Clinical review - Alzheimer's disease

Contributed by Dr Andrew Larner, consultant neurologist at the Walton Centre for Neurology and Neurosurgery, Liverpool, and Kathleen Storton, a dementia support worker at the Alzheimer's Society.

Scan of a normal patient (left) and AD patient (right). Blue/black areas show reduced brain activity (Photograph: SPL)
Scan of a normal patient (left) and AD patient (right). Blue/black areas show reduced brain activity (Photograph: SPL)

Section 1: Epidemiology and aetiology
Alzheimer's disease (AD) is the most commonly identified aetiology of dementia and cognitive impairment. Ageing is the most important risk factor for the development of AD, with numbers of individuals affected increasing exponentially after age 65 years.

The Dementia UK study estimated that 700,000 people in the UK have AD.1 This number is set to rise with the ageing of the population, not just in the UK but worldwide, with consequent social and financial repercussions.

Genetic determinants
In early-onset dementia (previously known as 'pre-senile dementia'), defined as those with age of onset less than 65 years AD and frontotemporal lobar degenerations ftlds may be equally common the differential diagnosis is broader.2 Early-onset AD may be genetically determined, demonstrating an autosomal dominant pattern of inheritance.

Such cases may be a consequence of deterministic mutations in three different genes: amyloid precursor protein, presenilin 1 (the most common), and presenilin 2. Presenilin 1 gene mutations may be associated with other neurological signs in addition to dementia, including myoclonus, epileptic seizures, Parkinsonism, (all of which may occur in late-onset sporadic disease), spastic paraparesis, and cerebellar ataxia.3

Pathophysiology
The biology of AD is similar in all age groups, hence the classification into earlyand late-onset disease is arbitrary. The key pathophysiological pathway, elucidated largely through study of genetically determined AD, is believed to be overexpression of amyloid beta-peptides which, particularly in the soluble and oligomeric forms, cause neuronal dysfunction and ultimately death.

Micrograph of AD brain tissues: large amyloid plaque (lower left) (Photograph: SPL)

Excess peptides may aggregate to form amyloid plaques, a neuropathological signature of AD although of uncertain pathophysiological relevance.

Neurofibrillary pathology, both as neurofibrillary tangles and threads, shows greater correlation with the degree of cognitive decline than plaque pathology, and follows a hierarchical pattern of spread from temporal cortex to association cortices.

Medication to disrupt these pathophysiological pathways remains a therapeutic goal. Attempts so far have floundered in the clinic despite encouraging animal model work in the laboratory.

Concurrent cerebrovascular disease is common in late-onset AD, where it may lower the threshold for the clinical expression of AD.

Loss of the cortical cholinergic input from the basal forebrain is one of the important neurochemical alterations in AD brain, which has proved to be a therapeutic target. Besides ageing, a number of possible risk factors for AD are recognised, some of which might be amenable to intervention.

These include midlife hypertension and possibly hypercholesterolaemia.

Section 2: Making the diagnosis
AD diagnosis is based on the clinical features, in particular the history, supplemented with investigations (rather than the other way round). Typically AD patients present with a history, usually given by relatives or carers, indicative of an amnesic syndrome.

This difficulty registering new information may be characterised by patients and carers as 'a problem with short-term memory'. For example, there may be repeated questioning over short periods of time (for example, 'What day is it?', 'Where are we going?') or repeated telling of the same information or stories.

Distant memories are often better preserved, indicative of a temporal gradient of memory dysfunction and the early predilection for hippocampal neurons. Patients are often largely unaware of these deficits, hence the importance of obtaining collateral history.

This unawareness may be characterised by relatives as 'denial' whereas it more likely represents cognitive anosognosia. Certainly, many AD patients appear to be able to conceal their symptoms to an extent, and make light of their difficulties when seen at consultation.

A high index of clinical suspicion, guided by the collateral history, may therefore be required, with longitudinal assessment in cases of uncertainty.

Primary care physicians are ideally placed for this.

Cognitive screening tests
Investigations are indicated to confirm or refute clinical suspicions. Simple cognitive screening tests are of particular value, although somewhat seldom reportedly used by primary care physicians.4

The mini mental state examination (MMSE), though sometimes recommended, is perhaps too long for routine use in primary care. Briefer tests specifically designed for use in the primary care setting include the six-item cognitive impairment test (6-CIT), the general practitioner assessment of cognition (GPcog), and the mini-cognitive assessment instrument (mini-cog), although there is little evidence to suggest that they have superseded the MMSE.4

The specificity and sensitivity of these instruments is reported to be around 80 per cent or better, with mini-cog claiming a particularly high sensitivity (99 per cent), which of course will also entail an increased risk of false positive diagnoses and a lower specificity.

Imaging
Guidelines for AD diagnosis recommend brain imaging.

Brain imaging can be used to exclude differential diagnoses (Photograph: SPL)

This has traditionally had a function of ruling out structural conditions which may present with cognitive decline, such as subfrontal brain tumour and normal pressure hydrocephalus. The observation of 'brain atrophy' is not equivalent to a diagnosis of AD, just as small vessel ischaemic (microangiopathic) change is not equivalent to a diagnosis of vascular dementia, both being common findings in normal older patients.

It should be emphasised that the differential diagnosis of memory complaints is broad.

Investigations for other possible, potentially reversible, causes of dementia may be undertaken (Hb, calcium, TFTs, vitamin B12), but the pick-up rate is low. Depression screening, such as the patient health questionnaire, may also be administered.

Section 3: Managing the condition
Management begins with explanation, provision of information, and support. Input from organisations such as the Alzheimer's Society can be invaluable at this stage, when patients and families are often dealing with the impact of the diagnosis, even when they have harboured suspicions about the possibility.

Patients may also need to be reminded of their statutory obligation to inform the DVLA of their change in status.

If the clinician has legitimate concerns about the safety of the patient and/or others, advice against driving may be given.

Pharmacotherapy
The spirit of therapeutic nihilism, which prevailed for many years, has now been superseded by a modest optimism with the advent of symptomatic drugs.

Current treatments include cholinesterase inhibitors (ChEIs) and memantine. ChEIs address the cholinergic deficit found in AD brains by inhibiting the enzyme acetylcholinesterase, responsible for acetylcholine breakdown.

Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is believed to reduce oxidant stress and thus protect neurones from damage.

Both drug classes are licensed for the symptomatic treatment of AD.

ChEIs are generally well-tolerated, GI upset being the most common adverse effect, but clinical benefits are generally modest. Transdermal formulations of ChEI may be tried if GI side-effects are limiting.

Epidemiological studies suggesting possible benefits of NSAIDs and of HRT in AD have not been borne out in randomised clinical trials.

Future therapies
The development of disease-modifying therapy remains a future goal. So called vaccines, which aim to remove amyloid from the brain by means of active immunisation, generated many headlines when first used in animal models, but their clinical application has been associated with safety and efficacy issues.

Passive immunisation with antibodies directed against amyloid beta-peptides has likewise run into difficulty. Drugs to inhibit the secretase enzymes responsible for biosynthesis of amyloid beta-peptides are also undergoing investigation, but have also had setbacks after promising pilot studies.

Behavioural and psychiatric symptoms
Behavioural and psychiatric symptoms of dementia (BPSD) become more prevalent as AD progresses. Widespread use of antipsychotic medication for these symptoms has been associated with an excess mortality from cerebrovascular disease, such that substantial reduction in the use of these medicines is a central component of current health policy.

Behavioural approaches are favoured, but this remains a difficult area when patients are a risk both to themselves and others as a consequence of BSPD.

Both ChEIs and memantine may help BPSD as well as cognitive symptoms.

Treatment of other AD complications such as epileptic seizures may also be required.

Section 4: Prognosis
Median survival from onset of AD to death is about seven years.

Follow-up to manage the clinical and social complications of AD is desirable. This may be through old age psychiatry services, or possibly in the primary care setting,5 along with support from voluntary sector agencies such as the Alzheimer's Society.

Loss of efficacy
Loss of efficacy of ChEIs over time may necessitate switching between the various forms, and memantine may have a role in more severe disease.

Both drugs have been shown individually or in combination to delay nursing home placement, although this may become inevitable, especially in the context of BPSD.

Support for carers
Support for carers is also key to the appropriate management of the patient with AD, for example with respite care. Ensuring power of attorney is in place before patients become too cognitively impaired is advisable.

Some patients and families may wish to develop advanced care directives.

Section 5: Case study
A 61-year-old man first noticed problems with his memory whilst still working full time, difficulties corroborated by his wife.

After performing initial investigations, his GP referred him to a consultant neurologist who conducted the MMSE. His score was 24 out of 30. A CT brain scan showed atrophy greater than expected for his age.

He was diagnosed with AD and commenced on donepezil.

A support worker from the Alzheimer's Society met the couple in the clinic at this time, and then visited them at home to explain more about the diagnosis and what help was available.

No extra input from health or social care professionals was required at this point.


Voluntary sector agencies can help manage social complications (Photograph: SPL)

Impact on life
The diagnosis had a significant impact on their lives.

They were due to retire to a holiday home abroad. His wife was concerned this might not be possible due to her husband's confusion. In unfamiliar surroundings he would become anxious and disorientated.

However, she also reported he seemed relaxed and at ease when at the holiday home. Access to health professionals was also a concern for the couple.

One year after diagnosis the patient was still working. His employers had been very understanding about the diagnosis and had put safeguards in place to ensure he could continue.

However, he was now making many mistakes leading his employers to advise him to be signed off sick. The patient also expressed concerns about his reaction times when driving.

MMSE was now 17/30, prompting switching his medication to galantamine.

The couple spent most of the following year abroad, taking with them a letter detailing the patient's diagnosis and treatment.

The patient decided it was too dangerous to continue driving and also finished work permanently.

Skills group
The man and his wife began attending the Alzheimer's Society maintaining skills group, specifically designed for those under 65.

The group gave the couple a chance to be around people going through a similar situation, to share experiences and find out useful information. It also helped to keep the patient active and involved.

The diagnosis of AD has dramatically altered this couple's lives, causing frustration, stress and sadness.

However, due to the early interventions with symptomatic drugs, regular contact with the consultant, and stimulus and social support from groups, this patient remains positive and is living well three years after his diagnosis of AD was made.

Section 6: Evidence base

Clinical trials

The many clinical trials of ChEIs and memantine in AD are summarised in Cochrane reviews:

Information for the patient on understanding dementia is useful (Photograph: SPL)

    Technology appraisal

    However, guidance from NICE ultimately determines availability of these medications to NHS patients:

    • NICE. Donepezil, galantamine, rivastigmine (review) and memantine for the treatment of Alzheimer's disease. Includes a review of NICE technology appraisal guidance 19. TA111. London, NICE, 2006. www.nice.org.uk/guidance/TA111

    New NICE guidance extending the use of ChEIs and memantine is expected to be issued in March 2011.

    Guidelines

    • NICE/Social Care Institute for Excellence. Dementia: supporting people with dementia and their carers in health and social care. NICE CG42. London, NICE, 2006. www.nice.org.uk/CG42
    • Scottish Intercollegiate Guidelines Network. Management of patients with dementia. Edinburgh, SIGN, 2006.
    • Waldemar G, Dubois B, Emre M, et al. Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol 2007;14:e1-26.
    • DoH. Living well with dementia: National Dementia Strategy. London, DoH, 2009.
    • DoH/Alzheimer's Society. Understanding dementia. A resource pack for GPs and patients. London, Alzheimer's Society, 2009.

    Key texts

    • Larner AJ. Alzheimer's disease. In: Cappa SF, Abutalebi J, Demonet JF, et al (eds.). Cognitive neurology: a clinical textbook. Oxford, Oxford University Press, 2008: 199-227.

    Online

    This is a list of fact sheets covering a wide range of dementia-related topics, including genetics and dementia, drug treatment for AD, and understanding and respecting the person with dementia. Fact sheets can be downloaded free as PDFs.

    This page provides e-learning resources freely available to all users. It includes a tour of the brain and how to deal with unusual behaviour.

    This page details how to obtain power of attorney, an issue which is important to someone with dementia and their families.

    Reflect on this article and add notes to your CPD Organiser on MIMS Learning

    CPD IMPACT: EARN MORE CREDITS

    These further impact points allow you to earn more credits claimed by increasing the time spent and the impact achieved.

    • Look at your practice prevalence of dementia. Are you on a par with the rest of your PCT or are you underdiagnosing it? If so, put measures in place to increase screening or improve coding of dementia.
    • Review your patients with a diagnosis of AD, audit how many have had brain imaging.
    • Consider the evidence for the use of antipsychotics in patients with AD and evaluate their therapeutic value given the risks of cerebrovascular disease.

      References
      1. Alzheimer's Society. Dementia UK. A report into the prevalence and cost of dementia prepared by the Personal Social Services Research Unit (PSSRU) at the London School of Economics and the Institute of Psychiatry at King's College London, for the Alzheimer's Society. London, Alzheimer's Society, 2007.

      2. Davies RR, Doran M, Larner AJ. Early-onset dementia. Prog Neurol Psychiatry 2011; in press.

      3. Larner AJ, Doran M. Genotype-phenotype relationships of presenilin-1 mutations in Alzheimer's disease: an update. J Alzheimers Dis 2009; 14: 259-65.

      4. Menon R, Larner AJ. Use of cognitive screening instruments in primary care: the impact of national dementia directives (NICE/SCIE, National Dementia Strategy). Fam Pract 2010; doi: 10.1093/fampra/cmq100.

      5. Greaves I, Jolley D. National Dementia Strategy: well intentioned - but how well founded and how well directed? Br J Gen Pract 2010; 60: 193-8.

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