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Alzheimer's Disease
Uni of Notts, Neurobiology of Disease, year 2, topic 11
| Term | Definition |
|---|---|
| Dementia | progressive irreversible syndrome involving decline in memory, reasoning, behaviour, communication, or daily functioning & changes in personality |
| Diagnostic criteria for dementia | Deficits in ≥2 cognitive domains of memory, language, behaviour, visuospatial or executive function, causing severe impairment to functioning not explained by another condition. Must be a decline from previous functioning |
| Earliest symptom of Alzheimer’s disease | Impaired formation of new memories due to early hippocampal dysfunction |
| Amyloid plaques | Extracellular aggregates of misfolded Aβ peptides, especially Aβ42, associated with gliosis and neurotoxicity |
| Gliosis | Non-specific reactive pathway where glia (especially astrocytes) proliferate or hypertrophy in response to damage to seal off damaged areas. "Glial scar" |
| Neurofibrillary (tau) tangles | Intracellular aggregates of hyperphosphorylated tau that disrupt axonal transport & neuronal function |
| Early Alzheimer’s disease | Synaptic loss & hippocampal degeneration (losing nAChRα7) causing memory impairment |
| Structural changes occuring in moderate Alzheimer’s disease | Cortical atrophy & ventricular enlargement with worsening language, judgement, & behaviour |
| Enlarged ventricles in Alzheimer’s disease | Loss of brain tissue causes compensatory expansion of CSF-filled ventricular spaces |
| Cholinergic pathways in Alzheimer’s disease | Loss of cholinergic neurons in the hippocampus/cortex contributes to memory & cognitive decline |
| Role of serotonin & noradrenaline loss in Alzheimer’s disease | Reduced serotonergic signalling contributes to emotional & behavioural symptoms & noradrenaline means less arousal & concentration |
| Glutamate links to Alzheimer’s neurotoxicity | Excess glutamatergic signalling causes excitotoxic Ca²⁺ influx & neuronal damage |
| Loss of GABAergic interneurons in Alzheimer’s disease | Reduced inhibition increases neuronal hyperexcitability & excitotoxic damage worsening AD |
| Therapeutic acetylcholinesterase inhibitors | Increase ACh concentration but only work in early AD since they require surviving cholinergic neurons capable of producing acetylcholine |
| Galantamine in Alzheimer’s disease | Inhibits acetylcholinesterase, prolonging acetylcholine signalling & slows cognitive decline. But hard to tell if dementia is AD so may not work |
| PET & fMRI limitations in early dementia diagnosis | Early pathological changes may occur before detectable metabolic or structural abnormalities appear |
| Amyloid cascade hypothesis | Aβ accumulation triggers inflammation, oxidative stress, tau pathology, excitotoxicity, & neuronal death |
| (Amyloid Precursor Protein) APP processing determining amyloid production | α-secretase cleavage is non-amyloidogenic, whereas β- & γ-secretase cleavage produces Aβ peptides |
| Why soluble APPα is considered neuroprotective | Supports neuronal survival, adhesion, synaptic plasticity, & protection from stress/ischaemia |
| ApoE allele most associated with sporadic Alzheimer’s disease | Randomly occuring rather than familial AD. ApoE4 strongly increases AD risk by impairing Aβ clearance & promoting aggregation |
| Microglia & astrocyte roles in AD | Are chronically activated, driving neuroinflammation & oxidative injury (excess gliosis) |
| Aβ42 aggregation compared to shorter Aβ peptides | Aggregates much more readily due to greater hydrophobicity promoting oligomerisation & plaque formation |
| Major therapeutic strategies for Alzheimer’s disease | Enhancing cholinergic signalling, modulating glutamate signalling, & targeting amyloid pathology |
| Alzheimer's disease doagnostics | Multiple cognitive deficits, purely cognitive (no physical cause), gradual onset & decline, deficits not related to other diseases or substances |
| Vascular dementia | Cognitive decline stemming from vascular neurological ischeamia or haemorrhage events. Diagnosed with a temporal link to a vascular event using imaging or history |
| Prevalence & burden of Alzheimer's disease | Rarely genetic, occurs sporadically in 11% over 65 & 50% over 85. 2x more likely in women. Costs £20 per year & avergage prognosis is 5-8 years, maximum 9 |
| Genetic risk factors | Inheriting Presenilin (PSN1 & 2) mutations causes severe APP miscleavage & some immune genes like TREM 1 prevent plaque targeting |
| Biochemical basis of Alzheimer's disease | Age-induced inflammation, increasing free radicals, & decrease in nerve growth factors |
Created by:
Denny12
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