Neuropathology of Alzheimer's Disease Flashcards
Identify the key neuropathological features of AD Compare and contrast the cholinergic and amyloid cascade hypotheses Evaluate the methods being developed to assess brain pathology and to confirm the diagnosis of AD in living patients Discuss the utility of post-mortem examination as an end point in clinical trials
What is the prevalence of Alzheimer’s disease in the 65-69 age group?
1.3%
What is the prevalence of Alzheimer’s disease in the 85-89 age group?
20.3%
Describe the 4 histopathological hallmarks of Alzheimer’s disease
Extracellular plaques, neurofibrillary tangles, cerebral amyloid angiopathy, neuronal loss
In which lobes of the brain is cerebral atrophy most pronounced in AD?
Frontal and temporal lobes
Describe the basis of the cholinergic hypothesis of AD
ACh turnover decreases with age, and a lack of ACh causes amnesia. A decrease in cholinergic markers appears to correlate with the clinical severity of dementia
Give three classes of drugs available to treat AD
Anti-cholinesterases, nicotinic receptor agonists, and glutamate antagonists
Name 2 anti-cholinesterases available to treat AD
Rivastigmine, donepezil, tacrine
Name a nicotinic receptor agonist available to treat AD
Galantamine
Name a glutamate antagonist available to treat AD
Memantine
Which type of dementia is memantine primarily used to treat?
Vascular dementia
What are neurofibrillary tangles?
Paired helical filaments of the microtubule associated protein tau, due to hyperphosphorylation of tau
Describe the classical appearance of extracellular plaques on immunostaining
A bullseye
Name two pathological features created by amyloid-beta
Extracellular (senile) plaques and cerebral amyloid angiopathy
Which protein is Alzheimer’s disease staged by - amyloid-beta or tau?
Tau
Which four areas of the brain are involved in the Braak staining of AD?
Anterior hippocampus, posterior hippocampus, temporal cortex, occipital cortex
Which area of the brain is affected by pathology first (Braak stage I)?
Transentorhinal region in the anterior hippocampus
Which region of the brain is affected in Braak stage II?
Entorhinal region in the anterior hippocampus
Which region of the brain is affected in Braak stage III?
Temporo-occipital gyrus in the posterior hippocampus, in addition to the entire anterior temporal lobe (entorhinal cortex)
Which region of the brain is affected in Braak stage IV?
Temporal cortex. Symptoms now become clinically relevant
Which region of the brain is affected in Braak stage V?
Peristriatal cortex in the occipital cortex
Which region of the brain is affected in Braak stage VI?
Striatal cortex in the occipital cortex
At which Braak stage do symptoms become clinically relevant?
IV (4)
Define amyloid
A general ter, for any aggregate of peptide protein
What is amyloid precursor protein?
A membrane-bound glycoprotein with a long extracellular amino acid and a short intracellular carboxy terminus
Describe the difference between normal and pathological processing of APP
In normal processing, APP is cleaved by alpha-secretase at the amyloid-beta terminus. In pathological processing, APP is cleaved by beta-secretase, allowing cleavage by gamma secretase to produce amyloid-beta - which tends to form a beta-pleated sheet structure and aggregate
Give 5 risk factors for AD
Ageing, family history, Down’s syndrome, previous head trauma, Parkinson’s disease, APOE4 genotype
Give 2 chromosomes which host mutations causing early onset familial AD
Chromosome 14 and chromosome 21
Which chromosome is the APP gene located on?
Chromosome 21
Why is it theorised that individuals with Down’s syndrome develop AD?
They have an extra copy of chromosome 21, which carries the APP gene - the extra copy seems to lead to AD via mass effect
Which gene is most commonly mutated in early-onset familial AD?
The gene encoding presenilin
What is presenilin>
An integral membrane protein with roles in intracellular signalling and the determination of cell fate
Which chromosome is apolipoprotein E encoded for on?
Chromosome 19
How many alleles does apolipoprotein E have?
3
How much does APOE4 increase the risk of AD?
2x in heterozygotes, 10x in homozygotes
What is the function of apolipoprotein E?
It is involved in lipid metabolism and membrane repair
