Alzheimer's disease

Notes

Overview

Alzheimer’s disease is the most common cause of dementia.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes significant deterioration in mental performance. This leads to impairment in normal social and occupational function. Unfortunately, AD is an incurable condition that has a variable clinical course. It is the most common cause of dementia.

Dementia

Dementia describes a clinical syndrome that is characterised by a significant deterioration in mental function that leads impairment of normal function.

In healthcare, we measure ‘normal function’ by activities of daily living (ADLs). These are a series of routine activities that people should be able to do without assistance. They can be broadly divided into personal tasks and domestic tasks.

  • Personal: washing, dressing, toileting, continence, transferring (e.g. bed to chair)
  • Domestic: cooking, cleaning, shopping, managing finances, taking medication

Types of dementia

Dementia can be caused by several conditions, which all manifest with poor mental performance and impaired normal functioning. The clinical manifestations of dementia can reflect the underlying aetiology.

For a comprehensive overview of dementia, see our Dementia note.

Epidemiology

Dementia is primarily a disease of older adults.

The World Health Organisation (WHO) estimates that almost 50 million people have a diagnosis of dementia worldwide. In the UK, it is estimated that > 500,000 people have a diagnosis of AD.

The prevalence of dementia increases with age. The estimated prevalence at 60-64 years is 0.9% compared to 41.1% in those aged 95 years and over. 

A significant proportion of patients with dementia remain undiagnosed and up to 54% of patients with dementia require care home placement.

Aetiology

The exact cause of AD remains unknown.

The overarching theory involves environmental and genetic risk factors that increase the chance of developing pathological processes, which lead to dementia. 

Commonly recognised risk factors

  • Age: older age is a major risk for AD
  • Genetics*: most cases of AD are sporadic. Small number of inherited causes exist (<5%, autosomal dominant inheritance). Inherited causes suggested by early-onset disease. Mutations in the amyloid precursor protein (APP) and presenilin genes (PSEN1, PSEN2) have been identified.
  • Cardiovascular disease: smoking and diabetes increase risk. Exercise decreases risk.
  • Depression
  • Low educational attainment
  • Low social engagement and support
  • Others: head trauma, learning difficulties.

*NOTE: alleles of the cholesterol-carrying apolipoprotein E (APOE) have also been identified as a biological risk factor for AD.

Pathophysiology

The neurodegeneration in AD is hypothesised secondary to altered amyloid and tau protein metabolism.

The brain is composed of billions of neurons. The normal functioning of theses neurons is dependent on surrounding supportive structures such as microtubules and the protein tau, which stabilise these microtubules. 

Pathological changes that occur in AD leads to interruption of key neuronal process including communication, metabolism and repair. This ultimately leads to neuronal cell death.

The two key pathological changes in AD are senile plaques and neurofibrillary tangles:

  • Senile plaques (SP): deposits of beta-amyloid (aggregation of protein with a beta-sheet secondary structure). Dense, insoluble. Occur outside of neurons (i.e. extracellular).
  • Neurofibrillary tangles (NFT): aggregations of hyperphosphorylated tau proteins. Typically occur in areas of the brain involved in memory. Promote neuronal cell death. Form inside neurons (i.e. intracellular)

Both SP and NFT are characteristic of AD but no pathognomonic. They can be seen in other neurodegenerative conditions. SP is also seen in normal ageing. Therefore, it is the amount of these pathological changes and the topographic location within the brain (e.g. hippocampus and medial temporal lobes) which is characteristic of AD. 

The amyloid deposition hypothesis is supported by identification of genetic mutations in the amyloid precursor gene APP leading to early-onset AD, and evidence of neuronal apoptosis on treatment of cells with beta-amyloid. However, some patients with severe AD do not have evidence of amyloid deposition on autopsy, and other patients who had no evidence of dementia have amyloid deposition. Therefore, it is not the complete story. 

Several additional mechanisms are part of the pathological processes in AD. Alongside SP and NFT, these result in neuronal cell death that leads to memory failure, personality changes and problems with activities of daily living (hallmarks of dementia). 

Clinical features

Dementia can be difficult to identify due to the insidious and non-specific symptoms.

Many clinical features are attributable to dementia. Some are characteristic of all dementias whereas others are typical of a particular type, like AD. There is usually a slow onset of symptoms and a lack of insight with accommodation to cognitive or functional changes.

The clinical features of dementia can be considered in the following domains:

  • Cognitive impairment: poor memory, disorientation, language problems
  • Behavioural and psychological symptoms of dementia (BPSD): agitation, depression, sleep cycle disturbance, motor disturbance
  • Disease-specific features: AD is characterised by early impairment of memory. This manifests as short-term memory loss and difficulty learning new information
  • Activities of daily living: an increasing reliance on others for assistance, problems with high-level functioning (e.g. work, finance), problems with basic personal care

For more comprehensive information on clinical features see our Dementia note.

Cognitive assessment

A formal mental status examination should be completed using a recognised cognitive assessment tool.

There are multiple cognitive assessment tools, which are designed to test different areas of higher cortical functioning. Cognitive domains assessed include:

  • Attention and concentration
  • Recent and remote memory
  • Language
  • Praxis: planned motor movement (e.g. perform a task)
  • Executive function
  • Visuospatial function

There are a variety of different cognitive assessment tools that range from basic screening tools, to in-depth assessments of each cognitive domain.

A comprehensive summary of cognitive assessment tools can be found in our Dementia note.

Diagnosis

It is essential to exclude all alternative causes before making a diagnosis of dementia.

Patients with suspected dementia are usually referred to a memory clinic.

At memory clinic, patients undergo a formal history and examination (including medication review), full complement of baseline investigations including bloods and neuroimaging to exclude an underlying cause, and formal cognitive assessment.

During these investigations, the specific type of dementia may become apparent. In AD, this may be reflected by the lack of other neurological symptoms, absence of major cardiovascular risk factors and predominant impairment in memory, thinking and behaviour. 

Diagnostic criteria

There is a diagnostic criteria for dementia based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). 

We have simplified this into three key components:

  • Functional ability: inability to carry out normal functions. Represents a decline from previous functional level
  • Cognitive domains: impairment involving ≥2 cognitive domains (see chapter on cognitive assessment)
  • Differentials excluded: clinical features cannot be explained by another cause (esp. psychiatric disorders and delirium)

Mild cognitive impairment

This describes cognitive deficits in one or more of the major cognitive domains, but the deficit is insufficient to interfere with independence in daily activities.

Mild cognitive impairment is an increasingly important term because it helps identify patients at risk of progression to dementia. Patients should have regular follow-up and be advised to undertake healthy brain activities (e.g. exercise, socialising).

Differential diagnosis

Dementia is a clinical syndrome that reflects deterioration from an underlying cause, the most common being AD. The main differentials to exclude in a patient with features of dementia are the three ‘D’s’:

  • Depression (and other psychiatric disorders): psychosis can be a feature of dementia. 
  • Drugs: consider drugs with anti-cholinergic effects (e.g. anti-histamines, anti-psychotics, anti-epileptics)
  • Delirium: acute confusional state. May be prolonged recovery following episode.

Investigations

Baseline investigations are essential to exclude an alternative diagnosis.

Typical baseline investigations involve a routine set of blood tests and neuroimaging.

Bloods

  • Full blood count
  • Erythrocyte sedimentation rate (ESR)
  • Urea and electrolytes
  • Bone profile
  • HbA1c
  • Liver function tests
  • Thyroid function tests
  • Serum B12 and folate levels

Other

  • ECG
  • Virology (e.g. HIV)
  • Syphilis testing
  • CXR

Neuroimaging

Typically magnetic resonance imaging (MRI) but CT may be used if MRI not available or unsuitable. Important to exclude an alternative diagnosis (e.g. brain tumour) and can be used to help characterise the type of dementia (e.g. small vessel disease in VD).

Future areas

The use of biomarkers and more advanced imaging (e.g. functional MRI) are being increasingly used in a research capacity to predict the likelihood of developing AD.

Management

Pharmacological therapy can be used in patients with AD, but it is only a small part of overall management.

The management of AD, and dementia as a whole, should involve a full assessment of the biological, psychological and social needs of the patient. With significant deterioration in normal activities of daily living, patients will become dependent on others. This means help from families, organisation of carers, and with more advancing symptoms, need for care home placement.

There are multiple facets to management, which we summarise.

  • Assess capacity and advanced care planning: ideally completed when patients still retain capacity. Consideration of advance statements/decisions and appointment of lasting power of attorney.
  • Physical and mental health: consider co-existing anxiety and depression. Manage physical health needs as normal. Consider delirium if any acute deterioration.
  • Driving: must inform the DVLA. Check website for guidance.
  • Pharmacological: (see below)
  • Non-pharmacological: programmes to improve/maintain cognitive function (e.g. structured group cognitive stimulation programmes). Also exercise, aromatherapy, therapeutic use of music/dancing, massage.
  • Managing BPSD: non-pharmacological interventions. Consider referral to old-age psychiatry if difficult to control. Pharmacological therapy should be used on specialist advice.
  • Care plans: people with dementia require a care manager and care plan. This includes details on diagnosis, treatment, environmental modifications and review plans.
  • End-of-life care: focus on physical, psychological, social and spiritual needs. Oral nutrition encouraged as long as possible. Long-term feeding (i.e. NG feeding, gastrostomy tube) inappropriate in severe dementia. No evidence for increased survival or reduced complications. Resuscitation discussions.

Pharmacological therapy

Medical therapy for the treatment of dementia should be initiated by a specialist in treating patients with dementia. The two main drugs are acetylcholinesterase inhibitors and N-methyl-D-aspartic acid receptor antagonists.

Pharmacological agents are primarily indicated in patients with AD. They should not be used in patients with mild cognitive impairment.

Choice of therapy depends on severity:

  • Mild-to-moderate AD: acetylcholinesterase inhibitors (e.g. donepezil, rivastigmine).
  • Moderate-to-severe AD: N-methyl-D-aspartic acid receptor antagonist (e.g. memantine). May be used in combination with acetylcholinesterase inhibitors.

Acetylcholinesterase inhibitors are associated with small improvements in cognition, neuropsychiatric symptoms, and ADLs in patients with mild-to-moderate AD. However, there is conflicting evidence on there impact on long-term outcomes (e.g. need for care home, effect on critical ADLs).

Memantine has modest effects in patients with moderate-to-severe AD in terms of reducing functional decline.


Last updated: May 2022
Author Dr. Benjamin Norton Ben is Medical Registrar in London. Outside of work he enjoys cricket and rugby.

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