Studies suggest that keeping the brain and body spry in middle age staves off later cognitive decline, but scientists are unsure why. A paper in the February 24 Neurology online suggests that contrary to some thinking, it may have nothing to do with changing the course of Alzheimer’s pathology. Researchers led by Prashanthi Vemuri, Mayo Clinic, Rochester, Minnesota, report that in the population as a whole, as people aged, their brains accumulated amyloid, shrank, and became less active regardless of their mental and physical prowess in midlife. Highly educated carriers of the ApoE4 allele were an exception. They better maintained neural activity in later life, and if they also kept up cognitive stimulation, they accumulated less amyloid. “Until now, no studies had examined if imaging biomarker trajectories correlated with physical and cognitive activities in midlife,” Vemuri told Alzforum.

Vemuri conducted this longitudinal study to resolve ambiguous data from cross-sectional analyses. Some researchers, including her group, had found that while lifelong cognitive activity correlated with better cognitive performance in old adults, it had no bearing on markers of AD pathology such as amyloid load, neural activity, neurofibrillary tangles, or hippocampal atrophy (Gidicsin et al., 2015Wilson et al., 2013; Jun 2014 news). On the other hand, other groups did report that mental stimulation or physical exercise lessens amyloid accumulation later in life (Wirth et al., 2014; Matthews et al., 2014Head et al., 2012). 

Vemuri and colleagues used data collected in the Mayo Clinic Study of Aging, which has followed people aged 70 to 89 in Olmsted County, Minnesota, since 2004. They studied 393 non-demented participants who were able to document their history of cognitive and physical activity. Of these, 53 at baseline had mild cognitive impairment (MCI) as per Petersen et al., 2010. The history came from a series of questionnaires that asked how often, between the ages of 50 and 65, the participants did things such as clean the house, manual labor, exercise, play music, read books, join social or group events, or use a computer. The researchers divided the cohort into two groups depending on whether a person had completed more or fewer than the median 14 years of school, and accounted for ApoE4 genotype. Everyone had been tested for two of three AD biomarkers: brain amyloid PET with Pittsburgh compound B (PiB), glucose metabolism with fluorodeoxyglucose (FDG) PET, or hippocampal volume with structural magnetic resonance imaging (MRI). Participants underwent at least two scans on average 2.5 years apart, beginning at around age 70.

On their first scans, ApoE4 carriers had lower glucose metabolism and more PiB uptake than non-carriers of the same age, as has been seen in other studies (Jagust and Landau, 2014Drzezga et al., 2009). Overall, however, neither physical nor mental stimulation in middle age altered the rate of any biomarker change later in life. PiB uptake in the brain rose with age, while glucose metabolism and hippocampal volume fell, regardless of cognitive or physical history, or ApoE genotype.

When the researchers analyzed the cohort by level of education, subtle differences emerged in ApoE4 carriers. Among the 59 highly educated carriers, 39 who exercised their brains more in midlife accumulated less amyloid by old age than did less cognitively active carriers. Lifetime intellectual enrichment seems important for ApoE4 carriers, Vemuri told Alzforum. “People with high education who continue learning throughout life seem to benefit from it,” she said.

Education also influenced glucose metabolism among ApoE4 carriers, as carriers with more schooling had baseline FDG uptake levels matching those of similarly educated non-carriers. “Highly educated people may have more efficient networks that protect them against genetic effects of ApoE4,” said Vemuri. The results are in line with other studies that suggest education boosts cognitive reserve (Bastin et al., 2012; Perneczky et al., 2006). 

Could this education benefit extend to everyone? Though her data suggest not, Vemuri thinks her study is not the last word on the question. She proposed that intellectual enrichment may, in fact, slow Aβ deposition regardless of genotype. It could be that it is just more obvious in ApoE4 carriers because they accumulate Aβ42 at an earlier age, she said. “In a larger study, or one with more sensitive measures, we may find that intellectual enrichment protects from Aβ deposition in non-carriers as well,” she said.

“This study does not support the idea that [lifestyle] can protect against AD pathology, at least as measured by these biomarkers,” said Kristian Steen Frederiksen, Danish Dementia Research Center, University of Copenhagen. Mental and physical activity may still delay disease onset through some other route, he said. Lisa Mosconi, New York University School of Medicine, agreed. “One negative study doesn't mean that intellectual or physical activity are not useful,” she wrote. While lifestyle factors don’t seem to move AD biomarkers in this analysis, epidemiological studies and clinical trials suggest they benefit the brain (Erickson et al., 2011; Willis et al., 2006). 

Why do some studies find that midlife activity sways biomarkers, and others do not? Vemuri suspects educational bias. Many previous studies that linked cognitive activity to AD biomarkers enrolled highly educated people. “In our study, dividing participants by education made a huge impact,” she told Alzforum.

A strength of this study is that it examines amyloid, metabolism, and brain volume together over time, said Frederiksen. A limitation is that it, like many previous studies, relies on retrospective questionnaires that ask elderly people to recall what they did more than a decade ago. Mosconi also questioned the accuracy of these surveys. Objective measures of activity would come from prospective studies. Vemuri agreed that a better controlled intervention trial could draw out cause-effect relationships. Such studies would span decades. Intervention trials such as FINGER and MAPT are underway in Europe, though they are too short to tease out effects of midlife activity on late-life dementia (Nov 2015 conference news).—Gwyneth Dickey Zakaib


  1. I think the authors did a very good job highlighting why we should be cautious in the interpretation of these results. First, in regard to assessing physical activity, this was done by self-report, and, if I understood this correctly, the participants were asked to recall their level of physical activity in midlife. Since these participants were aged 70-89 years at the time of the questionnaire, we need to consider the accuracy of this information. The same concern is applicable to the midlife cognitive activity.

    Thus, the finding of minimal effects of lifestyle enrichment on AD biomarker trajectories for the overall cohort needs to be thoughtfully considered. The lack of any great effect may be due to how the enrichment components were measured (i.e., rough/recall estimates versus more accurate measure).

    They did find that education was neuroprotective, as has been consistently reported. Notably, since it’s a matter of record, it is much easier for a person to accurately report his or her level of education than his or her midlife physical/cognitive activity.

    It is clear from this and other studies that PET imaging certainly offers us the opportunity to quantify AD-related biomarkers in vivo and investigate factors that might mitigate them. 

  2. I absolutely agree with the comments about self-report questionnaires. However, to understand the true causal effect of midlife cognitive and physical activities, we will need controlled intervention trials run over sufficiently long periods of time. Our study results suggesting a differential effect of education level on pathology trajectories will be important to consider when designing these future trials.

  3. I have been hearing about the need for longitudinal studies for decades. The problem is that by the time these studies are completed, many of the people who would have benefited from the data will already be hospitalized with AD. The results from animal models and findings from retrospective human studies and even case reports provide sufficient clues to lifestyle and environmental factors that may modify the progression of neurodegenerative disease. If these changes in lifestyle etc. have no negative consequences—and possible additional benefits such as an overall improvement in general well-being—then recommending that patients adopt these behaviors sooner rather than later is always the prudent thing to do.

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News Citations

  1. A Life of Cognitive Enrichment May Fend Off Dementia. But How?
  2. Health Interventions Boost Cognition—But Do They Delay Dementia?

Paper Citations

  1. . Cognitive activity relates to cognitive performance but not to Alzheimer disease biomarkers. Neurology. 2015 Jul 7;85(1):48-55. Epub 2015 Jun 10 PubMed.
  2. . Life-span cognitive activity, neuropathologic burden, and cognitive aging. Neurology. 2013 Jul 23;81(4):314-21. PubMed.
  3. . Neuroprotective pathways: lifestyle activity, brain pathology, and cognition in cognitively normal older adults. Neurobiol Aging. 2014 Aug;35(8):1873-82. Epub 2014 Feb 20 PubMed.
  4. . Physical Activity, Mediterranean Diet and Biomarkers-Assessed Risk of Alzheimer's: A Multi-Modality Brain Imaging Study. Adv J Mol Imaging. 2014 Oct;4(4):43-57. PubMed.
  5. . Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. Arch Neurol. 2012 Jan 9; PubMed.
  6. . Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging. Neurology. 2010 Sep 7;75(10):889-97. PubMed.
  7. . Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging. J Neurosci. 2012 Dec 12;32(50):18227-33. PubMed.
  8. . Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology. 2009 Apr 28;72(17):1487-94. PubMed.
  9. . Cognitive reserve impacts on inter-individual variability in resting-state cerebral metabolism in normal aging. Neuroimage. 2012 Nov 1;63(2):713-22. Epub 2012 Jul 13 PubMed.
  10. . Schooling mediates brain reserve in Alzheimer's disease: findings of fluoro-deoxy-glucose-positron emission tomography. J Neurol Neurosurg Psychiatry. 2006 Sep;77(9):1060-3. PubMed.
  11. . Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):3017-22. PubMed.
  12. . Long-term effects of cognitive training on everyday functional outcomes in older adults. JAMA. 2006 Dec 20;296(23):2805-14. PubMed.

Further Reading

Primary Papers

  1. . Effect of intellectual enrichment on AD biomarker trajectories: Longitudinal imaging study. Neurology. 2016 Mar 22;86(12):1128-35. Epub 2016 Feb 24 PubMed.