Alzheimer

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

review article
Mechanisms of Disease

Alzheimer’s Disease
Henry W. Querfurth, M.D., Ph.D., and Frank M. LaFerla, Ph.D.

M

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 afterdiagnosis. 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 of1275 new
cases per 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 bymid-century.3
Many 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.); the Department 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
IslandHospital, 563 Eddy St., 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
β -Amyloid

Cerebral plaques laden with β-amyloid peptide (Aβ) and dystrophic neurites in
neocortical terminal fields as well as prominent neurofibrillary tangles inmedial
temporal-lobe structures 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 from proteolysis 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 maybe the initiating factor in Alzheimer’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 intermediateassemblies8,9 (Fig. 1). β-amyloid can also grow into 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

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