Editorial |

The Origins of Alzheimer Disease:  A Is for Amyloid

Dennis J. Selkoe, MD
JAMA. 2000;283(12):1615-1617. doi:10.1001/jama.283.12.1615.
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Few public health problems have captured the attention of the biomedical and lay communities alike as has Alzheimer disease (AD). As the new millennium begins, it is becoming increasingly clear that a great many people will escape other major causes of mortality to reach the age when neurodegenerative diseases, particularly AD, become highly prevalent. To avoid an exacerbation of the personal and societal tragedy that AD already represents, clinicians and researchers must accurately define its cause and early pathogenesis and develop effective interventions, preferably agents that prevent the onset of symptoms. The study by Näslund et al1 in this issue of THE JOURNAL provides compelling evidence that the accumulation of small protein fragments called amyloid β-peptides (Aβ) in brain regions subserving memory and cognition is a very early pathogenic event that precedes both neurological impairment and the development of the other proteinaceous lesion of AD, the neurofibrillary tangle. Moreover, the authors show that the conversion from a presymptomatic to a symptomatic state and the subsequent progression of dementia correlate significantly with a dramatic increase in brain Aβ levels.

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Figure. Proteolytic Cleavages of APP That Produce Aβ Peptide
Graphic Jump Location
The β-amyloid precursor protein (APP) with amino (NH2) and carboxyl (COOH) termini indicated. The large wavy lines indicate the boundaries of the cell membrane and illustrate the portion of APP that spans the membrane (transmembrane or TM). Sequential proteolytic cleavages of APP by β- and -γ-secretases (small dotted lines) release the Aβ peptide (dark box). The γ cleavage occurs within the transmembrane domain of APP.



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