AD

Question 1

AD is a major cause of

Answer 1

dementia

Question 2

female to male ratio

Answer 2

2:1 *

Question 3

AD symptoms

Answer 3

memory loss, impaired ability to learn/reason, impaired ability to carry out daily activities, anxiety/suspicion/hallucination, can progress to motor dysfunction

Question 4

Neuropathology

Answer 4

• **Amyloid plaques: extracellular consisting of Aβ (amyloid-β peptide)
• **Neurofibrillary tangles: intracellular consisting of hyperphosphorylated tau
• Neuropathology primarily affects areas of **higher cognitive function: enterohinal cortex, hippocampus, neocortex
• Amyloid plaques and neurofibrillary tangles = destruction of synapses, This causes reduced neurotransmitter levels (Ach, 5-HT, NE, DA), Dysregulated glutamate = excess excitotoxicity and neurotoxicity

Question 5

Genetic evidence suggests a key role for AB

Answer 5

• Mutations in precursor protein (APP) linked to early onset AD
• Trisomy 21 (Down’s Syndrome) is associated with AD-like phenotype and **APP gene located on chromosome 21

Question 6

production of AB

Answer 6

• B-secretase and gamma-secretase release AB peptide from APP (toxic fragment)
• Cleavage by **a-secetase releases a non-toxic fragment
• **AB can be 40 or 42 amino acids in length, with the 42 AA fragment forming amyloid fibrils more readily
• Mutations in the gene encoding *PSEN1 or PSEN2 (components of γ-secretase) result in more Aβ formation

Question 7

tau pathology

Answer 7

-**Aβ aggregation is thought to promote tau hyperphosphorylation => disruption of axonal trafficking

Question 8

-AB aggregation on microglial activation

Answer 8

• Though to induce neurotoxicity by triggering microglial activation
• This increase release of pro-inflammatory cytokines = neuroinflammation
• Also release RNS and ROS to cause oxidative stress

Question 9

CV risk

Answer 9

• **AD risk is increased by increased LDL and/or decreased HDL
• Vascular disease may increase AD pathogenesis; Diabetes: toxic glucose metabolites in the brain could lead to decreased Aβ clearance
• ApoE: transports cholesterol in the brain; Defects in cholesterol metabolism = defects in membrane structure/function = affects AB deposition, Individuals with **one or two ApoE4 alleles have an increased risk of AD, whereas inheritance of the ApoE2 allele decreases AD risk

Question 10

current AD therapies

Answer 10

• Donepezil: specific, reversible inhibitor of acetylcholinesterase
• Rivastigmine: inhibits acetylcholinesterase and butyrlcholinesterase
• Galantamine: **selective, reversible inhibitor of acetylcholinesterase and enhances the action of acetylcholine on nicotinic receptors
• Memantine: NMDA antagonist that blocks glutaminergic neurotransmission (i.e. lowering neurotransmission)

Question 11

imaging with florbetapir

Answer 11

• **radiolabeled agent that binds β-amyloid, visualized by PET
• Does not establish AD diagnosis (amyloid involved in other diseases)

Question 12

non-AD dementias

Answer 12

• Vascular dementia: impaired judgment or executive function; occurs as a result of brain injury associated with vascular disease or stroke
• Dementia with Lewy Bodies: combination of cognitive decline and parkinsonian symptoms; neuropathology is characterized by cortical Lewy bodies
• Frontotemporal dementia: disinhibited behavior, poor impulse control, antisocial behavior; neuropathology is characterized by the presence of tau accumulation (Pick’s bodies for Pick’s disease)