PERSPECTIVE Personal Digital Educators

sources or the extension of clinical-information sys- “What’s the renal dosing?” One additional tap on
tems to render them compatible with PDAs. Second, the PDA screen provides the answer.
PDA use must be integrated into the curriculum 1. More physicians hold lives in the palms of their hands: sur-
and the workflow of the users. Whether users are vey reports one in four doctors now use handheld software as a
updating their software, requesting online infor- prime source for critical medical information. San Mateo, Calif.:
ePocrates, July 16, 2003. (Accessed February 15, 2005, at http://
mation, or logging clinical data, the processes must www2.epocrates.com/company/news/10132.html.)
be as nondisruptive as possible. For example, the 2. Sellman JS, Decarolis D, Schullo-Feulner A, Nelson DB, Filice
use of PDA technology by students should be coor- GA. Information resources used in antimicrobial prescribing. J Am
Med Inform Assoc 2004;11:281-4.
dinated with training in the use of the device and 3. Greenberg R. Use of the personal digital assistant (PDA) in
decision-support applications, as well as with edu- medical education. Med Educ 2004;38:570-1.
cation in the principles of evidence-based practice. 4. Leung GM, Johnston JM, Tin KY, et al. Randomised con-
trolled trial of clinical decision support tools to improve learning
In 2005, when the same question arises — of evidence based medicine in medical students. BMJ 2003;327:
“What’s his infection sensitive to?” — the PDA 1090.
comes into play immediately (see the figure). A 5. Ying A. Impact of hospital computer systems on resident
work hours. Boston: Medical Records Institute, 2004. (Accessed
few taps, and the PDA obtains the answer from the February 15, 2005, at http://www.medrecinst.com/pages/libArticle.
clinical-information system: “levofloxacin.” Then asp?id=26.)

Genetic Factors in Alzheimer’s Disease

Thomas D. Bird, M.D.
Related article, page 884

Nearly 100 years ago, Alois Alzheimer described
the clinical and pathological characteristics of a
50-year-old woman with the dementing illness that
now bears his name.1 She had no family history of
dementia. It soon became established dogma that
Alzheimer’s disease was a rare, noninherited cause
of presenile dementia.
The past 25 years have seen an astounding con-
fluence of seven new observations that have result-
ed in fundamental changes in our understanding
of this important disease. First, Alzheimer’s dis-
ease is by far the most common cause of dementia.
Second, the major pathological component of the
disease is the accumulation of a form of amyloid
termed Ab peptide. Third, this peptide is cleaved
from a larger protein, the amyloid precursor pro-
tein, the gene for which resides on chromosome 21.
Fourth, the pathological changes of Alzheimer’s
disease are found in the brains of adults with tri-
somy 21 (Down’s syndrome). Fifth, many families
Dr. Bird is a professor of neurology, medicine, and psychi- tase site). The next group of mutations was found
atry at the University of Washington and a research neurol- in the genes encoding two proteins called prese-
ogist at the Veterans Affairs Medical Center in Seattle.
have an abundance of members with Alzheimer’s
disease, suggesting autosomal dominant inheri-
tance. Sixth, mutations in any of three genes are suf-
ficient to cause the disease in certain of these fam-
ilies. And finally, the e4 allele of apolipoprotein E
is a risk factor for the most common type of
Alzheimer’s disease in the general population. The
dogma has now been reversed: Alzheimer’s dis-
ease is a common disease with important genetic
components.
Initially, the genetic discovery with the greatest
importance was that point mutations in any of three
genes could cause autosomal dominant inherited
forms of Alzheimer’s disease that were clinically
and pathologically identical to nongenetic forms of
the disease except that the age at onset was young-
er.2 The first mutations were found in the APP gene
on chromosome 21. These mutations tend to clus-
ter near sites where the Ab peptide is cleaved from
amyloid precursor protein (b- and g-secretase sites)
or where the Ab peptide itself is cleaved (the a-secre-
nilin 1 and 2. Subsequently, it was discovered that

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PERSPECTIVE
Adding up to Alzheimer’s Disease.
The known genetic causes of Alzheimer’s disease (left side) are responsible
for only a small number of the total cases. The possible environmental factors
(right side) are largely speculative; none are proven causes. The most likely
pathway resulting in Alzheimer’s disease in the general population (bottom)
involves predisposing genetic factors (such as the e4 variant of the APOE
gene) combined with a variety of environmental factors and interacting with
physiological aging processes in the brain.
these two proteins play a role in the g-secretase
cleavage of Ab from amyloid precursor protein.
Thus, it became clear that the primary consequence
of these mutations was an increase in the deposi-
tion of the pathogenic form of Ab, Ab(1¡42), in the
brain. These findings, combined with the under-
standing that Alzheimer’s disease in patients with
trisomy 21 probably resulted from a lifelong, mild
but consistent excess of Ab, provided the most im-
portant evidence supporting the amyloid-cascade
hypothesis for the pathogenesis of the disease.
This hypothesis emphasizes the critical role
of Ab deposition in the flow of events that lead to
plaque formation, synaptic loss, neuronal dysfunc-
tion, neuronal death, and clinical dementia. The hy-
pothesis is important in that it has led to prominent
strategies for possible treatment of the disease, in-
cluding vaccination with Ab peptide (or adminis-
tration of antibodies to Ab) and attempts to inhibit
b-secretase activity. In addition, the role of neu-
rofibrillary tangles in the pathogenesis of Alzhei-
mer’s disease requires further elucidation.
Mutations in the genes encoding amyloid pre-
cursor protein and presenilin 1 and 2 (APP, PS1, and
PS2) cause familial early-onset Alzheimer’s disease.
n engl j med 352;9 www.nejm.org march 3, 2005
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Genetic Factors in Alzheimer’s Disease
The age at onset in these families is typically in the
40s or 50s and, astonishingly, sometimes as early
as the 20s. The onset is almost never after 65 years
of age — in contrast to the typical age at the onset
of Alzheimer’s disease in the general population,
in which the frequency increases with every decade
after 70 years of age. Although mutations in the
APP, PS1, and PS2 genes cause less than 2 percent of
cases of Alzheimer’s disease, 25 percent of persons
with late-onset forms of the disease have had a close
relative with dementia. In fact, there are many fam-
ilies that have a heavy load of late-onset Alzheimer’s
disease but do not have mutations in APP, PS1, or
PS2. The hunt is on to identify additional genetic
factors in the more common late-onset form of the
disease.
One factor is the gene (APOE) encoding apoli-
poprotein E, a plasma-membrane protein involved
in lipid transport. The gene’s e4 allele is associated
with a shift to an earlier age at onset. For example,
a person of European descent who is homozygous
for the e4 allele (as about 2 percent of the popula-
tion is) has a lifetime risk of Alzheimer’s disease
that is three to four times as great as that for some-
one of European descent who does not have an e4
allele. Moreover, the age at onset is likely to be about
10 to 15 years earlier than that in the general pop-
ulation.
However, the APOE e4 genotype is neither nec-
essary nor sufficient for the occurrence of Alzhei-
mer’s disease. It is estimated that there are at least
two or three (and possibly five or six) additional
genes influencing the age at onset and the risk of
the disease.3 Genetic linkage analysis and similar
studies involving hundreds of families have pro-
duced evidence for a number of chromosomal re-
gions suspected of harboring genes related to
Alzheimer’s disease. These include regions on chro-
mosomes 6, 9, 10, 12, and 19.4 So far, careful scru-
tiny of these regions has not resulted in the iden-
tification of an unequivocal “Alzheimer’s disease
gene.” More than 100 genes have been implicated
through genetic-association studies, but none of
these findings have been fully replicated.5 The hunt
continues, driven by the need to better understand
the pathogenesis of the disease and improve diag-
nosis, treatment, and prevention.
Evidence for the latest candidate gene (UBQLN1,
encoding ubiquilin 1) is presented by Bertram and
colleagues in this issue of the Journal (pages 884–
894). UBQLN1 is intriguing as a candidate gene be-
863
PERSPECTIVE Genetic Factors in Alzheimer’s Disease

cause of its potential role in the proteasome degra- order to treat and prevent the disease. These remain
dation of proteins and its interaction with PS1 and the goals of the many scientists who are doggedly
PS2. As always, this new association requires repli- pursuing the puzzle of Alzheimer’s disease.
cation and confirmation in additional populations Dr. Bird reports having served on the speakers bureau for Athe-
na Diagnostics.
of patients with Alzheimer’s disease.
The role of environment cannot be ignored. The 1. Maurer K, Volk S, Gerbaldo H. Auguste D and Alzheimer’s
disease. Lancet 1997;349:1546-9.
days of debating nature versus nurture are long past: 2. Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s
it is clear that most disease is caused by a combina- disease. N Engl J Med 2003;348:1356-64. [Erratum, N Engl J Med
tion of genetic and environmental factors (see the 2003;348:2588.]
3. Daw WE, Payami H, Nemens EJ, et al. The number of trait
diagram). The key issues in complex conditions such loci in late-onset Alzheimer disease. Am J Hum Genet 2000;66:
as Alzheimer’s disease are identifying those specif- 196-204.
ic genetic and environmental factors, determining 4. Kamboh MI. Molecular genetics of late-onset Alzheimer’s
disease. Ann Hum Genet 2004;68:381-404.
their relative importance, understanding their in- 5. Bertram L, Tanzi RE. Alzheimer’s disease: one disorder, too
teractions, and capitalizing on this knowledge in many genes? Hum Mol Genet 2004;13 Special No. 1:R135-R141.

864 n engl j med 352;9 www.nejm.org march 3, 2005

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