Alzheimer disease

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

Build a chronology through the person and collateral: repeated questions, forgotten conversations, misplaced objects, navigation and appointment errors followed by difficulty with words, appliances and complex tasks. Document preserved strengths and assistance. Alzheimer disease is not ordinary ageing; functional effect and progression distinguish it from isolated subjective concern.

Exclude delirium whenever the trajectory changes abruptly. Review depression, hearing, vision, sleep, alcohol and anticholinergic or sedative medicines. Examine gait, focal neurology, parkinsonism and eye movements. Standard blood tests and structural imaging exclude treatable lesions and show vascular or atrophy patterns. Mixed disease is common and should be named when it changes risk management.

MRI is preferable when subtype or vascular burden matters and feasible; CT remains useful. Medial temporal atrophy supports the phenotype but occurs in other disease and may be subtle early. Specialist FDG-PET, CSF amyloid and tau or another validated biomarker is considered when diagnostic certainty will alter counselling or treatment, not to replace clinical assessment.

A memory service confirms subtype and discusses cognitive medicine. Before an AChE inhibitor check pulse, syncope, conduction disease, weight, peptic risk, asthma or COPD severity and interacting bradycardic or QT-active drugs. Titrate only after response and adverse-effect review. Nausea, diarrhoea, cramps, vivid dreams, bradycardia and weight loss can outweigh modest benefit.

Memantine is an NMDA-receptor antagonist used according to severity and tolerance. Titrate slowly and reduce the maximum in significant renal impairment. Dizziness, constipation, somnolence or confusion may occur. When adding to an AChE inhibitor, define the target—cognition, function or distress—and avoid attributing ordinary fluctuation to benefit.

Offer cognitive stimulation for mild-to-moderate dementia and support meaningful activity, exercise, vascular health, hearing and vision, nutrition and sleep. Simplify medicines and appointments. Occupational therapy can adapt cooking, medication and orientation routines. Avoid unproven supplements and do not frame risk-factor work as reversing established disease.

Address driving, finances, scams, falls, fire and getting lost with least-restrictive adaptation. A diagnosis requires DVLA notification where applicable, but driving fitness is assessed individually. Encourage lasting power of attorney and advance care planning while the person can choose. Capacity remains specific to each current decision.

Carers need diagnosis information, communication strategies, benefits and care advice, emergency contacts, respite and assessment of their own needs. Later care anticipates continence, dysphagia, pain communication, infection and end-of-life priorities. Review new distress for delirium, pain and environment before considering psychotropics.

Key points

Typical Alzheimer disease begins insidiously with impaired learning and retention of new episodic information, then affects orientation, language, visuospatial and executive function.
Diagnosis combines progressive cognitive change, interference with function, collateral evidence, examination, exclusion of delirium and contributors and structural imaging.
MRI commonly shows medial temporal and later generalised atrophy but imaging supports rather than proves the diagnosis.
Specialist CSF or amyloid biomarkers are reserved for meaningful diagnostic uncertainty; APOE testing is not a routine diagnostic test.
First-line cognitive treatment for mild-to-moderate Alzheimer disease is one acetylcholinesterase inhibitor: donepezil, galantamine or rivastigmine.
Memantine is recommended for moderate disease when AChE inhibitors are unsuitable or not tolerated, and for severe Alzheimer disease; combination may be considered with established AChE treatment.
Donepezil commonly starts 5 mg once daily and may increase to 10 mg after at least one month if tolerated; check pulse, weight, GI and interaction risk.
Memantine begins 5 mg daily and increases by 5 mg each week to 20 mg daily, with renal dose adjustment.
Do not stop a cognitive medicine solely because severity has increased; review benefit, adverse effects, adherence and the person's goals.
Pair medicine with activity, communication, sensory, vascular, nutrition, safety, advance-planning and carer support; no tablet replaces coordinated care.

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

Age and polygenic susceptibility

Age is the strongest risk factor; APOE-epsilon4 and many immune, lipid and endosomal variants alter probability but routine predictive testing is not diagnostic.

Rare autosomal dominant disease

Pathogenic APP, PSEN1 or PSEN2 variants cause uncommon early-onset familial Alzheimer disease and require specialist genetic counselling before testing.

Down syndrome association

Trisomy 21 increases amyloid-precursor gene dosage and substantially raises later-life Alzheimer risk, requiring adapted baseline and change assessment.

Vascular and reserve modifiers

Hypertension, diabetes, smoking, inactivity, hearing loss and lower cognitive reserve influence expression and mixed pathology without providing a single cause.

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

1
Amyloid accumulation
Abnormal beta-amyloid processing and clearance produces soluble oligomers and extracellular plaques that disrupt synaptic signalling early.
2
Tau-mediated degeneration
Hyperphosphorylated tau forms intracellular tangles that spread through connected networks and correlates with neuronal loss and clinical stage.
3
Medial temporal network injury
Hippocampal and entorhinal dysfunction impairs encoding and consolidation of new episodic memories before broader cortical deficits.
4
Inflammation and synaptic loss
Microglial and astrocytic responses, vascular injury and progressive synapse loss contribute to cognitive and functional decline.
5
Mixed late-life pathology
Cerebrovascular, Lewy-body and TDP-43 pathology commonly accompanies Alzheimer change and modifies gait, fluctuation and treatment response.

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

Early episodic-memory failure

New information is not retained despite cueing, causing repetition and forgotten appointments rather than simple slow retrieval.

Progressive IADL loss

Finances, medicines, navigation and complex cooking become unreliable before basic feeding and dressing.

Later cortical spread

Word finding, praxis, visuospatial ability, recognition and executive judgement decline as disease advances.

Superimposed deliriumRed flag

Acute inattention or altered arousal represents new physiological illness, not an overnight Alzheimer stage change.

Medicine adverse effectRed flag

Syncope, pulse slowing, weight loss or GI symptoms after titration may reflect cholinesterase inhibition.

Mixed-pathology clue

Focal signs, gait disorder, marked fluctuation or parkinsonism suggests vascular or Lewy-body contribution.

Red flags requiring action

Hours-to-days change, marked fluctuation or altered arousal suggests delirium superimposed on Alzheimer disease.
Rapid progression, early focal signs, seizure, gait or continence syndrome and severe headache requires an alternative neurological search.
Syncope, bradycardia, falls, weight loss, vomiting or gastrointestinal bleeding after a cholinesterase inhibitor requires urgent medicine review.
Getting lost, fire, medication errors, scams or unsafe driving needs immediate proportionate risk management and capacity assessment.
Suicide intent, severe depression, psychosis or carer violence and exhaustion requires same-day mental-health or safeguarding action.
Do not interpret increasing help as proof that every decision-making capacity is lost; assess each decision with support.

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
Collateral cognitive and function historyFirst step
Why
Establish the progressive amnestic phenotype.
Interpretation and limitations
Record onset, learning, orientation, language, visuospatial, executive, IADL and ADL change and hidden carer input.
02
Delirium and contributor assessment
Why
Prevent false stage or diagnosis.
Interpretation and limitations
Use 4AT for acute change and review mood, senses, sleep, alcohol and cognitive-burden medicines.
03
Validated cognitive testing
Why
Measure domains under fair conditions.
Interpretation and limitations
Use a complete approved tool with hearing, vision and language support and interpret against premorbid ability and function.
04
Blood and neurological assessment
Why
Exclude compounding medical and focal disease.
Interpretation and limitations
Use standard dementia blood work plus gait, parkinsonism, focal and cardiovascular examination, targeting additional tests to clues.
05
Structural imaging
Why
Exclude lesions and characterise atrophy and vascular burden.
Interpretation and limitations
MRI or CT supports subtype but neither medial temporal atrophy nor a normal early scan independently confirms or excludes Alzheimer disease.
06
Specialist biomarkers
Why
Resolve management-changing uncertainty. within a safe older-adult assessment.
Interpretation and limitations
CSF or imaging amyloid and tau evidence is selected by a specialist when clinical and structural assessment remains uncertain.

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

Delirium

Abrupt inattention and fluctuation is an acute medical syndrome, often superimposed on Alzheimer disease, and demands cause treatment.

Vascular cognitive impairment

Stepwise change, executive slowing, gait disorder, focal signs and imaging vascular burden suggest a dominant or mixed vascular mechanism.

Lewy-body dementia

Early formed visual hallucinations, pronounced cognitive fluctuation, REM-sleep behaviour and spontaneous parkinsonism favour DLB. Distinguish it through chronology, examination and targeted testing.

Depression and medicine effects

Low motivation, sleep change, anticholinergics and sedatives impair memory and may coexist; chronology and monitored treatment clarify contribution.

Other neurodegeneration or lesion

Early behavioural, language or motor change, hydrocephalus, subdural and tumour require phenotype-directed imaging and specialist review.

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

01Diagnostic sequenceConfirm progression, function and compatible subtypeFirst stepAn insidious amnestic and functional decline is reported.

1Exclude delirium and modifiable contributors and obtain detailed collateral with accessible cognitive testing.
2Complete examination, standard blood work and structural imaging and assess mixed pathology.
3Refer for specialist diagnosis, medicine eligibility, counselling, capacity and support planning.

02First-line medicineStart one AChE inhibitor safelyFirst lineMild-to-moderate Alzheimer disease is diagnosed and treatment is consistent with goals.

1Check pulse, conduction and syncope, weight, GI and respiratory history, interactions and administration support.
2Start the selected licensed agent at its initial dose and titrate only after tolerance and target review.
3Monitor cognition, daily function, adverse effects and carer observation and continue only while net benefit remains reasonable.

03Moderate-to-severe routeConsider memantine and intensify supportDisease is moderate with AChE intolerance or severe, or progresses on tolerated treatment.

1Confirm current subtype, delirium absence, renal function, adherence and personally important treatment target.
2Titrate memantine according to licence and consider combination with an existing AChE inhibitor under NICE guidance.
3Review nutrition, swallowing, falls, distress, carer capacity, advance care and increasing personal-care needs.

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

One first-line AChE inhibitor option for mild-to-moderate Alzheimer disease under memory-service or shared-care arrangements.

Donepezil

Start 5 mg orally once daily, often at night; after at least one month, increase to 10 mg once daily only if tolerated and clinically appropriate.

Check pulse, syncope, conduction and QT risk, weight, GI bleeding, asthma or COPD and interactions; monitor nausea, diarrhoea, dreams, cramps and falls.

Moderate Alzheimer disease when AChE inhibitors are unsuitable or not tolerated, and severe disease; may be added to established AChE treatment.

Memantine

Start 5 mg orally each morning and increase by 5 mg at weekly intervals to 20 mg once daily if tolerated; reduce the ceiling in significant renal impairment according to product information.

Check renal function and monitor dizziness, constipation, somnolence, hypertension and confusion; review administration and avoid continuation without a defined net benefit.

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

Progressive dependency

IADLs, navigation and medication management decline before personal care, eventually requiring continuous supervision and hands-on support.

Delirium, falls and frailty

Reduced reserve, sensory impairment and medicine burden increase acute brain failure, injury, immobility and hospital-associated decline.

Nutrition and swallowing problems

Apraxia, forgetting meals, dental difficulty and late dysphagia cause weight loss, dehydration and aspiration. Anticipatory multidisciplinary prevention and review are therefore important.

Behavioural distress and exploitation

Fear, wandering, hallucination, agitation and financial vulnerability can endanger the person and strain relationships. Anticipatory multidisciplinary prevention and review are therefore important.

Carer illness and crisis placement

Increasing supervision and sleep disruption can exhaust carers unless anticipatory formal support and respite develop. Anticipatory multidisciplinary prevention and review are therefore important.

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

Review pulse, syncope, falls, weight, appetite, GI effects and interactions after AChE initiation and every titration.
Track cognition with real-world IADLs, ADLs, navigation, medicines and carer observation rather than one score alone.
Repeat 4AT and medical assessment for sudden decline, hallucination or reduced intake before changing dementia treatment.
Review driving, finances, home safety, nutrition, swallowing, mood and sensory access as the functional stage changes.
Ask carers about sleep, supervision and strain and activate additional care before the current arrangement fails.

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

Encoding differs from retrieval

Alzheimer memory often fails to retain new information even with cues, rather than merely taking longer to recall.

Atrophy is supportive

Medial temporal change fits the phenotype but imaging never replaces chronology and function.

Mixed disease is ordinary

Vascular and Lewy-body changes frequently modify a late-life Alzheimer presentation.

Cognitive drugs are symptomatic

They may modestly slow functional worsening but do not restore lost neurons or eliminate care planning.

Severity alone does not stop treatment

Continuation depends on benefit, harm, adherence and goals rather than an arbitrary score threshold.

Capacity remains granular

Progressive memory loss does not remove the ability to decide every present question.

11Common pitfallsFrequent interpretation and management errors.

01
Calling an acute delirious deterioration Alzheimer progression.
02
Starting donepezil without checking syncope, pulse, weight and interacting medicines.
03
Interpreting medial temporal atrophy as a stand-alone gold-standard diagnosis.
04
Stopping a tolerated cognitive medicine solely because disease has become severe.
05
Following test scores while missing medication errors, weight loss and carer breakdown.
06
Using diagnosis to remove autonomy globally rather than assessing specific capacity.