Alzheimer disease

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Alzheimer disease is a progressive neurodegenerative disorder characterised pathologically by extracellular amyloid-beta plaques and intracellular tau pathology, but clinical expression and co-pathology vary. The typical amnestic syndrome begins with difficulty learning and retaining new information: repeated questions, missed appointments and getting lost. Remote autobiographical memory and social fluency can remain superficially reassuring early. As disease advances, language, praxis, recognition, judgement, behaviour and basic daily activities are affected.

Assessment establishes both syndrome and cause. The timeline should be gradual rather than stepwise or markedly fluctuating. Examination searches for parkinsonism, eye-movement disorder, motor neurone signs, gait abnormality and focal deficits that suggest alternative or mixed disease. MRI excludes structural pathology and may show a compatible atrophy pattern. Biomarkers are not required in every typical older patient but are valuable when diagnostic certainty will change counselling, genetic evaluation or a treatment pathway.

Current symptomatic medicines do not cure the disease but may improve or stabilise cognition, function or behaviour for a time. Disease-modifying anti-amyloid agents require biomarker-confirmed early disease, specialist infusion and MRI safety pathways, and NHS use must follow the latest NICE technology appraisal and commissioning decision; regulatory authorisation alone does not mean routine availability. Prescribing and follow-up should follow current local memory-service and safeguarding protocols.

Key points

Typical Alzheimer disease causes insidious progressive episodic memory impairment followed by broader language, orientation, executive and visuospatial difficulty that interferes with independent function.
Atypical phenotypes include posterior cortical atrophy with visuospatial dysfunction and a logopenic language syndrome; young-onset disease deserves specialist review rather than dismissal because memory is not the first complaint.
Diagnosis integrates progressive history, collateral functional evidence, cognitive profile, neurological examination and structural imaging after delirium, depression, medicine effects and systemic contributors are addressed.
MRI may show disproportionate medial temporal and parietal atrophy but a normal or non-specific scan does not exclude early disease; patterns support rather than replace clinical diagnosis.
CSF amyloid and tau or amyloid imaging can increase confidence in uncertain, young-onset or atypical cases when a result will alter management or access to a specialist therapy.
Donepezil, galantamine or rivastigmine are NICE options for mild to moderate Alzheimer disease; choose around adherence, comorbidity, interactions and adverse-effect profile.
Memantine is an option as monotherapy for severe disease or moderate disease when cholinesterase inhibitors are contraindicated or not tolerated, and may be added to an inhibitor in moderate or severe disease.
Do not stop a cholinesterase inhibitor solely because dementia has become severe; review benefit, adverse effects, swallowing, adherence and the person’s goals.
Distress and behavioural change first require pain, delirium, environment, communication and unmet-needs assessment; antipsychotics are reserved for risk of harm or severe distress and need frequent review.
Driving, capacity, medication support, nutrition, continence, falls, carer wellbeing, lasting power of attorney and advance care planning are integral treatment, not post-diagnostic extras.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Amyloid and tau pathology

Alzheimer disease is characterised by extracellular amyloid-beta plaques and intracellular tau pathology, although clinical expression and co-pathology vary between affected people.

Mixed cerebrovascular pathology

Cerebrovascular injury commonly coexists with Alzheimer pathology and can contribute to a mixed cognitive syndrome rather than a purely neurodegenerative presentation.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Amyloid dysregulation
Abnormal production or clearance permits amyloid-beta aggregation in extracellular plaques, altering synaptic signalling and promoting inflammatory and downstream degenerative responses.
2
Tau-mediated neuronal injury
Intracellular tau pathology accompanies progressive neurodegeneration across connected cortical networks, contributing to worsening memory, language, orientation and executive function.
3
Synaptic and neuronal loss
Progressive synaptic failure, inflammation and cell death affect hippocampal and association cortices, impairing new learning before language, praxis, visuospatial and executive networks.
4
Network-level functional decline
As pathology spreads, cognitive deficits interfere with instrumental and then basic daily activities, while reduced reserve increases vulnerability to delirium and environmental stress.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Amnestic presentation

Repeated questions, rapid forgetting despite cueing, missed recent events and progressive disorientation with initially fluent social interaction fit the common Alzheimer phenotype.

Posterior cortical phenotype

Progressive visuospatial, reading, object-location or calculation difficulty with relatively preserved early memory may reflect posterior cortical atrophy, often due to Alzheimer pathology.

Logopenic language phenotype

Word-finding pauses and impaired sentence repetition with preserved grammar and motor speech can represent an Alzheimer-related primary progressive aphasia and merits specialist language assessment.

Functional progression

Loss of ability to manage finances, medicines, travel, meals and later personal care shows clinically meaningful progression even when a brief score fluctuates.

Acute superimposed changeRed flag

Hours-to-days worsening, inattention, drowsiness or agitation signals delirium, medication toxicity, pain or another acute illness rather than sudden Alzheimer progression.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Detailed cognitive and functional historyFirst step
Why
Establish an insidious progressive amnestic or atypical syndrome and its effect on independence.
Interpretation and limitations
Use dated patient and informant examples. Rapid, stepwise or pronounced fluctuation redirects assessment towards delirium, vascular, Lewy body, inflammatory and other causes.
02
Domain-based cognitive testing
Why
Characterise memory encoding, language, visuospatial, executive and attention profiles and provide a baseline.
Interpretation and limitations
Poor delayed recall not restored by cueing supports impaired storage, but education, language, mood and hearing modify performance. No threshold alone confirms pathology.
03
MRI or CT brain
Why
Exclude treatable structural disease and assess regional atrophy, vascular burden and mixed pathology.
Interpretation and limitations
Medial temporal and parietal atrophy can support typical Alzheimer disease. Significant infarction, normal-pressure hydrocephalus features or a focal lesion changes the formulation.
04
CSF Alzheimer biomarkers or amyloid imaging
Why
Demonstrate an Alzheimer pathophysiological profile when uncertainty is clinically important.
Interpretation and limitations
Reduced amyloid with raised phosphorylated and total tau in the appropriate context supports the diagnosis. Borderline or discordant results need specialist interpretation and do not erase phenotype.
05
Pre-treatment cardiovascular and medicine review
Why
Identify bradycardia, conduction disease, syncope, weight loss and interactions before a cholinesterase inhibitor.
Interpretation and limitations
Record pulse, blood pressure, weight and relevant ECG indications. Anticholinergic medicines can oppose cognitive treatment and add delirium or urinary burden.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Dementia with Lewy bodies

Early visual hallucinations, marked cognitive fluctuation, REM sleep behaviour disorder and spontaneous parkinsonism favour Lewy-body disease over a predominantly amnestic Alzheimer presentation.

Vascular cognitive impairment

Stepwise decline, focal deficits, executive slowing and cerebrovascular lesions sufficient to explain the syndrome support vascular contribution, although mixed pathology is common.

Frontotemporal dementia

Early disinhibition, apathy, loss of empathy, compulsive behaviour or language-led decline with relatively preserved episodic memory suggests frontotemporal degeneration.

Delirium or depression

Hours-to-days fluctuation indicates delirium, while prominent low mood and effort-dependent performance may reflect depression; both can coexist with and temporarily obscure underlying dementia.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01DiagnoseEstablish phenotype and confidenceFirst stepProgressive cognitive and functional decline remains after initial reversible-factor assessment.

11. Reconstruct onset, progression and domain sequence with the patient and informant, separating chronic decline from any current delirium.
22. Use adapted cognitive testing, neurological examination and structural imaging to formulate typical Alzheimer, atypical Alzheimer, mixed or uncertain disease.
33. Request CSF or amyloid imaging through specialist services when uncertainty, age or treatment eligibility makes molecular confidence useful.
44. Communicate diagnosis and limits, assess emotional response and safety, and offer a named memory-service or primary-care contact for follow-up.

02Treat cognitionUse symptomatic medicine safelyAlzheimer disease is established and the person wishes to consider cognitive treatment.

11. Review pulse, syncope, gastrointestinal, respiratory, urinary, weight and interaction risks and identify how adherence will be supported.
22. For mild to moderate disease, select donepezil, galantamine or rivastigmine with specialist knowledge and titrate after tolerability review.
33. Use memantine for the NICE-indicated moderate or severe contexts and consider addition to an existing cholinesterase inhibitor as disease advances.
44. Review cognition, global function, behaviour, daily activity, adverse effects and carer observations, continuing treatment while worthwhile benefit outweighs burden.

03ProgressionSupport person and carers longitudinallyNeeds change through moderate or severe disease or a behavioural crisis occurs.

11. Look first for pain, infection, constipation, retention, sensory problems, sleep disruption, overstimulation and communication mismatch when distress changes.
22. Adapt environment and routines, use cognitive stimulation or occupational strategies, and provide carer education and planned respite.
33. Reassess driving, capacity, medicines, nutrition, swallowing, falls, continence and safeguarding, preserving supported choice wherever possible.
4Definitive4. Discuss future care, proxy decision-makers and treatment priorities early enough for the person to participate, revisiting rather than forcing one definitive conversation.

Key medicines and prescribing safety2 treatments · regimens, roles and cautions

NICE-recommended acetylcholinesterase inhibitor option for symptomatic treatment of mild to moderate Alzheimer disease.

Donepezil

Start 5 mg orally once daily, commonly at night, and after at least one month consider 10 mg once daily if tolerated and clinically appropriate under the memory-service or shared-care plan.

Check bradycardia, syncope, conduction disease, ulcer or bleeding risk, asthma, weight loss, sleep disturbance and interactions. Monitor gastrointestinal effects and falls; an ECG is indicated when the cardiovascular history warrants it.

NICE option for severe Alzheimer disease, moderate disease when cholinesterase inhibitors are unsuitable, and add-on treatment in established moderate or severe disease.

Memantine

Start 5 mg once daily and increase by 5 mg at weekly intervals to a usual 20 mg once daily if tolerated, using a lower maximum in significant renal impairment.

Review dizziness, headache, constipation, confusion, blood pressure and renal function. Adjust for renal impairment and evaluate continued global and functional benefit rather than cognition alone.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Loss of independence and safeguarding risk

Progressive memory, judgement and praxis impairment compromises medicines, finances, cooking, driving and self-care, increasing vulnerability to exploitation, accidents and unsafe living.

Behavioural distress and delirium

Hallucinations, agitation, apathy or sleep disruption may emerge, while reduced cerebral reserve makes infection, pain and medicines more likely to precipitate superimposed delirium.

Frailty, dysphagia and infection

Advanced disease impairs mobility, swallowing, continence and nutrition, increasing falls, aspiration pneumonia, pressure injury, weight loss and dependence for basic care.

Carer and family burden

Sustained supervision, behavioural change and complex decisions can cause psychological, financial and physical strain, making carer assessment and advance-care planning integral to management.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Review cognition, daily function, behaviour and global wellbeing with patient and carer evidence, avoiding automatic discontinuation from one score or disease severity alone.
Track pulse, syncope, weight, appetite, gastrointestinal symptoms, sleep and falls after cholinesterase inhibitor initiation or titration.
Monitor renal function where memantine dosing could change and reconcile anticholinergic, sedative and hypotensive medicines at each transition.
Screen recurrently for delirium, pain, depression, psychosis, wandering, driving and vulnerability when behaviour or function changes.
Assess carer health, ability and consent to continue support, connecting families with respite, benefits, social care and crisis contacts.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Recognition can exceed recall

In early typical Alzheimer disease, information is not stored effectively, so cueing and recognition may help less than in retrieval-dominant depression or subcortical disease.

Social fluency can mask decline

Warm conversation and preserved remote stories may coexist with serious recent-memory, medication and financial failures revealed by collateral history.

Atypical does not mean non-Alzheimer

Posterior visual or logopenic language syndromes may reflect Alzheimer pathology despite relatively preserved initial episodic memory.

Severity alone does not stop treatment

NICE advises against withdrawing a cholinesterase inhibitor solely because disease is severe; benefit and adverse burden require individual review.

Approval differs from access

A disease-modifying drug may hold a marketing authorisation while NICE and NHS commissioning still restrict routine use based on clinical and cost-effectiveness evidence.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing normal ageing from socially fluent conversation misses rapid forgetting and functional failures that emerge only through collateral examples.
02
Treating a sudden behavioural change as neurodegenerative progression delays diagnosis of delirium, pain, infection or medication toxicity.
03
Starting donepezil without reviewing bradycardia, syncope and weight can worsen falls and frailty in a vulnerable patient.
04
Using an antipsychotic for convenience before environmental and physical causes are addressed exposes the person to stroke, mortality and motor harms.
05
Promising that a biomarker or anti-amyloid treatment removes all uncertainty over course and benefit misrepresents individual variability and specialist eligibility.