Alzheimer’s Disease

Epidemiology

• Common cause of dementia (50-70% of cases).  Risk increases with age.  Females=males.

Aetiology

• Autosomal dominant in 5-10% of cases (early, pre-senile onset).
• Down’s syndrome patients are particularly at risk of early onset type (30-40 years old).
• Amyloid Precursor Protein gene mutations may play a role, as may presenilin 1 & 2, gamma secretase genes and Apolipoprotein E (ApoE- 3 alleles associated with dementia: e4 most causative; e2 preventative; e3 normal).
• Smoking, HRT and NSAIDs may be protective.

Pathophysiology

• Loss of cortical neurons with the presence of:
  • Intracellular neurofibrilliary tangles (NFTs)- phosphorylated Tau proteins
  • Extracellular senile plaques containing amyloid β protein
    • A fragment of the product of the amyloid precursor protein (APP) gene on Ch 21.
• Multiple neurotransmitter abnormalities with profound cholinergic loss.

Diagnosis

• Progressive deterioration in memory (usually early)
  • Insidious development over >10 years with prominent impairment of episodic memory
  • Disturbance of recent memory function before and more affected than distant memory (Ribot’s law)
• Deficits in 2 or more areas of cognition
  • Loss of ability to carry out daily tasks
  • Change in language (lexical ataxia)
  • Impairment of insight, judgement or planning
  • Orientation problems
  • Neuropsychiatric problems e.g. hallucination, delusion, mood change
• Behaviour and Psychological Symptoms of Dementia (BPSD)
  • Prominent throughout AD and include depression; delusions; hallucinations; aggression; apathy; agitation etc.  Can lead to carer stress and institutionalisation.
• Most often >65
• Absence of systemic disorders that could account for sx
• No disturbance of consciousness
• Full Cognitive testing (e.g. Addenbrookes) should be performed

End-stage symptoms

• Incontinence, motor disturbance, extra-pyramidal signs, stereotypic behaviour and primitive reflexes.

Staging

• Very mild (Mild cognitive impairment- MCI)
  • MMSE 27-30
  • Isolated deficits in memory but functions well
  • Around 15% will develop AD proper
• Mild AD
  • MMSE 20-26
  • Memory impairment is the most prominent deficit
  • Language well preserved other than isolated word-fingding problems
  • Deficits in reasoning and visuospatial processing
• Moderate AD
  • MMSE 10-19
  • Dependent on others for higher level daily activities- requiring prompts and reminders
  • Failure of recognition
  • Prominent disturbance of language
  • Neuropsychiatric symptoms
• Severe AD
  • MMSE <10
  • 24 hour care required
  • Motor apraxia also common
  • Seizures possible
  • Speech impoverished
  • Fragmentory cognition
  • Neuropsychiatric sx

Management

• Cognitive Enhancers (Acetylcholinesterase inhibitors)
  • Donepezil (aricept- OD- reversible competitive inhibitor)
  • Rivastigmine (Exelon- BD/patch- reversible competitive inhibitor/nicotinic receptor agonist)- also of interest for dementia in PD
  • Galantamine (Reminyl- OD- reversible non-competitive inhibitor)
• for “symptomatic treatment” of mild-moderate AD (also used in Lewy Body dementia sensitive to neuroleptic medication).  Should be used with caution, particularly in those with:
  • bradycardia/conductivity defects/sick sinus syndrome
  • GI ulcers
  • Epilepsy/ Parkinson’s disease
  • Severe COPD or any asthma
  • Urinary outflow obstruction
• due to their cholinergic side-effects (although these are usually mild and transient).
• Other side effects include
  • N&V&D
  • Headache, dizziness
  • Fatigue
  • Muscle cramps
  • Sweating
  • Bradycardia
  • Weight loss
  • Disturbed sleep
• Memantine
  • Non-competitive NMDA receptor antagonist- may protect neurons from glutamate excitotoxicity.  Only for moderate-severe AD.
  • Side effects include vertigo, excitation/agitation and insomnia
• For Behavioural and Psychological symptoms of dementia (BPSDs)
  • Use any psychotropic medications with great caution- avoid if possible.  Start low/slow.  Avoid particularly the typical antipsychotics- use newer atypicals.  Use short acting BZDs if required, but non-pharmacological therapies should be tried first where possible.
  • Search for a physical/organic cause in the first instance (i.e. most commonly delirium)

Advertisement