Alzheimer’s disease Flashcards
What is Alzheimer’s disease?
Progressive deterioration of cognitive function without antecedent cause, such as a stroke.
Characterised by multiple cognitive deficits, including memory dysfunction, especially the ability to learn new things, and deficits in at least one additional cognitive domain such as language, behaviour, visuospatial, or executive function.
Cognitive disturbances have to be sufficiently severe to cause impairment of occupational or social functioning and must represent a decline from a previous level of functioning, unable to be explained by delirium or another major psychiatric disorder.
Neuropathology
Extracellular amyloid plaques, formed from the long 42-aa variant of β-amyloid (Aβ 42) → cause gliosis.
Intraneuronal neurofibrillary tangles → disorganised filament bundles formed by hyperphosphorylated tau proteins, causing aggregation of the cytoskeleton → neurotransmission disruption and brain atrophy.
Imaging
Amyloid plaques and neurofibrillary tangles can be viewed using immunohistochemistry.
PET and fMRI imaging techniques have enabled visualisation of NFTs and amyloid plaques in vivo.
PET using Fludeoxyglucose (FDG) shows decreased cerebral glucose metabolism in AD.
Brain atrophy
Early AD - degeneration of cells in the hippocampus → forgetfulness
Mild-moderate AD - atrophy of the cerebral cortex → decline in judgement and language, emotional outbursts, forgetting how to perform simple daily tasks, inability to think clearly.
Advanced AD - further neurodegeneration → agitation and wandering, inability to recognise faces and communicate
Vesicles are enlarged
Neurotransmitter loss in the cortex and hippocampus
ACh → loss of: neurons in the nucleus of meynert projecting to the forebrain, choline acetyltransferase, α-7 nicotinic receptors → memory impairment
Noradrenaline + 5-HT → mood effects
Glutamate loss precedes amyloid plaque formation → early pathogenesis → cognitive decline
GABAergic interneurons → excitotoxicity
AChEIs
Donepezil, Rivastigmine, Galantamine, Tacrine
Increase synaptic ACh - slows disease course and delays nursing home placement by 20 weeks.
Early intervention needed
Amyloid Precursor Protein (APP) metabolism
Ubiquitous 1 TM domain protein, required for neuronal growth and repair.
Can be cleaved at 3 sited by α-, β- and 𝛾- secretase.
Non-amyloidogenic metabolism: α-secretase + 𝛾-secretase → large free peptide and a smaller cell-associated peptide which has a neuroprotective role and can be further degraded.
Amyloidogenic metabolism: β-secretase + 𝛾-secretase → secreted APPβ and intact β-amyloid is formed.
sAPPβ and β-amyloid
sAPPβ is neuroprotective, having the following roles: protease regulation, cell adhesion, neuronal survival, protecting against neurotoxic or ischemic insult, glutamate modulation, calcium homeostasis, regulating cytokine release (anti-inflammatory).
β-amyloid is neurotoxic: renders neurons vulnerable to excitotoxicity, disrupts calcium homeostasis, forms toxic aggregates, promotes cytokine release
Genetics - Familial AD
Familial AD is an autosomal dominant disease making up 5-10% of cases.
3 gene loci have been identified.
APP mutations increase likelihood of amyloidogenic metabolism.
Presenilin 1 (PS1) and PS2 mutations - PS is associated with 𝛾-secretase → mutations increase likelihood of generating the longer 42-aa ꞵ-amyloid.
All of these genes alter APP processing, favouring the production of of the long amyloid Aꞵ42, which aggregates more readily than the normal short Aꞵ40 form.
Genetics - Late-onset sporadic AD
E4 allele of apolipoprotein E (APOE4), involved in cholesterol homeostasis in neurons, is involved in 25% of cases.
TREM2 is involved in immune function - mutations double the risk of developing AD.
These alter the clearance of Aꞵ42.
Additional treatments
AChEIs are the first choice treatment, but other drugs can also be used.
Muscarinic agonists - pilocarpine, arecoline - boost excitatory activity - only tested in animal models
Piracetam is a nootropic agent that enhances cognitive function - controversial as it boosts glutamatergic function, and excitotoxicity is involved in AD
Memantine - NMDA antagonist - used to avoid excitotoxicity and promote neuronal survival
Targeting protein aggregates
Aducanumab - monoclonal antibody against Aβ → reduces amyloid load BUT has unpredictable side effects, can cause fatal neuroinflammation and only reduces AD symptoms by 30% → discontinued.
Donanemab and Lecanemab - newer Aβ antibodies.
β- and 𝛾-secretase inhibitors and α-secretase stimulators - used to promote the non-amyloidogenic metabolism - not been very effective and can cause renal toxicity.
Tau kinase inhibitors and tau aggregation inhibitors - prevent neurofibrillary tangles.
