Overview
Alzheimer's Disease
1. Clinical Overview
Summary
Alzheimer's disease (AD) is the most common cause of dementia, accounting for 60-80% of cases. It is a progressive neurodegenerative disorder characterised by extracellular amyloid-beta plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The hallmark early symptom is impaired episodic memory (forgetting recent events), with later involvement of language, visuospatial function, and executive abilities. While there is no cure, cholinesterase inhibitors and memantine provide symptomatic benefit. Early diagnosis allows for advance care planning, legal arrangements, and access to support services. The disease profoundly impacts patients and carers, with significant health and social care burden.
Key Facts
- Definition: Progressive neurodegenerative dementia with amyloid plaques and tau tangles
- Prevalence: 5-7% of over 65s; 30-40% of over 85s
- Mortality: Average survival 8-10 years from symptom onset (varies widely)
- Core Symptoms: Amnesia (episodic memory), Aphasia, Apraxia, Agnosia
- Key Management: AChE inhibitors (mild-moderate), Memantine (moderate-severe), supportive care
- Critical Finding: Hippocampal atrophy on MRI; FDG-PET hypometabolism
- Key Genetics: APOE ε4 (risk factor); Presenilin 1/2, APP (early-onset familial)
Clinical Pearls
"Episodic Memory First": Alzheimer's classically presents with impaired recent memory (episodic) before other cognitive domains. If personality change or language problems come first, consider frontotemporal dementia.
The 4 As: Amnesia, Aphasia, Apraxia, Agnosia — the core cognitive domains affected as AD progresses.
APOE ε4: The most important genetic risk factor for sporadic late-onset AD. Homozygotes have 10-15× increased risk compared to non-carriers. However, it is a risk factor, not deterministic — do NOT use for diagnostic genetic testing in isolation.
Why This Matters Clinically
Alzheimer's disease is a global health crisis with millions affected worldwide. Accurate early diagnosis distinguishes AD from treatable causes of cognitive decline (B12 deficiency, hypothyroidism, depression, normal pressure hydrocephalus). It enables timely use of disease-modifying therapies (where available), symptom management, advance care planning, and support for carers. The emotional and financial burden on families is immense.
2. Epidemiology
Incidence & Prevalence
- Prevalence (UK): ~850,000 people with dementia; ~500,000 with AD
- Prevalence globally: ~55 million with dementia worldwide
- Incidence: Approximately doubles every 5 years after age 65
- Trend: Increasing due to ageing population; age-specific incidence may be declining slightly
Demographics
| Factor | Details |
|---|---|
| Age | Rare <65; 5-10% at 65-74; 15-20% at 75-84; 30-50% at 85+ |
| Sex | Female:Male = 2:1 (females live longer and higher intrinsic risk) |
| Ethnicity | Higher prevalence in Black and Hispanic populations (possibly vascular risk factors, socioeconomic factors) |
| Geography | Lower in rural areas; higher in urban (possibly lifestyle, less physical activity) |
Risk Factors
Non-Modifiable:
- Advanced age (strongest risk factor)
- APOE ε4 allele (1 copy = 3× risk; 2 copies = 12× risk)
- Family history of dementia
- Female sex
- Down syndrome (trisomy 21 — APP gene on chromosome 21)
- Head trauma
Modifiable:
| Risk Factor | Relative Risk | Intervention |
|---|---|---|
| Hypertension (midlife) | 1.6 | BP control |
| Diabetes mellitus | 1.5-2 | Glycaemic control |
| Obesity (midlife) | 1.6 | Weight management |
| Physical inactivity | 1.4 | Regular exercise |
| Smoking | 1.6 | Smoking cessation |
| Low educational attainment | 1.6 | Cognitive reserve |
| Social isolation | 1.6 | Social engagement |
| Depression | 1.9 | Treatment of depression |
| Hearing loss | 1.9 | Hearing aids |
| Excessive alcohol | 1.2 | Moderate consumption |
The Lancet Commission on Dementia Prevention (2020)
Estimated that 40% of dementia cases could be prevented or delayed by addressing 12 modifiable risk factors.
3. Pathophysiology
Mechanism
Step 1: Amyloid-Beta Accumulation
- Amyloid precursor protein (APP) is cleaved by β-secretase and γ-secretase
- This produces amyloid-beta (Aβ) peptides, particularly Aβ42
- Aβ monomers aggregate into oligomers, then fibrils, then plaques
- Extracellular amyloid plaques are deposited in the brain
Step 2: Tau Pathology
- Hyperphosphorylation of tau protein
- Tau dissociates from microtubules, destabilising axonal transport
- Formation of intracellular neurofibrillary tangles (NFTs)
- NFT spread correlates with clinical symptoms and disease stage
Step 3: Neurodegeneration
- Synaptic dysfunction and loss
- Neuroinflammation (microglial activation)
- Oxidative stress
- Neuronal death
- Brain atrophy, particularly hippocampus and temporal cortex
Step 4: Cholinergic Deficit
- Loss of cholinergic neurons in nucleus basalis of Meynert
- Reduced acetylcholine in cortex and hippocampus
- Basis for AChE inhibitor therapy
Classification
| Type | Age of Onset | Genetics | Features |
|---|---|---|---|
| Sporadic (Late-Onset) | >65 years | APOE ε4 (risk factor) | Most common (95%); multifactorial |
| Familial (Early-Onset) | <65 years | Presenilin 1 (PSEN1), Presenilin 2 (PSEN2), APP | 1-5% of cases; autosomal dominant |
| Down Syndrome-Associated | 40s-50s | Trisomy 21 (extra APP) | Nearly all develop AD pathology |
Stages of Alzheimer's Disease
| Stage | Clinical Features | Pathology |
|---|---|---|
| Preclinical | No symptoms; biomarkers may be positive | Amyloid accumulation begins 15-20 years before symptoms |
| Mild Cognitive Impairment (MCI) | Subjective memory complaints; objective deficits; preserved ADLs | Hippocampal tau pathology |
| Mild AD | Clear memory impairment; getting lost; word-finding difficulties; preserved basic ADLs | Moderate atrophy; tau spread to temporal cortex |
| Moderate AD | Loss of ADLs; behavioural changes; agitation; delusions | Widespread cortical involvement |
| Severe AD | Bed-bound; non-verbal; incontinence; feeding difficulties | Extensive neuronal loss |
4. Clinical Presentation
Symptoms
Early Stage (Mild AD):
Middle Stage (Moderate AD):
Late Stage (Severe AD):
Signs
Red Flags
[!CAUTION] Red Flags — Consider alternative diagnosis if:
- Rapid progression (<6 months to severe) → CJD, autoimmune encephalitis, malignancy
- Prominent motor signs early → Lewy body, vascular, Parkinson's plus
- Personality change before memory loss → Frontotemporal dementia
- Early visual hallucinations → Dementia with Lewy bodies
- Gait + incontinence + dementia → Normal pressure hydrocephalus (potentially treatable!)
- Focal neurological signs → Stroke, tumour, subdural haematoma
- Seizures → Autoimmune encephalitis, tumour
Forgetting recent events (episodic memory loss)
Common presentation.
Repeating questions or stories
Common presentation.
Difficulty finding words (anomia)
Common presentation.
Losing or misplacing objects
Common presentation.
Difficulty with complex tasks (finances, medications)
Common presentation.
Getting lost in familiar places
Common presentation.
Subtle personality changes (apathy, withdrawal)
Common presentation.
5. Clinical Examination
Structured Approach
General:
- Nutritional status (cachexia in late disease)
- Self-care and grooming
- Signs of trauma (falls)
Cognitive Examination:
- Orientation: Time, place, person
- Attention: Months of year backwards, serial 7s
- Memory: Word recall (registration and delayed recall), name/address recall
- Language: Naming, comprehension, repetition, fluency
- Executive function: Clock drawing, verbal fluency
- Visuospatial: Copying figures, cube drawing
- Praxis: Miming actions (pretend to brush teeth)
Validated Cognitive Tools:
| Tool | Score Range | Interpretation | Duration |
|---|---|---|---|
| MMSE | 0-30 | <24 abnormal; <20 moderate; <10 severe | 8-10 min |
| ACE-III (Addenbrooke's) | 0-100 | <82 abnormal | 15-20 min |
| MoCA | 0-30 | <26 abnormal (sensitive for MCI) | 10 min |
| 6-CIT (Six-Item Cognitive Impairment Test) | 0-28 | >7 abnormal | 3 min |
| GP-COG | 0-9 | <5 significant impairment | 5-10 min |
Functional Assessment
- Instrumental ADLs (IADLs): Finances, medications, cooking, shopping, telephone
- Basic ADLs: Dressing, grooming, bathing, toileting, feeding, transfers
- Use standardised scales: Bristol ADL Scale, Barthel Index
6. Investigations
First-Line (Bedside)
- Cognitive screening — MMSE, ACE-III, MoCA
- Collateral history — Essential from family/carers
- Functional assessment — ADLs
Laboratory Tests (Exclude Reversible Causes)
| Test | Purpose | Finding in AD |
|---|---|---|
| Full blood count | Exclude anaemia | Usually normal |
| U&E, Calcium | Metabolic encephalopathy | Normal |
| Thyroid function tests | Hypothyroidism mimics dementia | Should be normal |
| Vitamin B12, Folate | B12 deficiency treatable | Exclude deficiency |
| Glucose/HbA1c | Diabetes, hypoglycaemia | May be elevated (risk factor) |
| Liver function | Hepatic encephalopathy | Normal |
| Syphilis serology | Neurosyphilis (rare) | If risk factors |
| HIV | HIV-associated dementia | If risk factors |
Imaging
| Modality | Findings | Indication |
|---|---|---|
| MRI Brain | Hippocampal atrophy, medial temporal lobe atrophy (MTA scale); generalised cortical atrophy | First-line imaging; characterises atrophy pattern |
| CT Head | Less sensitive; rules out structural lesions, hydrocephalus, SDH | If MRI contraindicated |
| FDG-PET | Temporoparietal hypometabolism | Atypical cases, young onset |
| Amyloid PET | Positive in AD (but also in many elderly normals) | Research; specialist use |
| CSF biomarkers | Low Aβ42, High total tau, High phospho-tau | Research; specialist centres; supports clinical diagnosis |
Diagnostic Criteria
NIA-AA Criteria (2011):
- Probable AD dementia: Gradual onset, clear-cut history of worsening, amnestic presentation (most common), no evidence of other causes
- Possible AD dementia: Atypical course or evidence of co-existing pathology
- Biomarker support: Amyloid and tau markers can increase diagnostic certainty
7. Management
Management Algorithm
Non-Pharmacological Management
| Intervention | Evidence | Notes |
|---|---|---|
| Cognitive Stimulation Therapy (CST) | 1a | Group-based, structured sessions; improves cognition and QoL |
| Physical exercise | 1a | Regular aerobic exercise slows decline |
| Occupational therapy | 2a | Home assessment, adaptive equipment |
| Music therapy | 2b | Reduces agitation, improves mood |
| Reminiscence therapy | 2b | Uses past memories to enhance engagement |
| Carer support and education | 1a | Reduces carer burden, delays institutionalisation |
Pharmacological Management
| Drug | Class | Indication | Dose | Notes |
|---|---|---|---|---|
| Donepezil | AChE inhibitor | Mild-moderate AD | 5mg OD → 10mg OD | Most common; once daily |
| Rivastigmine | AChE inhibitor | Mild-moderate AD; also Parkinson's dementia | Patch 4.6mg/24h → 9.5mg/24h | Patch preferred (less GI upset) |
| Galantamine | AChE inhibitor | Mild-moderate AD | 8mg BD → 12mg BD | Also nicotinic modulator |
| Memantine | NMDA antagonist | Moderate-severe AD | 5mg OD → 20mg OD | Add to or replace AChEI in later stages |
AChE Inhibitor Side Effects: Nausea, vomiting, diarrhoea, bradycardia, syncope, vivid dreams Monitoring: ECG if cardiac history; review after 3 months for response
Management of Behavioural Symptoms (BPSD)
| Symptom | First-Line | Second-Line | Notes |
|---|---|---|---|
| Agitation/aggression | Non-pharmacological (identify triggers) | Risperidone (short-term, last resort) | Antipsychotics increase mortality |
| Depression | SSRIs (sertraline, citalopram) | Mirtazapine | Common comorbidity |
| Sleep disturbance | Sleep hygiene, light exposure | Melatonin, low-dose trazodone | Avoid benzodiazepines |
| Delusions/hallucinations | AChE inhibitors | Risperidone (cautiously) | Only if causing distress |
Supportive Care and Planning
| Aspect | Details |
|---|---|
| Driving | Notify DVLA; assess driving safety |
| Legal capacity | Assess for Lasting Power of Attorney (while capacity exists) |
| Advance care planning | Discuss wishes for future care, DNACPR, preferred place of death |
| Carer support | Carer's assessment, respite care, financial support (Attendance Allowance, PIP) |
| Safety | Home hazard assessment, wandering risk, safeguarding |
| Day centres/memory clinics | Social stimulation, structured activities |
| End-of-life care | Palliative approach in advanced disease |
Disposition
- Community (most): Memory clinic follow-up, GP shared care, community mental health team
- Specialist input: Psychiatry of old age, neurology (atypical cases)
- Care home: When home care no longer safe/feasible
- Hospital: Only for acute medical illness; avoid if possible (delirium risk)
8. Complications
Immediate (Early Disease)
| Complication | Incidence | Presentation | Management |
|---|---|---|---|
| Falls | 30-50% annually | Injuries, fractures | Home assessment, physiotherapy |
| Medication errors | Common | Over/under-dosing | Supervision, dosette box |
| Getting lost | Common | Wandering, missing | GPS trackers, safe walking schemes |
| Driving accidents | Variable | RTAs | Driving assessment, cessation |
Intermediate (Moderate Disease)
- Behavioural and psychological symptoms of dementia (BPSD)
- Delirium (superimposed on dementia; common with illness)
- Weight loss and malnutrition
- Social isolation
- Carer burnout
Late (Severe Disease)
- Aspiration pneumonia: Leading cause of death
- Pressure ulcers: Immobility
- Contractures: Fixed limb positioning
- Infections: UTI, respiratory (immunosenescence, immobility)
- Dysphagia: Aspiration risk, nutritional failure
- DVT/PE: Immobility
9. Prognosis & Outcomes
Natural History
Alzheimer's disease is progressive and incurable with current treatments. The course is typically gradual decline over 8-12 years from symptom onset, though this varies widely. Death usually occurs from complications such as pneumonia or other infections.
Outcomes with Treatment
| Variable | Outcome |
|---|---|
| Average survival from diagnosis | 4-8 years (depends on stage at diagnosis, age) |
| Average survival from symptom onset | 8-12 years |
| Effect of AChE inhibitors | Delay decline equivalent to 6-12 months; modest symptomatic benefit |
| Effect of memantine | Modest benefit on cognition and function in moderate-severe |
| Institutionalisation | 50% require care home by moderate-severe stage |
Prognostic Factors
Good Prognosis (Longer Survival):
- Younger age at onset
- Higher educational attainment (cognitive reserve)
- Preserved insight early in disease
- Female sex (though higher risk of developing AD)
- Good nutrition
- Active social support
- Higher premorbid cognitive abilities
Poor Prognosis (Faster Decline):
- Older age at diagnosis
- Severe cognitive impairment at diagnosis
- Early language impairment
- Behavioural symptoms
- Extrapyramidal signs
- Rapid progression in first year
- Medical comorbidities (cardiovascular, diabetes)
10. Evidence & Guidelines
Key Guidelines
- NICE NG97: Dementia: assessment, management and support for people living with dementia and their carers (2018) — Comprehensive UK guidance on diagnosis, AChE inhibitors, behavioural management, carer support. NICE
- NIA-AA Criteria for Alzheimer's Disease (2011, updated 2018) — Diagnostic criteria incorporating biomarkers for research and clinical use.
- Lancet Commission on Dementia Prevention (2020) — 40% of dementias potentially preventable through risk factor modification.
Landmark Trials
DOMINO Study (2012) — Continued Donepezil vs discontinuation in moderate-severe AD.
- 295 patients
- Key finding: Continuing donepezil was associated with better cognition and function than stopping; combination with memantine showed additional benefit
- Clinical Impact: Continue AChE inhibitors into later stages
- PMID: 22404953
AD2000 Study (2004) — Pragmatic UK trial of donepezil.
- 565 patients
- Key finding: Modest cognitive benefit; no significant delay to institutionalisation
- Clinical Impact: Tempered expectations; benefit is symptomatic not disease-modifying
Lecanemab (CLARITY-AD, 2023) — Anti-amyloid monoclonal antibody.
- 1,795 early AD patients
- Key finding: 27% slowing of cognitive decline vs placebo at 18 months
- Clinical Impact: First disease-modifying treatment with meaningful clinical effect; FDA and MHRA approval
- PMID: 36449413
Evidence Strength
| Intervention | Level | Key Evidence |
|---|---|---|
| AChE inhibitors for mild-moderate AD | 1a | Cochrane reviews; consistent modest benefit |
| Memantine for moderate-severe AD | 1a | Meta-analyses; modest cognitive and global benefit |
| Cognitive Stimulation Therapy | 1a | RCTs; improves cognition and QoL |
| Antipsychotics for BPSD | 1a | Modest efficacy but increased mortality risk |
| Lecanemab for early AD | 1b | CLARITY-AD trial |
| Dementia risk reduction (exercise, BP, etc.) | 2a | Observational/epidemiological |
11. Patient/Layperson Explanation
What is Alzheimer's Disease?
Alzheimer's disease is a brain condition that gradually affects memory and thinking skills. It's the most common cause of dementia. In Alzheimer's, abnormal proteins build up in the brain, damaging and killing brain cells over time. It usually starts with forgetting recent events and eventually affects all thinking abilities.
Why does it happen?
The exact cause isn't fully understood, but we know:
- Abnormal proteins (amyloid plaques and tau tangles) build up in the brain
- Brain cells become damaged and die
- The brain shrinks, especially areas involved in memory
- Risk factors include age, family history, certain genes, and lifestyle factors like high blood pressure, diabetes, and lack of exercise
How is it treated?
There's no cure yet, but treatments can help:
- Medications: Donepezil, rivastigmine, or galantamine boost brain chemicals that help memory (for mild-moderate). Memantine works differently and is used for moderate-severe disease.
- Therapies: Cognitive stimulation (group activities that exercise the brain) can help maintain abilities.
- Support: Occupational therapy to stay independent longer; carer support groups; memory clinics.
- Planning: Making legal and financial arrangements while capacity is retained (Lasting Power of Attorney).
What to expect
- Alzheimer's is a gradual condition — the average time from diagnosis to death is 4-8 years, but many people live longer
- Symptoms will slowly worsen, but medications and support can help maintain quality of life
- Eventually, full-time care is usually needed
- Planning early for the future is important
When to seek help
- If you or a family member have concerns about memory — see your GP
- If someone with dementia becomes suddenly more confused — this could be delirium from an infection (urgent)
- For carer support and respite — ask the GP or memory clinic about services
12. References
Primary Guidelines
- National Institute for Health and Care Excellence. Dementia: assessment, management and support for people living with dementia and their carers. NICE guideline [NG97]. 2018. NICE
- McKhann GM, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the NIA-AA. Alzheimers Dement. 2011;7(3):263-269. PMID: 21514250
Key Trials
- Howard R, et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease (DOMINO). N Engl J Med. 2012;366(10):893-903. PMID: 22404953
- van Dyck CH, et al. Lecanemab in early Alzheimer's disease (CLARITY-AD). N Engl J Med. 2023;388(1):9-21. PMID: 36449413
- Livingston G, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446. PMID: 32738937
- Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2018;(6):CD001190. PMID: 29923184
Further Resources
- Alzheimer's Society UK: www.alzheimers.org.uk
- Dementia UK: www.dementiauk.org
- Admiral Nurses (dementia specialist nurses): www.dementiauk.org/get-support/admiral-nursing
- Alzheimer's Association (US): www.alz.org
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists. This content does not constitute medical advice for individual patients.