Alzheimer Disease

Alzheimer disease is the commonest cause of major neurocognitive disorder (dementia, covered under that broader diagnostic category). It is characterised pathologically by progressive cerebral accumulation of extracellular amyloid beta plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein.

This produces progressive neuronal loss and synaptic dysfunction. There is a characteristic, though not invariable, early and disproportionate involvement of the medial temporal lobe and hippocampal structures. This accounts for the early, prominent episodic memory impairment that typically dominates the early clinical presentation.

The disease follows a relentlessly progressive course over years.

In recent years there has been increasing therapeutic focus on disease modifying treatment that targets the underlying amyloid pathology directly. This is a significant evolution from the purely symptomatic approaches that have historically been the mainstay of management.

Pathophysiology

• Amyloid beta accumulation reflects an imbalance between production and clearance of this protein fragment, derived from cleavage of the larger amyloid precursor protein. It is believed to be a key, early and likely initiating event in the disease cascade.
• Downstream accumulation of hyperphosphorylated tau protein within neurofibrillary tangles correlates more closely with the pattern and severity of clinical cognitive decline. Neuroinflammation, synaptic dysfunction and, progressive neuronal loss follow.
• Early and disproportionate involvement of the medial temporal lobe and hippocampal structures, key to episodic memory formation and consolidation, accounts for the typical presentation with prominent, early episodic memory impairment.
• Disease progression then involves more widespread cortical regions. This produces the additional impairment of language, visuospatial function and executive function characteristic of more advanced disease.
• Genetic factors contribute to risk. Possession of the apolipoprotein E epsilon 4 allele confers well established, significant risk, with a dose dependent effect according to the number of alleles present.
• This allele is neither necessary nor sufficient for disease. Genetic testing for it is not generally recommended in routine individual diagnostic assessment, given its limited predictive value for the individual patient.
• Rare, highly penetrant mutations in the amyloid precursor protein, presenilin 1, and presenilin 2 genes cause early onset, autosomal dominant familial Alzheimer disease.
• Advancing age is the dominant contribution and the single strongest overall risk factor.

• The typical, core early feature is progressive, initially subtle, episodic memory impairment. It characteristically affects recent, newly formed memories disproportionately compared with remote, longstanding memories.
• Family members or close contacts frequently recognise it first, rather than the affected individual, given the limited insight into the developing memory impairment characteristic of this condition.
• Further cognitive domains become impaired progressively over the course of the illness.
• Language: word finding difficulty progressing to more significant expressive and, later, receptive language impairment.
• Visuospatial function: difficulty with navigation, even in previously highly familiar environments.
• Executive function: impaired planning, organisation and judgment.
• In many though not all patients, behavioural and psychological symptoms of dementia eventually develop (including agitation, apathy, depression and, in more advanced disease, psychotic symptoms). These are covered under major neurocognitive disorder generally.
• The disease has a gradual, insidious onset with slow, relentless progression over many years from initial symptom onset to advanced disease.
• This contrasts with the more abrupt onset and stepwise progression more typical of vascular dementia. The distinction is important, though not entirely absolute.
• Progressive functional decline reflects the underlying cognitive decline. More complex instrumental activities of daily living are affected first (financial management, medication management, driving). More basic activities (dressing, bathing, and eventually feeding) are impaired in advanced disease.
• Functional decline is a practical marker of disease stage and severity relevant to care planning.

• Full clinical assessment is the essential foundation of diagnosis. It includes a detailed history, ideally with collateral history from a family member or other close, reliable informant, given the limited insight characteristic of the affected individual.
• Formal, structured cognitive assessment uses a validated screening tool or, for more detailed characterisation, full neuropsychological assessment.
• Exclude alternative or contributing causes of cognitive impairment. Screen for depression, which can produce a cognitive impairment presentation with some clinical overlap. Use standard laboratory screening for reversible or contributing metabolic causes.
• Structural neuroimaging is recommended in the assessment of newly identified cognitive impairment. Magnetic resonance imaging is generally preferred over computed tomography given superior soft tissue and structural detail.
• Imaging excludes an alternative structural cause (including a mass lesion or significant cerebrovascular disease). In confirmed or strongly suspected Alzheimer disease, it identifies the characteristic pattern of medial temporal lobe and hippocampal atrophy. This finding is not entirely specific and requires careful clinical correlation.
• Cerebrospinal fluid biomarker assessment measures amyloid beta and tau protein concentrations. Reduced amyloid beta 42 with elevated total and phosphorylated tau supports the diagnosis.
• Amyloid and tau specific positron emission tomography imaging directly visualises the extent of the underlying amyloid and tau pathology within the brain.
• These tools are increasingly available and more specific. They are particularly valuable in diagnostic uncertainty, atypical presentation, or younger onset disease.
• They are of growing importance because the newer, amyloid targeted disease modifying therapies require biomarker confirmed evidence of underlying amyloid pathology before treatment initiation.
• Genetic testing and counselling is appropriate in suspected early onset, familial Alzheimer disease with a strongly suggestive family history pattern. It is not generally recommended as a routine component of assessment for the more common, sporadic, later onset presentation.

• Symptomatic pharmacological treatment is the longstanding, historical mainstay. Use acetylcholinesterase inhibitors (donepezil, rivastigmine, or galantamine) for mild to moderate disease. Use memantine (an N-methyl-D-aspartate receptor antagonist) for moderate to severe disease, or as an adjunct to an acetylcholinesterase inhibitor.
• These agents give modest, generally temporary symptomatic benefit for cognitive and functional symptoms in a proportion of treated patients. They do not alter the relentlessly progressive disease trajectory.
• Amyloid targeted monoclonal antibody therapy (including lecanemab and donanemab) is a genuinely disease modifying approach. It directly targets and reduces the cerebral amyloid burden.
• It has shown modest, statistically significant slowing of clinical progression in appropriately selected patients with early, mild cognitive impairment or mild dementia due to confirmed, biomarker positive Alzheimer disease. It is an important, genuinely novel development in this field.
• Careful patient selection is required, including biomarker confirmation of underlying amyloid pathology.
• Consider the risk profile carefully, particularly amyloid related imaging abnormalities (cerebral oedema or microhaemorrhage). These require structured magnetic resonance imaging monitoring throughout the treatment course.
• Deliver treatment within appropriately resourced specialist memory or neurology services with access to biomarker testing, treatment infrastructure and monitoring capability.
• Manage associated behavioural and psychological symptoms of dementia as detailed under major neurocognitive disorder generally.
• Full, structured psychosocial support for the affected individual and their family and carers is an essential, integral component across the full course of this progressive, life limiting condition. It addresses practical care planning, safety considerations, longer term care needs as the disease progresses and, where relevant, advance care and end of life planning discussions.
• Non-pharmacological interventions include structured cognitive stimulation programmes.
• Attend to modifiable cardiovascular risk factors. Evidence is accumulating that vascular risk factor optimisation supports overall cognitive health. Some degree of vascular pathology frequently coexists with the primary Alzheimer pathology, particularly in older patients.
• Regular, structured, ongoing multidisciplinary follow up includes periodic reassessment of cognitive and functional status, and ongoing support and education for the patient and family throughout the progressive course.
• Where relevant, coordinate with specialist palliative and end of life care services as the disease progresses to its advanced stages. This underpins compassionate, longitudinal management of this significant and increasingly prevalent condition.