Neurobiology of Aging 27 (2006) 1385–1394 Hippocampal atrophy in the healthy is initially linear and independent of age Robert M. Cohen ∗ , Joanna Szczepanik, Michael McManus, Nadeem Mirza, Karen Putnam, Jim Levy, Trey Sunderland Geriatric Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Clinical Research Center 2-5362, MSC 1274, 10 Center Drive, Bethesda MD 20892-1274, USA Received 4 March 2005; received in revised form 11 July 2005; accepted 21 July 2005 Available online 15 September 2005 Abstract Patients with minimal cognitive impairment (MCI) or Alzheimer’s disease (AD) have smaller hippocampal volumes (HV) and increased rates of HV loss (rHVL). A 6-year study was conducted to assess rHVL in healthy aging subjects (HC) in which four MRI scans, each 2 years apart, were obtained on 26 HC with a mean age of 58.8 years when entering the study. rHVLs were linear and significantly differed among subjects, even those sharing an identical apoliporotein E genotype, ranging from .027 to .191 cc/year (S.D. = .022 cc/year), and were not affected by age or sex. rHVL, but not HV, at time of subject entry, was found to predict performance on the delayed recall measure of the Selective Reminder Task obtained 6 years after subject entry into study. Although the molecular events underlying rHVL are unclear, the significance of rHVL in subjects in their sixth and seventh decades of life for predicting age-related cognitive trajectories and whether changes in rHVLs foreshadow the development of MCI are the subject of ongoing study. © 2005 Elsevier Inc. All rights reserved. Keywords: Aging; Memory; Hippocampus; Alzheimer’s disease; MCI 1. Introduction Consistent with microscopic post-mortem observations of the medial temporal lobe as the earliest site of neurofibril- lary tangles in Alzheimer’s disease (AD) [8], magnetic reso- nance imaging (MRI) studies have found smaller hippocam- pal volumes (HVs), age and sex corrected, to be sensitive indicators of early AD. Patients with early to moderate AD have a 25% smaller HV than healthy age-matched subjects (HC) [30,39,44] and patients with mild cognitive impairment (MCI) have HVs larger than AD patients, but smaller than HC [13,41,71]. Therefore, at some point prior to an individual’s diagnosis of MCI or AD that individual must have either had a greater rate of hippocampal volume change (rHVL) and/or a smaller HV prior to the onset of MCI or AD. ∗ Corresponding author. Present address: Cedar-Sinai Medical Center, Thalians Building, Rm. E101, 8730 Alden Drive, Los Angeles, CA 90048, USA. Tel.: +1 310 423 4070; fax: +1 301 480 2847. E-mail address: rcn1946@mac.com (R.M. Cohen). Although it is clear that individuals at the early stages of AD have an increased rHVL, only recently have data been available to determine whether an increased rHVL occurs in MCI patients. These data now strongly suggest that rHVLs are greater among subjects that proceed from MCI to AD as well as those proceeding from HC to MCI [34,57]. The question that remains is how long prior to the onset of MCI or AD do individuals destined to develop clinically significant age-related memory deficits have increased rHVLs. Although not definitive, two studies [12,47] of healthy subjects that found differences in the rHVL of individuals carrying one or more apolipoprotein E-4 (APOE-4) alleles, an allele known to increase the risk and shorten the time of onset of AD, and a more recent longitudinal study [57] suggest that an increased rHVL may precede the development of MCI and AD by a considerable number of years. Indirect evidence from a study of familial AD lends further credence [59] to the working hypothesis that an increased rHVL may precede clinical symptoms. 0197-4580/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2005.07.018