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Challenging assumptions about Alzheimer's disease Mild cognitive impairment and the cholinergic hypothesis.

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Challenging Assumptions
about Alzheimer’s Disease:
Mild Cognitive Impairment
and the Cholinergic
The cholinergic hypothesis states that basal forebrain
neurons are severely affected in Alzheimer’s disease
(AD) and result in a cerebral cholinergic deficit that
underlies the memory loss and other cognitive symptoms that are hallmarks of the illness.1 This hypothesis,
which served as the rationale for the development of
drugs currently approved for AD treatment,2 was based
on studies over 3 decades ago of the brains of individuals with advanced dementia. At that time, it was difficult for most clinicians to diagnose and accurately differentiate AD from other dementing disorders, much
less to identify the illness in its early stages. The subsequent development of standard, reliable, and valid
clinical diagnostic criteria and staging methods has resulted in an improved ability to detect AD at milder
levels of demential severity. Correspondingly, neurobiological changes now can be examined earlier in the
disease process, when presumably they are more relevant for the pathogenesis of AD.
The growing emphasis on early-stage AD has led to
investigations that challenge some long-held assumptions
about the disorder, including the cholinergic hypothesis.3 The compelling report by DeKosky and colleagues
in this issue4 underscores this point. Elderly individuals
enrolled in the Religious Orders Study (Rush
Presbyterian-St. Luke’s Medical Center, Chicago, IL)
were characterized during life as having no cognitive impairment, mild cognitive impairment (MCI), or AD; the
distinction between MCI and AD rested on whether
there were cognitive deficits in addition to memory impairment and whether the impairment interfered with
social, occupational, or other usual activities of the individuals. Most investigators do not consider MCI patients to meet current criteria for dementia.5 DeKosky
and colleagues examined the presynaptic cholinergic
marker choline acetyltransferase (ChAT) in the brains of
26 individuals with no cognitive impairment, 18 with
MCI, and 14 with mild-to-moderate AD. Regions assayed for ChAT activity included the hippocampus and
the superior frontal, inferior parietal, superior temporal,
and anterior cingulate cortex; ChAT activity in the inferior parietal cortex from an additional 12 end-stage
AD patients also was measured. Only in end-stage patients were ChAT levels reduced. In patients with MCI
and mild-to-moderate AD, ChAT levels generally were
not different from those found in nondemented aging
subjects. The surprising exception was elevated ChAT
activity (suggesting upregulation of cholinergic systems)
in the frontal cortex and hippocampus of individuals
with MCI. Consistent with other reports,3,6 these findings indicate that milder stages of AD are not characterized by cholinergic hypofunction, at least as measured by
ChAT activity. Although ChAT may be not the best
correlate of cholinergic function, these results cast doubt
on the relevance of the cholinergic hypothesis to early
AD and suggest that the modest efficacy of cholinesterase inhibitor drugs in mild-to-moderate AD may involve
mechanisms other than simple augmentation of a central
cholinergic deficit.
The study by DeKosky and colleagues demonstrates,
for what I believe is the first time, that cholinergic systems may be upregulated in MCI individuals. The authors propose that the loss of this apparent compensatory response may mark the conversion of MCI to
diagnosable AD and hence could be a therapeutic target. Although the authors consider MCI to be a separate condition from mild AD, their observation joins a
growing body of evidence that at least the subset of
MCI that is characterized by unexplained memory loss
for many individuals represents the earliest symptomatic stage of AD. In addition to involvement of the
cholinergic system now reported by DeKosky and colleagues, MCI individuals share other features of AD
(memory impairment, increased frequency of the apolipoprotein E ε4 allele, medial temporal atrophy, and
cerebral metabolic abnormalities);7 amnestic MCI individuals progress to more overt AD at an accelerated and
predictable rate;5,8 and the neuropathology of amnestic
MCI overwhelmingly is that of AD.8,9 Confirming the
latter point, DeKosky and colleagues found identical
neuropathologic AD profiles in the MCI and AD
groups; all individuals had histologic AD.
Is MCI the initial symptomatic stage of AD? Most
clinicians are reluctant to diagnose AD in MCI individuals, partly because deficits seemingly are restricted
to the memory domain, and partly because the impairment is so mild that everyday activities presumably are
preserved. Close evaluation of MCI individuals, however, often reveals very mild impairment both in function and in cognitive domains other than memory,8
thus satisfying standard diagnostic criteria for dementia. Assessment methods that rely on neuropsychological batteries may not detect subtle impairments because
test performance may not reflect the patient’s impaired
ability to carry out customary activities of daily living.
A history of declining cognitive and functional performance in relation to that individual’s previous abilities,
however, can be sensitive to early-stage dementia, even
when cognitive test performance is within a normal
range.10 –12 This history usually is obtained from some-
© 2002 Wiley-Liss, Inc.
one who knows the individual well, such as a family
member. Evaluation procedures that are based on neuropsychological tests rather than collateral source information may not detect subtle cognitive and functional
decline in MCI or in putatively nondemented individuals. Indeed, the high frequency (92%) of neuropathlogic AD in the nondemented individuals in the study
conducted by DeKosky and colleagues suggests that
even this “normal” sample may have been contaminated by individuals with unrecognized, very mild dementia.
Now that we have come to the threshold of testing
potentially disease-modifying treatment strategies; the
borderland between nondemented aging and the earliest stages of AD is of intense clinical interest. The important findings reported in this issue by DeKosky and
colleagues capitalize on the increased ability to clinically recognize early-stage individuals and provide a
strong challenge to the long-held assumption that cholinergic dysfunction is responsible for the cognitive deficits associated with the initial stages of AD. Further
work is needed to clarify whether at least some individuals with MCI already can be considered to represent AD, so that the disorder can be diagnosed and
treated when symptoms are only very mild. Although
sensitive clinical and neuropsychological assessment
methods can be helpful in this regard, the development
of a biological marker that relates directly to the clinical and pathological changes of AD ultimately may be
required to identify prodromal and preclinical states.
These states may be the optimal targets of eventual
disease-modifying treatments.
John C. Morris, MD
Department of Neurology and the Alzheimer Disease
Research Center
Washington University
St. Louis, Missouri
Annals of Neurology
Vol 51
No 2
February 2002
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408 – 414.
2. Grutzendler J, Morris JC. Cholinesterase inhibitors for Alzheimer’s disease. Drugs 2001;61:41–52.
3. Davis KL, Mohs RC, Marin D, et al. Cholinergic markers in
elderly patients with early signs of Alzheimer disease. JAMA
4. DeKosky ST, Ikonomovic MD, Styren S, et al. Upregulation of
choline acetyltransferase activity in hippocampus and frontal
cortex of elderly subjects with mild cognitive impairment. Ann
Neurol 2002;51:145–155.
5. Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment. Arch Neurol 1999;56:303–308.
6. Tiraboschi P, Hansen LA, Alford M, et al. The decline in synapses and cholinergic activity is asynchronous in Alzheimer’s
disease. Neurology 2000;55:1278 –1283.
7. Morris JC, Price JL. Pathologic correlates of nondemented aging, mild cognitive impairment, and early stage Alzheimer’s disease. J Mol Neurosci 2001;17:101–118.
8. Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer’s disease. Arch Neurol
2001;58:397– 405.
9. Kordower JH, Chu Y, Stebbins GT, et al. Loss and atrophy
of layer II entorhinal cortex neurons in elderly people
with mild cognitive impairment. Ann Neurol 2001;49:202–
10. Tierney MC, Snow WG, Reid DW, et al. Psychometric differentiation of dementia: replication and extension of the
findings of Storandt and coworkers. Arch Neurol 1987;44:
720 –722.
11. Crum R, Anthony J, Bassett SS, Folstein MF. Population-based
norms for the Mini-Mental State Examination by age and education level. JAMA 1993;269:2386 –2391.
12. Morris JC, Storandt M, McKeel DW, et al. Cerebral amyloid
deposition and diffuse plaques in “normal” aging: evidence for
presymptomatic and very mild Alzheimer’s disease. Neurology
DOI 10.1002/ana.10135
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challenging, mild, hypothesis, impairments, disease, assumptions, cognitive, alzheimers, cholinergic
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