Alzheimer's (done) Flashcards
What is dementia?
Progressive, irreversible clinical syndrome w a range of cognitive & behavioural symptoms –> including:
- Memory loss
- Problems with reasoning & communication
- Changes in personality
- Reduction in the person’s ability to carry out daily activities
What are multiple cognitive deficits?
- Memory dysfunction is major early symptom - especially learning new info
- Diagnosis req deficits in at least 2 cognitive domains: memory, language, behaviour, visuospatial, or exec function
What are the 2 main criteria req to diagnose dementia?
- Multiple cognitive deficits
- Cognitive disturbances
What are cognitive disturbances?
- Sufficiently severe to cause impairment of occupations or social functioning (activities of daily living; ADL)
- Must represent a decline from previous level of functioning
- Cannot be explained by delirium or other major psychiatric disorder
List the 10 causes of cognitive deterioration:
1 - Alzheimer Disease (pure ~40% & mixed ~70%)
2 - Vascular disease, Multi-Infarct Dementia
3 - Drugs, Depression, Delirium
4 - Ethanol (5-15%)
5 - Medical/Metabolic systems
6 - Endocrine (thyroid, diabetes), Ears, Eyes Environment
7 - Neurologic (other primary degenerations)
8 - Tumor, Toxin, Trauma
9 - Infection, Idiopathic, Immunologic
10 - Amnesia, Autoimmune, Apnea, Age-Associated Memory Impairment
(Alzheimer’s is main cause)
What are the 6 requirements for an AZD diagnosis?
A - Multiple cog deficits (1. memory impairment, 2. other cog impairments)
B - Deficits impair social/occupational life
C - Course shows gradual onset & decline
D - Deficits not due to: 1. other drug use, 2. substance-induced conditions
E - Do not occur exclusively during delirium
F - Not due to another psychiatric disorder
(Autopsy needed of +ive diagnosis)
What two diseases have different underlying causes but their outcome is similar?
Alzheimer’s disease & vascular dementia
What are the 4 requirements for a Vascular dementia diagnosis?
A - Multiple cog deficits (1. memory impairment, 2. other cog impairments)
B - Deficits impair social/occupational life
C - Focal neurological signs & symptoms or lab evidence indicating cerebrovascular disease eitology related to the deficits
D - Not due to delirium
When was AZD first described & how was it defined?
First described in 1906 by Alois Alzheimer
Progressive deterioration of cognitive function without antecedent cause, such as stroke
What are the 2 types of onset that can happen in AZD & what are they called?
Familial = early onset
Sporadic = late onset
Why is it important to understand AZD more?
Growing problem w an ageing pop –> more than 2% of population are over 65
It costs £20bn/yr in the UK
What is the prevalence of AD?
11% in 65 year old –> but rising to 50% of those over 85
What is the life expectancy of AD?
5-8 years from diagnosis
How is it determined what stage of AD you are at?
An MMSE test must be taken
This is marked out of 30
(Ranked; early diagnosis, mild-moderate 20 or below & severe 5 or below)
What is the main diagnostic marker of AD?
beta-amyloid plaques
What are beta-amyloid plaques?
- Large neurotoxic aggregates of insoluble protein (42 amino acid peptide termed “beta amyloid”
- Initially only possible to detect via post-mortem diagnosis
Where are beta-amyloid plaques found?
Outside the cell:
They are extracellular deposits that form in neural tissue –> causing gliosis
What are the two neuropathological elements found in AD?
The two markers seen in the brain
- Beta-amyloid plaques
- Neurofibrillary tangles
What are neurofibrillary tangles?
Disorganised bundles of filaments in the neuronal cytoplasm
How are neurofibrillary tangles formed?
Formed by hyperphosphorylated tau proteins, causing aggregation & precipitation of the cytoskeleton
How was AD initially certainly diagnosed?
A certain diagnosis could only be done via post-mortem histochemistry –> needed to identify beta-amyloid plaques & NFTs
How can we now diagnose AD?
Imaging techniques such as PET & fMRI enable us to see beta-amyloid plaques & NFTs in vivo
What happens to the brain pathology in early AD?
Degeneration of the cells in the hippocampus (links to memory loss)
What happens to the brain pathology in mild to moderate AD?
Atrophy of the cerebral cortex, enlarged ventricles
- Decline in reading judgement & language, emotional outbursts
- Forget how to do simple tasks (e.g. brushing teeth)
- Cannot think clearly
Why do patients with mild to moderate AD begin to experience emotional outbursts?
The thinning of the gyrus occurs here - emotional effects begin when the amygdala is affected
The amygdala controls emotions
What is the brain pathology like in advanced to final AD?
- Death of more nerve cells
- Agitation, wandering
- Inability to recognise faces & communicate
What are the transmitter systems that are involved in AD pathogenesis?
- Loss of specific NT pathways to cortex & hippocampus (*later flashcard details what these are)
- Reduction in glutamate levels (precedes Abeta plaques)
- Loss of GABAergic cortical interneurons
What are the specific NT pathways from cortex & hippocampus that are lost during AD? *
- Cholinergic ACh (correlated w dementia)
- Noradrenaline (NA)
- Serotonin (5-HT)
What is one of the first NTs we see loss of in AD?
ACH (forebrain ACh)
How does decreased forebrain ACh in AD occur?
Reduced ChAT (responsible for the synthesis of ACh) = red ACH synthesis
- Selective loss of nicotinic receptor subtypes in hippocampus & cortex (nAChRa7)
What is the main symptomatic treatment used with decreased ACh levels in AD?
Blocking ACh degradation by inhibiting acetylcholine esterase (AChE) = major symptomatic treatment
How does blocking ACh degradation by inhibiting (AChE) help symptoms?
- Inc ACh at synapses (different drugs not he market)
- May improve, maintain or slow the decline of cognitive, behavioural & functional performance in patients w mild-moderate AD
Needs early intervention to work
How do AChE blockers impact the patient?
Shows an improvement in function, behaviour & cognition
Treatment delays nursing home placement (20 weeks)
What are some example of AChE blockers used to treat AD & how effective are they?
- Donepezil = 38 weeks
- Rivastigmine = 38-42 weeks
- Galantamine = 52 weeks (24-30% better)
(Weeks show how long they significantly improve over placebo)
Essentially these do work but not very well
What are major events of neurotoxicity in AD?
Major events are:
- Loss of Ca2+ homeostasis
- Excitotoxicity
How does neurotoxicity in AD occur?
A multi-stage process involving multiple cell types (astrocytes, microglia & neutrons)
Major pathogenic theory is the “amyloid cascade hypothesis”
What are the 5 stages of the “amyloid cascade hypothesis”?
1 - Mis-metabolism of Amyloid Precursor Protein (APP)
2 - Oxidative stress
3 - Neurotoxic insult
4 - Excessive excitatory receptor activation (glutamate)
5 - Apoptosis (cell death)
What are the 2 major pathwaysof APP metabolism (stage1)?
- Non-amyloidogenic (good news)
- Amyloidogenic (bad news)
What is amyloid precursor protein (APP)?
A single transmembrane domain protein
- Expressed everywhere (req for neural growth & repair)
- Has a short half-life & rapidly metabolised
APP can be cleaved at 3 sites by sectretase enzymes:
1 - What are these called?
a- , b- and y-secretase
APP can be cleaved at 3 sites by sectretase enzymes:
2 - Where do each of the 3 enzymes act?
y-secretase found in both non-amyloidogenic & amyloidogenic pathways –> on the intracellular side
a-secretase found in non-amyloidogenic (good)
b-secretase found in amyloidogenic (BAD)
Why is amyloidogenic processing of APP bad?
In amyloidogenic processing, APP is cleaved by b-secretase
b-secretase cuts slightly higher up protein than a-secretase
From this we get the Ab aggregates (the 42 ones are most aggressive)
Which of these two is neurotoxic & what is the other?
Secreted form of APPb & AB peptide
Secreted form of APPb = Neuroprotective
AB peptide = neurotoxic
What does Secreted form of APPb do? (7points)
- Regulates proteases
- Involved in cell adhesion
- Promotes neuronal survival
- Protects against neurotoxic or ischaemic insult
- Modulates glutamate responses
- Regulates intracellular Ca2+
- Regulated cytokine release = anti-inflammatory
What does AB peptide do? (4 points)
- Renders neurons vulnerable to excitotoxicity
- Disrupts neuronal Ca2+ homeostasis
- Aggregation of b-amyloid increases toxicity
- Promotes cytokine release = inflammatory
How does dominantly inherited AD start the amyloid cascade hypothesis?
1 - Missense mutations in the APP or PS1 or PS2 genes
2 - Increased Ab42 production throughout life
3 - Rest of amyloid cascade hypothesis
How does non-dominantly inherited AD start the amyloid cascade hypothesis?
1 - Failure of Ab clearance mechanisms (e.g. Inheritance of ApoE4, faulty Ab degradation, etc)
2 - Gradually rising Ab42 levels in brain
3 - Rest of amyloid cascade hypothesis
What is the rest of the amyloid cascade hypothesis?
3 - Accumulations & oligomerization of Ab42 in limbic & association cortices
4 - Subtle effects of Ab oligomers on synaptic efficacy
5 - Gradual deposition of Ab42 oligomers as diffuse plaques
6 - Microglial & astrocytic activation & attendant inflammatory responses
7 - Altered neuronal ionic homeostasis; oxidative injury
8 - Alerted kinase/phosphatase activities lead to tangles
9 - Widespread neuronal/synaptic dysfunction & selective neuronal loss w attendant NT deficits
= Dementia
What % of AD is familial (inherited)?
Only 5-10% –> usually early onset
Most cases not directly genetic/familial!
What are the 3 important genetic loci involved in familial AD?
1 = APP –> chromosome 21
2 = Presenilin 1 (PS1) –> chromosome 14
3 = Presenilin 2 (PS2) –> chromsome 1
What genes increase the risk of sporadic AD?
1 - Inc risk w E4 allele of apolipoprotein (ApoE4) –> Involved in ~25% of AD cases
2 - Inc risk w some immune-related genes (e.g. TREM2 - doubles risk)
What do the genetic loci that cause inherited & sporadic AD do?
Familial = all 3 genetic loci alter APP PROCESSING –> favouring Ab42 (more aggregative)
Sporadic = alter CLEARANCE of Ab42 aggregates
What are the genetic risk factors for AD?
Familial = APP mutations, presenilins 1&2 (inc Ab production)
Sporadic = ApoE4 & other genes (dec Ab clearance)
What are the biochemical factors of AD?
- Inflammation
- Free radicals
- Nerve growth factor
What are the 3 risk factors for AD?
- Genetic factors
- Biochemical factors
- Other risk factors
What are the other risk factors for AD?
- Age
- Gender - 2x more freq in women
- Head size - larger head = more risk
- Educational level - more time in education = lower risk
- Stress
What is the overall neuropathology of AD?
- b-amyloid plaques
- Neurofibrillary tangles
- Neuronal loss
- Synaptic loss
What is the neurochemical pathology of AD?
- ACh deficit
- NA deficit
- 5-HT deficit
What are the 3 current therapeutic strategies for treating AD?
1 - Boost cholinergic transmission
2 - Alter glutamatergic function
3 - Anti-amyloid immunisation
What are the 2 methods of boosting cholinergic transmission treat AD?
AChE inhibitors –> several drugs approved (donazepil, galantamine, tacrine & rivastigmine)
Muscarinic agonists (arecoline, pilocarpine)
How good are AChE inhibitors when used to treat AD? (Boost cholinergic transmission)
- Slows progress & boost cognition
- Need to be administered early on
- Produces modest, temporary improvements in 2/3 of patients (12-18 moths)
How good are muscarinic agonists when used to treat AD? (Boost cholinergic transmission)
Only tested in animal models –> some efficacy but side effects unknown
What are the 2 methods used to alter glutamatergic function to treat AD?
- Nootropic agents (e.g. paracetamol) –> enhance cog function, but mechanism is controversial (bc boosts glutamatergic function)
- NMDA antagonists (e.g. memantine)
How was anti-amyloid immunisation used to treat AD?
Monoclonal antibody against Ab (approved in 2021) –> targets amyloid plaques
Highly effective at reducing amyloid load in animal models –> some +ive results in clinical trials in humans
Why was anti-amyloid immunisation discontinued in 2024 as a treatment for AD?
Other mAbs targeting different stages of amyloid deposition have been developed
This is promising - effect sizes are moderate –> does this call into questions amyloid hypothesis?
What are the 5 future therapeutic strategies being developed?
- b & y-secretase inhibitors/a-secretase stimulators
- Anti amyloid immunisation
- Anti-inflammatory drugs
- Tau kinase inhibitors
- Tau aggregation inhibitors (immunisation)
Please refer to slide 6.2 as each of these drugs relate to a stage in the amyloid cascade hypothesis
Review the summary slide
Well done x
