Does a Stimulating Childhood Stem Amyloid Plaques in Golden Years?
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A childhood rich with intellectual stimulation may help the brain resist the onslaught of Alzheimer’s disease decades later, according to a study published June 29 in JAMA Neurology. Researchers led by David Bennett at Rush University Medical Center in Chicago found fewer Aβ plaques and tau tangles in the brains of people who had spent their youths steeped in a cognitively rich environment. Such early life enrichment also came with slower cognitive decline in the final years of life, an effect that was partially mediated by protection against AD pathology. The findings suggest that an early life investment in cerebral pursuits pays off decades down the road.
- Early life cognitive enrichment associated with reduced AD pathology later.
- This correlated with less cognitive decline.
- This pathology finding accounts for one-fifth of the observed cognitive protection.
“This is the largest study on the association between early life cognitive enrichment and AD pathology to date. Its findings highlight the importance of the first two decades of life for healthy aging occurring decades later,” commented Michael Ewers of the University of Munich.
Multiple studies have linked early life markers of intelligence or educational attainment to reduced risk for dementia in late life (Snowdon et al., 1996; Russ et al., 2017; Oct 2018 news). Even so, the question remains whether these intellectual investments make the brain more resistant to developing neuropathology in the first place, and/or more resilient in the presence of a given amount of neuropathology (Jun 2014 news).
First author Shahram Oveisgharan and colleagues investigated associations between childhood cognitive enrichment, AD pathology, and cognitive decline among 813 participants in the Rush Memory and Aging Project. The participants were tracked for cognitive changes for an average of seven years before they died. At enrollment, they filled out extensive questionnaires about their lives, and the researchers used this information to develop a composite measure of their early life cognitive enrichment. ELCE scores comprised four main components: early life socioeconomic status, based on education levels of the parents and the number of children in the family; availability of cognitive resources, such as a newspaper subscription, encyclopedias, or a globe, at 12 years of age; frequency of participation in cognitively stimulating activities such as reading; and years of foreign-language instruction by 18 years of age. Each of these four indicators were weighted differently and standardized, and a participant’s total ELCE score ranged from -2.0 to 1.7, with a median of 0. Higher scores denoted more enrichment. The researchers acknowledge a recall bias in their study, as participants, most of whom were in their 70s by the time they enrolled, were asked to remember events that took place in their first years of life.
Even so, strong associations emerged. The researchers found that higher ELCE scores associated with lower burdens of Aβ plaques, fewer tau tangles, and lower global AD pathology scores, which take both pathologies into account. For context, a 1-unit increase in ELCE had a similar impact on AD pathology as did being eight years younger. Neither ApoE genotype, age at death, sex, nor vascular risk factors muddled the relationship between ELCE and AD pathology. Strikingly, the association also remained when the researchers controlled for the participants’ self-reported socioeconomic status at enrollment, or their participation in cognitive activities in late life, suggesting that the effect was not driven by late-life advantages reaped from cognitive seeds sown in childhood.
The researchers found no association between ELCE and any of eight other non-AD brain pathologies measured in the study. Together, the findings suggested that early life cognitive enrichment somehow imbued the brain with resistance to AD pathology.
Furthermore, higher ELCE scores correlated with a more gradual cognitive slide late in life, such that a 1-unit increase in ELCE came with a 25 percent slower rate of decline. Ultimately, the researchers calculated that reduced AD pathology accounted for 20 percent of ELCE’s association with cognitive decline, leaving 80 percent of the association independent of amyloid and tau pathology.
“Although only 20 percent of the variability in the rate of cognitive changes explained by ELCE could be attributed to ELCE’s association with lower AD pathology, the effect of ELCE on Aβ and pathologic tau is remarkable,” Ewers wrote, adding that studies assessing lifestyle and cognitive enrichment in mid- and late life have not found links to AD pathology.
Oveisgharan was struck by the connection between ELCE and AD pathology. While the mechanisms involved are unclear, he hypothesized that cognitive stimulation in early life may be particularly suited to protect the brain against the AD neuropathological cascade, which starts decades prior to symptom onset.
ELCE may also boost cognitive resilience in the face of any brain pathology that does develop, including AD pathology or cerebrovascular disease, Oveisgharan noted.
Though the observational study cannot prove causation, Oveisgharan said the findings support the idea that intellectual stimulation in early childhood not only opens to the door to educational and job opportunities, but also improves cognitive health decades down the road. This makes enrichment programs that serve youth in disadvantaged or marginalized communities all the more important, he said.
In their accompanying editorial, Timothy Hohman of Vanderbilt University Medical Center in Nashville and Catherine Kaczorowski of the Jackson Laboratory in Bar Harbor, Maine, agreed. “Such policy reform has critical implications for reducing the burden of age-related cognitive impairment and would counteract systemic injustices that perpetuate health inequities and contribute to the well-documented disparities in AD,” they wrote.
“If the findings stand up to further scrutiny, the public health implications are obvious,” wrote Perminder Sachdev of the University of New South Wales in Sydney. He noted that to make early life enrichment universal, attention should go to improving the educational experience itself. “One must of course remember that data from this study refers to experiences in the early 20th century, as the participants in this study were a mean 90.1 years at the time of their death,” Sachdev added. “Whether the same would be true of childhood experiences a century later is difficult to know.”
Rachel Buckley of Massachusetts General Hospital in Boston added that the cohort is more female, white, and highly educated than the general U.S. population, so understanding the benefits of early life cognitive enrichment on downstream pathology in a more diverse sample is important. To Buckley’s mind, the study raised questions such as: “What is the exact nature of this early life enrichment? Does it remain important to downstream events even if someone ‘lapses’ in their enrichment when they are older? Or is it more about setting up ‘good practices’ while someone is young? What part of the enrichment process lends most to these positive downstream effects, or are all things ‘equally good’?”—Jessica Shugart
References
News Citations
- Intelligence Matters More for Brain Reserve, but Education Helps
- A Life of Cognitive Enrichment May Fend Off Dementia. But How?
Paper Citations
- Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR. Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study. JAMA. 1996 Feb 21;275(7):528-32. PubMed.
- Russ TC, Hannah J, Batty GD, Booth CC, Deary IJ, Starr JM. Childhood Cognitive Ability and Incident Dementia: The 1932 Scottish Mental Survey Cohort into their 10th Decade. Epidemiology. 2017 May;28(3):361-364. PubMed.
Further Reading
Papers
- Bezerra AB, Coutinho ES, Barca ML, Engedal K, Engelhardt E, Laks J. School attainment in childhood is an independent risk factor of dementia in late life: results from a Brazilian sample. Int Psychogeriatr. 2012 Jan;24(1):55-61. PubMed.
Primary Papers
- Oveisgharan S, Wilson RS, Yu L, Schneider JA, Bennett DA. Association of Early-Life Cognitive Enrichment With Alzheimer Disease Pathological Changes and Cognitive Decline. JAMA Neurol. 2020 Jun 29; PubMed.
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Ludwig Maximilian University
A large body of research has focused on identifying protective lifestyle factors that may enhance cognitive resilience against the effect of primary Alzheimer’s pathology on cognition, but only little is known about those factors that may slow down the development of primary AD pathology itself. Oveisgharan and colleagues investigated, in a large postmortem study, early life cognitive enrichment (ELCE) as a protective factor against late-life AD pathology and cognitive decline.
The authors report that higher, retrospectively assessed, ELCE between 6 and 18 years of age was associated with lower rates of late-life cognitive decline and with lower levels of amyloid plaques and tangles in the brain. Although only 20 percent of the variability in the rate of cognitive changes explained by ELCE could be attributed to ELCE’s association with lower AD pathology, the effect of ELCE on Aβ and pathologic tau is remarkable.
This is, to date, the largest study on the association between ELCE and AD pathology. Its finding highlights the importance of the first two decades of life for healthy aging occurring decades later.
However, it is unclear how the influence of cognitive enrichment and lifestyle on AD pathology changes during the life span. Recent neuroimaging studies including amyloid PET, such as the A4 study in almost 4,500 elderly individuals or the community-based Mayo Clinic Study on Aging, suggest that late-life lifestyle factors such as exercise and midlife intellectual enrichment are not protective against Aβ accumulation (Sperling et al., 2020; Vemuri et al., 2017). One possibility is that the early to midlife phase is a critical time window for reduced risk of AD pathology in late life, where intellectual enrichment assessed between ages 6 and 40 years but not afterwards is associated with lower amyloid accumulation in later life (Landau et al., 2012; Wirth et al., 2014). On the other hand, childhood cognitive ability at age 6 years, or education, were recently found not to be associated with AD pathology in late life (Lu et al., 2019; Wilson et al., 2019).
Apart from methodological differences that may explain some of the inconsistencies between studies, it needs to be acknowledged that years of education or self-reported information on intellectual enrichment are only coarse proxy measures, where the constructs such as education or intellectual enrichment remain vague. Although education, cognitive enrichment, and early childhood cognitive abilities are correlated, important differences may exist with regard to the effects on late-life cognition, which, however, are not yet understood. Furthermore, little is known about which brain changes correspond to intellectual enrichment. The current study brings the early phase of life to the forefront and encourages us to investigate early brain changes that may contribute to reduced AD pathology later in life.
References:
Sperling RA, Donohue MC, Raman R, Sun CK, Yaari R, Holdridge K, Siemers E, Johnson KA, Aisen PS, A4 Study Team. Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals. JAMA Neurol. 2020 Jun 1;77(6):735-745. PubMed.
Vemuri P, Knopman DS, Lesnick TG, Przybelski SA, Mielke MM, Graff-Radford J, Murray ME, Roberts RO, Vassilaki M, Lowe VJ, Machulda MM, Jones DT, Petersen RC, Jack CR Jr. Evaluation of Amyloid Protective Factors and Alzheimer Disease Neurodegeneration Protective Factors in Elderly Individuals. JAMA Neurol. 2017 Jun 1;74(6):718-726. PubMed.
Landau SM, Marks SM, Mormino EC, Rabinovici GD, Oh H, O'Neil JP, Wilson RS, Jagust WJ. Association of Lifetime Cognitive Engagement and Low β-Amyloid Deposition. Arch Neurol. 2012 Jan 23; PubMed.
Wirth M, Villeneuve S, La Joie R, Marks SM, Jagust WJ. Gene-environment interactions: lifetime cognitive activity, APOE genotype, and β-amyloid burden. J Neurosci. 2014 Jun 18;34(25):8612-7. PubMed.
Lu K, Nicholas JM, Collins JD, James SN, Parker TD, Lane CA, Keshavan A, Keuss SE, Buchanan SM, Murray-Smith H, Cash DM, Sudre CH, Malone IB, Coath W, Wong A, Henley SM, Crutch SJ, Fox NC, Richards M, Schott JM. Cognition at age 70: Life course predictors and associations with brain pathologies. Neurology. 2019 Dec 3;93(23):e2144-e2156. Epub 2019 Oct 30 PubMed.
Wilson RS, Yu L, Lamar M, Schneider JA, Boyle PA, Bennett DA. Education and cognitive reserve in old age. Neurology. 2019 Mar 5;92(10):e1041-e1050. Epub 2019 Feb 6 PubMed.
Massachusetts General Hospital/Harvard Medical School
I find this paper very exciting for a few reasons:
The authors nicely illustrate that early life cognitive enrichment (as measured with parental socioeconomic status, 12-year-old enrichment exposures, the frequency of participation in stimulating activities in childhood, and foreign-language instruction in early life) has associations with global amyloid pathology at death (perhaps slightly more so with tau than amyloid) but not on indices of non-AD-associated neuropathologies.
Even more intriguingly, greater early life enrichment seems to have benefits on later-life cognitive change independent of any resiliency it may provide against AD pathology. One important point to bear in mind, however, is the demographic distribution of this cohort—we are talking about a largely female, white, and more highly educated group of participants than the general U.S. population, and so understanding the benefits of early life cognitive enrichment on downstream pathology in a more diverse sample is really critical.
Some intriguing questions that pop into in my mind after reading this paper are: What is the exact nature of this early life enrichment? Does it remain important to downstream events even if someone "lapses" in their enrichment when they are older? Or is it more about setting up "good practices" while someone is young? Does a young person have agency over their early life enrichment, that is, do some children just naturally gravitate toward more enriching experiences, or is this largely set by their parents and the environment around them? What part of the enrichment process lends most to these positive downstream effects, or are all things "equally good"?
Regardless, this paper was a very thorough examination of the concept, and the accompanying commentary provides a good dive into the literature.
References:
Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006 Sep;7(9):697-709. PubMed.
University of New South Wales
Dementia researchers have long been intrigued by reports that early life experiences can influence the risk of dementia later in life. Much of the work has related to education or socioeconomic status as proxies of this experience (Valenzuela et al., 2007), with some research on the impact of trauma and adversity in childhood on the risk of dementia (Donley et al., 2018). This study takes this story one step further, showing that early life cognitive enrichment (ELCE) was associated with a slower rate of cognitive decline later in life as well as lower levels of Alzheimer’s disease pathology. This association was present after accounting for educational differences in the sample. The findings, if validated in an independent sample, would suggest that not only does ELCE increase resilience to neurodegenerative changes in late life, it also makes the brain more resistant to the development of pathology.
If the findings stand up to further scrutiny, the public health implications are obvious. There is overwhelming evidence that education and high socio-economic status protect against dementia. To add ELCE to the mix suggests that early life experiences need to be enriched further. To make this universal, attention should go to the educational experience itself and how it can be enriched. One must of course remember that data from this study refers to experiences in the early 20th century, as the participants in this study were a mean 90.1 years at the time of their death. Whether the same would be true of childhood experiences a century later is difficult to know.
It is not easy to replicate the findings of such a study as comparable data are generally lacking. The fact that such studies rely on retrospective recall of childhood is another limitation. There are, however, some birth cohorts that have been followed for a long enough period to be able to address this question more assuredly, at least partially.
We must also try to understand the mechanisms by which ELCE may increase resilience and resistance. Some molecular mechanisms related to cognitive enrichment have been described (Valenzuela et al., 2007) that are worthy of further exploration. Since investigators usually rely on animal models to examine molecular mechanisms, selecting the right models is extremely important, as model systems for dementia have many limitations (Neuner et al., 2019). It must also be remembered that cognitive enrichment in early life often leads to a life-long pattern of cognitively complex activities, and the benefit may well be due to more cognitive activity more proximate to the time of the development of pathology.
In conclusion, this study brings new impetus to the importance of complex cognitive activity across the life span and should spur further work and its translation into practice.
References:
Valenzuela MJ, Breakspear M, Sachdev P. Complex mental activity and the aging brain: molecular, cellular and cortical network mechanisms. Brain Res Rev. 2007 Nov;56(1):198-213. Epub 2007 Jul 31 PubMed.
Donley GA, Lönnroos E, Tuomainen TP, Kauhanen J. Association of childhood stress with late-life dementia and Alzheimer's disease: the KIHD study. Eur J Public Health. 2018 Dec 1;28(6):1069-1073. PubMed.
Neuner SM, Heuer SE, Huentelman MJ, O'Connell KM, Kaczorowski CC. Harnessing Genetic Complexity to Enhance Translatability of Alzheimer's Disease Mouse Models: A Path toward Precision Medicine. Neuron. 2019 Feb 6;101(3):399-411.e5. Epub 2018 Dec 27 PubMed.
University of Rochester Medical Center
This paper is from one of the top groups worldwide for this type of work. The cohort is one of the major studies that has been ongoing for years. The findings are important, in that they reinforce the importance of mentally stimulating activity relatively early in life. Much of the work has focused on adult periods, where things like complex occupations or mentally stimulating leisure activities reduce the risk of dementias, but the focus on the preadult years is less common.
The ELCE measure is fairly good; it is basically an average of several factors like parental education, being read to, reading, etc. Participants reported these things at the very start of the study, before they showed substantial cognitive impairment, and these are general things that most will likely remember. Therefore, while some don’t like the “recollected” nature of these kind of reports of childhood, they are reasonable in many cases and I don’t think pose a big problem here. Problems arise when extremely specific things are asked, and/or people are already cognitively compromised. The authors chose an aggregate or averaging approach to the different indicators, which is common when several interrelated measurements of a general construct like early cognitive engagement are involved.
It is not terribly surprising that the measure predicted a lower degree of cognitive decline, measured by neuropsychological tests in later life. However, the AD pathology measure is based on several biomarkers from brain autopsy, and it is rarer to see that type of association (in part because few have the bank of autopsied brains this team does). The data suggest that early life cognitive exposures may set people on a road to more cognitively engaged lifestyles as adults. Here, they show that completed education is an important pathway, for instance. This does seem linked to neuropathological changes in the brain in later life.
So overall, the paper is a nice empirical demonstration of what we suspect and hypothesize, but for which data on this particular combination of factors is rather rare. Many studies have reports of early life factors and cognitive tests, but the brain autopsies allowing them to show the neurodegenerative piece are uncommon.
As the authors note, the implications are that early life enrichment ought to stave off AD in future generations. This is important because people will live longer and therefore be at greater risk of the disease. The good news is that most social and health policy makers already underscore the importance of early enrichment programs for a number of other reasons. To the extent that these initiatives continue to expand, the population burden of AD ought to be less 70 years down the line for them.
BarcelonaBeta Brain Research Center, Barcelona, Spain; Mayo Clinic, Rochester, Minnesota; and INSERM, Caen, France
This clinical-pathological study provides convincing evidence that ELCE is associated with AD pathologies and slower rate of cognitive decline over seven years.
It has been well-documented that ELCE has long-lasting effects on late-life health outcomes. However, the mechanisms underlying these effects are a matter of controversy in the field. This study encourages further research on the molecular mechanisms by which ELCE lowers the risk of having AD pathologies later in life, a protective pathway that we have recently termed “resistance to AD” (Arenaza-Urquijo et al., 2018; Montine et al., 2019).
Several aspects of this study are noteworthy: (1) It is the largest investigation to date (n=813) looking at associations of ELCE with AD neuropathology. Only one previous study (n=25) reported association of early life linguistic ability with more abundant neurofibrillary tangles in the hippocampus and neocortex (Snowdon et al., 1996). (2) The study presents a comprehensive approach to ELCE, including parental education, number of children, availability of cognitive resources, frequency of cognitively stimulating activities, and early life foreign-language instruction. This is important because years of education alone is frequently used as a proxy of ELCE. (3) The study reports a specific association of ELCE with AD pathologies, but not with other non-AD related pathological changes, including vascular, which is surprising (Bennett et al., 2014). (4) Finally, the results show that the association of ELCE with the rate of cognitive decline persists when adjusting for AD pathologies. This may imply that multiple pathways—not only resistance pathways—explain the ultimate effect of ELCE on cognition later in life (see below).
This being said, it is important to put this research in context:
1. The associations between ELCE and AD pathologies are often observed in highly educated cohorts. In vivo and pathological studies have provided controversial results with respect to the effects of ELCE variables on AD pathologies (Bennett et al., 2014; Arenaza-Urquijo et al., 2017; Gidicsin et al., 2015; Landau et al., 2012; Vemuri et al., 2016; Wirth et al., 2014). In this study, participants had more than 14 years of education on average. Two previous studies from the Berkeley Aging Cohort (average 17 years of education) showed similar associations using in vivo amyloid PET imaging (Wirth et al., 2014; Landau et al., 2012). In the ADNI cohort (average 16 years of education), higher education, occupation, and premorbid intelligence were also associated with slower decline in Aβ measured in CSF (Lo, 2013). A study from the population-based Mayo Clinic Study of Aging showed that the associations of cognitive activity with lower amyloid burden were only present in the higher education strata of the population (>14 years) (Vemuri et al., 2016). Further studies are warranted to clarify whether other variables associated with socioeconomic status are playing a role in these findings.
2. Early life vs late-life cognitive engagement. Although very limited evidence is available, previous studies point out the importance of the early life period, rather than late life, for promoting resistance to AD pathologies. As the authors mention, it is possible that because individuals harbor higher pathological burdens in late life, lifestyle factors may have less impact on further accumulation during late life. Amyloidosis is a slow and protracted process that might be influenced by the synaptic activity throughout the lifespan. Indeed, it has been suggested that individuals with higher engagement in cognitively stimulating activities may develop more efficient neural processing, which may result in less Aβ deposition (Jagust and Mormino, 2011). Besides cognitive engagement, promoting other lifestyle factors (such as sleep quality) could result in a slower Aβ accumulation (Carvalho et al., 2018). While this idea is promising, there is still no solid evidence in this regard. Understanding the mechanisms of resistance to AD pathologies is a major challenge in the field (Arenaza-Urquijo and Vemuri, 2020).
3. Multiple pathways. As pointed out above, in this study the direct relation of ELCE with slower rates of cognitive decline constituted 80 percent, and the indirect relation through AD 20 percent, of the effect. This suggests the involvement of different pathways explaining the effects of ELCE on cognition. Indeed, a single unitary mechanism is unlikely to explain the complex relationships between protective factors and cognitive decline. Besides resistance, lifespan cognitive engagement as well as other protective factors, may increase brain resilience (and reserve) (Arenaza-Urquijo et al., 2018) through brain structure and function. Higher brain resilience would therefore counteract the effects of AD pathologies on cognitive decline. Interestingly, studies are starting to show that even in the presence of AD pathologies, better lifestyles (for example, exercise) may be associated with slower atrophy rates and better cognitive outcomes (Rabin et al., 2019). Understanding whether and how brain resilience can be promoted in the context of AD pathologies will be critical to inform prevention strategies.
Overall, this relevant study stimulates further research on the mechanisms underlying resistance to AD pathology. Cross-talk between animal research, life span, aging, and AD researchers will be a critical step to ensure that the field advances toward a better understanding of mechanisms as well as identification of optimal time windows to maximize preventive efforts. If resistance can be promoted early in life, the implications these findings may have in terms of health and social policies cannot be ignored.
Mayo Clinic and Foundation
These results are very promising and are consistent with our previous paper, where we found evidence for associations between amyloid and intellectual enrichment in those who are highly educated (Vemuri et al., 2016).
However, it was surprising to see no associations with vascular risk and pathologies, which we believe are causally linked to the resilience pathway (Vemuri et al., 2019).
References:
Vemuri P, Lesnick TG, Przybelski SA, Knopman DS, Machulda M, Lowe VJ, Mielke MM, Roberts RO, Gunter JL, Senjem ML, Geda YE, Rocca WA, Petersen RC, Jack CR Jr. Effect of intellectual enrichment on AD biomarker trajectories: Longitudinal imaging study. Neurology. 2016 Mar 22;86(12):1128-35. Epub 2016 Feb 24 PubMed.
Vemuri P, Lesnick TG, Knopman DS, Przybelski SA, Reid RI, Mielke MM, Graff-Radford J, Lowe VJ, Machulda MM, Petersen RC, Jack CR Jr, MD. Amyloid, Vascular, and Resilience Pathways Associated with Cognitive Aging. Ann Neurol. 2019 Dec;86(6):866-877. Epub 2019 Oct 17 PubMed.
Columbia University
This article supports two themes that have been developing: cognitive reserve and brain maintenance. Brain maintenance is the idea that life enrichment might actually maintain the brain itself, and thus the brain areas/networks underlying cognitive performance. This has been quite well-established for normal aging, but the idea that brain maintenance might help prevent Alzheimer's pathology has been under discussion. Susan Landau, Bill Jagust, and colleagues had a paper a while ago where they reported in a convenience sample that cognitively normal elders who had engaged in more midlife cognitive activities had lower levels of amyloid PET. This article is further support for the idea that enriching activities might help prevent aggregation of AD-related pathologies (Landau et al., 2012).
The concept of cognitive reserve is complementary, that is, once brain changes or pathologies develop, people with higher CR can cope better with these changes. The current article offers support for this idea, as well: early life enrichment is responsible for better cognition over and above the effect of reducing AD pathology.
References:
Landau SM, Marks SM, Mormino EC, Rabinovici GD, Oh H, O'Neil JP, Wilson RS, Jagust WJ. Association of Lifetime Cognitive Engagement and Low β-Amyloid Deposition. Arch Neurol. 2012 Jan 23; PubMed.
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