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Chronically mad as a hatter Anticholinergics and Alzheimer's disease pathology.

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References
1. Goate AM, Chartier-Harlin MC, Mullan MC, et al. Segregation of a missense mutation in the amyloid precursor protein
gene with familial Alzheimer’s disease. Nature 1991;349:
704 –706.
2. Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene
bearing missense mutations in early-onset familial Alzheimer’s
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3. Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for
the chromosome 1 familial Alzheimer’s disease locus. Science
1995;269:973–977.
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␤-protein similar to that in the senile plaques of Alzheimer’s
disease is increased in vivo by the presenilin 1 and 2 and APP
mutations linked to familial Alzheimer’s disease. Nat Med
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6. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s
disease: progress and problems on the road to therapeutics. Science 2002;297:353–356.
7. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of
apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261:921–923.
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DOI: 10.1002/ana.10624
Chronically Mad as a
Hatter: Anticholinergics and
Alzheimer’s Disease
Pathology
Drugs with anticholinergic properties are used for a variety of neurological, psychiatric, and other medical
conditions. Some medications are specifically intended
to antagonize muscarinic acetylcholine receptors, for
example, to treat movement disorders (eg, trihexyphenidyl, benztropine), urinary incontinence (eg,
tolterodine; oxybutynin), and dizziness (eg, meclizine).
Many other medications are not primarily targeted at
cholinergic receptors, but nonetheless have substantial
anticholinergic actions, including a long list of drugs
used for common ailments such as antidepressants, antihypertensives, antipsychotics, and antihistamines.1
These anticholinergic side effects reflect acute blockade
of central and peripheral muscarinic receptors. Generations of medical students remember these side effects
by using the mnemonic “mad as a hatter” (delirium),
“blind as bat” (mydriasis), “red as a beet” (flushed),
“dry as a bone” (dry skin), and “hot as a hare” (hyperthermia)”. In this issue of Annals, the Perrys and colleagues provide evidence for a new and potentially
more serious consequence of chronic anticholinergic
exposure: increased Alzheimer’s disease (AD)–like pathology.2 Remarkably, in this pathological study, the
investigators found increased density of A␤ amyloid
plaques and neurofibrillary tangles in cases with longterm anticholinergic drug use, albeit at a lower density
than occurs in AD.
Patients with Parkinson’s disease (PD) commonly receive anticholinergic medications for tremor or urinary
incontinence, indications that typically require chronic
treatment. The neuropathological study by Perry and
colleagues examined records from 120 PD cases and
compared the density of Alzheimer-type pathology in
groups with different exposure to anticholinergic drug.
Amyloid plaque and neurofibrillary tangle densities
were blindly rated. The major finding was that chronic
use of anticholinergic medications (ie, 2 or more years)
was associated with significantly increased densities of
both plaques and tangles compared with those cases
with less than 2 years of drug treatment. Importantly,
none of the PD cases had coexistent AD based on clinical or pathological criteria. That is, patients were not
sufficiently symptomatic to warrant a diagnosis of dementia clinically, and, on postmortem examination,
the number of neocortical plaques was not sufficient to
be labeled “definite AD.” Nonetheless, there was an increase in AD-type pathology in frontal cortex of those
subjects with prolonged anticholinergic exposure. Although this association study cannot prove causation,
the findings fuel interest in the cholinergic regulation
of amyloidogenesis and tangle formation.
Abundant evidence now implicates amyloidogenesis
as a critical event in AD pathogenesis.3 A␤ is derived
from sequential proteolytic processing of the amyloid
precursor protein (APP). An initial cleavage occurs at
either the ␣-secretase or ␤-secretase site. The
N-terminal fragments are secreted, whereas the
membrane-tethered C-terminal protein fragments subsequently are cleaved by a ␥-secretase to liberate either
a small inconsequential P3 peptide (derived from the
␣-␥␳-␥ cleavages) or A␤ peptide (derived from the ␤␥ cleavages). The nonamyloidogenic pathway via ␣and ␥-secretase precludes formation of A␤. Normally,
most of APP is processed via the ␣-secretase pathway.
Relatively small shifts in the equilibrium toward the
amyloidogenic pathway over many years may promote
A␤ deposition and AD pathogenesis. The secretases
that directly govern A␤ production are now prospective molecular targets for new therapies for AD.
Although cholinergic therapies for AD were developed and are currently used for amelioration of symptoms rather than for any disease-modifying effects,
cholinergic neurotransmission might play a broader
role in disease pathogenesis via muscarinic modulation
of the APP ␣-secretase pathway. Stimulation of certain
muscarinic acetylcholine receptor subtypes increases
␣-secretase processing of APP and reduces A␤ formation in vitro and in vivo in animal studies.4 Augmentation of cholinergic function in patients with AD also
reduces A␤ concentration in cerebrospinal fluid.5,6 Because cortical APP processing is regulated by the cholinergic basal forebrain projections,7 loss of cholinergic
neurotransmission as occurs in AD might exacerbate
disease pathogenesis by increasing A␤ production. It
therefore is reasonable to consider the possibility that
prolonged use of anticholinergic drugs could poten-
tially shift APP processing toward increased A␤ production and plaque formation in humans. The study
by Perry and colleagues now provides neuropathological evidence for this possibility by linking exposure to
anticholinergic drugs, including those used for tremor
and overactive bladder in Parkinson’s disease, with increased A␤ plaque density. Altered cholinergic regulation of APP processing may underlie the observed increase in amyloid plaques in Parkinson’s disease
patients treated with anticholinergics.
Cholinergic signaling also regulates intracellular
events that could influence neurofibrillary tangle formation. Preclinical studies previously have linked muscarinic cholinergic signaling with tau phosphorylation
in addition to the effects on APP processing.8 Tau is a
microtubule-associated protein that stabilizes the cytoskeleton. Tau isoforms are phosphorylated and accumulate as the major constituent of neurofibrillary tangles in AD and also in many other brain disorders
known as “tauopathies.” Because stimulation of certain
muscarinic receptors promotes tau dephosphorylation,
cholinomimetics potentially could reduce tangle formation, whereas muscarinic antagonists might promote
tangles. The Perry study now provides the first evidence from human data to link the cholinergic system
with tangles, and specifically, increased tangle formation in PD cases with chronic anticholinergic treatment. Although this association is concerning given the
widespread use of anticholinergic medications, there
may also be an upside. Unlike the situation for amyloid, where research advances have opened the door for
many different approaches to reduce A␤ experimentally, the prospects for therapies targeted at neurofibrillogenesis are extremely limited. Moreover, neurofibrillary tangles play a critical and likely central role in a
wide variety of neurodegenerative diseases, including
progressive supranuclear palsy, corticobasal degeneration, frontotemporal degeneration, and others. The hypothesis that cholinomimetics may reduce tangle formation needs to be tested clinically, because this might
represent an important first step forward for neuroprotective strategies for tauopathies.
If the relationship between anticholinergics and
plaques and tangles is confirmed by subsequent studies,
a major concern will be that long-term exposure to anticholinergics may increase the risk of AD or accelerate
AD pathogenesis. It will be important to determine
whether or not any long-term effects of anticholinergic
drugs are clinically relevant. If so, many other questions will arise about the duration of the exposure, interaction with AD risk factors, and differences among
anticholinergic drugs. Because there are five distinct
muscarinic receptor subtypes, each with different patterns of expression and functions in brain,9 one or
more of these receptors may be responsible for effects
on A␤ and tau, and there may be regionally specific
Levey: Anticholinergics and AD Pathology
145
changes. Moreover, anticholinergic drugs have varying
affinities for receptor subtypes, suggesting that some
medications will have more influence on amyloidogenesis and tangle formation than others.
The significance of these findings for the millions of
healthy elderly patients taking anticholinergic drugs remains to be clarified. Clearly, there are important health
benefits of many anticholinergic drugs. However, polypharmacy is extremely common in the elderly and numerous drugs have anticholinergic properties. Serum anticholinergic burden correlates with delirium,1 for which
the risks, complications, and costs to society are considerable. The deleterious consequences of anticholinergics
could be even more serious than currently recognized if
these drugs influence brain pathology. Until more is
learned about the effects of anticholinergics on AD pathology, physicians should prescribe anticholinergics judiciously, particularly in the elderly, and these medications should not be used chronically without periodic
review and assessment of their benefits.
Allan I. Levey, MD, PhD
Center for Neurodegenerative Disease and Department
of Neurology
Emory University School of Medicine
Atlanta, GA
146
Annals of Neurology
Vol 54
No 2
August 2003
References
1. Tune LE. Serum anticholinergic activity levels and delirium in
the elderly. Semin Clin Neuropsychiatry 2000;5:149 –153.
2. Perry EK, Kilford L, Lees AJ, et al. Increased Alzheimer pathology in Parkinson’s disease associated with antimuscarinic drugs.
Ann Neurol 2003;54:235–238.
3. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s
disease: progress and problems on the road to therapeutics. Science 2002;297:353–356.
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6. Nitsch RM, Deng M, Tennis M, et al. The selective muscarinic
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7. Rossner S, Ueberham U, Yu J, et al. In vivo regulation of amyloid precursor protein secretion in rat neocortex by cholinergic
activity. Eur J Neurosci 1997;9:2125–2134.
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DOI: 10.1002/ana.10667
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