Alzheimer's Disease

See related articles on dementia.

Alzheimer's disease is the name given to a form of cortical dementia, affecting higher mental functions, and is the most common cause of dementia. Patients experience irreversible global, progressive impairment of brain function leading to to reduced intellectual ability.
Neurodegeneration in Alzheimer's disease is estimated to start 20-30 years before clinical onset.

• Alzheimer's disease is the most common form of dementia, accounting for 50%-60% of all cases.¹
• The prevalence of dementia is below 1% in individuals aged 60-64 years, but shows an almost exponential increase with age, so that in people aged 85 years or older the prevalence is between 24% and 33% in the Western world.
• Representative data from developing countries are sparse, but about 60% of patients with dementia are estimated to live in this part of the world.
• Sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide.¹ The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors.
• Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset.²

Risk factors

• Ageing
• Caucasian
• More common in women than men

Apolipoprotein E4 variant is associated with an increased risk of Alzheimer's disease presenting at an earlier age.
Several epidemiological studies have shown that head injury could be a risk factor, and other risk factors are associated with vascular disease, i.e hypercholesterolaemia, hypertension, atherosclerosis, coronary heart disease, smoking, obesity, and diabetes.

Sporadic Alzheimer's disease has been shown to have a significant genetic background. A large population-based twin study showed that the extent of heritability for the sporadic disease is almost 80%.

Studies have suggested that the risk of the disease is reduced in patients treated with non-steroidal anti-inflammatory drugs

Alzheimer's disease is a slowly progressive disorder, with insidious onset and progressive impairment of episodic memory; instrumental signs include aphasia, apraxia, and agnosia, together with general cognitive symptoms, such as impaired judgment, decision-making, and orientation.

Behavioural signs, such as aggression, psychomotor agitation, and psychosis (hallucinations and delusions), are very common in patients with Alzheimer's disease, especially in the late stages of the disease.
Therefore features include:

• Memory: both recall and new memory formation are affected early causing a severe amnesia.
• Aphasia occurs fairly early: difficulties with word meaning, word finding, object naming and definitions.
• Attention and visuospatial problems are quite common.
• Personality and behaviour are well preserved until later stages.
• Visuospatial, perceptual and problem solving skills are initially preserved.
• Neurological examination is normal.
• A score of 23/30 in the Mini Mental State Examination is generally considered to be diagnostic of dementia.

Cognitive changes with ageing may be very difficult to distinguish in the mildly affected, early stages of Alzheimer's disease.

• Other forms of dementia - see dementia article
• Normal pressure hydrocephalus
• Parkinson's disease
• Hypothyroidism
• Drug-induced cognitive impairment, e.g. benzodiazepines
• Vitamin B12 deficiency
• Depression, schizophrenia
• Acute confusional state, amnesia
• Neurosyphilis, AIDS-dementia complex

• In very early cases, neuropsychological testing can help to obtain objective signs of memory disturbances.¹
• Laboratory studies - at the time of presentation: FBC, electrolytes, calcium, glucose, renal and liver function, thyroid function tests, serum vitamin B12 and folate levels.
  Testing for syphilis serology or HIV should not be routinely undertaken (consider only in those with histories suggesting they are at risk or if the clinical picture dictates).³
• Neuroimaging, CT and MRI may be appropriate: to exclude alternative causes of dementia, such as brain tumour and subdural haematoma.
  Cerebral atrophy, visualised as enlarged ventricles and cortical sulci, is also identified by CT and MRI, but the overlap with normal ageing and other dementias is too large to have any diagnostic value.¹
  Neuroimaging is valuable to detect cerebrovascular disease, such as cerebral infarcts and white-matter lesions, which is of importance to identify vascular dementia or mixed dementia (Alzheimer's disease/vascular dementia).
• Further investigations will depend on the individual context and may include EEG, lumbar puncture, echocardiogram, autoantibody screen, cerebral biopsy.

• About 50% of patients with neuropathological disease have significant concomitant cerebrovascular pathology.
• There is also a large overlap in pathology between Alzheimer's disease and Lewy-body dementia.

Management must focus on both treating patients and supporting their carers. A coordinated and integrated multi-agency approach is required in the treatment and care of people with dementia and their carers. Ideally there should be locally agreed written policies; and a combined care plan agreed by health and social services that takes into account the changing needs of the person with dementia and his or her carers.³ Such support may include respite care, day-centres or longer term residential care.

• There should be a named health and/or social care staff to operate the care plan.
• The plan should be endorsed by the person with dementia and/or carers.
• Formal reviews of the care plan should occur.

Drug treatment

Four drugs are available in the UK for treatment of dementia:

Acetylcholinesterase inhibitors

The three drugs in this class (donepezil, galantamine or rivastigmine) are all licensed for mild to moderate dementia (mini mental state examination (MMSE) score of between 10 and 20). They should only be started by specialists in the care of dementia (psychiatrists, neurologists and geriatricians), after appropriate discussion with family and carers. These drugs have cholinergic side effects and should be started at a low dose. The dose should then be titrated according to response, and the patient should be reviewed every 6 months by MMSE score, global, functional and behavioural assessment by the specialist team or in an agreed shared care arrangement.

• Donepezil is initiated at 5 mg at night and if necessary increased to 10 mg.⁴
• Galantamine has nicotinic receptor agonist properties as well as being a reversible inhibitor of acetylcholinesterase. The usual dose is initially 4 mg twice daily for 4 weeks increased to 8 mg twice daily for 4 weeks. The maintenance dose is 8-12 mg twice daily.⁵
• Rivastigmine is a reversible non-competitive inhibitor of acetylcholinesterases.⁶ It is initially given at a dose of 1.5 mg twice daily, increasing in steps of 1.5 mg twice daily at intervals of at least 2 weeks according to tolerance and response. The usual range is 3-6 mg twice daily, with a maximum of 6 mg twice daily. The notable gastrointestinal side effects are more common in women than in men.⁷

Other assessment tools other than the MMSE are allowed where the former is not appropriate (eg foreign language, learning difficulty, sensory impairment etc.).

N-methyl-D-aspartate (NMDA) antagonists

Memantine is a N-methyl-D-aspartate (NMDA) antagonist. It is not recommended by NICE except as part of a clinical trial (for moderately severe to severe dementia).^8,9

There is currently considerable controversy about the treatment of Alzheimer's Disease. The Scottish Intercollegiate Network (SIGN) has released guidance,¹⁰ which differs significantly from that of the National Institute for Clinical Excellence (NICE).¹¹

NICE recommend that patients with moderate Alzheimer's disease (whose Mini Mental State Examination (MMSE) score is between 10 and 20 points) should be initiated on an acetylcholinesterase inhibitors.¹¹ For this group of patients they also cite further requirements:

• The diagnosis is made in a specialist clinic according to standard clinical diagnostic criteria.
• A carer or care-worker who is in sufficient contact with the person to ensure compliance with the drug is available.
• The views of the person's carer on the person's condition at baseline are sought.
• The treatment is initiated by a specialist.
• Therapy should be initiated with the drug with the lowest acquisition cost.
• There is an agreed GP/specialist shared-care protocol that specifies clear treatment end points.
• The patient's MMSE score is reviewed, and either a global, functional and behavioural assessment made every six months by an appropriate specialist team, or a locally agreed shared care protocol is operating.
• The prescription should furthermore only be continued if:
  • The patient's MMSE score remains above 10 points.
  • The patient's global, functional and behavioural condition remains at a level where the drug is considered to be having a worthwhile effect.
• The views of the person's carer at follow-up are sought.

• Acetylcholinesterase inhibitors should be considered for all Alzheimer's patients, irrespective of whether the dementia is mild, moderate or severe.
• People with mild stage Alzheimer's disease should be eligible for treatment at the earliest opportunity after diagnosis. This would enable the patient to be involved in decisions about their care, and give time for carers to be educated.
• It would be wrong to exclude a patient from treatment after he or she has been diagnosed when they would be more likely to regain higher levels of ability than would be possible later in the illness.
• The MMSE is not sensitive enough to differentiate patients who would benefit from treatment from those who would not, and was not designed for this use. Performance can be affected by several factors including intelligence, ability to speak English and co-existing physical illness on the day of taking the test. Minor variations can occur from day to day in the same individual.
• 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.
• Acquisition cost should be taken into account, but should not over-ride other clinical considerations.
• Concentrating on treatment in the severe stage of the illness could deter GPs from referring at an early stage.
• If a patient is taken off medication because their MMSE score has fallen below 10 and there is a subsequent marked deterioration in their condition, they should be entitled to have their medication restored.
• Not all patients have ready access to a specialist or specialist clinic, especially in remote rural areas. In these cases, GPs should be allowed to initiate treatment.^3,11

Treatment of behavioural problems

• Several short-term trials show efficacy of risperidone and olanzapine in reducing the rate of aggression, agitation, and psychosis.
• Alternative treatments include anticonvulsants, such as divalproate and carbamazepine, and short-acting benzodiazepines, such as lorazepam and oxazepam.¹
• The cholinergic deficits can contribute to the development of behavioural symptoms, and treatment with acetylcholinesterase inhibitors also shows improvements in behavioural symptoms.

• Patients deteriorate over time in activities of daily living and in their ability to care for themselves.
• If they have the disease long enough patients commonly develop various problems, including incontinence, sleep-wake cycle disturbance, and wandering.
• Patients can also have affective and psychotic psychiatric symptoms.
• Inability to feed self leads to weight loss, malnutrition, and dehydration.
• Immobility, mutism, pressure ulcers, and infections are all complications of dementia.
  The difficulties with care can cause a great deal of difficulty for families and carers, who therefore need a great deal of support.

• 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. Medications may also help control behavioral symptoms.
• The course of Alzheimer's disease varies from person to person, with some people having the disease for 5 years, and others for up to 20 years.
• The most common cause of death is infection.¹

• Fruit and vegetable juices may play an important role in delaying the onset of Alzheimer's disease, particularly among those who are at high risk for the disease.¹³
• Some evidence suggests that dietary intake of homocysteine-related vitamins (vitamin B12 and folate), antioxidants (e.g. vitamin C and 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 base any definite conclusions or recommendations.
• Statins do not reduce the risk of developing Alzheimer's but there is some evidence that lowering cholesterol may slow the progression of the disease.