Alzheimer’s disease

What is Alzheimer’s disease?

Alzheimer’s disease is a chronic progressive neurodegenerative disorder characterised by three primary groups of symptoms. The first group (cognitive dysfunction) includes memory loss, language difficulties, and executive dysfunction (that is, loss of higher level planning and intellectual coordination skills). The second group comprises psychiatric symptoms and behavioural disturbances—for example, depression, hallucinations, delusions, agitation—collectively termed non-cognitive symptoms.2 The third group comprises difficulties with performing activities of daily living (deemed “instrumental” for more complex activities such as driving and shopping and “basic” for dressing and eating unaided). The symptoms of Alzheimer’s disease progress from mild symptoms of memory loss to very severe dementia (figure⇓). Increasingly, the coexistence of vascular disease and Alzheimer’s disease is being recognised clinically, pathologically, and epidemiologically.4

Symptom progression in Alzheimer’s disease. Adapted from Feldman et al3

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What is the relation between normal ageing and Alzheimer’s disease?

Population studies of ageing and cognition suggest that impairment in multiple cognitive domains is observable several years before a clinical diagnosis of Alzheimer’s disease is made.5 This observed cognitive dysfunction is not qualitatively different from that seen in normal ageing, suggesting continuity rather than discontinuity in the shift from normal ageing to preclinical dementia.6 Global cognitive deterioration, affecting memory and other aspects of cognitive functioning (verbal ability, visuospatial skills, attention, and perceptual speed), is almost always a presenting symptom.^w1 There is considerable overlap in cognitive performance between normal ageing and this stable phase,^w2 and little evidence exists as yet that these changes are detectable in clinical encounters. A person with symptoms of Alzheimer’s disease is about 30% more likely to display the clinical features of dementia if they have coexisting symptoms of vascular disease.4

What is the benefit of identifying mild cognitive impairment?

Longitudinal studies suggest that cognitive impairments in this early stage may remain relatively constant for several years.^w3 This phase corresponds to the clinical concept of mild cognitive impairment, in which the individual has subjective symptoms (predominantly of memory loss) and measurable cognitive deficits but without notable impairment in defined activities of everyday life (box 1). Controversy surrounds the concept of mild cognitive impairment: is it really an identifiable precursor ripe for preventive interventions, or is it merely medicalising normal ageing? The debate continues, but prospective studies have shown that people with amnestic mild cognitive impairment (the form characterised by memory loss) are up to 15 times more likely to have developed dementia at follow-up,^w4 suggesting it may be a precursor to Alzheimer’s disease .

Currently, stringent tests of episodic memory are the best neuropsychological predictors of subsequent conversion from mild cognitive impairment to Alzheimer’s disease at group level. Imaging techniques can identify early brain changes, both structural and metabolic, but no single technique if used as a screening test can accurately identify individuals with mild cognitive impairment who will subsequently develop Alzheimer’s disease or other dementias.7 A combination of neuropsychological testing and neuroimaging improves the diagnostic accuracy of predicting cognitive decline in people in this phase compared with that achieved with either modality alone.8 However, the tools for identifying the early changes of Alzheimer’s disease are outpacing the therapeutic options, so the usefulness of such early “preclinical” diagnosis remains uncertain.^w5

The stable phase of mild cognitive impairment ends with a detectable decline in cognitive function, lasting two to five years, in which semantic memory (the store of facts and general knowledge) and implicit memory (the non-conscious influence of past experience on subsequent performance) also becomes degraded.9 Trial evidence shows that early recognition of cognitive impairment and clinical assessment and management at this point delays the subsequent need for nursing home care and reduces the risk of misdiagnosis and inappropriate management.^w5

How does Alzheimer’s disease present?

Memory loss is universal and is the first symptom in the vast majority of cases. The gradual onset of memory loss means that it may (understandably) be misattributed to normal ageing and is often recognised only in retrospect as the onset of Alzheimer’s disease. The onset is insidious, emerging with mild loss of memory and difficulty with word finding, symptoms that are common in everyday life to varying degrees. It is only when the symptoms interfere significantly with social and work activities, or are recognised by others, who sense they are progressing, that suspicion of a dementia is justified. Emotional changes are common, major depression occurs in 24-32% of cases, anxiety in 17-27%, apathy in up to 41%, and delusions in 23%.10

How do we diagnose and assess Alzheimer’s disease?

The clinical diagnosis of Alzheimer’s disease follows a logical sequence: the history should include information from an informant; a mental state assessment should include a validated cognitive function test; and the physical examination should focus on vascular and neurological signs supplemented by investigations. Assessment of dementia involves a two step process. Firstly, it is important to distinguish dementia syndromes from other conditions that can mimic them, such as depression, delirium, and mild cognitive impairment. Secondly, once dementia syndrome is recognised, the diagnosis of a subtype is important because it may determine the kind of treatment possible. Current criteria for the main causes of dementia (Alzheimer’s disease,11 12 vascular dementia,13 14 and Lewy body dementia15) are well summarised by Dubois.12

For cognitive screening in general practice, the clock test is popular because of its non-confrontational nature and because the normal drawing of a clock more or less excludes the presence of important cognitive impairment. However, the rules for scoring the tests can be quite complex and using a solitary cognitive test to screen for the presence of a dementia syndrome does not do justice to the wide variety of symptoms that make up the clinical syndrome of dementia. Activities of daily living are assessed alongside cognition, but there is less consistency in the assessment instruments used.

What is the cause of Alzheimer’s disease?

The cause of Alzheimer’s disease is unknown, but case-control studies have linked several risk factors with the disease including age, family history, apolipoprotein (Apo) E4 status, head injury, depression, hypertension, diabetes, high cholesterol, atrial fibrillation, presence of cerebral emboli, and low physical and cognitive activity (box 2). Some risk factors are potentially modifiable.

Neuritic (or senile) plaques and neurofibrillary tangles are the primary histological features of Alzheimer’s disease; the presence of phosphorylated tau is the hallmark of the former, and the deposition of the insoluble protein amyloid denotes the latter. Both have been correlated with the severity of the clinical features of the dementia syndrome (as has synaptic density, a measure of neuronal loss).^{w12 w13}

What is the genetic contribution to Alzheimer’s disease?

Familial aggregation of Alzheimer’s disease has been known for some 75 years, and the risk for first degree relatives of people with the disease is estimated at 10-40% higher than in unrelated people.^w14 Twin studies have found that concordance is higher in monozygotic twins than in dizygotic twins, indicating the presence of a genetic component, although the modest concordance levels in monozygotic twins (who share 100% genetic material) would suggest that environmental factors are at play as well.^w15

Mutations have been described in three genes: the amyloid precursor protein, presenilin 1, and presenilin 2, on chromosomes 21, 14, and 1 respectively. For late onset Alzheimer’s disease, the only known genetic risk factor is ApoE, located on chromosome 19. Three gene forms exist (ApoE e2, ApoE e3, and ApoE e4), with possession of one e4 allele being associated with a threefold risk for the development of Alzheimer’s disease, whereas those with the homozygous condition have an eightfold risk.^w16 The importance of environmental factors is confirmed by the fact that the strongest association is not true across all races and 50% of white patients with Alzheimer’s disease do not carry an e4 allele.

What treatments work for Alzheimer’s disease?

Although we focus here on treatments for Alzheimer’s disease, many psychosocial interventions are appropriate for the clinical syndrome of dementia regardless of its cause. As most psychosocial interventions and some drug treatments are for symptomatic benefit they do not rely for their efficacy on modifying the underlying pathophysiology. For example, the treatment of depression in dementia is essentially the same whether the dementia results from Alzheimer’s disease or vascular dementia, alone or in combination.

In clinical practice, non-drug interventions should be tried first^w17 especially when symptoms are neither causing distress nor placing a person at risk to themselves or others.16 Therapeutic interventions that are tailored to the individual and establish a good rapport with the person with dementia and their carers are essential. Continuity of clinical care may also be important because it permits a complex appreciation of individuals. For example, a person’s own awareness of changes in their cognitive function is associated with better treatment outcomes after cognitive rehabilitation, but awareness can be difficult to assess as individuals with Alzheimer’s disease may deny problems in one context but report awareness of them in another.^w18 General practitioners are well placed to have this understanding of their patients, and collaboration between specialists and general practitioners in the care of people with Alzheimer’s disease is essential.

Amnesia and activities of daily living

Non-drug approaches are not effective in modifying memory loss, although memory retraining techniques can offer support and improve wellbeing in people with mild dementia.^w21 Both cholinesterase inhibitors and memantine produce modest but identifiable improvements in activities of daily living.17 Patients and their carers often report that improvements in activities of daily living make the biggest positive impact on their lives.^w20

How can behavioural and psychological difficulties be managed?

Carers’ needs

Loss of function and psychological and behavioural symptoms in people with Alzheimer’s disease are sources of stress and a burden for carers. Some interventions reduce psychological morbidity in carers and help people with dementia stay at home longer; programmes that involve both the patients and their families and are more intensive and modified to carers’ needs may be more successful.23

The PREVENT trial found significant improvements in care processes and outcomes for both people with dementia (increased prescribing of cholinesterase inhibitors and antidepressant drugs and fewer behavioural and psychological symptoms) and family carers (improved depression scores and higher carer satisfaction ratings).24 Multicomponent interventions that included, for example, educational sessions, group support, and practical training were the most successful interventions for both people with dementia and their family carers.23 ^w25

Is prevention of Alzheimer’s disease possible?

Evidence is growing that some interventions may delay the onset of Alzheimer’s disease. Predicting the onset of dementia is possible (table⇓). Prevention is a complex area: interventions with single agents (such as antihypertensive drugs or statins) are unlikely to result in a large scale reduction because many risk factors are involved and intervention studies would therefore be complex to design and execute. Whether interventions affect the core biological mechanisms of Alzheimer’s disease or are mediated through reduction of vascular risk factors is unclear. For example, statins not only reduce cholesterol but also have, for example, antithrombotic and anti-inflammatory actions. Ageing and family history (genetic) factors are traditionally regarded as non-modifiable risk factors, but that view may be challenged by the avoidance of the effects of chronological ageing by lifestyle interventions and perhaps ultimately by gene therapy. Public interest in the possibility of preventing Alzheimer’s disease is high (box 4).

Conclusion

The ageing of populations in industrialised and developing countries makes Alzheimer’s disease everybody’s business. It requires all practitioners working with older patients to understand the insidious onset, main features, and impact of dementia and to be aware of the range of responses available.