Alzheimer's Disease
Summary
Alzheimer's Disease (AD) is the most common cause of dementia, accounting for 60-70% of all cases. It is a progressive neurodegenerative disorder characterised by insidious onset and gradual decline in memory (particularly recent/episodic memory), followed by deterioration in other cognitive domains including language, visuospatial function, and executive function. Pathologically, it is defined by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (Tau protein) in the brain. The typical patient is over 65 years old with gradual memory decline noted by family members. Diagnosis is clinical, supported by neuroimaging (MRI showing hippocampal atrophy) and cognitive testing (MMSE, ACE-III). Management involves acetylcholinesterase inhibitors (Donepezil, Rivastigmine, Galantamine) for mild-to-moderate disease, Memantine for moderate-to-severe disease, and non-pharmacological interventions. The condition is progressive and ultimately fatal, with median survival of 8-10 years from diagnosis. [1,2,3]
Clinical Pearls
"Memory First": Alzheimer's typically starts with MEMORY loss (especially recent memory). If personality/behaviour changes come first, consider Frontotemporal Dementia.
"Hippocampal Atrophy": MRI shows bilateral medial temporal lobe atrophy (Hippocampus). Correlates with memory impairment.
"Aβ Plaques and Tau Tangles": The pathological hallmarks. Amyloid Cascade Hypothesis drives research.
Cholinesterase Inhibitors: Symptomatic treatment only. Donepezil, Rivastigmine, Galantamine. Do NOT cure or slow disease.
Demographics
| Factor | Notes |
|---|---|
| Prevalence | ~7-8% of over 65s. 40% of over 85s. |
| Age | Risk doubles every 5 years after age 65. |
| Sex | Women > Men (Partly longevity). |
| Inheritance | Sporadic (95%). Familial/Genetic (5%). |
Risk Factors
| Risk Factor | Notes |
|---|---|
| Age | Strongest risk factor. |
| Family History | First-degree relative = 2-3x risk. |
| APOE ε4 Allele | Major genetic risk factor. Heterozygotes (1 allele) = 3x risk. Homozygotes (2 alleles) = 12x risk. |
| Female Sex | Higher prevalence. |
| Down Syndrome (Trisomy 21) | APP gene on Chromosome 21. Near-universal AD by age 40. |
| Cardiovascular Risk Factors | Hypertension, Diabetes, Obesity, Smoking, Hypercholesterolaemia. |
| Low Educational Attainment | Less "Cognitive Reserve". |
| Head Trauma | History of TBI increases risk. |
Protective Factors
- Higher education ("Cognitive Reserve").
- Physical activity.
- Mediterranean diet.
- Social engagement.
Hallmark Pathological Features
| Feature | Description |
|---|---|
| Amyloid-Beta (Aβ) Plaques | Extracellular deposits of Aβ peptide (Cleaved from Amyloid Precursor Protein – APP). Neuritic plaques with surrounding dystrophic neurites. |
| Neurofibrillary Tangles (NFTs) | Intracellular aggregates of hyperphosphorylated Tau protein. Spread follows disease progression (Braak staging). |
| Neuronal Loss | Progressive neuronal death, especially in Hippocampus (Memory) and Temporal Cortex. |
| Cholinergic Deficit | Loss of cholinergic neurons in Nucleus Basalis of Meynert → Acetylcholine deficiency. Basis for cholinesterase inhibitor therapy. |
Amyloid Cascade Hypothesis
- Aβ Accumulation: Abnormal processing of APP → Accumulation of Aβ42 (Oligomers are toxic).
- Synaptic Dysfunction: Aβ impairs synaptic function.
- Tau Hyperphosphorylation: Triggers formation of NFTs.
- Neuroinflammation: Microglial activation.
- Neuronal Death: Progressive atrophy and cognitive decline.
Genetic Causes (Familial AD – Young Onset)
| Gene | Chromosome | Notes |
|---|---|---|
| APP (Amyloid Precursor Protein) | 21 | Early-onset familial AD. Also explains AD in Down Syndrome. |
| PSEN1 (Presenilin 1) | 14 | Most common cause of early-onset familial AD. |
| PSEN2 (Presenilin 2) | 1 | Rare. Early-onset. |
| APOE ε4 | 19 | Risk gene (Not deterministic). |
| Condition | Key Features |
|---|---|
| Alzheimer's Disease | Gradual onset, Memory-predominant, Hippocampal atrophy, Elderly. |
| Vascular Dementia | Stepwise decline, Vascular risk factors, Multiple strokes on imaging. |
| Frontotemporal Dementia (FTD) | Behaviour/Personality change FIRST, Language variants, Younger onset (50-60s). |
| Lewy Body Dementia (DLB) | Visual hallucinations, Parkinsonism, REM sleep behaviour disorder, Fluctuating cognition. |
| Parkinson's Disease Dementia | Parkinsonism FIRST (>1 year), then dementia. |
| Mild Cognitive Impairment (MCI) | Cognitive complaint beyond normal ageing, but functional independence preserved. May convert to AD. |
| Depression (Pseudodementia) | Treatable. Low mood, Apathy. Poor effort on testing. Responds to antidepressants. |
| Delirium | Acute onset, Fluctuating, Reversible cause (Infection, Drugs, Metabolic). |
| Normal Pressure Hydrocephalus | Triad: Dementia + Gait disturbance + Urinary incontinence. Reversible with shunting. |
| CJD (Creutzfeldt-Jakob Disease) | RAPID dementia (weeks-months), Myoclonus, EEG changes. |
Stages of Cognitive Decline
| Stage | Features |
|---|---|
| Preclinical | Pathological changes present but NO symptoms. |
| Mild Cognitive Impairment (MCI) | Subjective memory complaints, Objective impairment on testing, Functional independence preserved. ~10-15% per year convert to AD. |
| Mild AD | Recent memory loss, Word-finding difficulties, Getting lost in familiar places, Losing items. IADL impairment (Finances, Medication). |
| Moderate AD | Remote memory affected, Disorientation to time/place, BPSD (Behavioural and Psychological Symptoms of Dementia), Needs supervision for ADLs. |
| Severe AD | Profound memory loss (May not recognise family), Total ADL dependence, Incontinence, Minimal speech, Bedridden, Swallowing difficulties. |
Key Clinical Features
| Domain | Features |
|---|---|
| Memory | Recent (Episodic) memory affected first. Forgetting conversations, Repeating questions, Losing items. |
| Language | Word-finding difficulties (Anomia), Circumlocution, Late: Echolalia, Mutism. |
| Visuospatial | Getting lost, Difficulty driving, Trouble with complex figures (Clock drawing). |
| Executive Function | Poor planning, Judgement errors, Financial mismanagement. |
| BPSD | Apathy, Agitation, Depression, Anxiety, Psychosis (Delusions, Hallucinations), Wandering, Aggression. |
Cognitive Assessment
| Tool | Notes |
|---|---|
| MMSE (Mini-Mental State Examination) | 30-point screening tool. less than 24 suggests dementia (Adjust for education). |
| ACE-III (Addenbrooke's Cognitive Examination) | More sensitive. 100 points. Assesses 5 domains. less than 88 (Cut-off). |
| Montreal Cognitive Assessment (MoCA) | Sensitive for MCI. |
| Clock Drawing Test | Quick screen for visuospatial/executive function. |
Blood Tests (Exclude Reversible Causes)
| Test | Exclude |
|---|---|
| FBC | Anaemia. |
| U&E, LFTs | Metabolic encephalopathy. |
| TFTs | Hypothyroidism. |
| B12, Folate | Deficiency. |
| Calcium | Hypercalcaemia. |
| Glucose | Diabetes. |
| Syphilis Serology | Neurosyphilis (If risk factors). |
| HIV | HIV-associated dementia (If risk factors). |
Neuroimaging
| Modality | Findings in AD |
|---|---|
| MRI Brain | Bilateral Medial Temporal Lobe (Hippocampal) Atrophy. Generalised cortical atrophy. Normal for age vessels (Differentiates from Vascular Dementia). |
| CT Brain | May show atrophy. Less sensitive than MRI. Used if MRI contraindicated. |
| FDG-PET | Hypometabolism in Temporoparietal cortex. |
| Amyloid PET | Positive in AD. Research/Specialist use. |
CSF Biomarkers (Specialist – Not Routine)
| Biomarker | AD Pattern |
|---|---|
| Aβ42 | Decreased (In plaques). |
| Tau | Increased. |
| Phospho-Tau | Increased. |
Management Algorithm
SUSPECTED ALZHEIMER'S DISEASE
(Gradual memory decline, Elderly patient)
↓
INITIAL ASSESSMENT
- Collateral history from family/carer
- Cognitive assessment (ACE-III, MMSE)
- Blood tests (Exclude reversible causes)
- MRI Brain (Hippocampal atrophy)
↓
CONFIRM DIAGNOSIS (Memory Clinic)
- Specialist review
- Exclude other dementias
↓
PHARMACOLOGICAL MANAGEMENT
┌──────────────────────────────────────────────────────────┐
│ MILD-TO-MODERATE AD: │
│ ACETYLCHOLINESTERASE INHIBITORS (AChEIs) │
│ - **Donepezil** 5-10mg OD (Most commonly used) │
│ - **Rivastigmine** (Patch or Capsules) │
│ - **Galantamine** (Modified release) │
│ - Monitor response at 6 months │
│ │
│ MODERATE-TO-SEVERE AD: │
│ - Continue AChEI if tolerated PLUS │
│ - **Memantine** 20mg OD (NMDA receptor antagonist) │
│ OR Memantine monotherapy if AChEI not tolerated │
└──────────────────────────────────────────────────────────┘
↓
NON-PHARMACOLOGICAL MANAGEMENT
- Cognitive Stimulation Therapy (CST) groups
- Occupational Therapy (ADL adaptations, safety)
- Reminiscence therapy
- Music therapy
- Physical activity
- Carer support and education
↓
BPSD MANAGEMENT
- Identify and treat underlying cause (Pain, Infection, Constipation)
- Non-pharmacological first (Distraction, Environmental modification)
- Pharmacological: Avoid antipsychotics if possible (Stroke risk in dementia)
- If severe: Low-dose Risperidone (Short-term)
↓
ADVANCE CARE PLANNING
- Lasting Power of Attorney
- Advance Decisions to Refuse Treatment
- End-of-life care discussions
- DNAR if appropriate
Medication Details
| Drug | Mechanism | Notes |
|---|---|---|
| Donepezil | AChEI | Once daily. Best tolerated. |
| Rivastigmine | AChEI | Patch preferred (Less GI side effects). |
| Galantamine | AChEI + Nicotinic Modulator | Modified release. |
| Memantine | NMDA Receptor Antagonist | Moderate-Severe AD. Can combine with AChEI. |
Side Effects of AChEIs
- GI: Nausea, Vomiting, Diarrhoea.
- Bradycardia: Check ECG if cardiac history.
- Insomnia, Vivid dreams (Donepezil – Give in morning if issue).
| Complication | Notes |
|---|---|
| Falls and Fractures | Gait instability, Spatial disorientation. |
| Aspiration Pneumonia | Swallowing difficulties in late stage. |
| Pressure Ulcers | Immobility. |
| Malnutrition/Dehydration | Forgetting to eat/drink. |
| Carer Burnout | Significant burden on family carers. |
| Institutional Care | Nursing home placement often required. |
| Death | Usually from aspiration pneumonia, Infection, Falls. |
| Factor | Notes |
|---|---|
| Disease Course | Progressive. No cure. |
| Median Survival | 8-10 years from symptom onset. 4-5 years from diagnosis. |
| Rate of Decline | Variable. Faster in younger onset, APOE ε4 carriers. |
| Treatment Effect | AChEIs provide modest cognitive benefit (~6-12 month delay in decline). Do NOT halt progression. |
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Dementia: Assessment, Management, and Support | NICE NG97 (2018) | AChEIs for mild-moderate, Memantine for moderate-severe, CST. |
| World Alzheimer Report | Alzheimer's Disease International | Global prevalence and burden. |
Emerging Treatments
- Lecanemab / Donanemab: Anti-amyloid monoclonal antibodies. Show modest slowing of decline in early AD. FDA approved. Under NICE review.
- ARIA: Amyloid-Related Imaging Abnormalities (Brain oedema/microhaemorrhages) – Risk with anti-amyloid therapies.
What is Alzheimer's Disease?
Alzheimer's is the most common type of dementia. It is a brain disease where abnormal proteins build up in the brain, causing brain cells to die over time. This leads to problems with memory, thinking, and eventually daily activities.
What are the symptoms?
Early signs include forgetting recent conversations, repeating questions, misplacing items, and getting confused in familiar places. Over time, people may need help with dressing, eating, and eventually all daily care.
Is there a cure?
There is no cure yet. However, medications (like Donepezil) can help with symptoms for a while. Keeping active – physically, mentally, and socially – is important.
Is it hereditary?
Most cases are not directly inherited. Having a close relative with Alzheimer's slightly increases risk, but most people with a family history will NOT develop the condition.
What about driving?
Patients with dementia must notify the DVLA. An assessment will determine whether driving is still safe. Many will need to stop driving at some stage.
Primary Sources
- National Institute for Health and Care Excellence. Dementia: assessment, management and support for people living with dementia and their carers (NG97). 2018. nice.org.uk/guidance/ng97
- Jack CR Jr, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-562. PMID: 29653606.
- Scheltens P, et al. Alzheimer's disease. Lancet. 2021;397(10284):1577-1590. PMID: 33667416.
Common Exam Questions
- Pathological Hallmarks: "What are the two key pathological findings in Alzheimer's?"
- Answer: Amyloid-beta (Aβ) Plaques and Neurofibrillary Tangles (Tau).
- First-Line Treatment: "What is the first-line pharmacological treatment for mild-to-moderate Alzheimer's?"
- Answer: Acetylcholinesterase Inhibitors (Donepezil, Rivastigmine, Galantamine).
- MRI Finding: "What is the characteristic MRI finding?"
- Answer: Bilateral Hippocampal (Medial Temporal Lobe) Atrophy.
- Risk Gene: "What is the major genetic risk factor for sporadic Alzheimer's?"
- Answer: APOE ε4 allele.
Viva Points
- MMSE Limitations: Ceiling effect (Misses mild impairment). Floor effect (Severe dementia scores 0). ACE-III is more sensitive.
- Down Syndrome and AD: APP gene on Chromosome 21 → Trisomy 21 = Extra APP → AD develops by age 40 in almost all.
- Reversible Dementias: Always screen for B12, TFTs, Depression (Pseudodementia), Normal Pressure Hydrocephalus.
- Driving: Must notify DVLA. DVLA decides, not the doctor.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.