Parahippocampal Tau Pathology in Healthy Aging, Mild Cognitive Impairment, and Early Alzheimer’s Disease Thomas W. Mitchell, VMD, PhD, 1,2 Elliott J. Mufson, PhD, 5 Julie A. Schneider, MD, 5 Elizabeth J. Cochran, MD, 5 Jonathan Nissanov, PhD, 4 Li-Ying Han, 2 Julia L. Bienias, ScD, 5,6 Virginia M.-Y. Lee, PhD, 1 John Q. Trojanowski, MD, PhD, 1 David A. Bennett, MD, 5 and Steven E. Arnold, MD 2,3 Abnormally phosphorylated tau accumulates as neurofibrillary tangles and neuropil threads in older persons with and without Alzheimer’s disease. The relationship between neurofibrillary tangles and neuropil threads and how they relate to cognitive function is unknown. This study investigated the relationship between phosphorylated tau lesions and cognitive function in 31 persons participating in the Religious Orders Study, a prospective, longitudinal clinicopatho- logical study of aging and Alzheimer’s disease. All subjects underwent detailed neuropsychological performance testing within a year of death and evidenced a spectrum of cognitive performance ranging from normal abilities to mild de- mentia. Measures of neurofibrillary tangle density and phosphorylated tau immunoreactive structures (predominantly neuropil threads) in the entorhinal and perirhinal cortices by quantitative image analysis were significantly correlated (r  0.5). In multiple linear regression analyses controlling for age, sex, and education, parahippocampal neurofibrillary tangles and neuropil threads were significantly lower in persons without cognitive impairment compared to those with mild cognitive impairment and/or Alzheimer’s disease. Further, neurofibrillary tangles were significantly correlated to measures of episodic memory but not other cognitive abilities; neuropil tangles were not significantly related to memory or other cognitive functions. These data indicate that phosphorylated tau pathology in the ventromedial temporal lobe develop prior to the onset of clinical dementia and their presence is associated with cognitive impairment, particularly impairment of episodic memory. Ann Neurol 2002;51:182–189 DOI 10.1002/ana.10086 The transition from “normal” aging to dementia caused by neurodegenerative disease in the elderly is characterized by subtle gradations of cognitive dysfunc- tion. Characterizing the neuropathological lesions re- sponsible for the earliest changes is important because it points to targets for therapeutic intervention in the preclinical or initial phases of disease. The most com- mon neurodegenerative dementia is Alzheimer’s disease (AD), which is characterized by a progressive decline in memory and other cognitive abilities associated with a decline in function. Because AD begins insidiously, it is increasingly recognized that many persons with mild cognitive impairment (MCI) are exhibiting the earliest clinical features of AD. 1–3 The hallmark neuropatho- logical lesions of AD are neurofibrillary tangles (NFTs) and neuropil threads (NTs), both of which are com- posed of hyperphosphorylated tau (PHFtau) arranged in paired helical filaments, as well as senile plaques (SPs) composed of ß-amyloid peptides. There is a highly selective topographical, laminar, and cell-type distribution of neurofibrillary lesions in the AD brain. Certain regions, such as the perirhinal and entorhinal cortices in the parahippocampal gyrus of ventromedial temporal lobe are consistently and se- verely affected with NFTs and NTs, 4–6 whereas neo- cortical regions are less consistently affected. However, little data are available regarding the relation of neuro- fibrillary changes to specific cognitive functions. We characterized parahippocampal PHFtau pathol- ogy in the brains of participants in the Religious Or- ders Study (ROS), a prospective, longitudinal, clinico- pathological study of aging and AD among older From the Departments of 1 Pathology and Laboratory Medicine, 2 Psychiatry, and 3 Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA; 4 Computer Vision Laboratory for Ver- tebrate Brain Mapping, Department of Neurobiology and Anatomy, MCP Hahnemann University, Philadelphia, PA; 5 Rush Alzheimer’s Disease Center and Rush Institute for Healthy Aging and 6 Depart- ment of Internal Medicine, Rush-Presbyterian St. Luke’s Medical Center, Chicago, IL. Received May 7, 2001, and in revised form Aug 30. Accepted for publication Oct 4, 2001. Published online Jan 31, 2002 Address correspondence to Dr Arnold, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, 142 Clin- ical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104. E-mail: sarnold@mail.med.upenn.edu 182 © 2002 Wiley-Liss, Inc.