People with a lot of cognitive reserve generally cope better with advancing dementia, but might they be protected from disease pathology as well? According to a study published April 20 in JAMA Neurology, older adults with at least 16 years of education under their belts had less evidence of neurodegeneration in their cerebrospinal fluid than people with less education. The researchers, led by Ozioma Okonkwo of the University of Wisconsin in Madison, concluded that cognitive reserve may help stave off pathological changes in the brain that herald dementia. Other factors associated with a college education, such as socioeconomic status, social interaction, and cognitive stimulation throughout life, all could have played a role in beefing up the brain’s defenses, Okonkwo said.

Cognitive reserve was originally defined as the extra protection against cognitive decline afforded to people with greater intellectual enrichment (see Stern et al., 2012). Given the same amount of brain pathology, people with a higher cognitive reserve (often measured as a great number of years of formal education) were found to be less susceptible to cognitive decline than people with a lesser reserve. Viewed from a different angle, others reported that given the same level of cognitive performance, people with higher reserves tended to have more brain pathology, indicating that their mental acuity was somehow shielded from the encroaching pathology (see Nov 2008 news). 

However, some recent studies have suggested that cognitive reserves may do something even better—prevent pathology from occurring in the first place. For example, William Jagust’s group at the University of California, Berkeley, reported that AD biomarker signatures in the cerebrospinal fluid developed more slowly in people with higher cognitive reserves, and that ApoE4 carriers with higher cognitive reserves had less Aβ accumulation in their brains (see Lo et al., 2013, and Wirth et al., 2014). However, others have failed to find such a relationship (see Vemuri et al., 2012).

First author Rodrigo Almeida and colleagues wanted to measure whether cognitive reserve could weaken the relationship between age and AD biomarker levels. The researchers performed a cross-sectional study on 268 people, averaging 62 years of age, in the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center. Of these, 211 were cognitively normal while 57 had mild cognitive impairment due to AD or mild AD. Diagnoses of MCI or AD were based on criteria from the National Institute on Aging, and decided by panel consensus (see Albert et al., 2011, and McKhann et al., 2011). One CSF sample was taken from each volunteer at one time point, and the researchers measured levels of Aβ42, total tau, and p-tau.

The researchers first established a link between age and AD biomarker levels. They found that levels of total and phospho-tau, and the ratios of each of these species to Aβ42, were higher in older subjects (average age 80) than younger (average age 50). Oddly, CSF Aβ42, which usually falls as AD sets in, actually tracked higher with age in those who were cognitively impaired. Other studies have reported that CSF Aβ42 can go up just prior to going down (see Reiman et al., 2012).

The researchers next determined how cognitive reserve affected the relationships between age and biomarkers. They started by using a statistical analysis to determine the interaction between age and biomarker levels, and then measured whether that interaction changed depending on years of education. They found that the difference in CSF p-tau and total tau between younger and older people was larger in the 88 people with less than 16 years of education than it was in the 180 with at least 16 years of schooling. For those with low cognitive reserves, levels of CSF t-tau were 272 ng/mL higher in the older group, but among people with high cognitives reserve the older subjects only had 70 ng/mL more t-tau than their younger counterparts. Likewise, p-tau tracked 29 ng/mL higher in older folks with less than 16 years of education, but only 8 ng/mL higher in those with greater cognitive reserves. This suggested that education could temper increases in CSF p-tau and t-tau that come with age. The protection vanished when the researchers lowered the educational bar to 12 years of schooling. Oddly enough, cognitive reserve seemed to offer slightly better protection to those with AD or MCI due to AD because it reduced their age-related uptick in CSF p-tau by 1.6 ng/L more than it did in the normal group.  The authors drew no conclusions about what this small difference might reveal about underlying pathology.

How would a few extra years of schooling alter the development of pathology in the brain over time? This study offers no concrete answers to that question. Okonkwo said that those mechanistic answers are beyond the scope of clinical research, but pointed out that animal studies have indicated cognitive stimulation increases the density of neurons, synapses, and dendrites, and reduces AD related pathology.

Regardless of how the brain builds reserve, Okonkwo said that education may be only one of the factors driving the protective effect seen in his study. Education associates with several other variables that could affect the brain, including socioeconomic status, social interaction, occupational attainment, exposure to toxins, physical activity, and other health issues such as diabetes, obesity, and cardiovascular disease. “All of these are interconnected,” he said. His study did not attempt to disentangle their contributions, although previous studies have concluded that education itself provides a protective benefit. Other studies have also found that physical activity, or cognitive enrichment outside of school, can help prevent cognitive decline. “All of these things converge on the same point: There is something happening differently in those with high reserve or resilience,” Okonkwo said.

Since some studies have found that cognitive reserve protects against a given amount of pathology, while others, including Okonkwo’s, have found that it actually prevents that pathology, which is likely to be true? Okonkwo thinks the answer could be both, but said it is difficult to draw conclusions because each study was conducted using different proxies of cognitive reserve and different study populations, and measured different biomarkers and outcomes. Prashanthi Vemuri of the Mayo Clinic in Rochester, Minnesota, agreed. One of her previous studies reported that lifestyle enrichment had no effect on Aβ deposition (see Vemuri et al., 2012), but she later found that enrichment did delay dementia (see Vemuri et al., 2014). “While there has been a recent flurry of papers investigating cognitive reserve, biomarkers, and cognition, there is no clear consensus on these interrelationships,” she said. “However, all the studies as well as this one have found that cognitive reserve may be helpful in reducing the deleterious effects of dementia.”

Jagust, who found that lifetime of cognitive enrichment can affect pathology, agreed that it was difficult to reconcile all of the studies. “You can draw two conclusions from all this: (1) there is growing information that lifestyle directly affects AD biomarkers, not simply the 'response' to such biomarkers, and (2) the data are not in agreement about what lifestyle factors are important nor what biomarkers are affected,” he wrote.

Yaakov Stern of Columbia University in New York, one of the early proponents of the theory of cognitive reserve, said that he had originally never considered the idea that such reserves could alter brain pathology; rather, they could boost resistance to it. Now, the idea that lifestyle factors such as cognitive stimulation or even exercise could also dynamically influence brain pathology is gaining traction, he said. He added that Okonkwo’s study sample was relatively small and did not parse out the contributions of other factors associated with education. However, he said the results raise the interesting possibility that the people with higher cognitive reserves in the study may be spared not only from elevated CSF biomarkers, but also from the onslaught of dementia. —Jessica Shugart


  1. A possible physiological explanation for the inverse relationship between cognition and dementia that is worthy of consideration derives from the models of Raichle et al., 2001; Buckner et al., 2005, 2008; Cirrito et al, 2005; and Bero et al., 2011, on the activity of default mode network (DMN) neurons, cognitive resting-state conditions, and regional amyloid accumulation.

    The influence of neuronal activation on synaptic amyloid release, interstitial amyloid quantities, and regional amyloid accumulation has been described by Cirrito et al. and Bero et al.

    Buckner et al. proposed that accumulations of amyloid in the brains of subjects with Alzheimer’s disease overlap DMN regions that are persistently active or overactive during cognitive resting-state conditions in young adults.

    The proposed relationship between cognitive resting, increased DMN activity, and amyloid accumulation suggests that the protective effect of cognitive stimulation on the brain results from the effect cognitive challenges have on deactivating DMN regions that are vulnerable to amyloid. Perhaps "cognitive reserve" is a metaphor for the long-term effects that cognitive stimulation has on deactivating the DMN.

    Bero et al. proposed that education might be protective to brains, based in part on the putative relationship between neuronal activity and amyloid accumulation in the DMN. The proposal discussed by Bero et al. provides a possible physiological explanation for the inverse relationship between long-term cognitive enrichment and dementia. 


    . Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci. 2011 Jun;14(6):750-6. Epub 2011 May 1 PubMed.

    . Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci. 2005 Aug 24;25(34):7709-17. PubMed.

    . The brain's default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci. 2008 Mar;1124:1-38. PubMed.

    . Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005 Dec 22;48(6):913-22. PubMed.

    . A default mode of brain function. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):676-82. PubMed.

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News Citations

  1. Imaging Studies Support Cognitive Reserve Theory

Paper Citations

  1. . Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurol. 2012 Nov;11(11):1006-12. PubMed.
  2. . Effect of Cognitive Reserve Markers on Alzheimer Pathologic Progression. Alzheimer Dis Assoc Disord. 2013 Apr 1; PubMed.
  3. . Gene-environment interactions: lifetime cognitive activity, APOE genotype, and β-amyloid burden. J Neurosci. 2014 Jun 18;34(25):8612-7. PubMed.
  4. . Effect of lifestyle activities on Alzheimer disease biomarkers and cognition. Ann Neurol. 2012 Nov;72(5):730-8. PubMed.
  5. . The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):270-9. Epub 2011 Apr 21 PubMed.
  6. . The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. PubMed.
  7. . Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol. 2012 Dec;11(12):1048-56. PubMed.
  8. . Association of lifetime intellectual enrichment with cognitive decline in the older population. JAMA Neurol. 2014 Aug;71(8):1017-24. PubMed.

Further Reading

Primary Papers

  1. . Effect of Cognitive Reserve on Age-Related Changes in Cerebrospinal Fluid Biomarkers of Alzheimer Disease. JAMA Neurol. 2015 Jun;72(6):699-706. PubMed.