Chronic organic brain syndrome: dementias. Alzheimer’s disease, vascular dementia, and dementia with Lewy bodies. Clinical features, etiology, and treatment

01Definition and overview

Dementia is a syndrome, not a single disease: an acquired decline from a previous level in memory and other cognitive functions, such as language, orientation, judgement, planning and visuospatial skills, with clear consciousness, which interferes with independence in everyday life. Changes in emotional control, behaviour and motivation often come with it or before it. ICD-10 asks for at least six months of symptoms for a confident diagnosis.

A decline that can be measured but leaves independence intact is mild cognitive impairment. In clinic samples about 1 in 10 people with it progress to dementia each year, fewer in the community, and some return to normal. Dementia beginning before the age of 65 is young-onset dementia.

ICD-11 also grades dementia as mild, moderate or severe and names Lewy body disease, which ICD-10 has no code for. Older texts divide dementias into cortical (Alzheimer's, frontotemporal: amnesia, aphasia, apraxia, agnosia) and subcortical (vascular, Parkinson's, Huntington's, HIV: slowness, apathy, poor retrieval), a useful but rough distinction.

02Etiology and pathophysiology

The shares are approximate and differ between clinical and post-mortem series; in people over 80, mixed Alzheimer's and vascular disease, often with Lewy bodies, is the rule.

Alzheimer's disease

In the amyloid hypothesis, a simplification of a debated sequence, amyloid-β made from amyloid precursor protein builds up as plaques for 15 to 20 years before symptoms. It is followed by the spread of tangles of hyperphosphorylated tau from the entorhinal cortex and hippocampus to the association cortex, by inflammation and by loss of synapses and neurons. Loss of the cholinergic neurons of the basal forebrain lowers cortical acetylcholine, the basis of the cholinesterase inhibitors. Criteria revised by the US Alzheimer's Association in 2024 define Alzheimer's disease by its biology, abnormal amyloid and tau biomarkers, even before symptoms; an international working group and clinical practice keep the diagnosis for people with symptoms.

• Age is the strongest risk: prevalence roughly doubles every five years after 65.
• The APOE ε4 allele on chromosome 19 is the main common risk gene. About a quarter of Europeans carry one copy, which roughly triples the risk; about 2 in 100 carry two, with a risk about ten times higher or more and an earlier onset. ε2 protects.
• Mutations in APP, PSEN1 or PSEN2 cause autosomal dominant Alzheimer's disease, under 1 per cent of cases, with onset often in the 40s or 50s.
• People with Down syndrome have three copies of APP; most develop Alzheimer's pathology by 40 and many dementia by their 50s and 60s.

Vascular dementia

Cognitive impairment follows cerebrovascular disease: several cortical infarcts, a single infarct in a strategic place such as the thalamus, or, most often, small vessel disease with lacunes and white matter damage. The risk factors are those of stroke: hypertension, diabetes, smoking, atrial fibrillation, high cholesterol.

Lewy body dementias

Aggregates of α-synuclein form Lewy bodies in the brainstem, limbic system and cortex. The cholinergic loss is deeper than in Alzheimer's disease, which is why cholinesterase inhibitors often help, and nigrostriatal dopamine loss explains the parkinsonism and the sensitivity to dopamine blockers. Dementia with Lewy bodies and Parkinson's disease dementia are one spectrum, separated by a convention, the one-year rule: dementia before or within a year of parkinsonism is dementia with Lewy bodies; dementia after more than a year of established Parkinson's disease is Parkinson's disease dementia.

Frontotemporal dementia

Frontotemporal lobar degeneration has tau, TDP-43 or FUS inclusions. About 4 in 10 patients have a family history; the commonest genetic causes are a repeat expansion in C9orf72, which also causes motor neurone disease, and mutations in MAPT and GRN. A minority of patients develop motor neurone disease.

Other and reversible causes

Dementias that reverse completely are rare, but treatable conditions that worsen cognition are common, so they are always sought.

Modifiable risk

The 2024 Lancet Commission linked about 45 per cent of dementia worldwide to 14 risk factors: less education in early life; hearing loss, high LDL cholesterol, depression, head injury, physical inactivity, diabetes, smoking, hypertension, obesity and heavy drinking in midlife; and social isolation, air pollution and untreated loss of vision in later life. Hearing loss and high LDL cholesterol carry the largest shares. These are associations from observational studies, and the share is an estimate, but the age-specific incidence of dementia has fallen in several high-income countries.

03Clinical features

Alzheimer's disease begins with episodic memory, the learning of new information, and spreads to language (word-finding, then comprehension), visuospatial skills, praxis and recognition; less common onsets are visual (posterior cortical atrophy), language (logopenic aphasia) or frontal. Frontotemporal dementia can also start with language: semantic dementia, losing the meaning of words and objects, or progressive non-fluent aphasia, effortful, ungrammatical speech.

In dementia with Lewy bodies the four core features are fluctuating cognition, recurrent well-formed visual hallucinations, REM sleep behaviour disorder and parkinsonism. Two of them, or one with a supporting test such as a dopamine transporter scan, make the diagnosis probable. Severe sensitivity to antipsychotics, falls, fainting and autonomic failure support it.

Behavioural and psychological symptoms affect most people with dementia at some stage: depression, anxiety, apathy, agitation and aggression, wandering, disturbed sleep, and psychotic symptoms such as delusions of theft or visual hallucinations. They distress patients and carers more than the memory loss and are a common reason for moving into a care home. In severe dementia people need help with all care, lose speech and mobility, become incontinent and have difficulty swallowing; death usually comes from pneumonia or another infection.

04Diagnosis and management

Assessment

1. 1

   History

   From the patient and someone who knows them well: what changed, when, how fast and in what order; daily function, safety, driving and finances; mood; drugs and alcohol; vascular risk; family history.
2. 2

   Exclude mimics

   Look for delirium, which is acute and fluctuating, and depression, and review drugs with anticholinergic effects.
3. 3

   Cognitive testing

   A validated brief test in primary care, such as the Mini-Cog or the 6-item cognitive impairment test; in memory clinics the ACE-III, MoCA or MMSE. A normal score does not exclude dementia, especially frontotemporal.
4. 4

   Tests

   Full blood count, ESR or CRP, urea and electrolytes, calcium, HbA1c, liver and thyroid function, B12 and folate; syphilis and HIV serology where there is a risk; structural imaging, usually MRI, to find vascular disease, tumours, subdural haematoma or hydrocephalus and the pattern of atrophy.
5. 5

   Specialist tests

   When the type is uncertain: FDG-PET or perfusion SPECT, cerebrospinal fluid amyloid and tau, or amyloid PET for Alzheimer's disease; a dopamine transporter scan for Lewy body dementia. Blood tests for phosphorylated tau are entering specialist practice.

The diagnosis is given honestly and with support, with time for questions, information about the type of dementia, and planning while the person can still decide: a lasting power of attorney (in the UK, with equivalents elsewhere), advance decisions and care preferences. Driving is reviewed, and in the UK the patient must tell the licensing agency.

Drugs for cognition

Cholinesterase inhibitors slow the heart and can cause bradycardia, heart block and syncope, so the pulse is checked first and they are used with care in conduction disease. Their benefit is modest on average, a small improvement or a delay in decline over months, though some patients gain more. UK guidance:

• Offer donepezil, rivastigmine or galantamine for mild to moderate Alzheimer's disease.
• Offer memantine for moderate disease if the inhibitors are not tolerated, and for severe disease; consider adding it to an inhibitor in moderate disease, and offer it in severe.
• Do not stop an inhibitor because of severity alone.
• Offer donepezil or rivastigmine in dementia with Lewy bodies.
• Do not use these drugs in vascular dementia without coexisting Alzheimer's or Lewy body disease, nor in frontotemporal dementia, where they can worsen behaviour. They do not help mild cognitive impairment.

Antibodies against amyloid

Lecanemab and donanemab are monoclonal antibodies that clear amyloid plaques. They are the first treatments shown to slow the disease, but by a small amount, and their main harm, amyloid-related imaging abnormalities, needs repeated MRI.

The absolute difference was under one point on an 18-point dementia rating scale, and how much it means for patients is debated. Amyloid-related imaging abnormalities are brain oedema (ARIA-E) and microbleeds or superficial siderosis (ARIA-H). Most are seen on MRI without symptoms in the first months, but they can cause headache, confusion, seizures and, rarely, fatal haemorrhage.

In the EU both are authorised only for mild cognitive impairment or mild dementia due to Alzheimer's disease, with amyloid confirmed by PET or cerebrospinal fluid, in people who are not APOE ε4 homozygotes, which needs genetic testing and counselling first. Treatment is not started in people on anticoagulants or with more than four microbleeds or other signs of amyloid angiopathy on MRI. They are given within a controlled access programme with scheduled MRI scans and a patient card. The UK regulator licensed both in 2024 for the same groups, but NICE did not recommend either for routine NHS use in 2025. Appeals succeeded and the appraisals were reopened in 2026. In mid-2026 NICE paused its final guidance on lecanemab, and offered the same for donanemab, so that the companies could negotiate prices with NHS England; neither is yet available for routine NHS use. Availability varies between European countries.

Behavioural and psychological symptoms

The first step is to look for a cause: pain, constipation, infection or delirium, hunger, fear, a noisy or unfamiliar place, or care that does not suit the person. Person-centred care, activities, music, exercise, and support and training for carers come next. Cognitive stimulation therapy in groups is offered for mild to moderate dementia.

Antipsychotics are only for people at risk of harming themselves or others, or with agitation, hallucinations or delusions that cause severe distress. They raise the risk of stroke about threefold and of death by about 1.5 to 1.7 times in dementia, and cause falls, sedation and faster cognitive decline. Risperidone is the one licensed in the UK and much of Europe, for up to six weeks of persistent aggression in moderate to severe Alzheimer's disease. The dose is the lowest that works, reviewed at least every six weeks, and the drug is stopped when there is no clear benefit. In Lewy body dementias antipsychotics, above all haloperidol, can cause severe sensitivity reactions; a specialist decides if one is unavoidable.

Antidepressants work little better than placebo for mild to moderate depression in dementia, so psychological approaches come first. Valproate is not used for agitation, and hypnotics and anticholinergic drugs are avoided.

05Epidemiology

living with dementia worldwide in 2021

57 millionpeopleliving with dementia worldwide in 2021

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10 millionnew cases a yearworldwide

worldwide, and a leading cause of disability in older people

5thleading cause of deathworldwide, and a leading cause of disability in older people

Dementia affects about 5 to 8 in 100 people over 60. The prevalence roughly doubles with every five years of age, from about 1 in 100 in the early 60s to around 1 in 5 in the late 80s, and higher still over 90. The number of people affected is expected to grow with the ageing of the population, most in low- and middle-income countries, where over 60 per cent of patients already live. More women than men have dementia, mainly because women live longer. Young-onset dementia is much rarer, with Alzheimer's and frontotemporal dementia the commonest causes. The annual cost worldwide was estimated at about 1.3 trillion US dollars in 2019, about half of it informal care by families.

06Prognosis

Dementia shortens life. From diagnosis, people with Alzheimer's disease live on average about 4 to 8 years, fewer when diagnosed late in life and more when young; vascular dementia often runs a shorter course, with death from heart disease or stroke; dementia with Lewy bodies progresses at least as fast as Alzheimer's; frontotemporal dementia about 8 years on average, and only 2 to 3 when motor neurone disease is added. Sporadic Creutzfeldt–Jakob disease is usually fatal within a year.

The drugs available change symptoms and, with the antibodies, slow early Alzheimer's disease modestly, but none stops the disease. Outcomes depend much on good care: treating other illnesses, avoiding harmful drugs, supporting carers, and planning for the last stage, when comfort and dignity matter more than prolonging life. Hospital admissions, with their risk of delirium, are best avoided where possible.