27 Jun 2014

When it comes to investing in your mental piggybank, early is best, but it’s never too late. Two new studies report that stimulating your brain in mid-, as well as early, life, helps fend off cognitive impairment and related pathology, respectively. One paper, published in the June 23 JAMA Neurology by Clifford Jack’s group at the Mayo Clinic in Rochester, Minnesota, reports that a life filled with intellectual enrichment delays the onset of cognitive impairment by several years. Another study published June 18 in the Journal of Neuroscience by William Jagust’s group at the University of California, Berkeley, linked a cognitively stimulating life to lower Aβ accumulation in the brain, at least in people who carry the ApoE4 allele. How cognitive exercise protects the brain—either by directly thwarting Alzheimer pathology or by beefing up the brain’s capacity to withstand it—is still up for debate. However, both studies support the idea that those who make lifelong contributions to their cerebral nest egg could reap the benefits in older age.

Many lifestyle factors—ranging from socioeconomic status to education level to challenging cognitive activities—have been associated with a reduction or delay in cognitive impairment or dementia (see Wilson et al., 2012; Sattler et al., 2012; and Stern et al., 1994). However, disentangling the relative contributions of these factors, and determining how late in the game a person can begin and still reap protective rewards from them, remains a tall order. 

ApoE4 carriers who live lives rich in cognitively invigorating activities have lower levels of Aβ in their brains than their less-stimulated brethren. (Image courtesy of Wirth et al., 2014, Journal of Neuroscience.)

First author Prashanthi Vemuri and colleagues at the Mayo Clinic sought to chip away at these questions by stratifying cognitive enrichment into two categories: engagement in early life as measured by education and occupation level, and mid- to late-life stimulation as gauged by the frequency of other cognitive activities such as reading books, doing crafts, or using the computer. The researchers recorded these factors and tracked cognitive performance in a population-based cohort of nearly 2,000 older people without dementia, of whom almost 300 had mild cognitive impairment. All participants completed a battery of neuropsychological tests at baseline, and then at regular intervals for an average of more than three years. The researchers found that both categories of cognitive engagement correlated with better performance on the tests. Interestingly, people with lower educational or occupational attainment benefited more from mid- to late-life activities than those with higher attainment early on. Vemuri attributes this effect to the huge contribution education and occupation make to a person’s cognitive reserve account. Those with a lower balance from early life may have more to gain by making deposits later on. “The key point, irrespective of how much education or level of occupation someone had, is they could still gain from high mid-late life activity,” Vemuri said.

Did a life brimming with intellectual activity slow the rate of decline in aging? Tracking cognitive performance in the cohort, the researchers found that only high mid-/late-life cognitive activity did, and only slightly. Educational and occupational level had no effect. This small effect paled in comparison to the large baseline shift in performance afforded by either measure of enrichment.

To measure potential consequences of this shift, the researchers extrapolated into the future the cognitive decline they measured, and quantified how long it would take to cross a predetermined threshold of cognitive impairment on a combination of tests. They estimated that for people with average levels of education and occupation—such as a high school graduate who worked in a sales job—taking part in cognitively stimulating activities in mid- to late life could delay the onset of cognitive impairment by more than seven years. For those carrying the ApoE4 allele, the predicted delay was more than three years.

Catherine Roe of Washington University in St. Louis appreciated the extrapolations calculated by Vemuri and colleagues. “Putting numbers to this effect really demonstrates how important this is,” she said. “We’re not talking about a delay of a month or two; we’re talking years.” The results also stress the importance of increasing access to quality education, she told Alzforum.

Vemuri hypothesized that lifetime enrichment staves off cognitive impairment by boosting the person’s overall level of cognitive performance. “Lifetime intellectual enrichment builds up cognitive reserve. You have to lose a certain amount of it to fall to the level of cognitive impairment,” she said. She does not believe the effect acts via amyloid or tau deposition.

David Salmon of the University of California, San Diego, agrees. “In my opinion, cognitive stimulation does not really change the underlying pathology of AD, but it gives you cognitive reserve that decreases your sensitivity to it.” Salmon, who was not involved in the study, likened the effect of cognitive enrichment to that of cholinergic therapy. “It protects from the early manifestation of the brain damage, but the trajectory of the underlying disease is the same.”

Aβ Extinguished in Cog-Savvy ApoE4 Carriers
Even so, could a lifetime of brain strengthening also mount a direct attack on AD pathology? Previously, Jagust and colleagues reported that cognitive enrichment was associated with lower brain Aβ levels as seen on PET scans (see Feb 2012 news story). Other studies reported that lifestyle factors such as physical exercise and vascular health also correlated with less Aβ accumulation, however those effects were only significant in ApoE4 carriers (see Jan 2012 news story on Head et al., 2012; May 2013 news story; and Brown et al., 2012). A study led by Jack found no evidence for an effect of lifetime cognitive stimulation on the level of Aβ accumulation regardless of ApoE genotype (see Vemuri et al., 2012). 

Jagust and colleagues dug deeper into this issue, as reported in the present paper. First author Miranka Wirth, now at Charité Universitätsmedizin Berlin, and colleagues measured levels of Aβ in 118 cognitively normal people from the Berkeley Aging Cohort. These volunteers answered a questionnaire designed to assess their level of cognitive activity in different periods throughout life (see Wilson et al., 2003). Unlike Vemuri’s, Wirth’s analysis controlled for education and occupational levels and only considered cognitive activities that went beyond school and work (although overall, members of the Berkeley cohort had higher levels of education than members of the Mayo group).

In ApoE4 carriers, the level of lifetime cognitive activity correlated with lower levels of Aβ as measured by cortical Pittsburgh compound B retention. Interestingly, the reduction in Aβ was significant only for people who engaged in intense cognitive stimulation in early or midlife, but not for those who had recently jumped aboard the cognitive training bandwagon. The researchers observed no correlation between cognitive enrichment and Aβ in ApoE4 non-carriers.

“What impressed me about this study is that they were able to tease out this effect within a relatively small sample size,” Elizabeth Head of the University of Kentucky in Lexington told Alzforum. She added that this offers some hope for ApoE4 carriers. “Even if you are carrying that risk factor for AD, you can still benefit from this early intervention,” she said.

Why didn’t the Vemuri group detect this correlation between lifetime cognitive enrichment and Aβ in their 2012 study? It’s difficult to tell, Vemuri said, as the two studies looked at very different populations and used different methods to measure lifetime cognitive enrichment. Wirth looked only at relatively well-educated, cognitively normal people, while Vemuri’s study featured a wide range of educational attainment and included some people with MCI.

Whether cognitive enrichment staves off dementia by boosting reserve, reinforcing synaptic networks, or fighting on the front lines of the Aβ battle—or all of the above—researchers agree on at least one thing about the brain: Those who don’t use it may be the first to lose it. —Jessica Shugart

Comments

1. • Meghan Mitchell
     Massachusetts General Hospital
   • Posted: 01 Jul 2014

   This study demonstrated in a community-based, non-demented sample of older adults that self-reported engagement in cognitively stimulating activities in middle age and later life (i.e., at ages 50-65 and in the past 12 months) had protective effects on cognition over time. The authors showed that cognitive enrichment in earlier life (as indicated by one’s years of formal education and one’s occupation) was a strong predictor of older adults’ cognitive performance at a given point in time, but that the trajectory of cognitive decline over time was not significantly influenced by these indicators of cognitive enrichment in earlier life. Indicators of cognitive engagement in later life did appear to reduce or delay the effects of cognitive aging. This finding is encouraging, as the implication is that cognition is modifiable in later life; older adults can engage in activities that may delay the effects of aging on their cognitive function.

   In contrast to these findings, in an earlier study we did not find that self-reported cognitive activity at a baseline visit was predictive of rate of change in several different aspects of cognitive function, including memory, fluency, reasoning, and semantic knowledge (Mitchell et al., 2012). Perhaps this difference was due to the way in which we measured cognitive function by domain versus Vemuri’s use of a global measure of cognition. As was suggested in Vemuri’s paper, there is a considerable amount of work to be done to understand what specific activities might be most beneficial for older adults, and which activities might be less useful. For example, as is shown in the rehabilitation literature, cognitive rehabilitation techniques that use massed practice of cognitive skills in a simulated setting (e.g., computerized brain-training programs) do not consistently show generalized effects on cognition and function outside of the practice effects seen on the training tools themselves. It is thus critical to further understand the mechanisms by which some cognitive activities are impacting cognition in day-to-day life in a meaningful way. 

   Finally, as Vemuri and colleagues discuss, it is important to recognize the relatively small effect that cognitive activity in later life had on cognitive trajectories relative to the level that it had cross-sectionally, and the even greater effect that cognitive enrichment earlier in life had on baseline cognitive function. These findings emphasize the importance of taking a lifespan approach to cognitive enrichment, and should not only make older adults feel empowered to make changes in their current level of cognitive engagement, but also provide supportive evidence for investment in programs to improve access to education, particularly in underserved populations, who will be particularly vulnerable to the forecasted dementia epidemic. 

   View all comments by Meghan Mitchell

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References

News Citations

1. Not Just Fun and Games—Cognitive Engagement Deters Amyloid 1 Feb 2012
2. On Your “Virtual” Bike! Exercise and Exergames Bring Benefits 27 Jan 2012
3. Controlling Blood Pressure May Lower Amyloid in ApoE4 Carriers 22 May 2013

Paper Citations

1. Wilson RS, Segawa E, Boyle PA, Bennett DA. Influence of late-life cognitive activity on cognitive health. Neurology. 2012 Apr 10;78(15):1123-9. PubMed.
2. Sattler C, Toro P, Schönknecht P, Schröder J. Cognitive activity, education and socioeconomic status as preventive factors for mild cognitive impairment and Alzheimer's disease. Psychiatry Res. 2012 Mar 30;196(1):90-5. PubMed.
3. Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R. Influence of education and occupation on the incidence of Alzheimer's disease. JAMA. 1994 Apr 6;271(13):1004-10. PubMed.
4. Head D, Bugg JM, Goate AM, Fagan AM, Mintun MA, Benzinger T, Holtzman DM, Morris JC. Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. Arch Neurol. 2012 Jan 9; PubMed.
5. Brown BM, Peiffer JJ, Taddei K, Lui JK, Laws SM, Gupta VB, Taddei T, Ward VK, Rodrigues MA, Burnham S, Rainey-Smith SR, Villemagne VL, Bush A, Ellis KA, Masters CL, Ames D, Macaulay SL, Szoeke C, Rowe CC, Martins RN. Physical activity and amyloid-β plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing. Mol Psychiatry. 2012 Aug 14; PubMed.
6. Vemuri P, Lesnick TG, Przybelski SA, Knopman DS, Roberts RO, Lowe VJ, Kantarci K, Senjem ML, Gunter JL, Boeve BF, Petersen RC, Jack CR. Effect of lifestyle activities on Alzheimer disease biomarkers and cognition. Ann Neurol. 2012 Nov;72(5):730-8. PubMed.
7. Wilson R, Barnes L, Bennett D. Assessment of lifetime participation in cognitively stimulating activities. J Clin Exp Neuropsychol. 2003 Aug;25(5):634-42. PubMed.

Further Reading

Papers

1. Vemuri P, Mormino EC. Cognitively stimulating activities to keep dementia at bay. Neurology. 2013 Jul 23;81(4):308-9. Epub 2013 Jul 3 PubMed.