Alzheimers Disease

What are the main two types of onset for Alzheimer's Disease?

• Early onset (familial), which has a genetic component.

• Late onset (sporadic), which is more common and does not have a clear genetic link.

What are the key neuropathological features of Alzheimer's Disease?

• Extracellular amyloid plaques: Large aggregates of insoluble beta-amyloid protein that accumulate in neural tissue causing gliosis (scars). Preceded by amyloid-beta plaques

• Neurofibrillary tangles: Abnormal collections of filaments in the cytoplasm, caused by hyperphosphorylated tau proteins causing aggregation and precipitation of the cytoskeleton

• Can be visualised in PET imaging or in autopsy

What neurotransmitters are associated with Alzheimer's Disease?

Acetylcholine is the neurotransmitter most linked to the cognitive deficits experienced in Alzheimer's disease. Forebrain SCh neurones are lost as well as ChAT activity being reduced (less synthesis)

There is a general loss of specific neurotransmitter pathways to the cortex and the hippocampus (noradrenaline and 5-HT)

What is the primary mechanism of action of Acetylcholinesterase inhibitors in treating Alzheimer's Disease?

• These inhibitors work to increase acetylcholine levels at synapses, enhancing communication between nerve cells.

• only useful with early intervention, and only slows progression slightly

What are some risk factors for developing Alzheimer's Disease?

• Age: Increases risk as people get older

• Gender: Women are generally more at risk

• Head size: Smaller brain sizes may correlate with higher risk

• Educational level: Lower levels may be associated with increased risk

• Genetic factors: Particularly the APOE E4 allele.

What is the amyloid cascade hypothesis?

• This theory explains how increased Aβ42 production (due to mis-metabolism of APP) and accumulation lead to neuronal dysfunction and loss in Alzheimer's Disease.

How does the amyloid cascade hypothesis lead to neurotoxicity?

• Amyloidogenic processing of the Amyloid Precursor Protein results in the production of A-beta peptides which form aggregates

• A-beta peptides disrupt neuronal Ca2+ homeostasis and promote the release of inflammatory cytokines.

• This causes oxidative stress and excessive excitatory glutamate receptor activation, eventually leading to cell death.

What types of treatments are currently available for AD?

• Cholinergic transmission boosters (AChE inhibitors) to enhance neurotransmitter action.

• Glutamatergic function modifiers (e.g., NMDA antagonists). enhance cognitive function

• Anti-amyloid immunization therapies for reducing amyloid load (moderate side effects), not currently available

Describe the pathology of Alzheimer’s

1. Degeneration of the hippocampal neurons

2. Atrophy of the cerebral cortex, enlarged ventricles

3. Even more death of neuronal cells