The n e w e ng l a n d j o u r na l of m e dic i n e

Cross-study comparisons are limited. There Mark N. Levine, M.D.

are important differences between the U.K. and McMaster University
Canadian trials that could account for the dis- Hamilton, ON, Canada
crepancy in findings (e.g., a shorter follow-up, Jim A. Julian, Ph.D.
inclusion of node-positive patients, and the use Ontario Clinical Oncology Group
Hamilton, ON, Canada
of boost radiation and anthracyclines).1-3 Further-
Since publication of their article, the authors report no fur-
more, our analysis on tumor grade was post hoc ther potential conflict of interest.
and only one of five factors that we considered.
1. Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy
The differential effect between treatments in pa- fraction size on tumour control in patients with early-stage
tients with high-grade tumors requires validation breast cancer after local tumour excision: long-term results of a
through future research. Meanwhile, we believe randomised trial. Lancet Oncol 2006;7:467-71. [Erratum, Lancet
Oncol 2006;7:620.]
it is premature to make any decisions concern- 2. The START Trialists’ Group. The UK Standardisation of
ing the avoidance of hypofractionated radiation Breast Radiotherapy (START) Trial A of radiotherapy hypofrac-
in treating women with high-grade tumors. tionation for treatment of early breast cancer: a randomised trial.
Lancet Oncol 2008;9:331-41.
Timothy J. Whelan, B.M., B.Ch. 3. Idem. The UK Standardisation of Breast Radiotherapy (START)
Juravinski Cancer Centre Trial B of radiotherapy hypofractionation for treatment of early
Hamilton, ON, Canada breast cancer: a randomised trial. Lancet 2008;371:1098-107.
tim.whelan@jcc.hhsc.ca

Alzheimer’s Disease
To the Editor: In their article on Alzheimer’s
disease, Querfurth and LaFerla (Jan. 28 issue)1
stated that “the level of muscarinic acetylcholine
receptors, or receptor coupling, is reduced in the
brains of patients with Alzheimer’s disease.” How-
ever, a recent review indicated that not all studies
reported such reductions and that they may not
occur until the disease is advanced.2 Current study
methods do not generally allow determination of
muscarinic type 1 (M1) receptor density or recep-
tor coupling status in specific neuronal path-
ways. In fact, in vivo studies suggest an apparent
increased sensitivity to some of the effects of the
M1 agonist arecoline in relatively early stages of
Alzheimer’s disease.3,4 Presynaptic M1 receptors
in CA3 pyramidal neurons of the hippocampus
have been shown to play a critical role in meta­
botropic glutamate receptor-mediated long-term
depression of Schaffer collaterals.5 Thus, if con-
firmed, hypersensitivity of M1 receptors in Alz­
heimer’s disease, especially in this neuronal path-
way, could be an additional mechanism that
contributes to synaptic failure and memory dys-
function in Alzheimer’s disease.
Nunzio Pomara, M.D.
John J. Sidtis, Ph.D.
Nathan S. Kline Institute for Psychiatric Research
Orangeburg, NY
pomara@nki.rfmh.org
No potential conflict of interest relevant to this letter was re-
ported.
1. Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J
Med 2010;362:329-44.
2. Thathiah A, De Strooper B. G protein-coupled receptors,
cholinergic dysfunction, and Abeta toxicity in Alzheimer’s dis-
ease. Sci Signal 2009;2(93):re8.
3. Pomara N, Stanley M, LeWitt PA, Galloway M, Singh R,
Deptula D. Increased CSF HVA response to arecoline challenge in
Alzheimer’s disease. J Neural Transm Gen Sect 1992;90:53-65.
4. Tariot PN, Cohen RM, Welkowitz JA, et al. Multiple-dose
arecoline infusions in Alzheimer’s disease. Arch Gen Psychiatry
1988;45:901-5.
5. Kamsler A, McHugh TJ, Gerber D, Huang SY, Tonegawa S.
Presynaptic m1 muscarinic receptors are necessary for mGluR
long-term depression in the hippocampus. Proc Natl Acad Sci
U S A 2010;107:1618-23.
To the Editor: I wonder whether Querfurth and
LaFerla have an opinion as to whether Alzhei­
mer’s is a single disease. Could it be that there
are multiple causes of Alzheimer’s “disease,” some
of which respond better, albeit still poorly, to
some interventions than others — hence the var-
iable progression of the syndrome? Might we be
wiser to call it Alzheimer’s syndrome?
Knight Steel, M.D.
Hackensack University Medical Center
Hackensack, NJ
ksteel@humed.com
No potential conflict of interest relevant to this letter was re-
ported.
The authors Reply: The question of the level
and function of muscarinic acetylcholine receptors

1844 n engl j med 362;19  nejm.org  may 13, 2010

Downloaded from www.nejm.org on June 13, 2010 . Copyright © 2010 Massachusetts Medical Society. All rights reserved.
 correspondence
in Alzheimer’s disease highlights the conflicting
literature on biomarkers in samples of postmor-
tem tissue affected by the disease. The problems
arise from differences in the handling of the
samples, the brain regions selected for study, and
the method of measuring receptor binding. Cor-
rections for regional brain atrophy and the rela-
tive involvement of receptor subtypes are often un-
defined. The controversy is important because
much effort has gone into testing nonspecific
agonists, such as arecholine, and the more recent
selective M1 agonists and allosteric modulators.
Muscarinic acetylcholine receptors are G-protein–
coupled receptors, of which there are five subtypes
(M1 to M5) in the central nervous system. The
most studied is the M1 receptor, which is coupled
to the Gq protein and expressed primarily in
postsynaptic elements. M1 stimulation is associ-
ated with cognitive enhancement, reduces levels
of β-amyloid and tau, and sensitizes N-methyl-D-
aspartate receptor currents and long-term poten-
tiation. The M2 and M4 receptors are mainly pre-
synaptic and are coupled to Gi proteins. These
receptors depress neurotransmitter release and
neuronal responses. Presynaptic M1 receptors may
play a similar role.
Several studies report the loss of M2 or M4
receptors in Alzheimer’s disease,1 but these and
other studies2 generally report no change in the
level of M1 receptors — one study reported an in-
crease. An in vivo single-photon-emission com-
puted tomographic study performed with a dual
M1 and M4 agonist labeled with radioiodine
showed significant reductions in the frontal and
temporal brain regions of patients with Alzhei­
mer’s disease3; the results were confirmed by im-
munohistochemical testing.4 Many studies also
reported a loss of functional coupling of the M1
receptor to its signaling G-protein in Alzheimer’s
disease.2 If it is correct, this finding alone may
limit the extent to which muscarinic acetylcho-
line receptor agonists can improve cognition in
clinical trials. It is hard to reconcile this fact
with an M1 receptor hypersensitivity hypothesis
for synaptic failure in Alzheimer’s disease, un-
Comparative Effectiveness and Health Care Spending
To the Editor: Weinstein and Skinner (Feb. 4
issue)1 provide a helpful framework for visualiz-
ing the relationship of aggregate medical expen-
ditures to aggregate outcomes. In their article, they
n engl j med 362;19  nejm.org  may 13, 2010
Downloaded from www.nejm.org on June 13, 2010 . Copyright © 2010 Massachusetts Medical Society. All rights reserved.
less presynaptic M1 receptors are shown to have
a more important role and need to be dampened,
as suggested for the M2 receptors.5
Insofar as sporadic Alzheimer’s disease is a
relatively homogeneous entity in terms of clinical
presentation, pathology, and treatment, it may be
viewed as a single disease. However, there are
probably several distinct molecular pathways, de-
pending partly on a host of discrete risk factors,
that lead to this state (see the figure in the Sup-
plementary Appendix to our article, available with
the full text of the article at NEJM.org). Once spe-
cific treatments can be assigned to these path-
ways, which can be identified by the molecular
signatures in a given individual, Alzheimer’s dis-
ease could come to be regarded as a collection of
diseases. An example of such evolution is pro-
vided by carcinoma of the breast, in which human
epidermal growth factor receptor type 2 (HER2)
status or estrogen-receptor status has defined dif-
ferent pathogeneses and treatment outcomes with
the use of monoclonal antibodies, aromatase in-
hibitors, or paclitaxel.
Henry W. Querfurth, M.D., Ph.D.
Warren Alpert Medical School at Brown University
Providence, RI
henry_querfurth@brown.edu
Frank M. Laferla, Ph.D.
University of California, Irvine
Irvine, CA
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Mulugeta E, Karlsson E, Islam A, et al. Loss of muscarinic
M4 receptors in hippocampus of Alzheimer patients. Brain Res
2003;960:259-62.
2. Pakrasi S, Colloby SJ, Firbank MJ, et al. Muscarinic acetyl-
choline receptor status in Alzheimer’s disease assessed using
(R,R) 123I-QNB SPECT. J Neurol 2007;254:907-13.
3. Shiozaki K, Iseki E, Hino H, Kosaka K. Distribution of m1
acetylcholine receptors in the hippocampus of patients with Alz­
heimer’s disease and dementia with Lewy bodies — an immuno-
histochemical study. J Neurol Sci 2001;193:23-8.
4. Tsang SW, Lai MK, Kirvell S, et al. Impaired coupling of
muscarinic M1 receptors to G-proteins in the neocortex is as-
sociated with severity of dementia in Alzheimer’s disease. Neu-
robiol Aging 2007;27:1216-23.
5. Koch HJ, Haas S, Jürgens T. On the physiological relevance
of muscarinic acetylcholine receptors in Alzheimer’s disease.
Curr Med Chem 2005;12:2915-21.
first propose “induc[ing] providers to cut back on
cost-ineffective services” and later write that “If
we can induce hospitals and health plans to im-
prove efficiency  .  .  .  health costs  .  .  .  will come
1845