Comparison of Neuropathologic Criteria for the Diagnosis of Alzheimer’s Disease J. W. GEDDES,*† 1 T. L. TEKIRIAN,*† N. S. SOULTANIAN,* J. W. ASHFORD,*‡ D. G. DAVIS*§ AND W. R. MARKESBERY*§¶ *Sanders-Brown Center on Aging, and the †Departments of Anatomy and Neurobiology, ‡Psychiatry, §Pathology, and ¶Neurology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA GEDDES, J. W., T. L. TEKIRIAN, N. S. SOULTANIAN, J. W. ASHFORD, D. G. DAVIS AND W. R. MARKESBERY. Comparison of neuropathologic criteria for the diagnosis of Alzheimer’s disease. NEUROBIOL AGING 18(S4) S99 –S105, 1997.—The National Institute on Aging and Reagan Institute (NIA-RI) criteria, and other neuropathologic criteria for Alzheimer’s disease (AD), were compared with the clinical diagnosis of dementia in a well defined population of Catholic sisters. The 47-participant subset examined in this study were college educated and lacked complicating conditions such as brain infarcts or diffuse Lewy body disease. Sixteen participants had a clinical diagnosis of dementia. The NIA-RI criteria imply a perfect correlation between neuritic plaque (NP) density and neurofibrillary tangle distribution. However, NP density often did not coincide with tangle distribution. As a result, it was not possible to categorize many of the participants using the NIA-RI guidelines. The ‘high likelihood’ category of the NIA-RI criteria for AD research settings (neocortical Braak stage and frequent neocortical NP) had relatively high specificity (90% of nondemented participants did not meet this criteria). However, only half of the demented participants were in this category. Neuropathologic criteria requiring the presence of neocortical tangles (rather than neocortical Braak stage) had relatively high sensitivity, accounting for 87–94% of participants with dementia, but also included 32–35% of nondemented participants. Criteria based on neocortical NP or senile plaques had 100% sensitivity, but a majority of nondemented participants also met these criteria. The results support consideration of both tangles and NP for the neuropathologic diagnosis of AD, but indicate that refinement of the NIA-RI criteria is necessary. A possible refinement is suggested for further consideration. © 1997 Elsevier Science Inc. Alzheimer’s disease Cerebral cortex Cognition disorders Epidemiology Neurofibrillary tangles Prospective studies Psychological tests Diagnosis Pathology A definitive diagnosis of Alzheimer’s disease (AD) requires both a clinical history of dementia and neuropathologic confirmation at autopsy. However, there are no universally accepted neuropatho- logic criteria for AD, and the use of different criteria can alter the clinicopathologic correlation (31). Previous recommended neuro- pathologic criteria for AD include those established by the Neu- ropathology Panel of a workshop sponsored by the National Institute on Aging and other agencies and organizations, as reported by Khachaturian (18), referred to hereafter as the Kha- chaturian criteria and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), as described by Mirra et al. (22). The Khachaturian criteria (18) are based on the number of senile plaques (SP) [SP, includes both neuritic and diffuse plaques] and neurofibrillary tangles (NFT) in neocortex (frontal, temporal, and parietal lobes). Because AD neuropathology becomes increasingly prevalent in nondemented individuals with advancing age, the criteria consider the age of the individual (Table 1). The Khacha- turian criteria require SP for all ages and NFT for individuals younger than age 75 (18). CERAD criteria (22) are based on the semiquantitative assessment of neocortical neuritic plaques (NP), and it also uses specific criteria for different age groups. The reliance on SP density for the neuropathologic diagnosis of AD is consistent with studies in which the number of SP in various neocortical regions correlated with the severity of dementia (6,28). However, the density of neocortical SP in nondemented individu- als can be sufficient to meet the Khachaturian criteria (10,16). Other reports indicate that the presence and severity of neocortical NFT may provide a better agreement with a clinical diagnosis of probable AD (2,5,11,12,17,21,24). Tierney and colleagues (31) examined three sets of neuropathologic criteria for AD based on the presence of one or more NFT and NP in hippocampus (A1 criteria), neocortex (A3 criteria), or both hippocampus and neo- cortex (A2 criteria). Their results indicated that the A1 criteria provided the greatest agreement with a clinical diagnosis of probable AD (31). In a previous report from the Nun Study (29), neuropathologic diagnosis of AD was based on the Khachaturian criteria for individuals age 75 or older and the presence of neocortical NFT. Braak and Braak (8) described six stages of AD neuropathol- ogy based on the pattern of neurofibrillary changes (NFT, neuropil threads, and plaque dystrophic neurites), but they did not compare neuropathology with clinical symptoms. However, they did spec- ulate that the entorhinal stages (I/II) represent clinically silent periods of the disease, the limbic stages (III/IV) correspond to 1 To whom requests for reprints should be addressed. James W. Geddes, Ph.D., Sanders-Brown Center on Aging, Room 209, University of Kentucky, 800 S. Limestone, Lexington, KY 40536-0230. Neurobiology of Aging, Vol. 18, No. S4, S99 –S105, 1997 Copyright © 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0197-4580/97 $17.00 + .00 PII:S0197-4580(97)00063-8 S99