Challenging Assumptionsabout Alzheimer’s Disease:Mild Cognitive Impairmentand the CholinergicHypothesis

The cholinergic hypothesis states that basal forebrainneurons are severely affected in Alzheimer’s disease(AD) and result in a cerebral cholinergic deficit thatunderlies the memory loss and other cognitive symp-toms that are hallmarks of the illness.1 This hypothesis,which served as the rationale for the development ofdrugs currently approved for AD treatment,2 was basedon studies over 3 decades ago of the brains of individ-uals with advanced dementia. At that time, it was dif-ficult for most clinicians to diagnose and accurately dif-ferentiate AD from other dementing disorders, muchless to identify the illness in its early stages. The sub-sequent development of standard, reliable, and validclinical diagnostic criteria and staging methods has re-sulted in an improved ability to detect AD at milderlevels of demential severity. Correspondingly, neurobi-ological changes now can be examined earlier in thedisease process, when presumably they are more rele-vant for the pathogenesis of AD.

The growing emphasis on early-stage AD has led toinvestigations that challenge some long-held assumptionsabout the disorder, including the cholinergic hypothe-sis.3 The compelling report by DeKosky and colleaguesin this issue4 underscores this point. Elderly individualsenrolled in the Religious Orders Study (RushPresbyterian-St. Luke’s Medical Center, Chicago, IL)were characterized during life as having no cognitive im-pairment, mild cognitive impairment (MCI), or AD; thedistinction between MCI and AD rested on whetherthere were cognitive deficits in addition to memory im-pairment and whether the impairment interfered withsocial, occupational, or other usual activities of the indi-viduals. Most investigators do not consider MCI pa-tients to meet current criteria for dementia.5 DeKoskyand colleagues examined the presynaptic cholinergicmarker choline acetyltransferase (ChAT) in the brains of26 individuals with no cognitive impairment, 18 withMCI, and 14 with mild-to-moderate AD. Regions as-sayed for ChAT activity included the hippocampus andthe superior frontal, inferior parietal, superior temporal,and anterior cingulate cortex; ChAT activity in the in-ferior parietal cortex from an additional 12 end-stageAD patients also was measured. Only in end-stage pa-tients were ChAT levels reduced. In patients with MCI

and mild-to-moderate AD, ChAT levels generally werenot different from those found in nondemented agingsubjects. The surprising exception was elevated ChATactivity (suggesting upregulation of cholinergic systems)in the frontal cortex and hippocampus of individualswith MCI. Consistent with other reports,3,6 these find-ings indicate that milder stages of AD are not character-ized by cholinergic hypofunction, at least as measured byChAT activity. Although ChAT may be not the bestcorrelate of cholinergic function, these results cast doubton the relevance of the cholinergic hypothesis to earlyAD and suggest that the modest efficacy of cholinester-ase inhibitor drugs in mild-to-moderate AD may involvemechanisms other than simple augmentation of a centralcholinergic deficit.

The study by DeKosky and colleagues demonstrates,for what I believe is the first time, that cholinergic sys-tems may be upregulated in MCI individuals. The au-thors propose that the loss of this apparent compensa-tory response may mark the conversion of MCI todiagnosable AD and hence could be a therapeutic tar-get. Although the authors consider MCI to be a sepa-rate condition from mild AD, their observation joins agrowing body of evidence that at least the subset ofMCI that is characterized by unexplained memory lossfor many individuals represents the earliest symptom-atic stage of AD. In addition to involvement of thecholinergic system now reported by DeKosky and col-leagues, MCI individuals share other features of AD(memory impairment, increased frequency of the apo-lipoprotein E ε4 allele, medial temporal atrophy, andcerebral metabolic abnormalities);7 amnestic MCI indi-viduals progress to more overt AD at an accelerated andpredictable rate;5,8 and the neuropathology of amnesticMCI overwhelmingly is that of AD.8,9 Confirming thelatter point, DeKosky and colleagues found identicalneuropathologic AD profiles in the MCI and ADgroups; all individuals had histologic AD.

Is MCI the initial symptomatic stage of AD? Mostclinicians are reluctant to diagnose AD in MCI indi-viduals, partly because deficits seemingly are restrictedto the memory domain, and partly because the impair-ment is so mild that everyday activities presumably arepreserved. Close evaluation of MCI individuals, how-ever, often reveals very mild impairment both in func-tion and in cognitive domains other than memory,8

thus satisfying standard diagnostic criteria for demen-tia. Assessment methods that rely on neuropsychologi-cal batteries may not detect subtle impairments becausetest performance may not reflect the patient’s impairedability to carry out customary activities of daily living.A history of declining cognitive and functional perfor-mance in relation to that individual’s previous abilities,however, can be sensitive to early-stage dementia, evenwhen cognitive test performance is within a normalrange.10–12 This history usually is obtained from some-

EDITORIAL

© 2002 Wiley-Liss, Inc. 143

one who knows the individual well, such as a familymember. Evaluation procedures that are based on neu-ropsychological tests rather than collateral source infor-mation may not detect subtle cognitive and functionaldecline in MCI or in putatively nondemented individ-uals. Indeed, the high frequency (92%) of neuropath-logic AD in the nondemented individuals in the studyconducted by DeKosky and colleagues suggests thateven this “normal” sample may have been contami-nated by individuals with unrecognized, very mild de-mentia.

Now that we have come to the threshold of testingpotentially disease-modifying treatment strategies; theborderland between nondemented aging and the earli-est stages of AD is of intense clinical interest. The im-portant findings reported in this issue by DeKosky andcolleagues capitalize on the increased ability to clini-cally recognize early-stage individuals and provide astrong challenge to the long-held assumption that cho-linergic dysfunction is responsible for the cognitive def-icits associated with the initial stages of AD. Furtherwork is needed to clarify whether at least some indi-viduals with MCI already can be considered to repre-sent AD, so that the disorder can be diagnosed andtreated when symptoms are only very mild. Althoughsensitive clinical and neuropsychological assessmentmethods can be helpful in this regard, the developmentof a biological marker that relates directly to the clin-ical and pathological changes of AD ultimately may berequired to identify prodromal and preclinical states.These states may be the optimal targets of eventualdisease-modifying treatments.

John C. Morris, MD

Department of Neurology and the Alzheimer DiseaseResearch Center

Washington UniversitySt. Louis, Missouri

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3. Davis KL, Mohs RC, Marin D, et al. Cholinergic markers inelderly patients with early signs of Alzheimer disease. JAMA2000;281:1401–1406.

4. DeKosky ST, Ikonomovic MD, Styren S, et al. Upregulation ofcholine acetyltransferase activity in hippocampus and frontalcortex of elderly subjects with mild cognitive impairment. AnnNeurol 2002;51:145–155.

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6. Tiraboschi P, Hansen LA, Alford M, et al. The decline in syn-apses and cholinergic activity is asynchronous in Alzheimer’sdisease. Neurology 2000;55:1278–1283.

7. Morris JC, Price JL. Pathologic correlates of nondemented ag-ing, mild cognitive impairment, and early stage Alzheimer’s dis-ease. J Mol Neurosci 2001;17:101–118.

8. Morris JC, Storandt M, Miller JP, et al. Mild cognitive impair-ment represents early-stage Alzheimer’s disease. Arch Neurol2001;58:397–405.

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10. Tierney MC, Snow WG, Reid DW, et al. Psychometric dif-ferentiation of dementia: replication and extension of thefindings of Storandt and coworkers. Arch Neurol 1987;44:720 –722.

11. Crum R, Anthony J, Bassett SS, Folstein MF. Population-basednorms for the Mini-Mental State Examination by age and ed-ucation level. JAMA 1993;269:2386–2391.

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DOI 10.1002/ana.10135

144 Annals of Neurology Vol 51 No 2 February 2002