n e w e ng l a n d j o u r na l
m e dic i n e
Mechanisms of Disease
Henry W. Querfurth, M.D., Ph.D., and Frank M. LaFerla, Ph.D. ore than 35 million people worldwide — 5.5 million in the United States — have Alzheimer’s disease, a deterioration of memory and other cognitive domains that leads to death within 3 to 9 years after diagnosis.Alzheimer’s disease is the most common form of dementia, accounting for 50 to 56% of cases at autopsy and in clinical series. Alzheimer’s disease combined with intracerebral vascular disease accounts for another 13 to 17% of cases. The principal risk factor for Alzheimer’s disease is age. The incidence of the disease doubles every 5 years after 65 years of age, with the diagnosis of 1275 new casesper year per 100,000 persons older than 65 years of age.1 Data on centenarians show that Alzheimer’s disease is not necessarily the outcome of aging2; nevertheless, the odds of receiving the diagnosis of Alzheimer’s disease after 85 years of age exceed one in three. As the aging population increases, the prevalence will approach 13.2 to 16.0 million cases in the United States by mid-century.3Many molecular lesions have been detected in Alzheimer’s disease, but the overarching theme to emerge from the data is that an accumulation of misfolded proteins in the aging brain results in oxidative and inflammatory damage, which in turn leads to energy failure and synaptic dysfunction.
From the Department of Neurology, Caritas St. Elizabeth’s Medical Center, Brighton, MA (H.W.Q.); theDepartment of Neurology, Tufts Medical Center, Boston (H.W.Q.); the Department of Neurology, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence (H.W.Q.); and the Department of Neurobiology and Behavior, University of California, Irvine, Irvine (F.M.L.). Address reprint requests to Dr. Querfurth at the Department of Neurology, Rhode Island Hospital, 563 EddySt., Providence, RI 02903-4923, or at henry_querfurth@ brown.edu. N Engl J Med 2010;362:329-44.
Copyright © 2010 Massachusetts Medical Society.
Pro tein A bnor m a l i t ie s in A l zheimer’s Dise a se
Cerebral plaques laden with β-amyloid peptide (Aβ) and dystrophic neurites in neocortical terminal fields as well as prominent neurofibrillary tangles in medial temporal-lobestructures are important pathological features of Alzheimer’s disease. Loss of neurons and white matter, congophilic (amyloid) angiopathy, inflammation, and oxidative damage are also present. Aβ peptides are natural products of metabolism consisting of 36 to 43 amino acids. Monomers of Aβ40 are much more prevalent than the aggregation-prone and damaging Aβ42 species. β-amyloid peptides originate fromproteolysis of the amyloid precursor protein by the sequential enzymatic actions of beta-site amyloid precursor protein–cleaving enzyme 1 (BACE-1), a β-secretase, and γ-secretase, a protein complex with presenilin 1 at its catalytic core4 (Fig. 1). An imbalance between production and clearance, and aggregation of peptides, causes Aβ to accumulate, and this excess may be the initiating factor inAlzheimer’s disease. This idea, called the “amyloid hypothesis,” is based on studies of genetic forms of Alzheimer’s disease, including Down’s syndrome,5 and evidence that Aβ42 is toxic to cells.6,7 Aβ spontaneously self-aggregates into multiple coexisting physical forms. One form consists of oligomers (2 to 6 peptides), which coalesce into intermediate assemblies8,9 (Fig. 1). β-amyloid can also growinto fibrils, which arrange themselves into β-pleated sheets to form the insoluble fibers of advanced amyloid plaques. Soluble oligomers and intermediate amyloids are the most neurotoxic forms of
n engl j med 362;4
january 28, 2010
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