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Kenneth L. Davis, MD; Richard C. Mohs, PhD; Deborah Marin, MD; Dushyant P. Purohit, MD; Daniel P. Perl, MD; Melinda Lantz, MD; Gregory Austin; Vahram Haroutunian, PhD

JAMA. 1999;281:1401-1406.

Context  A central tenet of Alzheimer disease (AD) is the loss of cortical cholinergic function and cholinergic markers in postmortem brain specimens. Whether these profound deficits in cholinergic markers found in end-stage patients are also found in patients with much earlier disease is not known.

Objective  To determine whether cholinergic deficits in AD precede, follow, or occur in synchrony with the earliest signs of cognitive deterioration.

Design, Setting, and Patients  Postmortem study of nursing home residents with Clinical Dementia Rating (CDR) Scale scores of 0.0 to 2.0 and 4.0 to 5.0 who underwent autopsy between 1986 and 1997, comparing the activity of the cholinergic marker enzymes in the cortices of 66 elderly subjects with no (CDR score=0.0; n=18), questionable (CDR score=0.5; n=11), mild (CDR score=1.0; n=22), or moderate (CDR score=2.0; n=15) dementia vs subjects with severe dementia (CDR score=4.0-5.0; n=15).

Main Outcome Measures  Activity of the cholinergic marker enzymes choline acetyltransferase and acetylcholinesterase in 9 neocortical brain regions.

Results  The activity of choline acetyltransferase and acetylcholinesterase in 9 neocortical brain regions did not differ significantly in subjects with CDR scores of 0.0 to 2.0, but was significantly lower in subjects with severe dementia (CDR score=4.0-5.0). Choline acetyltransferase levels were significantly correlated with severity of neuropathological lesions of AD, as measured by density of neuritic plaques and neurofibrillary tangles.

Conclusions  Although neocortical cholinergic deficits are characteristic of severely demented AD patients, in this study, cholinergic deficits were not apparent in individuals with mild AD and were not present until relatively late in the course of the disease. These results suggest that patients with more severe disease should be a target for cholinergic treatment.

Author Affiliations: Departments of Psychiatry (Drs Davis, Mohs, Marin, and Haroutunian and Mr Austin) and Pathology (Drs Purohit and Perl), Mount Sinai School of Medicine, and the Jewish Home and Hospital (Dr Lantz), New York, NY.

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