Aetiology

• Genetic: Genetic factors play a role in both familial and sporadic cases of AD. Familial AD has a prevalence of less than 0.1%, has a younger age of onset (<65 years) and an autosomal dominant inheritance. Point mutations in three genes associated with amyloid processing, the amyloid precursor protein (APP) (on chromosome 21), presenilin 1 (PS1) (on chromosome 14) and presenilin 2 (PS2) (on chromosome 1) are known to be causative.
  
• Apolipoprotein E (ApoE): This gene is thought to be important in the earlier development of sporadic (non-familial) AD; there are three allelic variants, including E2–E4. Possession of two E4 alleles is thought to increase the risk of developing AD.

Associations/Risk Factors

• Increasing age: Approximately 10% of people over 75 years of age will develop dementia rising to 20% over age 85 years; rare under the age of 60 years.
  
• Family history of dementia in first-degree relative (see above).
  
• Level of educational achievement: Lower levels of achievement and occupational attainment have been associated with an increased risk of developing AD.

Pathology/Pathogenesis

• Cerebral atrophy tends to involve the hippocampus and medial temporal lobe structures first, before affecting the rest of the cortex.
  
• Neuropathological examination: Intracellular neurofibrillary tangles and extracellular amyloid plaques. These pathological processes result in biological changes in the brain, including neurotransmitter loss, dendritic pruning of neurons and cell death. This forms the basis of use of acetylcholinesterase inhibitors for symptomatic improvement in AD.

History

• In AD, symptoms of memory loss are the commonest initial complaint. Forgetfulness is often reported by family or friends and work performance may decline. If memory loss is the only deficit and day-to-day functioning is preserved, a patient is given the diagnosis of mild cognitive impairment (MCI); 80% of these patients will develop AD over a 5 year period.
  
• If an individual has memory loss and further cognitive decline, for example speech disturbance, or impaired judgement, affecting their day-to-day functioning, they may be given a diagnosis of AD (according to certain criteria). Characteristically, personality is preserved until later in the disease process which can help differentiate AD from other types of dementia (e.g. FTD).
  
• As the disease progresses over a 6–8 year period, patients display severe global intellectual decline and loss of ability to care for themselves, including incontinence.

Examination

• Conscious level is not impaired. MMSE is essential (scores usually less than 24/30) and demonstrates deficits in two or more areas of cognition (e.g. memory and naming).
  
• In the earlier stages of AD, a neurological examination is usually normal; in later stages of the disease, primitive reflexes, for example pout, palmomental, and grasp may emerge with increased tone (gegenhalten pattern). The presence of major neurological deficits suggests other possible diagnoses for dementia (see Section ‘Differential Diagnoses’).

Investigations