AD I

Question 1

AD stats

Answer 1

1 in 11 over 65 have dementia
more cases of dementia in females than males (males more affected by CV diseases)
dementia is multifactorial (population/age/BAME background have lower diagnosis rates)

Question 2

what is the leading cause of death in the UK

Answer 2

dementia
followed by ischaemic heart disease

Question 3

9 lifestyle changes which reduce the risk of dementia

Answer 3

1) stay in education until 15 (learn throughout life)
2) socialise
3) stay active
4) start depression treatment early
5) reduce high bp
6) weight watching
7) prevent type 2 diabetes
8) reduce smoking
9) treat hearing loss

Question 4

clinical symptoms of AD

Answer 4

gradual loss of learning and memory
affects communication, movement, personality
early signs: forgetting faces/names/events/asking same question in short timespan

Question 5

Which areas have neurodegeneration

Answer 5

shrinkage of cerebral cortex
enlarged ventricles
shrinkage of hippocampus (involved in learning and memory)

Question 6

neuropathological hallmarks of AD

Answer 6

neurofibrillary tangles (NFT) of tau
amyloid beta plauques

increase during disease development (in defined patterns)
pathology progression is Braak staging

Question 7

AB plaque braak staging

Answer 7

phase I - begins in neocortex
phase II-III spreads to entorhinal cortex/hippocampus/cortical regions
phase IV-V reach subcortical/BS/cerebellar region

Question 8

NFT braak staging

Answer 8

stage I-II begin in locus coeruleus and entorhinal cortex
stage III-IV hippocampal regions and neocortex
stage V-VI further progression in neocortex

Question 9

role of braak staging

Answer 9

characterises post mortem tissue as a proxy for disease progression and other pathologies can be assessed against this

Question 10

what is a limitation of braak staging

Answer 10

only occurs in post mortem tissue and cannot track disease progression within individuals or therapeutic efficiency

Question 11

how to track AD pathology

Answer 11

structure - MRI (traces water)
function - positron emission tomography (PET) requires radio-labelled ligands red=high glucose metabolism (less in AD)

Question 12

AD time course

Answer 12

AB - tau accumulation - synaptic dysfunction - neuronal death - AD (combination of events)

Question 13

AB production

Answer 13

cleavage of amyloid precursor protein APP
AB has a role in synaptic plasticity

aggregation: monomers - oligomers (toxic) - protofibrils - fibrils
non amyloidogenic processing - a-secretase amyloidogenic processing - b/y secretase

Question 14

risk factors (GWAS)

Answer 14

apolipoprotein E (APOE) - increases risk of AD the most
use in cholesterol/lipid transport in the ER - reduced risk by low fat diet

Question 14

gene mutants which increase AB42

Answer 14

mutations in genes encoding APP and y-secretase complex (PSEN1/2) cause early onset AD
additonal copy of APP from trisomy 21 (down syndrome) increases risk of early onset AD

Question 15

tau accumulations

Answer 15

microtubule-binding protein which stabilises MT and causes elongation and axon transport
tau undergoes hyperphosphorylation where it dissociates from MT and accumulates in the cell body and is prone to aggregate into tangles
cell-to-cell tau spreading through neuronal networks

neuron - MT-hyperphosphorylation of tau - paired helical filaments PHF - NFT

Question 16

neuroinflammation in AD

Answer 16

process by which the immune cells in the brain become activated by AB plaques e.g CNS glia (astrocytes and microglia clear debris via phagocytosis)
overactivation of glia causes degrading synapses and secreting high levels of toxic cytokines
neuroninflammation is the cause of decline once disease starts (AB/tau levels plateaued)

Question 17

appraisals of amyloid hypothesis

Answer 17

elderly people have normal cognition and plaques - plaques do not cause disease - plaques are presymptomatic stage of the disease

tau tangles correlate better with cognitive dysfunction than plaque burden - soluble oligomers are more toxic than plaques plaque haloes of soluble AB can distinguish between early AD (Esparza et al., 2013)

repeated failures of drug targetting AB in clinical trials