Cognitive reserve moderates the association between hippocampal volume and episodic memory in middle age

Eero Vuoksimaa, Matthew S. Panizzon, Chi Hua Chen, Lisa T. Eyler, Christine Fennema-Notestine, Mark Joseph A. Fiecas, Bruce Fischl, Carol E. Franz, Michael D. Grant, Amy J. Jak, Michael J. Lyons, Michael C. Neale, Wesley K. Thompson, Ming T. Tsuang, Hong Xian, Anders M. Dale, William S. Kremen

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Cognitive reserve is hypothesized to help people withstand greater brain pathology without manifesting clinical symptoms, and may be regarded as a preventive factor of dementia. It is unclear whether the effect of cognitive reserve is evident only among the older adults or after conversion to dementia, or if it can also be seen earlier in life before the prominent effects of cognitive aging become apparent. While finding a main effect of cognitive reserve on cognitive outcome may be consistent with the reserve hypothesis, in our view, it is unnecessary to invoke the idea of reserve if only a main effect is present. Rather, it is the interaction between a measure of reserve and a brain measure on cognitive outcome that is key for confirming that the effects of brain pathology affect people differently according to their cognitive reserve. We studied whether general cognitive ability at an average age of 20 years, as a direct measure of cognitive reserve, moderates the association between hippocampal volume and episodic memory performance in 494 middle-aged men ages 51 to 60. Whereas there was no statistically significant direct relationship between hippocampal volume and episodic memory performance in middle age, we found a statistically significant interaction such that there was a positive association between hippocampal volume and episodic memory only among people with lower general cognitive ability at age 20, i.e., lower levels of cognitive reserve. Our results provide support for the hypothesis that cognitive reserve moderates the relationship between brain structure and cognition in middle age, well before the onset of dementia.

Original languageEnglish (US)
Pages (from-to)1124-1131
Number of pages8
Issue number6
StatePublished - May 2013

Bibliographical note

Funding Information:
This work was supported by grants from the National Institute on Aging [R01 AG022982, R01 AG018386, and R01 AG022381, R01 AG018384]; National Institute of Drug Abuse [DA029475]; National Institute of Neurological Disorders and Stroke [NS056883], National Center for Research Resources [P41-RR14075, BIRN002, U24 RR021382 ]; National Institute for Biomedical Imaging and Bioengineering [EB006758 ]; National Center for Alternative Medicine [RC1 AT005728-01]; National Institute for Neurological Disorders and Stroke [NS052585-01, 1R21NS072652-01, 1R01NS070963]; the Ellison Medical Foundation; Academy of Finland; and a Sigrid Juselius Foundation Fellowship (E.V.). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the NIA or the NIH.

Funding Information:
The Cooperative Studies Program of the U.S. Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. Numerous organizations have provided invaluable assistance in the conduct of this study, including: Department of Defense; National Personnel Records Center, National Archives and Records Administration; the Internal Revenue Service; National Opinion Research Center; National Research Council, National Academy of Sciences; the Institute for Survey Research, Temple University. This material was, in part, the result of work supported with resources of the VA San Diego Center of Excellence for Stress and Mental Health. Most importantly, the authors gratefully acknowledge the continued cooperation and participation of the members of the VET Registry and their families. We also appreciate the time and energy of many staff and students on the VETSA projects.


  • Cognitive reserve
  • Episodic memory
  • General cognitive ability
  • Hippocampus
  • Verbal learning


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