Neuropathology of older persons without cognitive impairment from two community-based studies D.A. Bennett, MD; J.A. Schneider, MD; Z. Arvanitakis, MD; J.F. Kelly, MD; N.T. Aggarwal, MD; R.C. Shah, MD; and R.S. Wilson, PhD Abstract—Objective: To examine the relation of National Institute on Aging–Reagan (NIA-Reagan) neuropathologic criteria of Alzheimer disease (AD) to level of cognitive function in persons without dementia or mild cognitive impairment (MCI). Methods: More than 2,000 persons without dementia participating in the Religious Orders Study or the Memory and Aging Project agreed to annual detailed clinical evaluation and brain donation. The studies had 19 neuropsychological performance tests in common that assessed five cognitive domains, including episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. A total of 134 persons without cognitive impairment died and underwent brain autopsy and postmortem assessment for AD pathology using NIA-Reagan neuropathologic criteria for AD, cerebral infarctions, and Lewy bodies. Linear regression was used to examine the relation of AD pathology to level of cognitive function proximate to death. Results: Two (1.5%) persons met NIA-Reagan criteria for high likelihood AD, and 48 (35.8%) met criteria for intermediate likelihood; 29 (21.6%) had cerebral infarctions, and 18 (13.4%) had Lewy bodies. The mean Mini-Mental State Examination score proximate to death was 28.2 for those meeting high or intermediate likelihood AD by NIA-Reagan criteria and 28.4 for those not meeting criteria. In linear regression models adjusted for age, sex, and education, persons meeting criteria for intermediate or high likelihood AD scored about a quarter standard unit lower on tests of episodic memory (p = 0.01). There were no significant differences in any other cognitive domain. Conclusions: Alzheimer disease pathology can be found in the brains of older persons without dementia or mild cognitive impairment and is related to subtle changes in episodic memory. NEUROLOGY 2006;66:1837–1844 It has long been known that older persons without dementia accumulate neuropathologic changes of Alzheimer disease (AD). 1 This observation has been replicated by numerous groups over the past 20 years. 2-13 However, the extent to which the presence of AD pathology in persons without cognitive impair- ment is associated with level of cognition has not been extensively investigated. We are aware of only three studies that have examined the relation of AD pathology to cognition in persons without demen- tia. 6,14,15 However, two of these studies did not ex- clude persons with mild cognitive impairment (MCI). 6,14 Since there is increasing evidence that per- sons with MCI often have AD pathology, 13,16,17 it would be of interest to examine the relation of AD pathology to cognition in persons without dementia or MCI. We are conducting two large, community-based, longitudinal clinical-pathologic studies of aging and AD: The Religious Orders Study 13 and the Rush Memory and Aging Project. 18 Both studies enroll per- sons without dementia who must agree to annual detailed clinical evaluation and organ donation at the time of death. The studies have identical diag- nostic procedures and 19 cognitive performance tests in common. To date, 134 persons without cognitive impairment close to the time of death have died and had a complete postmortem examination. This pro- vided us with an opportunity to examine the relation of AD pathology to level of function in different cog- nitive abilities in a large number of persons. Methods. Religious Orders Study. Participants were older Catholic nuns, priests, and brothers without known dementia who agreed to annual clinical evaluations and signed an informed con- sent and an Anatomic Gift Act donating their brains to Rush investigators at the time of death. 13 The study was approved by the Institutional Review Board of Rush University Medical Cen- ter. Subjects come from about 40 groups in 12 states across the Editorial, see page 1801 From Rush Alzheimer’s Disease Center (D.A.B., J.A.S., Z.A., J.F.K., N.T.A., R.C.S., R.S.W.) and Departments of Neurological Sciences (D.A.B., J.A.S., Z.A., N.T.A., R.S.W.), Pathology (Neuropathology) (JAS), Internal Medicine (J.F.K.), Family Practice (R.C.S.), and Behavioral Sciences (R.S.W.), Rush University Medical Center, Chicago, IL. Supported by National Institute on Aging grants P30AG10161, R01AG15819, R01AG17917, K08AG00849, and K23AG23675. Disclosure: The authors report no conflicts of interest. Received May 19, 2005. Accepted in final form February 23, 2006. Address correspondence and reprint requests to Dr. David A. Bennett, Rush Alzheimer’s Disease Center, 600 South Paulina, Suite 1028, Chicago, IL 60612; e-mail: dbennett@rush.edu Copyright © 2006 by AAN Enterprises, Inc. 1837 by DAVID BENNETT on June 26, 2006 www.neurology.org Downloaded from