Alzheimer Disease: Mechanistic Understanding Predicts Novel Therapies

Clinical Principles

Alzheimer disease usually begins with gradual failure of recent memory with preserved alertness and motor function.

The syndrome of minimal cognitive impairment (mild cognitive impairment)—a subtle decrease in short-term declarative memory with otherwise normal cognition—is often a harbinger of Alzheimer disease.

Alzheimer disease progresses slowly to involve many cognitive spheres and shortens life expectancy, with most patients ultimately dying of secondary respiratory complications (for example, aspiration and pneumonia).

Treatment with acetylcholinesterase inhibitors can temporarily alleviate some symptoms but does not modify disease progression.

A noncompetitive N-methyl-d-aspartate–receptor antagonist (memantine) has recently been approved as a noncholinergic symptomatic treatment.

Epidemiologic data suggest that long-term use of certain cyclooxygenase-1 or -2 inhibitors (for example, ibuprofen) or statin drugs may be associated with a decreased risk for Alzheimer disease.

Methods to image cerebral amyloid deposits are in early clinical development.

Pathophysiologic Principles

A clinical diagnosis of Alzheimer disease is confirmed by observing numerous neuritic (amyloid) plaques and neurofibrillary tangles in the hippocampus, amygdala, and association neocortex.

The plaques (extracellular) are composed of the 42- and 40-residue β-amyloid proteins, whereas the tangles (intraneuronal) are composed of modified forms of the microtubule-associated protein, tau.

β-Amyloid protein is generated normally throughout life from a large, receptor-like precursor (β-amyloid precursor protein) through proteolytic cleavages by the β- and γ-secretases.

Mutations in 3 genes (β-amyloid precursor protein, presenilin 1, and presenilin 2) that cause Alzheimer disease increase cerebral β-amyloid production, whereas inheritance of the apolipoprotein E4 polymorphism enhances its stability, leading to β-amyloid …