuronal loss and number of synapses in the brain is greatly reduced
• Neurons develop tangles and die (brain shrinks)

Question 17

First regions to show tangles are:

Answer 17

entorhinal and hippocampal regions (new memories) of the temporal cortex

Question 18

Cholinergic neurons in the nucleus basalis of meynert and septum leads to:

Answer 18

• Innervate the hippocampus and provide diffuse innervation of cerebral cortex
• Release ACh which facilitates synaptic plasticity (new synapses formation) in their targets
• Septal neurons promote learning and memory
But this doesn’t happen with the loss of cholinergic neurons

Question 19

Process of AD

Answer 19

 Amyloid deposits first appear in ventral regions of frontal and temporal cortex and then spread to all cortical association areas
 Entorhinal cortex → hippocampus → association areas (recognizable by pts at this point)
 As the disease progresses, tangles increase by number and they appear in primary regions of the cortex → subcortical structures (striatum, thalamus, hypothalamus, brainstem)
 LONG prodromal phase: pathology without clinical symptoms

Question 20

Degree of dementia is:

Answer 20

• NOT correlated with the number of senile plaques BUT they are required for the disease
• WEAKLY correlated with the number of tangles
• BEST correlated with neuronal and synaptic loss

Question 21

PET scan with P-deoxyglucose shows:

Answer 21

metabolic deficits that precede the cognitive symptoms → neurodegeneration is not bad enough to impair function
- Cognitive function decreases = cerebral glucose utilization decreases

Question 22

How does memory dysfunction occur:

Answer 22

 Lesions of the hippocampus = anterograde amnesia (can’t remember new memories)
 Cholinergic cells facilitate neuronal plasticity in hippocampus and cortex → break this you’ll have deficits in behavioral tests of learning and memory due to less innervation of the hippocampus
 Entorhinal cortex connects the hippocampus with the neocortex so destruction → disconnection of the hippocampus to neocortex and that interferes with memory consolidation

Question 23

Cholinesterase inhibitors do what?

Answer 23

reduce the clearance of ACh which keeps neuroplasticity (learning) intact but these neurons decrease with disease progression

Question 24

Amyloid Hypothesis

Answer 24

• APP derived BA4 is cleaved by alpha secretase normally and released into the ECF
o Non-amyloidogenic
• APP (amyloid precursor protein) is clipped by beta-secretase (BACE) at the N terminal and gama-secretase cleaves at the C terminal → BA4 peptide

Question 25

What happens with the BA4 pepride is released?

Answer 25

Prone to aggregate → oligomers (toxic form of BA4) → fibrils → larger aggregates that are nonsoluble → plaques o Presenilin 1/2 are subunits of gama-secretase and are mutated in AD leading to cleavage of APP so more BA4 are produced which is different version then before and is more amyloidogenic o ApoE and ApoJ bind BA4 and reduce the amount available for amyloidogenesis normally but these are mutated too

Question 26

What happens to TAU after it is created?

Answer 26

 Tau becomes abnormally phosphorylated and no longer binds microtubules  Structure is disrupted → it forms paired helical filaments that are polymers of hyperphosphorylated tau