neurodegenerative disorders

What is the definition of dementia?

A chronic, progressive mental disorder that adversely affects higher cortical functions including memory, thinking, and comprehension,

What are the four main types of dementia?

• Alzheimer's disease

• Vascular dementia

• Dementia with Lewy Bodies

• Frontotemporal dementia

Name the two pathological hallmarks of Alzheimer's disease

• Amyloid plaques (extracellular deposits of Aβ peptide)

• Neurofibrillary tangles (intracellular hyperphosphorylated Tau).

What cognitive assessment tools are used to diagnose dementia?

MMSE (Mini-Mental State Examination), Mini-Cog

What does FDG-PET measure and what does it show in AD?

FDG-PET measures glucose metabolism. In AD, it shows reduced metabolism compared to healthy controls, reflecting reduced neuronal activity/function.

What imaging modalities are used to detect amyloid plaques and Tau tangles in vivo?

• Amyloid-PET detects plaques.

• Tau-PET detects neurofibrillary tangles.

How long before clinical diagnosis does AD pathology begin to develop?

Often 10–20+ years before diagnosis. Significant pathology is present before clinical symptoms emerge.

Name three modifiable risk factors for dementia in midlife

hearing loss, depression, physical inactivity

What type of genetic mutation causes familial AD (fAD)?

Rare, inherited, autosomal dominant mutations in APP, PSEN1, or PSEN2

What is APOE4 and what is its significance in AD?

APOE4 is the most well-known genetic risk allele for AD which moderately increases risk. Having two copies significantly increases risk further.

What proteins do PSEN1 and PSEN2 encode, and why are they relevant to AD?

They encode presenilin 1 and 2, which are catalytic subunits of the γ-secretase complex. Mutations in these genes shift APP processing towards the amyloidogenic pathway, increasing Aβ production.

Describe the physiological (non-amyloidogenic) processing of APP

• α-secretase cleaves APP within the Aβ region → APPsα + α-CTF.

• γ-secretase then cleaves α-CTF → p3 (non-toxic) + AICD

• No Aβ is generated.

Describe the pathological (amyloidogenic) processing of APP.

• β-secretase (BACE-1) cleaves APP → APPsβ + β-CTF

• γ-secretase cleaves β-CTF → Aβ peptide + AICD

• Aβ accumulates and forms plaques.

Why does α-secretase cleavage prevent Aβ formation?

Because α-secretase cleaves APP within the Aβ sequence itself, making it impossible for the intact Aβ peptide to be produced

What is BACE-1?

β-site APP Cleaving Enzyme 1 — the β-secretase responsible for the first cleavage step in the amyloidogenic pathway. A major drug target for AD

Summarise the Amyloid Cascade Hypothesis.

Increased Aβ production and/or decreased degradation → Aβ accumulates → oligomers and plaques form → synaptic toxicity → Tau hyperphosphorylation → NFTs → neuroinflammation (glial activation) → neuronal loss → cognitive decline

Name the four drug strategies targeting APP processing

• BACE-1 inhibitors

• γ-secretase inhibitors

• γ-secretase modulators

• α-secretase activators

What is the cholinergic hypothesis of AD?

In AD, there is a selective loss of cholinergic neurons and reduced ACh signalling in the brain. Since ACh is critical for learning and memory, boosting cholinergic transmission should improve cognitive symptoms.

How is acetylcholine (ACh) synthesised?

Acetyl CoA + choline → ACh, catalysed by choline acetyltransferase (ChAT)

How is ACh broken down, and what enzyme is targeted by AChE inhibitors?

ACh is hydrolysed by acetylcholinesterase (AChE) → choline + acetate. AChE inhibitors block this enzyme, increasing synaptic ACh.

Why does the effectiveness of AChE inhibitors reduce as AD progresses?

They work by boosting signalling in surviving cholinergic neurons. As neuronal death increases with disease progression, fewer neurons remain, so there is less cholinergic activity to enhance.

Are AChE inhibitors disease-modifying?

No. They improve symptoms by boosting cholinergic signalling but do not slow the underlying neurodegenerative process.

What are the main side effects of AChE inhibitors?

GI effects at high doses: nausea, vomiting, diarrhoea (due to peripheral cholinergic stimulation)

Name the two main types of ACh receptor

1. Nicotinic receptors (nAChRs)

• Ionotropic (ligand-gated ion channels)

• Mediate rapid excitatory responses.

2. Muscarinic receptors (mAChRs)

• Metabotropic (G-protein-coupled receptors)

• Mediate slower modulatory parasympathetic effects.

Why is glutamate relevant to AD?

Glutamate is the principal excitatory neurotransmitter, essential for learning, memory, and synaptic plasticity. In AD, excess glutamate release leads to excitotoxicity and neuronal death.

What is excitotoxicity?

Overstimulation of excitatory (particularly NMDA) receptors by excessive glutamate → excessive Ca²⁺ influx → activation of destructive enzymes → neuronal death.

What is the mechanism of action of memantine?

Memantine is a non-competitive antagonist at NMDA receptors. It blocks excessive glutamatergic activity and excitotoxicity while allowing normal synaptic transmission.

At what stage of AD is memantine most effective, and what are its limitations?

• Most effective at late stages

• Has potential drug interactions with antipsychotics, warfarin, analgesics, and muscle relaxants.

Name three glutamate receptor types at the postsynaptic membrane.

• NMDA receptors

• AMPA receptors (AMPAR)

• Kainate receptors

How is glutamate cleared from the synapse?

astrocytic GLAST and GLT1. In astrocytes, glutamate is converted to glutamine by glutamine synthetase

What is the difference between active and passive immunotherapy for AD?

• Active immunotherapy (vaccines) stimulates the patient's own immune system to generate antibodies against Aβ.

• Passive immunotherapy involves administering pre-formed monoclonal antibodies directly.

why has drug development for AD been so challenging

• complex multifactorial disease

• blood-brain barrier limits biologic delivery

• late diagnosis means irreversible damage already exists

What are the two current symptom-management drug classes approved for AD?

• Acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine)

• NMDA receptor antagonist (memantine)