Alzheimer's disease

Alzheimer's disease (AD) is a common neurodegenerative disease, responsible for the majority of all dementias, and imposing a significant burden on developed nations.

Epidemiology

Alzeimer's disease is the most common cause of dementia, and accounts for two thirds of cases of dementia in patients aged 60 - 70 years ². The prevalence is stongly linked to age, with >1% of 60-64 year old patients being diagnosed with the condition, compared to 20-40% of those over 85-90 years of age _².

Epidemiological risk factors have been identified, including ²:

• advanced age
• female gender
• apolipoprotein E (APOE) ε4 allele carrier status
• current smoking
• family history of dementia
• fewer years of formal education
• lower income
• lower occupational status

Clinical presentation

Traditionally Alzheimer's disease has been clinically characterised by predominantly memory deficits, at least in initial stages. It has become increasingly evident that in addition to the typical presentation, a number of atypical clinical patterns, which are nonetheless pathologically Alzheimer's disease, exist. 

Classical / typical Alzheimer's disease

The typical patient with Alzheimer's disease will present initially with antegrade episodic memory deficits. Over time (often years) the disease progresses with eventual involvement of attentional and executive processes, semantic memory, praxis and visuoperceptual abilities ¹. Neuropsychiatric symptoms are also common, and eventually affect almost all patients. These include apathy, depression, anxiety, aggression/agitation, and psychosis (delusions and hallucinations) ².

Atypical / variant Alzheimer's disease

These entities, often recognised clinically well before they were identified to be pathologically identical to Alzheimer's disease are characterised by slowly progressive focal cortical atrophy, with symptoms and signs matched to the affected area ¹. Examples include:

• posterior cortical atrophy
• frontal variant of Alzheimer's disease
• a minority of cases of semantic dementia

Diagnosis

Clinical diagnosis is made by identifying progressive decline in memory both with clinical examinations and neuropsychologic tests. Although using such longitudinal clinical criteria is highly sensitive in diagnosing a dementia of any type (> 90%), they are relatively innacurate (<70%) in diagnosing Alzheimer's disease specifically ³.

The only definitive diagnostic test is brain biopsy. A combination of clinical features and neuroimaging are usually considered sufficient although especially with the recognition of variants, this approach undoubtedly misdiagnoses a significant number of cases. 

A number of CSF biomarkers are being used which may further help diagnosis. They include beta-amyloid, total tau, and hyperphosphorylated tau ².

Pathology

Alzheimer's diseas is characterized by the accumulation within the brain of senile (neuritic) plaques, neuritic (neurofibrillary) tangles, and progressive loss of neurons ².

The progression of pathology initially involves the transentorhinal region and then spreads to the hippocampal complex and mesial temporal lobe structures and eventually the temporal lobes and basal forebrain ¹.

The underlying reason for accumulation of senile (neuritic) plaques and neurofibrillary tangles remains poorly understood, as does the reason for non uniform distribution in the cortex.

Radiographic features

Although CT is able to demonstrate the characteristic patterns of cortical atrophy, MRI is more sensitive to these changes, and better able to exclude other causes of dementia (e.g. multi-infarct dementia) and as such is the favoured modality. 

MRI

The primary role of MRI (and CT for that matter) in the diagnosis of Alzheimer's disease is the assessment of volume change in characteristic locations which can yield a diagnostic accuracy of up to 87% ³. 

The diagnosis should be made on the basis of two features:

1. mesial temporal lobe atrophy
2. temporoparietal cortical atrophy 

Mesial temporal lobe atrophy can be viewed directly by assessing for hippocampal and parahippocampal decrease in volume, or indirectly by examining enlargement of the parahippocampal fissures. The former is more sensitive and specific but ideally requires actual volumetric calculations rather than 'eye-balling' the scan ³. 

Nuclear medicine

SPECT and PET are able to detect regional hypoperfusion / hypometabolism in a bi-parietal and bi-temporal distribution.

Pittsburgh Compound B, a molecule that binds preferentially to beta-amyloid fibrils is being used with PET and may be able to improve the specificity of antemortem diagnosis, although there is considerable overlap with normal controls ².

Treatment and prognosis

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Differential diagnosis

This article has just been started. More to come so hold on to your hats. If you want to, feel free to edit / contribute.