Alzheimer’s disease

Essentials

  • Alzheimer’s disease (AD) progresses from a clinically asymptomatic phase to an early disease stage and then stages that involve dementia.
  • Diagnostic examinations concerning AD should be started when mild cognitive changes appear (early stage).
  • In the most common type of Alzheimer's disease, the symptoms focus on memory problems (about 85% of cases). Symptoms usually begin as memory disturbances: the patient´s ability to learn new things is reduced.
  • Atypical disease forms include posterior cortical atrophy (PCA), logopenic progressive aphasia (LPA), and, beginning with behavioural symptoms, a disease form that resembles frontal lobe dementia. The early symptoms, before clear symptoms of memory loss, may involve impairment of visual perception, linguistic functions or executive functioning, or behavioural symptoms.
  • Clinical diagnosis is correct in about 90% of cases.
  • The progress of AD is usually slow but steady, although periods of slower and faster deterioration may occur. Disease duration from the first symptoms to death is 12 years on average (range from 2 to over 20 years).
  • Individually planned services and support activities are the starting point of the treatment.
  • Response to pharmacotherapy can be seen as improved/preserved functional capacity, alleviation of neuropsychiatric symptoms and preservation of cognitive functioning (primarily through improvement of mental alertness, no effect on memory) [Evidence Level: B]. No curative medication or medication to prevent the progress of the disease is available so far.

Risk factors and protective factors


Table 1. Risk factors and protective factors of Alzheimer’s disease
Risk factors Protective factors
Advanced age
Family history
High blood pressure (at middle age) Treatment of elevated blood pressure
Disturbances of fat metabolism (at middle age) Treatment of hypercholesterolaemia, diet containing fish and vegetables, antioxidants
Impaired glucose tolerance Normal glucose balance
Overweight (at middle age) Normal weight
Unhealthy diet Healthy diet
Smoking Not smoking
Low level of physical activity Physical activity
Ample use of alcohol and drugs of abuse Sobriety
Stress and sleeping problems
Earlier severe depression
Cerebrovascular diseases
Hereditary factors (especially ApoE4) Identifying the aetiology of any cerebrovascular disease, addressing risk factors, treating detected diseases
Low level of education High level of education
Low level of mental activity High level of mental activity
Severe head trauma Use of a helmet according to recommendations
Loneliness, lack of social network Social activity, relationship with a partner

Diagnosis

  • Core symptoms include
    • Significant impairment of episodic memory, visuospatial perception or linguistic functions such as speech production or ability to comprehend speech.
    • Mild depressive symptoms, suspiciousness, apathy and agitation are common already in early AD.
  • Biological signs supporting diagnosis
    • On MRI or CT scan, atrophy of the medial temporal lobe (hippocampus, entorhinal cortex, amygdala) or atrophy of the parietal lobel focusing on the region of the cingulate gyrus (posterior cortical atrophy)
    • Abnormal biomarkers in the cerebrospinal fluid (decreased beta-amyloid 42 and increased tau and phospho-tau protein concentrations)
    • Typical findings on a PET scan (reduced glucose metabolism in the temporoparietal cortical or posterior cingulate gyrus regions or detection of amyloid plaques with the aid of specific markers)
  • Symptoms and signs against Alzheimer’s disease
    • Sudden onset, early occurrence of gait disturbances, seizures
    • Focal neurological findings, such as hemiparesis or early extrapyramidal symptoms
    • Other diseases that may account for cognitive symptoms, such as cerebrovascular disease, severe depression, other illness capable of causing dementia
  • Alzheimer’s disease can be diagnosed with certainty when
    • the clinical and neuropathological criteria are fulfilled or
    • the clinical criteria are fulfilled and the patient has the Alzheimer’s disease causing gene mutation on chromosome 1, 14 or 21.
  • Since Alzheimer's disease caused by a single gene change is very rare, the criteria required for a certain diagnosis are fulfilled only rarely during an individual's lifetime, and therefore gene testing is usually not performed in persons with AD. Usually, a criteria-based diagnosis of probable Alzheimer's disease is set.

Laboratory investigations

  • Alzheimer’s disease is not associated with any changes in routine laboratory investigations.
  • At present, genetic testing is not generally used in clinical practice due to the complexity of testing (several different genes would need to be tested for various mutations) and because the hereditary disease forms are rare compared with the overall prevalence of the disease.

Progression of Alzheimer’s disease

Mild stage

  • The patient often tries to hide or is dismissive of his/her symptoms.
  • Memory impairment (impaired ability to learn new information or to recall previously learned information)
  • Impaired visuospatial perception leading to the patient easily losing his/her way, especially in strange surroundings
  • Sense of time deteriorates.
  • Difficulty finding the right words
  • The understanding of complicated and abstract ideas becomes difficult.
  • Problems in managing financial matters and taking care of other errands
  • Problems in following instructions concerning medication
  • Executive function deteriorates and complex activities of daily living, for example, pose problems.
  • Ability to work and driving ability decline
  • The patient may be inactive and withdrawn.
  • Sometimes the patient is depressed, paranoid or even aggressive. A triggering factor can usually be identified for aggressive behaviour, such as treatment that the patient considers unappreciative or procedures he/she is unable to understand.
  • Physical examination is normal.

Moderate stage

  • The patient’s insight into the illness is lost.
  • The patient may lose his/her way even in familiar surroundings.
  • The patient may experience different hallucinations.
  • Weight loss is inevitable, unless particular attention is paid to nutritional needs.
  • There is a need for help in activities of daily living (e.g. dressing, washing).

Severe stage

  • The ability to comprehend speech and to speak is significantly impaired or totally lost.
  • The limbs stiffen with the increasing muscle tonus, and the patient adopts a stooped posture and a shuffling gate. The ability to walk will deteriorate and be totally lost, unless the patient receives appropriate physiotherapy.
  • Problems with urinary and faecal incontinence
  • Epileptic seizures may sometimes occur.
  • The patient is no longer able to cope with activities of daily living (dressing, washing, toileting and finally eating).

Treatment

  • Making an appropriate, early diagnosis either by a neurologist, geriatrician or a physician familiar with memory diseases as well as early treatment and rehabilitative measures are cost-effective.
  • Comprehensive therapy also involves support for relative(s) caring for the patient (Treatment of a patient with memory disease).
  • With individually planned services and supportive measures as well as targeted, appropriately timed pharmacotherapy, it is possible to postpone the need for long-term care and to support the continuation of a lifestyle as familiar as possible to the patient.
  • Provision of support and non-pharmacological therapies
    • Assessment of risks in the environment: safety at home and in nearby areas, driving ability, hobbies, mental stimulation, connections to the relatives and support services
    • Clarify what is the patient's ability to decide on matters that concern him/herself and, for example, the ability to understand his/her economic situation.
    • At the early phase, it is useful to prepare for the future, such as by making a living will and an authorisation to supervise one's interests. Find out about local policies.
    • Review of current medication and, if possible, discontinuation of drugs that entail harmful effects (anticholinergic drugs, benzodiazepines, other sedative drugs). If the patient is losing weight, the cause may also be in too strong other medication, such as drugs for diabetes or blood pressure.
    • Appropriate, safe physical exercise and muscle excercises to maintain balance
    • Potential therapy forms include music therapy [Evidence Level: D], arts, dance, mainentance of manual skills.
  • Pharmacotherapy for the memory disease
    • The aim of the therapy is to maintain/improve functional capacity, to prevent the development of behavioural symptoms and alleviate them, and to prolong the time of coping in outpatient care.
    • The benefit of pharmacotherapy may only be assessed after about half a year from its start. Not all patients benefit from these drugs and their effect may decrease over time.
    • Response to pharmacotherapy can be seen as improved/preserved functional capacity, alleviation of neuropsychiatric symptoms and preservation of cognitive functioning (primarily through improvement of mental alertness, no effect on memory)
    • When starting pharmacotherapy, it is necessary to monitor the patient, and the benefits and harms must be assessed individually.
    • Pharmacotherapy is discontinued when it is no longer beneficial. If, when the patient enters institutional care, it is suspected that the effect of a drug has ended, discontinuing the medication for a period of 1–2 weeks may be tried. If functional capacity reduces or neuropsychiatric symptoms increase, the medication is started again.
    • Of acetylcholinesterase inhibiting drugs (AChEIs) donepezil [Evidence Level: B], rivastigmine [Evidence Level: B] and galantamine [Evidence Level: B] are available.
      • An ECG must be performed before starting AChEI therapy.
      • Contraindications to AChEIs include, among others, sick sinus syndrome without pacemaker, recent myocardial infarction and peptic ulceration.
      • No significant differences in the relative efficacy of the drugs has been detected.
      • Possible gastroinstestinal adverse effects include nausea, abdominal pain and diarrhoea. Oral drugs must always be taken after a meal to prevent these adverse effects.
      • A transdermal rivastigmine patch is associated with less gastrointestinal adverse effects compared with drugs in tablet form.
      • In order to minimize adverse effects, the medication should be started using a small dose and increasing the dose gradually until maintenance dose has been reached.
    • Evidence exists on the benefit of memantine in the treatment of moderate to severe Alzheimer’s disease [Evidence Level: B]. Memantine can be combined with an AChEI.[Evidence Level: B]
    • Find out about locally relevant reimbursement policies.
    • Several studies concerning pharmacotherapy for AD are underway, with the aim to slow down disease progress.
  • Nutritional products
    • It has been suggested that a clinical nutritional product would slow down the development of symptoms and cerebral changes and to preserve functional capacity when the treatment is started at the early stage. There is no evidence on benefit in the moderate stage.
    • In a meta-analysis involving 3 randomized trials and over 1,000 patients, no clear evidence on slowing down the disease progress was found [Evidence Level: B].
    • In a newer (2021) trial 3 , the clinical nutritional product slowed down the progress of symptoms and cerebral changes in the early stage disease, and the beneficial effect lasted for 3 years.
  • Other medication
    • The patients are susceptible to adverse effects of sedative drugs. To the extent possible, these drugs should be avoided or they should be used for as short periods and in as low doses as possible for the treament of difficult neuropsychiatric symptoms.
    • Low doses of intermediate-acting benzodiazepines may be used for a short time in the treatment of neuropsychiatric symptoms of a patient with AD, as necessary and after careful consideration if AChEIs or memantine do not provide adequate alleviation of such symptoms. Benzodiazepines do, however, impair cognitive information processing functions and increase the risk of confusion and falling.
    • Antidepressant medication may be indicated if AD is associated with moderate or severe depressive state. [Evidence Level: B]
    • Antipsychotic medication may sometimes be needed, if non-pharmacological treatment methods or AChEIs do not have an effect on behavioural symptoms, but one should watch out for adverse effects [Evidence Level: B].
      • Risperidone at the dose 0.25–0.5 mg twice daily has been shown to be moderately effective for the management of behavioural symptoms in a severe disease, and this is an official indication of the drug. Often risperidone causes, however, extrapyramidal symptoms already at a low dose. Continuous treatment lasting longer than 6 weeks is not recommended.
      • Quetiapine and olanzapine are usable in low doses, but neuropsychiatric symptoms of AD are not their official indication.
  • For treatment of a patient with memory disease, see (Treatment of a patient with memory disease).

Evidence Summaries

References

1. Morris JC, Blennow K, Froelich L ym. Harmonized diagnostic criteria for Alzheimer's disease: recommendations. J Intern Med 2014;275(3):204-13.  [PMID:24605805]
2. Grossberg G, Sadowsky C, Fröstl H, Frölich L, Nagel J, Tekin S, Zechner S, Ros J, Orgogozo JM. Safety and tolerability of the rivastigmine patch: results of a 28-week open-label extension. Alzheimer Dis Assoc Disord 2009 Apr-Jun;23(2):158-64.  [PMID:19484917]
3. Soininen H, Solomon A, Visser PJ et al. 36-month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer's disease. Alzheimers Dement 2021;17(1):29-40.  [PMID:32920957]
4. 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;7(3):270-9.  [PMID:21514249]
5. Rosenvall A, Sääksvuori L, Finne-Soveri H et al. Potential cost savings for selected non-pharmacological treatment strategies for patients with Alzheimer's disease in Finland. J Rehabil Med 2020;52(9):jrm00106.  [PMID:32778901]

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