. Association of Early-Life Cognitive Enrichment With Alzheimer Disease Pathological Changes and Cognitive Decline. JAMA Neurol. 2020 Jun 29; PubMed.

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  1. 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:

    . Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals. JAMA Neurol. 2020 Apr 6; PubMed.

    . Evaluation of Amyloid Protective Factors and Alzheimer Disease Neurodegeneration Protective Factors in Elderly Individuals. JAMA Neurol. 2017 Jun 1;74(6):718-726. PubMed.

    . Association of Lifetime Cognitive Engagement and Low β-Amyloid Deposition. Arch Neurol. 2012 Jan 23; PubMed.

    . Gene-environment interactions: lifetime cognitive activity, APOE genotype, and β-amyloid burden. J Neurosci. 2014 Jun 18;34(25):8612-7. PubMed.

    . 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.

    . Education and cognitive reserve in old age. Neurology. 2019 Mar 5;92(10):e1041-e1050. Epub 2019 Feb 6 PubMed.

    View all comments by Michael Ewers
  2. I find this paper very exciting for a few reasons:

    1. Rodent models of enriched environments have long been explored as moderators of neurodegenerative disorders (Nithianantharajah and Hannan, 2006),
    2. The notion of cognitive reserve was, until recently, largely explored using education levels—which is an early life exposure to cognitive enrichment (of sorts), and
    3. This is a perfect cohort for testing multiple neuropathological indices in relation to early life enrichment.

    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:

    . Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006 Sep;7(9):697-709. PubMed.

    View all comments by Rachel Buckley
  3. 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:

    . 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.

    . 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.

    . 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.

    View all comments by Perminder Sachdev
  4. 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.

    View all comments by Benjamin Chapman
  5. 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.

    View all comments by Eider Arenaza-Urquijo
  6. 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:

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

    . Amyloid, Vascular, and Resilience Pathways Associated with Cognitive Aging. Ann Neurol. 2019 Dec;86(6):866-877. Epub 2019 Oct 17 PubMed.

    View all comments by Prashanthi Vemuri
  7. 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:

    . Association of Lifetime Cognitive Engagement and Low β-Amyloid Deposition. Arch Neurol. 2012 Jan 23; PubMed.

    View all comments by Yaakov Stern

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