Clinical syndrome caused by a number of brain disorders which cause memory loss, decline in some other aspect of cognition, and difficulties with activities of daily living

Aetiology

Some of the more common causes of dementia are:

• Alzheimer’s disease - most common cause, 50-70% of cases of dementia
  • Usually occurs in old age - 1/5 of individuals over 80 years old are affected
• Vascular dementia - accounts for ~25%
  • Brain damage due to cerebrovascular disease: either major stroke, multiple smaller unrecognised strokes (multi-infarct) or chronic changes in smaller vessels (subcortical dementia)
• Dementia with Lewy bodies - about 15% of cases
  • Deposition of abnormal protein (⍺-synuclein) within neurons in the brain stem and neocortex
• Frontotemporal dementia - < 5% of cases
  • Specific degeneration/atrophy of the frontal and temporal lobes of the brain
• Potentially treatable dementias (<5%)
  • Metabolic e.g. uraemia
  • Toxic e.g. alcohol
  • Vitamin deficiency - B12 and thiamine
  • Traumatic - severe or repeated brain injury
  • Intracranial lesions e.g. subdural haematoma, tumours
  • Infections e.g. HIV
  • Endocrine e.g. hypothyroidism
  • Psychiatric - depression causing 'pseudodementia'

Rare causes

• Huntington’s disease
  • Autosomal dominant trait
  • Onset usually between 30 and 50 years - age dependant penetrance
• Parkinson's disease
• CJD

Pathophysiology

Molecular pathology and aetiology of Alzheimer's disease

• The pathological hallmarks of AD include:
  • Loss of cortical neurones
  • Neurofibrillary tangles
  • Senile plaques - extracellular protein deposits containing amyloid β protein
• Initial symptoms generally forgetfulness
• Degeneration of medial hippocampus + later parietal lobes: forgetfulness → apraxia/visuospatial difficulties
• Genetics have been implicated in AD
  • A first-degree relative with AD confers a doubled lifetime risk of AD
  • There are rare autosomal dominant monogenic early-onset forms of familial AD with high penetrance, caused by mutations in specific genes
  • Genes which have been linked to the development of AD include: the E4 allele of the apolipoprotein E gene, point mutations in the APP gene, and mutations in presenilin (PS)-1 and 2
  • The presence of three copies of the APP gene on chromosome 21 in Down’s syndrome patients is responsible for the high incidence of AD in that condition - onset in 3rd or 4th decade
• <65 years - early onset AD, genetic influences, may be atypical presentation
• <65 years - sporadic AD, environmental > genetic influences, usually typical initial forgetfulness