Alzheimer's disease is the most common cause of dementia, and involves a progressive degeneration of the cerebral cortex. There is widespread cortical atrophy. Neurons affected develop surrounding amyloid plaques, neurofibrillary tangles, and produce less acetylcholine. The cause is not yet known. Patients experience irreversible global, progressive impairment of brain function, leading to reduced intellectual ability.
Neurodegeneration in Alzheimer's disease probably begins at least a decade before clinical onset.
- Alzheimer's disease is the most common form of dementia, accounting for around 50% of cases.It is estimated to affect 496,000 people in the UK.
- Dementia affects 5.4% of the population over the age of 65, and prevalence increases with age.
- Sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide.The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing along with a complex interaction of genetic and environmental risk factors.
- Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset.
- Family history. Small increased risk - 3.5-fold increase if a first-degree family member is affected.
- It is more common in women. (67% is in women, and 55% in men, unlike other types of dementia.)
- Apolipoprotein E4 variant - the largest known genetic risk factor in late-onset sporadic Alzheimer's disease, but wide differences in prevalence of the genotype in populations studied.[7, 8]
- Head injury.
- Risk factors associated with vascular disease; particularly hypercholesterolaemia, hypertension and diabetes implicated.
- Drinking wine seems to be protective.
Dr Hayley Willacy would like to draw your attention to a recent paper that shows self-reporting poor sleep was associated with greater alzheimer-related pathology in cognitively healthy adults at risk for the disease. As there are effective strategies for improving sleep, this may be a treatable target for early intervention to attenuate the disease.
The National Institute for Health and Care Excellence (NICE) guidelines recommend the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) diagnostic criteria be used for the assessment of Alzheimer's disease.Alternatives are the ICD-10 or DSM-IV (now DSM-5 since the guidelines were written) criteria.[11, 12]
The NINCDS/ADRDA criteria were proposed in 1984 and revised in 2011.Core features for diagnosis of Alzheimer's disease include:
Probable Alzheimer's disease
- Dementia established by clinical examination and neuropsychological tests.
- Deficits in two or more areas of cognition.
- Insidious onset over months to years, and progressive worsening of memory and other cognitive functions.
- No disturbance of consciousness.
- Onset between ages of 40 and 90. (Criterion removed in latest revision.)
- Absence of systemic disorders or other brain diseases that could account for the symptoms.
Possible Alzheimer's disease
- Dementia with an atypical onset or course (ie sudden onset or insufficient documentation of progressive decline); OR
- Aetiologically mixed presentation (ie other criteria fit the diagnosis, but features of other brain disorders or causes of dementia are present).
Mild cognitive impairment due to Alzheimer's disease
Newer diagnostic criteria have attempted to classify the symptomatic, pre-dementia stage of Alzheimer's disease. The work group which revised the NINCDS/ADRDA criteria in 2011 refers to this stage as "mild cognitive impairment" with clinical diagnostic criteria as follows:
- Concern regarding a change in cognition (from patient, informer or clinician)
- Impairment of one or more cognitive domains
- Preservation of independence in functional abilities
- Not having the features of dementia
DSM-5 refers to this earlier stage as mild neurocognitive disorder (mild NCD) and there is ongoing debate in this area.
Onset of Alzheimer's disease is insidious, and it usually progresses slowly over 7-10 years.
Symptoms in early stages include:
- Memory lapses
- Forgetting names of people and places
- Difficulty finding words for things
- Inability to remember recent events
- Forgetting appointments
As the disease progresses, symptoms include:
- Difficulties with language
- Problems with planning and decision making
In the later stages, symptoms include:
- Wandering, disorientation
- Psychiatric symptoms - depression, hallucinations, delusions
- Behavioural problems - disinhibition, aggression, agitation
- Altered eating habits
Cognitive changes with ageing may be very difficult to distinguish in the mildly affected, early stages of Alzheimer's disease.
- Normal ageing
- Other forms of dementia - see separate article Dementia. There is often significant overlap.
- Normal pressure hydrocephalus.
- Parkinson's disease.
- Drug-induced cognitive impairment - eg, benzodiazepines.
- Vitamin B12 deficiency.
- Depression, schizophrenia.
- Acute confusional state, amnesia.
- Neurosyphilis, AIDS dementia complex.
There are several tools available for screening for cognitive impairment, and other routine investigations are detailed in the separate article Dementia. MRI scans are the investigation of choice to exclude other cerebral pathology. To differentiate Alzheimer's disease from vascular dementia or frontotemporal dementia, NICE guidance advises perfusion hexamethylpropyleneamine oxime (HMPAO) single-photon emission computed tomography (SPECT). This is not useful if the person has Down's syndrome.
Note that cognitive screening tests such as the mini mental state examination (MMSE) are not diagnostic of dementia, but are useful screening tools to assess who should be referred to specialist services.
- People with dementia benefit from person-centred care. This means not only respecting the person and their carer, and taking account of their perspective and interactions, but tailoring the management to them as an individual.
- People with dementia should not be discriminated against when considering treatment options for other conditions. They should benefit from support appropriate to their needs, and should not be discriminated against in terms of race, language, religion or sexuality.
- Early discussions should take place to allow advance planning. This involves discussion about advance statements or decisions, lasting power of attorney and preferred place of care plans. This is one of the most important reasons for early diagnosis and referral.
- A memory assessment service should act as the single point of referral for all patients with a suspected diagnosis of dementia. 50% of those diagnosed with mild cognitive impairment go on to develop dementia, according to NICE guidelines, so primary care professionals should consider referring at this stage.
- Valid consent should be sought for treatment, wherever possible. This may mean making information available to them in an appropriate form. The use by patients and carers of advocacy services and voluntary organisations should be encouraged. If patients are not competent to make a decision, the requirements of the Mental Capacity Act 2005 should be followed.
- Carers should receive an assessment of needs as required by the Carers and Disabled Children Act 2004 and the Carers (Equal Opportunities) Act 2004. Carers should be offered individual or group psycho-education and psychological therapy, peer-support groups, information in a variety of media, and training courses. Issues such as transport, night-sitting, and respite care should also be considered. See the separate article Supporting the Family of People with Dementia.
- Health and social care managers should take a joint approach to management, and this should include joint written policies and procedures, and joint planning of services which take on board the views of local service users and carers. Care managers and co-ordinators should ensure that a combined care plan, which takes account of the changing needs of the patient and the carers, is reviewed regularly, and receives the endorsement of the patient and carers. Named health and/or social care staff should be assigned to operate the plan.
- Following diagnosis the patient and carers should be given written information about:
- The symptoms and signs of dementia
- Course and prognosis
- Local care and support services
- Support groups
- Sources of financial and legal advice, and advocacy
- Medico-legal issues, including driving
- Local information sources, including libraries and voluntary organisations
- Health and social care staff should aim to promote independence where possible, including mobility. Strategies to cope with disabilities should be promoted, such as modifications to the living environment and simplification of daily activities.
- Young people with dementia and those with learning disabilities have special needs, and require specialist advice and focused support.
- People with mild-to-moderate dementia should be given the opportunity to participate in a structured group cognitive stimulation programme (which includes reality orientation). This may help maintain cognitive skills and day-to-day functioning.
- Memory enhancement strategies: reminder notes, lists, reorganisation of possessions.
- Cognitive behavioural therapy (CBT) for those with Alzheimer's disease who are experiencing depression or anxiety, involving their carers.
- Non-pharmacological approaches for those with anxiety, depression or challenging behaviour include:
- Therapeutic use of music and dance
- Animal-assisted therapy
- Multi-sensory stimulation
- Reminiscence therapy
- Volunteers should be involved where helpful and appropriate.
Management: pharmacological treatment
Four drugs are available in the UK for treatment of dementia.
In 2011, NICE reviewed its guidance on the use of these drugs in mild and moderate Alzheimer's disease.It then incorporated this into its 2006 dementia guideline, updating the relevant sections. This brought it more in line with the Scottish Intercollegiate Guidelines Network (SIGN).
- Acetylcholinesterase (AChE) inhibitor treatment (donepezil, galantamine or rivastigmine) should be considered in patients with mild or moderate Alzheimer's disease. It should only be started by dementia specialists (psychiatrists, neurologists, and physicians specialising in the care of older people), after appropriate discussion with family and carers. These drugs have cholinergic side-effects and should be started at a low dose, and then be titrated according to response. The drug with the lowest cost should be used as first choice. They should not be prescribed for mild cognitive impairment.
- Memantine (a N-methyl-D-aspartate (NMDA) antagonist) is recommended by NICE as a second-line option for managing patients with moderate Alzheimer's disease where AChE inhibitors are not tolerated or are contra-indicated, or in the treatment of severe Alzheimer's disease.
- Drug treatment should be continued only as long as it is having a worthwhile effect on cognitive, global, functional or behavioural symptoms.
- Patients on treatment should be reviewed regularly by an appropriate specialist team, or by shared care with GPs where such an agreement exists. This should include cognitive, global, functional and behavioural assessments and discussion with carers.
- The MMSE should be part of a full assessment of a patient, including quality of life changes and social interaction. Clinicians should be free to treat patients after this assessment, and should not be precluded from doing so on the basis of the MMSE score. The MMSE is not sensitive enough to differentiate between patients who would benefit from treatment and those who would not, and was not designed for this use.
Evidence from clinical studies and Cochrane reviews suggests that there is benefit from AChE inhibitors in mild-to-moderate Alzheimer's disease, but that the benefits are small.[19, 20]There is some evidence that continuing use in moderate-to-severe disease confers some benefit.
Pharmacological treatment of other features
- Where antidepressants are needed, avoid tricyclic antidepressants and other anti-cholinergics, as they may have an adverse effect on cognition.
- Antipsychotics should be avoided where possible in Alzheimer's disease. Where needed for psychotic features or agitation:
- Discuss the risks (sedation, risk of stroke, worsening cognition) and consider other cerebrovascular risk factors.
- Ideally treat under specialist advice.
- Monitor effects regularly.
- Use the lowest possible dose and titrate up slowly where necessary.
- Treatment should be time limited.
- Consider risperidone as first choice.
- Occasionally aggression, violence or agitation pose a threat to safety, and where non-pharmacological measures have failed, benzodiazepines or antipsychotics may be required urgently:
- Oral medication should be used where possible; intramuscular (IM) route is safer than intravenous (IV) where it is not possible.
- Lorazepam, haloperidol or olanzapine should be used where IM administration is required. IM diazepam and chlorpromazine are not recommended.
- Effects should be closely monitored.
Management: palliative and end-of-life care
Physical, psychological, social and spiritual support should be offered, and dementia patients should have the same access to palliative care services as any other patient. Oral nutrition should be encouraged for as long as possible. Percutaneous endoscopic gastrostomy (PEG) feeding may be appropriate in patients with transient dysphagia but is not recommended in patients with severe dementia, as there is no evidence of increased survival or reduced complications.[22, 23, 24]
Decisions to withhold nutritional support should be taken within a legal and ethical framework.Fever may be managed with antipyretics and mechanical cooling. Palliative antibiotics should be given after an individual assessment of the patient. Resuscitation is unlikely to succeed in patients with severe dementia. If no advanced decision has been taken by the patient, the decision to resuscitate should take into account the views of the carers and the multidisciplinary team, the Resuscitation Council UK's guidance, and the Mental Capacity Act 2005.The decisions should be recorded in the notes and care plan.
- Alzheimer's disease is a progressive condition for which there is currently no cure and no known way to slow the progression of this disease.
- Symptoms in some people in the early and middle stages of the disease may be relieved by medication.
- The course of Alzheimer's disease varies from person to person, with some people having the disease for five years, and others for up to 20 years.
- The most common cause of death is infection.
- No treatment is known to reduce the risk of Alzheimer's disease.
- There is research ongoing into whether fruit and vegetable juices may play a role in delaying the onset of Alzheimer's disease, particularly among those who are at high risk for the disease.
- Some evidence suggests that dietary intake of homocysteine-related vitamins (vitamin B12 and folate), antioxidants (eg, vitamin C and vitamin E), unsaturated fatty acids and also moderate alcohol intake (especially wine) may reduce the risk of Alzheimer's disease, but the evidence is currently too weak to allow any definite conclusions or recommendations.
- It may be that reducing cardiovascular risk factors also reduces the risk of developing dementia, but there is currently no convincing evidence for this.
Further reading and references
Services for younger people with Alzheimer's disease and other dementias; Royal College of Psychiatrists, 2006
Schmidt R, Hofer E, Bouwman FH, et al; EFNS-ENS/EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer's disease. Eur J Neurol. 2015 Jun22(6):889-98. doi: 10.1111/ene.12707. Epub 2015 Mar 25.
Dementia; NICE CKS, March 2010 (UK access only)
Guidelines for the diagnosis and management of Alzheimer's disease; European Federation of Neurological Societies (2010)
Blennow K, de Leon MJ, Zetterberg H; Alzheimer's disease. Lancet. 2006 Jul 29368(9533):387-403.
Alzheimer Disease, AD; Online Mendelian Inheritance in Man (OMIM)
Burns A, Iliffe S; Alzheimer's disease. BMJ. 2009 Feb 5338:b158. doi: 10.1136/bmj.b158.
Sadigh-Eteghad S, Talebi M, Farhoudi M; Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer`s disease. A meta-analysis. Neurosciences (Riyadh). 2012 Oct17(4):321-6.
Ward A, Crean S, Mercaldi CJ, et al; Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer's disease: a systematic review and meta-analysis. Neuroepidemiology. 201238(1):1-17. doi: 10.1159/000334607. Epub 2011 Dec 17.
Sprecher KE, Koscik RL, Carlsson CM, et al; Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults. Neurology. 2017 Jul 5. pii: 10.1212/WNL.0000000000004171. doi: 10.1212/WNL.0000000000004171.
Dementia: Supporting people with dementia and their carers in health and social care; NICE Clinical Guideline (November 2006, last updated September 2016)
The ICD-10 Classification of Mental and Behavioural Disorders; World Health Organization
Highlights of Changes from DSM-IV-TR to DSM-5; American Psychiatric Association, 2013
McKhann GM, Knopman DS, Chertkow H, et al; The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May7(3):263-9. doi: 10.1016/j.jalz.2011.03.005. Epub 2011 Apr 21.
Albert MS, DeKosky ST, Dickson D, et al; The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May7(3):270-9. doi: 10.1016/j.jalz.2011.03.008. Epub 2011 Apr 21.
Dementia; NICE Quality Standard, June 2010
Dementia: independence and wellbeing; NICE Quality Standard, April 2013
Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease; NICE Technology Appraisal Guidance, March 2011
Management of patients with dementia; Scottish Intercollegiate Guidelines Network - SIGN (Feb 2006)
Birks J, Grimley Evans J, Iakovidou V, et al; Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev. 2009 Apr 15(2):CD001191. doi: 10.1002/14651858.CD001191.pub2.
Birks J; Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006 Jan 25(1):CD005593.
Howard R, McShane R, Lindesay J, et al; Donepezil and memantine for moderate-to-severe Alzheimer's disease, N Engl J Med 2012 366:893-903
Sampson EL, Candy B, Jones L; Enteral tube feeding for older people with advanced dementia. Cochrane Database Syst Rev. 2009 Apr 15(2):CD007209.
Kurien M, McAlindon ME, Westaby D, et al; Percutaneous endoscopic gastrostomy (PEG) feeding. BMJ. 2010 May 7340:c2414. doi: 10.1136/bmj.c2414.
Westaby D, Young A, O'Toole P, et al; The provision of a percutaneously placed enteral tube feeding service. British Society of Gastroenterology Guideline, published in Gut. 2010 Dec59(12):1592-605.
Nutritional Advice in Common Clinical Situations; British Geriatrics Society, 2009
Do Not Attempt CPR (DNACPR); Resuscitation Council (UK)
Dai Q, Borenstein AR, Wu Y, et al; Fruit and vegetable juices and Alzheimer's disease: the Kame Project. Am J Med. 2006 Sep119(9):751-9.
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