Early brain development and cognitive aging – a global challenge

Written by Chapko D, Sandu AL, McNeil C, Murray A (University of Aberdeen, UK)

The global dementia epidemic

The number of people living with dementia worldwide is currently estimated at 47 million and this number is predicted to triple by 2050 [1]. Importantly, nearly 60% of people with dementia live in low- and middle-income countries (LMICs). There is currently no disease-modifying treatment for diseases that cause dementia, and dementia related care is costly and complex; some of the main challenges associated with dementia include its economic impact on families, caregivers and communities, and the associated stigma and social exclusion [2].
What can be done?

Understanding the life-course determinants of resilience to brain aging could significantly reduce the burden of cognitive impairment and dementia on individuals and societies at large through prevention. The concept of cognitive resilience is relatively new [3] and proposes that cognitive functions are maintained or recovered in face of an adversity [4]. Cognitive reserve (CR) is a specific type of cognitive resilience whereby the underlying adversity is organic in nature. The CR concept accounts for phenomenon that some individuals are able to remain cognitively healthy despite the accumulation of neuropathology. One review has estimated that 10–40% of individuals with Alzheimer’s disease (AD)-like brain pathology had no signs of cognitive impairment during life [5]. This suggests that there are moderating factors which allow one to preserve cognitive functions despite the underlying brain disease [6]. Identifying practical and modifiable sources of CR would inform the design of effective and scalable interventions that prevent dementia. Social, cultural, environmental and lifestyle factors may be as effective as a new drug, which is especially relevant in the context of LMICs that have a particular requirement for cost-effective strategies.

The key – understanding the early-life origins of cognitive aging

Our systematic review of CR literature identified a major knowledge gap in the understanding of how early-life factors influence (or ‘program’) the brain’s resilience to dementia-related neuropathologies. This seems surprising in the light of Barker’s hypothesis regarding the developmental origins of health and disease (DOHaD) [7]. In particular, cerebrovascular disease contributes to 45% of dementias, while obesity and type 2 diabetes mellitus are correlated with late-life impaired cognition and have been shown to originate in fetal life. Investigating links between perinatal stress, brain disease burden, the mediating effect of environmental and biological factors across the life course and cognitive decline and dementia is of relevance to global dementia prevention. We now have the opportunity to address this knowledge gap by making better use of routinely collected and cohort data along with utilizing ‘big data’ approaches.

Early-life origins of cognitive aging based on Aberdeen Birth Cohorts

Using the Aberdeen Birth Cohort of 1936 (ABC1936) and 1921 (ABC1921) we found that childhood intelligence at 11 years of age predicts between 40 and 60% of brain function in late-life [8] [9] [10]. Furthermore, recent research supports the idea that children from disadvantaged backgrounds, in addition to having brain developmental and cognitive delays, acquire more age-related brain pathologies. Staff et al. [11] demonstrated that older adults without dementia with low childhood socioeconomic circumstances had smaller hippocampi. A second study performed within the same cohort [12] found that early-life socioeconomic disadvantage is associated with increased brain imaging evidence of white matter lesion burden (cerebrovascular disease) in late-life, with its established negative consequences for cognition, stroke, dementia and survival. Importantly, Sandu et al. [13] found that structural brain complexity in late-life measured using fractal dimension applied to magnetic resonance images is associated with higher cognitive ability and predicts longitudinal retention of cognitive ability within late-life. Mustafa et al. [14] showed that structural brain complexity correlates with childhood ability and predicts maximal ability attained. These findings are important because late-life complexity patterns of the brain seem to be predefined from early-life: the intra-individual variability of complexity varies less than inter-individual variability [13].

Since childhood cognitive abilities and socio-economic circumstances at 11 years of age are strong predictors of brain aging, a reasonable approach is to look at earlier-life determinants that potentially cause childhood intelligence and brain development differences impacting later brain health [15]. Birth weight, in addition to maternal smoking and breast feeding, has been proposed as an important factor [15]. In a study based on the more recent cohort Aberdeen Children of the 1950s (ACONF), we examined the relationship between birth weight and gestational age treated as markers for suboptimal conditions in utero and cognitive functions over the life course. We found that those with low birth weight and/or born pre-term delivery performed significantly worse on intelligence tests compared to the normal group at 7 or 9 years of age. Importantly, the negative effects of low birth weight and/or pre-term delivery on childhood cognitive abilities reappeared in mid-life. This, overall, further emphasizes the importance of healthy pregnancy and identifies individual differences that may have health and cognitive consequences in later life.

Call for extending CR research to culturally and socio-economically diverse populations

On average, people across the world, including in LMICs, live longer – this is mostly due to the large reduction in infant mortality accompanied by socioeconomic development globally over the past 50 years [16]. For example, although the population structure in sub-Saharan Africa is relatively young, the number of older adults in this region is expected to grow from 46 million in 2015 to 157 million by 2050 – the fastest growth globally [16]. Therefore the quest for healthy aging is also relevant to the developing world.

Much of what is already known about the brain’s resilience to cognitive aging is based on participants from high income countries. The effects of poverty on the developing and aging brain’s structure and function in low-resource settings are understudied. Research using the pediatric imaging and neurogenetic (PING) dataset in North America has shown that the relationship between family income and cortical surface is logarithmic and steepest at poorest incomes [17]. This provides challenges and opportunities for developing countries. The challenge is that the impact of poor early-life ‘experience’ may be more widespread and severe than we see in the Aberdeen Birth Cohorts, with the resultant impact on later life CR more profound. The opportunity is that even marginal increases in early-life socioeconomic circumstance could bear fruit in better later life CR.

The looming dementia epidemic requires urgent action to prevent catastrophic socioeconomic consequences in LMICs least equipped to deal with these. The Medical Research Council (MRC), as part of the Global Challenges Research Fund, has just announced a new set of funding opportunities positioning Global Mental Health Research at its core. In particular, as part of this initiative the aim is to understand how biological, social, cultural, or environmental factors affect early brain development with its consequences on mental illness and cognition in a global context. Now is the perfect time to think about ways of extending the life-course approach on CR to LMICs.

The CR theory in developing countries has gradually been recognized in recent years; the differences in educational attainment across countries globally and their effects on CR and dementia diagnosis have been pointed out [18]. New ways to effectively study CR in the developing world are being developed. For example, the MYNAH cohort in India has been recently reported as the first life-course birth records cohort study in the developing world with cognitive outcomes in older adults [19]. Ideally, through the identification and creation of such life-course cohorts in developing countries, it will be possible to extend research on CR and the coverage of the big data platforms (e.g. Dementia Platform UK) to culturally and socio-economically diverse populations. Such resources will be vital to validate and compare the findings from high income countries and to increase our understanding of CR and its mechanisms across the life-course. Overall, our understanding of CR and its developmental origins leads us to awareness that preventing dementia requires a life-course approach and that effort should be concentrated in early-life.


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