Alzheimers disease

Question 1

Epidiemology of alzheimers

Answer 1

Main risk factor: age
Exponetial rise of incidence with age
Huge economic costs to NHS
2 forms of the disease -age related and early onset alzheimers (much rarer-gene mutations (APP, PSEN, ApoE))

Question 2

CLinical symptoms of alzheimers

Answer 2

Memory loss-especially recent
disorientation/confusion
Language issues-stop in middle of sentence
personality changes and poor judgment

Question 3

What is the amyloid hypothesis of pathophysiology of alzheimers

Answer 3

Main theory on the pathophysiology - amyloid plaques in dead bodies
amyloid-normal protein produce-function unfound
Requires 2 enzyes for physiological amyloid (alpha and gamma SEC -cleaved in that order)
They cleave precursors of amyloid precursor protein (APP) in membrane

In pathyphysiology, belive production of B SECretase instead of alpha
Cleaved first, then gamma-in a different site-leaves longer product in the membrane -> produces B-amyloid
Not removed, coaslesce/aggragate->form clumps in and out of neurons (toxic aggregates-maybe responsible for alzheimers (why-unsure. Immune reaction? Plaque themselves toxic?)

Question 4

What is the Tau hypothesis of alzheimers pathophysiology?

Answer 4

Tau protein in soluble protein present in neuronal axons
Help assemble/stablise microtubules joining cell body and pre-synapse

Pathophysiology-
Hyperphosphorylated Tau protein make them insoluble-self agreggate and form neurofibrlil tangles
neurotoxic agreggates IN CELLS
also loss of microtubule instability

not necessarily opposite/incompatible with B-amyloid theory-can happen

Question 5

What is the inflammation hypothesis of pathophysiology of alzheimers

Answer 5

Again not mutually exclusive to other
Microglial cells causing abherrent immune reaction-> Inflam mediators, phagocytosis and reduced neuroprotection => destroy directly

what activates them? unsure-maybe B amyloid/tau

Question 6

What is one type of anti alzheimers disease drugs?

Answer 6

Anti-Cholinesterase -> NMDA receptors targetted
Cholinesterase breaks down ACh in CNS->

Doneprezil-
reversible cholinesterase inhbitor (long plasma half life-once daily)

Rivastigmine-Pseudo reversible (not sure if reversible or not) cholinesterase inhbitor (Acetyl and Butyrl (causes some side effects)
8h-and can be given transdermal

galantamine
reversible cholinesterase inhbitor -8h half life-acetyl esterase only
Also effect: nAChR agonist-neural type (a7)

why they work is unsure-but can reverse/inhbit symptoms of alzheimers diseases
licensed to treat mild to moderate alzheimers-dont act very long
Doneprazil is first line

Question 7

What is the second type of alzheimer drug?

Answer 7

NMDA receptor blocker-Memantine
Non competitive and use dependent (only act with excess activity)
Tend to get overactive NMDA in neurodegenerative-usually glu acting on NMDA
Long plasma half life
licensed for moderate-severe Alzheimers

Question 8

What are the 3 main failures in drug development in alzheimers

Answer 8

Y-Sectase inhbitors-lots of trials taken place (eg: Tarenflurbil, Semagacestat). Tarenflurbil bind APP (not helping Semegacestat-small molecule inhbitor (made people worse-skin cancer)
No B-secretase have shown sucess either

B-amyloid targetting
Bapineuzumab-massive failure, solanezumab-also fail but does reduce B-amyloid
mAb Aducanumab-> targets a bit better (monomers and fibrils)-> phase III trials -maybe?
vaccines against B-amyloid in development

Tau inhbitors
Methylene blue -already licences for methaemeglobineamiea