Alzheimer disease and the dementias: approach

• Alzheimer disease (AD) is the commonest cause of dementia and is defined by its biology: amyloid-beta plaques and abnormal tau tangles in the brain, not by memory loss alone.^[2]
• It usually begins with difficulty forming new memories, then spreads to other cognitive domains and to independence in daily life.
• Dementia is a syndrome; many other diseases copy it, so the diagnosis is a process of ruling in AD and ruling out mimics.
• Cognitive tests screen; they do not diagnose. Structural brain imaging and, when needed, cerebrospinal fluid or amyloid imaging confirm.
• Symptomatic treatments help for a while: cholinesterase inhibitors for mild to moderate disease, memantine for moderate to severe disease. Anti-amyloid monoclonal antibodies now offer modest disease slowing in selected early-stage patients. ^[3]
• Good dementia care is mostly non-pharmacological: diagnosis, disclosure, carer support, safety, medication review, and planning.

By the end of this page you should be able to:

1. Describe the pathological hallmarks of AD and how they spread through the brain.
2. Take a history and examination for dementia and distinguish AD from other causes of cognitive decline.
3. Interpret cognitive screening tests and list the blood, imaging and biomarker tests that matter, with their cut-offs.
4. Work through a dementia diagnostic algorithm, including screening for reversible causes.
5. Start and monitor treatment with cholinesterase inhibitors, memantine and anti-amyloid therapies according to current named guidelines.
6. Discuss care, safety, capacity and prognosis with patients and carers.

Alzheimer disease is best understood as a biological disease that produces a clinical illness. In the 2024 revised NIA-AA criteria, AD is defined by abnormal core biomarkers of amyloid-beta proteinopathy (and later tau), even when a person has no symptoms.^[2] A person can have AD biology long before they, or anyone else, notice a problem.

Clinically, AD usually presents as an amnestic syndrome: progressive difficulty with new learning. It then widens to involve attention, executive function, language and visuospatial skills. In clinical practice, dementia due to AD is often staged as mild, moderate or severe based on the loss of independence, not on a single test score.

• Mild cognitive impairment (MCI). Objective cognitive decline with largely preserved independence. A risk state for dementia, not yet dementia. The 2018 AAN guideline uses this term.^[5]
• Dementia due to AD (mild, moderate, severe). Cognitive decline plus loss of independence.
• Atypical AD. Logopenic (language-dominant), posterior cortical atrophy (visuospatial), and frontal (behavioural) forms. They exist and are worth remembering, but the typical amnestic form is what most patients have.
• Preclinical AD. Abnormal biomarkers without symptoms. Currently mainly a research and prevention category.
• Young-onset AD. Onset before 65 years. Some cases are genetic.^[3]

AD is the most common cause of dementia, accounting for about 60 to 80% of all dementia cases.^[1] Prevalence rises steeply with age: just over 1% of people aged 60 to 64 years, rising to roughly 20 to 40% of those older than 85 to 90 years.^[1] About 6.7% of people aged 60 to 64 have MCI, rising to 25.2% of those aged 80 to 84.^[5] The most important risk factor is age, but age alone is not enough; it interacts with genes, vascular health and lifestyle.^[1]

Dementia and its precursors are common enough that they are under-detected. In the 2018 AAN MCI guideline, about 14.9% of people with MCI over 65 progressed to dementia over 2 years.^[5] That is a risk, not a prediction for any individual.

• APOE epsilon-4. The best-characterised susceptibility allele for late-onset, sporadic AD. One copy raises risk roughly three-fold; two copies raise it roughly eight-fold.^[1]
• Autosomal dominant mutations. Mutations in APP, PSEN1 or PSEN2 cause early-onset familial AD, mainly by increasing the longer, aggregation-prone amyloid-beta-42 relative to amyloid-beta-40.^[1]
• Down syndrome. Trisomy 21 carries an extra copy of APP on chromosome 21 and leads to Alzheimer-type pathology by middle age; it is a natural model of accelerated amyloid deposition.^[1]
• Young-onset disease can have a genetic cause in some people.^[3]

• Age is the strongest predictor.
• Female sex is associated with higher prevalence, probably through a mix of longevity, hormones and risk-factor profiles.^[1]
• Vascular and lifestyle factors: hypertension, physical inactivity, smoking, diabetes, dyslipidaemia, and untreated chronic inflammation.^[1]
• Head trauma, particularly moderate or severe traumatic brain injury, increases later-life dementia risk.^[1]
• Family history of dementia adds risk, combining genes and shared environment.^[1]

Higher education, complex jobs and strong social support build cognitive reserve. These individuals often compensate for early brain change and present later, sometimes with strikingly advanced brain atrophy by the time they reach clinic.^[1]

Everything in AD follows from two proteins behaving badly: amyloid-beta (A-beta) and tau.

• Amyloid precursor protein (APP) is a normal transmembrane protein. Cleavage by beta- and gamma-secretase releases amyloid-beta peptides. The longer amyloid-beta-42 aggregates.
• Senile plaques are dense, insoluble extracellular deposits of amyloid-beta around neurons and glia. They appear in the hippocampus and association cortices and may start as early as the fifth decade.^[1]
• Soluble amyloid-beta oligomers may be the most neurotoxic species. They disrupt synaptic plasticity and long-term potentiation before plaques are widespread.^[1]
• Tau normally stabilises microtubules. In AD it becomes hyperphosphorylated, leaves the microtubules, and aggregates into neurofibrillary tangles (NFTs) inside neurons. This disrupts axonal transport.^[1]
• NFTs spread in a fairly stereotyped order: transentorhinal and entorhinal cortex first, then limbic regions (hippocampus), then widespread neocortical association areas.^[1]
• Amyloid burden correlates poorly with clinical severity; tau burden and topography track cognitive impairment much better.^[1]

Under the microscope, AD means:

• extracellular senile (amyloid) plaques of amyloid-beta peptide with associated dystrophic neurites and glia;
• intraneuronal neurofibrillary tangles of hyperphosphorylated tau;
• loss of synapses and neurons, particularly in medial temporal and association cortex;
• activated microglia and astrocytes, oxidative stress and (often) small vessel disease.^[1]

The brain shrinks. Cortical atrophy, enlarged ventricles and hippocampal volume loss reflect this. Plaque deposition can coexist with no cognitive impairment in very old people, so diagnosis is never made by pathology alone in life; it is a biological-clinical integration.

AD most often starts insidiously over months to years.^[1]

• Memory for recent events. Difficulty forming new memories, repeated questions, misplacing items, losing track of conversations. Remote memories are relatively preserved early.^[1]
• Executive function. Declining planning, organisation, money management and problem-solving as pathology leaves the medial temporal lobe.^[1]
• Language. Word-finding difficulty and vague speech; fluent but empty in later stages.
• Visuospatial. Getting lost on familiar routes, difficulty with complex spatial tasks.
• Neuropsychiatric. Apathy is common and often precedes obvious functional loss; depression, anxiety, irritability, sleep disturbance, agitation and, later, delusions and hallucinations.^[1]
• Functional decline. Loss of instrumental activities first (finances, medications, shops), then basic self-care.

Red flags for something else:

• sudden or stepwise decline (think vascular)
• early visual hallucinations and fluctuation (Lewy body)
• early behavioural change or language breakdown (frontotemporal)
• young age, rapid progression or family clustering (genetic or prion).

Look for what is not there as much as what is: many examinations are surprisingly normal early on.

• General. Appearance, self-care, gait, affect.
• Cognitive. Orientation, attention, memory, executive function, language, praxis, visuospatial. Use a validated brief tool: MMSE or MoCA in skilled hands.
• Neurological. Usually no focal signs. Look for parkinsonism, apraxia, visual field or cortical sensory deficits. Pronounced focal signs point away from pure AD.
• Functional. Ask about cooking, medications, driving, money and self-care; use an informant.
• Mood and behaviour. Screen for depression, because depression both mimics and coexists with dementia.

The exam is also an opportunity to look for reversible contributors: infection, delirium, depression, sensory impairment, and medicines with anticholinergic burden.^[3]

Use a validated brief instrument, never a single score alone. NICE lists acceptable brief screeners including the 10-point cognitive screener (10-CS), 6-item cognitive impairment test (6CIT), 6-item screener, Memory Impairment Screen (MIS), Mini-Cog and Test Your Memory (TYM).^[3] MMSE and MoCA are widely used in specialist practice.^[3]

No single bedside finding separates all dementias. The table uses the feature that most often points one way rather than another. Use validated criteria for each subtype.^[3]

Two points worth keeping. First, mixed pathology is the rule in very old brains: AD plus vascular lesions, plus Lewy bodies, plus TDP-43. Second, a purely amnestic decline in someone over 80 may not be "just Alzheimer disease".

The purpose of testing is not simply to confirm AD but to exclude reversible causes, characterise the syndrome, and decide whether knowing more would change management.^[3]

1. History from the patient and a reliable informant.
2. Cognitive assessment with a validated instrument.
3. Physical examination.
4. Blood and urine tests to exclude reversible causes.
5. Structural brain imaging (CT or MRI) unless dementia is well established and the subtype is clear.^[3]
6. Specialist assessment (memory clinic, old-age psychiatry or neurology).
7. Further tests only if they would change the diagnosis or management.^[3]

NICE recommends appropriate blood and urine tests to exclude reversible causes of cognitive decline before referral. Typical routine tests include full blood count, urea and electrolytes, calcium, glucose, liver and thyroid function, vitamin B12 and, where epidemiology requires, syphilis or HIV serology. The exact panel should follow local protocol and the patient's context. Delirium, depression and sensory impairment must also be considered. NICE flags medicines that increase anticholinergic burden as a reversible contributor and recommends reviewing them.^[3]

Use a validated brief instrument, never a single score alone. NICE lists acceptable brief screeners including the 10-point cognitive screener (10-CS), 6-item cognitive impairment test (6CIT), 6-item screener, Memory Impairment Screen (MIS), Mini-Cog and Test Your Memory (TYM).^[3] MMSE and MoCA are widely used in specialist practice.

MRI (or CT where MRI is contraindicated or unavailable) looks for reversible or contributory causes: infarcts, tumours, normal-pressure hydrocephalus, subdural haematoma, white-matter disease. It also shows atrophy patterns (medial temporal for AD, posterior cortical for PCA, perisylvian for FTD). NICE advises structural imaging unless dementia is well established and the subtype is clear.^[3] Do not diagnose vascular dementia from lesion burden alone, and do not rule out AD on the basis of CT/MRI.^[3]

• FDG-PET or perfusion SPECT can show temporoparietal hypometabolism when the diagnosis is uncertain and changes management.^[3]
• Amyloid PET confirms amyloid pathology; in the NIA-AA 2024 framework it is a Core 1 biomarker and is diagnostic of AD when positive.^[2]
• Tau PET is a later Core 2 marker used for staging and prognosis rather than for first diagnosis.^[2]

When diagnosis is uncertain and AD is suspected, CSF can be examined for total tau, phosphorylated tau-181, amyloid-beta-42 (or amyloid-beta-40).^[3] In older people, false positives are more likely.^[3] Do not use APOE genotyping or EEG to diagnose AD.^[3]

The NIA-AA 2024 criteria define AD by biology, not by symptoms.^[2] An abnormal Core 1 biomarker is sufficient to diagnose AD:

• amyloid PET;
• CSF amyloid-beta 42/40;
• CSF phosphorylated-tau 181 divided by amyloid-beta 42;
• CSF total tau divided by amyloid-beta 42;
• or an accurate plasma assay whose performance matches approved CSF assays in the intended-use population.^[2]

Core 1 biomarkers become abnormal around the same time as amyloid PET and can identify AD in both symptomatic and asymptomatic people. Core 2 biomarkers (tau PET and selected fluid tau fragments) change later and increase confidence that symptoms are due to AD and help stage disease.^[2] The criteria set a minimum accuracy of 90% for biomarkers intended for clinical diagnosis in the intended-use population.^[2]

Combinations of biomarkers and copathologies are common in older adults. A negative amyloid biomarker result in a person with suspected tauopathy does not fit AD.

Use validated clinical criteria, not test scores alone.^[3] NICE lists accepted subtype criteria including NIA (National Institute on Aging) Alzheimer criteria, McKeith/consensus Lewy body criteria, Rascovsky behavioural-variant FTD criteria, Gorno-Tempini language variants and NINDS-AIREN vascular criteria.^[3]

Staging in practice:

• Biological staging follows the NIA-AA 2024 integrated scheme: amyloid stage, then tau stage, then neurodegeneration and clinical stage.^[2]
• Syndromic staging. Unimpaired (stage 0), MCI, mild, moderate, severe dementia.
• Braak staging describes the anatomical spread of tau: entorhinal (I-II), limbic (III-IV), neocortical (V-VI).^[1]
• Clinical staging guides care far more than any number: can the person make decisions, manage money, live alone, wash, eat?

There is no single pathway. The aim is to diagnose, treat reversible and contributing factors, slow progression where possible, and support independence and quality of life. NICE recommends involving the patient and family in decisions, giving oral and written information at diagnosis, naming a care coordinator, and offering interventions to promote cognition and wellbeing.^[3]

• Treat delirium, depression, pain, infection and sensory impairment.
• Review medicines that increase anticholinergic burden and stop or reduce them.^[3]
• Safety: address falls, wandering, driving and cooking fire risk.
• Share the diagnosis with the patient (with family, if the patient consents) and plan.

NICE technology appraisal TA217 and guideline NG97 recommend:

• Donepezil, galantamine or rivastigmine as monotherapy for mild to moderate AD.^[3][4]
• Memantine monotherapy for moderate AD when a person is intolerant of or has a contraindication to an acetylcholinesterase inhibitor, or for severe AD.^[3][4]
• For a patient already taking an acetylcholinesterase inhibitor, consider memantine in addition for moderate disease and offer it in addition for severe disease.^[3]
• Do not stop acetylcholinesterase inhibitors solely because of disease severity.^[3]
• For an established AD diagnosis, primary care prescribers may start memantine without specialist advice.^[3]

Acetylcholinesterase inhibitors (AChEIs) work by slowing breakdown of acetylcholine, partly compensating for lost cholinergic neurons; this improves symptoms in some patients but does not change the disease course. Expected benefits are modest: stabilisation or modest improvement of cognition, function and behaviour in a subset of patients for months rather than years. Adverse effects are mainly gastrointestinal (nausea, vomiting, diarrhoea), bradycardia and dizziness.^[1][4]

Typical adult dosing from TA217:

• Donepezil: 5 mg once daily at night, increasing after one month to a maximum of 10 mg once daily if needed.^[4]
• Galantamine (modified-release capsules): 8 mg once daily for 4 weeks, then 16 mg once daily for at least 4 weeks; maintenance 16 to 24 mg once daily according to benefit and tolerability.^[4]
• Rivastigmine: start 1.5 mg twice daily, increasing in steps of 1.5 mg twice daily at intervals of at least 2 weeks to a maximum of 6 mg twice daily. Transdermal patch: start 4.6 mg per day, increasing to 9.5 mg per day after at least 4 weeks.^[4]
• Memantine: start 5 mg once daily, increasing in 5-mg steps each week to a maximum of 20 mg daily.^[4]

When choosing an acetylcholinesterase inhibitor, start with the one with the lowest acquisition cost, taking daily dose and price into account, but switch if side effects, comorbidity, interactions or dosing profile favour another.^[3] A baseline cognitive assessment helps interpret later change.

NICE also says not to offer acetylcholinesterase inhibitors or memantine to alter progression with diabetes medicines, antihypertensives, statins or NSAIDs (including aspirin), and not to offer them for frontotemporal dementia, most vascular dementia (unless comorbid AD, DLB or Parkinson disease dementia is suspected) or multiple-sclerosis-related cognitive impairment.^[3]

NICE recommends offering donepezil or rivastigmine for mild to moderate dementia with Lewy bodies, considering galantamine only if those are not tolerated, and considering donepezil or rivastigmine for severe DLB and memantine if AChEIs are not tolerated.^[3] Note that antipsychotics can worsen parkinsonism or trigger neuroleptic sensitivity reactions in DLB.^[3]

Anti-amyloid monoclonal antibodies (lecanemab, donanemab) reduce amyloid plaque and, in trials, produced modest slowing of cognitive decline in selected early-stage patients:

• Lecanemab in CLARITY-AD slowed decline over 18 months with robust amyloid reduction.^[1]
• Donanemab in TRAILBLAZER-ALZ 2 showed slowing of decline in early symptomatic AD with intermediate tau burden.^[1]

They are not yet incorporated into the opened NICE NG97 recommendations (last reviewed October 2025), and availability is region-dependent. Product labels state:

• Lecanemab (LEQEMBI): treated patients with MCI or mild dementia. Starting dose: intravenous 10 mg/kg once every 2 weeks (infused over about an hour) or subcutaneous 500 mg once weekly; after 18 months, continue or transition to intravenous maintenance 10 mg/kg once every 4 weeks or subcutaneous 360 mg once weekly. Check APOE epsilon-4 status before starting; homozygotes carry higher ARIA risk. Dilute in 250 mL of 0.9% sodium chloride for intravenous use.^[6]
• Donanemab (KISUNLA): intravenous 350 mg (infusion 1), 700 mg (infusion 2), 1,050 mg (infusion 3), then 1,400 mg every 4 weeks. Given as a 30-minute infusion, with baseline MRI and repeat MRI before the 2nd, 3rd, 4th and 7th infusions. Consider stopping based on amyloid PET reduction.^[7]

Safety issues with this drug class:

• ARIA (amyloid-related imaging abnormalities): vasogenic oedema (ARIA-E) or microhaemorrhages/superficial siderosis (ARIA-H), most often in the first months; more common in APOE epsilon-4 carriers (homozygotes more).^[1][6][7]
• ARIA may be asymptomatic or may present with headache, confusion, focal deficits or seizures. Careful patient selection and MRI surveillance are essential.^[1]
• Infusion reactions and hypersensitivity (donanemab).
• These agents do not reverse cognitive loss; the absolute benefit is modest and the risk-benefit discussion should be individualised, especially in people with vascular risk factors or microbleeds.

The 2018 AAN guideline on MCI (itself an update of a 2001 parameter, and now marked retired) recommends: assess for MCI with validated tools; evaluate modifiable risk factors; assess functional impact; monitor over time; wean cognitively impairing medications where possible; do not routinely offer cholinesterase inhibitors, and if offering them, disclose the lack of evidence; recommend regular exercise (twice weekly); consider cognitive training; and discuss diagnosis, prognosis and planning.^[5] No pharmacological agent is approved for MCI.^[5]

• Progressive loss of independence in instrumental then basic activities of daily living, often requiring full care.
• Neuropsychiatric and behavioural symptoms (apathy, depression, agitation, hallucinations) that drive carer burden and hospitalisation.^[1][3]
• Delirium superimposed on dementia, especially during hospital admission; risk awareness is essential.^[3]
• Falls, fractures and immobility from gait and perceptual impairment.
• Weight loss and swallowing problems in late disease; NICE advises not routinely using enteral feeding in severe dementia.^[3]
• Medication-related harm: anticholinergic burden, over-sedation, infection from immobility.
• Carer morbidity: depression and burnout; carers of people with dementia are at increased risk of depression.^[3]
• Neuroleptic sensitivity in DLB if antipsychotics are used.^[3]

Prognosis in AD is variable and is shaped by age at diagnosis, comorbidity, stage at presentation and the support available. NICE emphasises that decline is unpredictable and that planning should start early.^[3] There is no fixed survival figure in the sources used here, and averages are a poor guide for an individual. Discuss prognosis honestly but without false precision, and encourage advance care planning, lasting power of attorney, wills and driving decisions before capacity is lost.^[3] Reversible factors (medication, depression, sensory loss) can improve the picture; first presentations labelled as dementia sometimes improve back towards normal cognition.

• Mid-life risk reduction is the strongest lever: control blood pressure, treat diabetes and dyslipidaemia, stop smoking, increase physical activity, reduce harmful alcohol use and manage weight.^[1] NICE has a separate guideline on mid-life approaches to delay or prevent dementia (NG16).^[3]
• Mental and social activity: cognitive stimulation and meaningful activity are encouraged; group cognitive stimulation therapy is recommended by NICE for mild to moderate dementia.^[3]
• Exercise: regular exercise is recommended in MCI and is associated with reduced dementia risk.^[1][5]
• Diet: patterns such as Mediterranean or MIND diets are associated with better cognitive outcomes, though evidence quality varies.^[1]
• Screening and case finding. NICE says only conduct case finding for suspected dementia as part of a clinical trial that also provides an intervention.^[3] The Medicare Annual Wellness Visit in the US requires an assessment to detect cognitive impairment rather than relying on subjective complaints alone.^[5]
• Non-drug treatments with no benefit. NICE does not recommend acupuncture, ginseng, vitamin E, herbal formulations, cognitive training or interpersonal therapy to treat mild to moderate AD, and does not recommend non-invasive brain stimulation outside trials.^[3]
• No pharmacological prevention. NSAIDs, statins, antihypertensives or diabetes medicines are not offered specifically to slow progression outside trials.^[3]

• Older adults. Diagnosis is complicated by comorbidity, sensory impairment and medication burden; tailor assessment scales to any disability.^[3] Mixed pathology is common.
• Young-onset (under 65 years). May be genetic; involve specialist services. Prompt APOE or monogenic testing only when it changes counselling.^[3]
• Down syndrome and other intellectual disability. Alzheimer-type pathology emerges earlier; use adapted assessments and pathways.^[1][3]
• Pregnancy is rarely relevant to AD itself; management of a younger person with genetic disease requires specialist reproductive and genetics counselling.
• Children are not affected by typical AD; rarer paediatric dementia syndromes belong to different topics.
• Carers and family members are a "special group" in practice: they are patients too, with elevated depression risk, and need training, respite and planning support.^[3]

• Dementia is a syndrome, not a diagnosis; AD is its commonest cause, responsible for roughly 60 to 80% of cases.^[1]
• AD is defined by amyloid and tau pathology, and by abnormal Core 1 biomarkers, even before symptoms appear.^[2]
• Age is the dominant risk factor, with prevalence rising from about 1% at 60-64 years to 20 to 40% over 85-90 years.^[1]
• APOE epsilon-4 raises late-onset AD risk roughly three-fold (one allele) to eight-fold (two alleles); rare APP, PSEN1 and PSEN2 mutations cause early-onset disease.^[1]
• Clinical onset is usually insidious amnestic cognitive decline, with relative sparing of remote memory early on.^[1]
• Validated criteria, not scores alone, make the diagnosis of dementia subtype.^[3]
• MMSE is usually interpreted with a cut point around 24; MoCA uses 26 and over as its normal range (25 or below impaired), adjusting for education.^[8][9]
• Structural imaging is routine; FDG-PET/SPECT, CSF and amyloid PET are reserved for cases where the result changes management.^[3]
• Reversible causes (delirium, depression, infection, sensory loss, anticholinergic medicines) must be sought and treated first.^[3]
• Cholinesterase inhibitors are first-line pharmacological treatment for mild to moderate AD; memantine for moderate (intolerance/contraindication) or severe disease, added to an AChEI in moderate to severe disease.^[3][4]
• Typical adult dosing: donepezil 5 mg nightly then up to 10 mg; galantamine 8 mg then 16-24 mg; rivastigmine 1.5 mg twice daily up to 6 mg twice daily (or 4.6-9.5 mg patch); memantine 5 mg up to 20 mg daily.^[4]
• Anti-amyloid monoclonal antibodies (lecanemab, donanemab) give modest slowing in selected early-stage disease but carry ARIA risk and require MRI surveillance.^[1][6][7]
• AChEIs are not offered for MCI; exercise, risk-factor control and planning are the mainstays.^[5]
• Mixed pathology is common in older brains; "Alzheimer disease alone" is an oversimplification in the very old.^[1]
• Advance care planning, carer support, medication review, safety and driving decisions are as important as any drug.^[5]

• Cognitive assessment and delirium in older adults
• Vascular dementia and mixed dementia
• Dementia with Lewy bodies and Parkinson disease dementia
• Frontotemporal dementia
• Depression in older adults
• Drivers of dementia prevention and risk reduction>