AD and dementia Flashcards
Outline impact of dementia on society
Dementia is most common condition resulting from neurodegeneration: economic cost of $818 billion.
65% of people living with dementia are women.
Prevalence of dementia
Age is a major risk factor of dementia: prevalnce doubles every 5 years.
Estimated prevalnce is 60-64 years = 0.9%
95yrs and older = 41.1%
Dementia verus normal lapses of memory
Dementia: not recognising family member, forgetting to serve meal just cooked, not recognising numbers, dramatic change in personality.
Normal lapses of memory: forgetting a name, leaving the kettle on, losing things, gradual changes with ageing.
How to test for dementia
Mini Mental State Examination(MMSE): ask date/location, recall of objects, simple calculations.
When asked to draw a clock face: will completely forget or draw completely wrong.
Does MCI lead to dementia
MIld cognitive impairment can sometimes indicate prodromal AD (period between initial AD symptoms and full development of disease).
For o.
thers, this will not progress beyond MCI.
State different types of dementia
1) Alzheimer’s disease: over 50%
2) Vascular dementia: 20%
3) Dementia with Lewy body: 15%
4) Frontotemporal dementia (FTD): 2%
5) Rare causes: Parkinson’s disease dementia, Huntington’s disease, prion disease, others.
State risk factors of dementia
Age
Genetics: most cases are sporadic but rarely can be inherited (APP mutations presenilin genes).
Cardiovascular disease: smoking and diabetes increase risk where exercise decreases risk.
Depression
Head trauma
State physiological role of alphaBeta and how it plays a part in pathology of AD
ABeta monomer - physiological: synaptic function, BBB protection, antimicrobial effect.
ABeta oligomers - pathological: synaptic damage, microglia activation, Ca2+ dyshomeostasis.
State physiological role of tau and how it plays a part in pathology of AD
tau monomer - : DNA protection, microtubule stabilisation, dendritic development.
tau oligomers - pathological: disturbed neural circuits, microtubule degradation, synaptic loss
Outline the non-amyloidogenic pathway and state role
This is the ‘good’ pathway: produces sAPPalpha (neuronal survival, neurite outgrowth, neural stem cell proliferation, enhances LTP).
sAPP is created by APP being cleaved by alpha-secretase (ADAM)
* Gamma-secretase then goes on to produce P3 and AICD from other part of APP that have no known role.
Outline the amyloidogenic pathway and state role
This is the ‘bad’ pathway: produces sAPPBeta which lacks the neuroprotective effects of sAPPAlpha, ABeta protein that forms plaques.
Beta-secretase (BACE1): sAPPBeta and other part(C99). Gamma-secretase then goes on to cleave left over into ABeta and AICD.
ABeta: different lengths created with 42 amino acid length being the worst.
AICD: translocated to nucleus and activates transcription of target genes such as GSK3-Beta
Why is BACE1 a target of research and what did research find?
BACE1: if this enzyme doesn’t exist = ABeta plaques would not form.
Unfortunately, BACE1 KO causes hypomyelination (including the optic nerve) and frequent epileptic seizures.
Outline how ABeta aggregates to form plaques
Secondary structure: is predominantly alpha-helical but global conformational rearrangement and formation of beta-sheet structures (similar to prion) by fibrillization.
APP forms monomers, dimers, oligomers, protofibrils, fibrils and amyloid plaques.
Outline progression of AmyloidBeta plaque deposition.
Neocortex (bar M1), allocortical, subcortical structures as the disease progresses.
This revealed from PET scans and postmortems.
Outline targeted treatment of AD via AmyloidBeta
Beta-secretase inhibitors, active and passive immunisation to try and clear the plaques and gamma-secretase inhibitors. All failed to pass clinical trial due to severe side effects and lack of positive side effects bar aducanumab.
Aducanumab: antibody therapy that targets amyloidBeta. This is controversial…
* Reduced visible plaques in brain (surrogate outcome) = no patient benefit.
* No noticeable effect on patient outcomes (quality of life or dementia).
Serious adverse effects are common: edema and hemorrhage in the brain which causes dizziness, headache, nausea which can lead to hospitalisation and long-term impairment.
Overall, can conclude that ABeta plaques alone don’t cause AD.
