Alzheimer’s disease - Disorders of consciousness and memory

Alzheimer’s disease

Definition

A primary degenerative cortical dementia.

Incidence

Most common neurodegenerative disorder and cause of dementia.

Age

The onset can be in middle age, but the incidence rises with age. The annual risk of developing Alzheimer’s disease (AD) is 1% in people aged 70–74 years, 2% in those aged 75–79 years and then steeply rises to 8% in those over 85 years.

Aetiology/pathophysiology

Risk factors include family history, Down’s syndrome and previous head injury.

Molecular analysis of the amyloid found in the brains of patients with AD shows that it is derived from a family of normal cell membrane proteins called amyloid precursor proteins (APP) encoded on Chr 21. When APPs are cleaved by specific enzymes called secretases, a highly amyloidogenic protein is produced which is referred to as β-amyloid protein or Aβ42 protein. It is thought that these plaques then cause inflammation and hence neurotoxicity and apoptosis.

Mutations on Chr 21 in Down’s syndrome cause over-production of APP.

Some cases of early onset AD are due to an autosomal dominant disorder with mutations on Chr 14 or 21 – these cause increased activity of the secretases.

Apolipoprotein ε4 (apoε4) genotype on Chr 19 is over-represented in AD patients compared with the other alleles ε2 and ε3. Heterozygotes have approximately twofold relative risk for developing AD and homozygotes have a fourfold or 50% risk.

Neurochemical analysis reveals that patients with Alzheimer’s disease have widespread neurotransmitter defects, particularly loss of acetylcholine esterase and acetylcholine from the cortex/subcortical structures.

Clinical features

The features are those of dementia, but with an insidious onset and progressive decline in memory and at least one of:

·        Dysphasia: Loss in language skills, especially with names and understanding speech.

·        Apraxia: Inability to execute a skilled or learned motor act, e.g. inability to brush teeth, write, get dressed despite intact muscle function and comprehension.

·        Agnosia: Loss of ability to recognise objects, people, sounds, shapes or smells despite normal sensory functions. Usually classified by the sense affected, e.g. visual agnosia.

·        Disturbance in executive functioning (higher mental

·        functions such as planning, abstract thought, organisation).

With progression over a number of years patients become immobile and emaciated. Death is commonly due to a complication of immobility or other diseases.

Macroscopy

The brain is small, with shrinkage of the gyri and widening of the sulci. Temporal lobe atrophy is prominent, particularly in the parahippocampal gyrus but also in the frontal and parietal lobes.

Microscopy

There are several abnormalities.

·        Senile plaques in the cerebral cortex – spherical deposits with a central core of amyloid composed of β (A4) protein. Amyloid is also seen deposited in cerebral arteries causing amyloid angiopathy.

·        Neurofibrillary tangles – intraneuronal inclusions comprising bundles of abnormal filaments. The tangles are composed of a microtubule binding protein called Tau protein, and are frequently flame shaped and occupy much of the space within the neuronal cytoplasm.

·        Cortical nerve processes become twisted and dilated (neuropil threads) due to the accumulation of the same fibres that cause the tangles.

·        Lewy bodies – eosinophilic cytoplasmic neuronal inclusions, in some cases. These are also seen in Lewy body dementia.

·        Neuronal loss is seen from the cortex particularly in patients under the age of 80 years.

Investigations

The diagnosis is clinical although investigations to exclude other causes of dementia are necessary. AD cannot be definitively diagnosed until brain tissue is obtained, e.g. at post-mortem, but in most cases a clinical diagnosis is accurate.

Management

The management of AD includes those used for all types of dementia.

In addition, for early AD, acetylcholinesterase inhibitors such as donepezil, have been shown to improve cognitive function and delay decline by the equivalent of 2 months per year.

The gene of one of the enzymes which cleaves APP (β secretase) has been cloned, leading to hopes of other targeted therapies.

Prognosis

Most patients die within 5–10 years of diagnosis. Younger patients appear to progress more slowly.