The role of population-level preventive care for brain health in ageing

Abstract

Over the last decades, Western countries and many other nations have gone through major demographic transitions which resulted in an increasing number of older adults with chronic neurological conditions. These neurological conditions, which have a profound impact on cognitive function and physical ability of the older adults, also have a long preclinical phase. This feature provides a unique opportunity for implementing population-wide and high-risk group preventive practice measures to reduce the burden of neurological diseases in our ageing population. In recent years, the concept of brain health has emerged as the overarching theme to define overall brain functions independent of underlying pathophysiological processes. In this paper, we will review the concept of brain health from ageing and preventive care perspectives. We will discuss the mechanisms underpinning ageing and brain ageing, highlight the interplays of various forces resulting in deviation from brain health towards brain disease and provide an overview on strategies to advance brain health with a life course approach.

Introduction

Over the last century, Western countries and many other nations have gone through an epidemiologic transition. Morbidity and death from “degenerative and man-made diseases” has surpassed infectious causes.¹ While the COVID-19 pandemic adds variability to this pattern, the overall trend persists. Following this trend, public health practice has shifted to chronic disease control and prevention. The campaign to end smoking was a signature achievement.² Government funding for large cohort studies permitted researchers to identify more modifiable risk factors, thus expanding the potential for interventions at the population level to reduce the burden of chronic diseases, in particular cardiovascular conditions.³ In contrast, health care systems that are limited by an illness-based payment system have been slower to incorporate effective primordial prevention.⁴ At present, this efforts falls mostly to overstretched primary care providers, but this limited preventive approach has had significant downstream consequences for a wide range of specialties. Recognizing the burden of vascular risk factors and the limitations of the current model, cardiology has proposed a new subspecialty called preventive cardiology.⁵ Development of preventive cardiology has resulted in several major advancements in cardiovascular health including inception of several population-based cohort studies, support for trials focused on primary prevention, and changes in guidelines for cholesterol and blood pressure management.⁶ With the rapid ageing of populations and increasing burden of neurological conditions, there is an urgent need for further collaborative efforts between the neuroscience community, primary care specialists and other specialists to focus on brain health and prevention of age-related brain diseases.⁷

In this paper, we will review the concept of brain health from ageing and preventive care perspectives. We will review the mechanisms underpinning ageing and brain ageing, and discuss the interplay of various forces that result in deviations from brain health to brain disease. We will conclude with recommendations regarding strategies to boost brain health with a life course approach.

Ageing and Brain Ageing

Globally, human life expectancy has steadily increased over the last several decades. During the 20^th century, several theories of ageing emerged. An early theory was that ageing is merely a population control mechanism, but this was quickly discarded.⁸ With the discovery of DNA and genes, the scientific community shifted attention towards a genetic cause. A known genetic-based theory for ageing is antagonistic pleiotropy where a genetic variant that offers benefit in early life is detrimental in late life.⁹ Such theories have been largely unproven and subsequent genome-wide studies showed that genes account for no more than 25% of variability in human life span.¹⁰ Given the limitations of genetic-based theories for ageing, researchers turned to the frame work of ageing as a continuous, lifelong process rather than one that was strictly genetically predetermined. The ‘disposable soma theory’ is based on the observation that there is reduced fidelity in somatic DNA replication and maintenance compared to germline DNA.¹¹ The theory posits that there is limited energetic investment by the organism in the maintenance of the somatic DNA. Thus, over time, defects occur and accumulate due to failure of repair mechanisms as the ‘energy investment’ wanes.⁸ A more recent and generally accepted definition defines ageing as a “time-dependent and environmentally accelerated accumulation of damage in a biological system.”¹² Allostatic load is an important and helpful concept in outlining ageing. McEwen and Stellar introduced the theory of allostatic load in the early 1990s.¹³ Allostasis is the natural, dynamic cycle between stress and repair. Allostatic load is when stressors accumulate and the system tips into dysregulation because of failure of repair and regulatory mechanisms.

The brain is a complex biological system, and its ageing appears to result from the same hypothesized mechanisms seen in other tissues, many of which overlap and interact.¹⁴ Functionally, we recognize brain ageing as decline in cognition, social skills, strength or balance.¹⁵ Researchers have assessed various structural and radiographic brain changes as markers of brain ageing like cortical thinning, global brain atrophy, white matter hyperintensities and brain weight.¹⁶ Molecularly, telomeres have received much research attention as markers of ageing, but telomere length does not consistently associate with other markers of brain ageing (e.g.- hippocampal volume change).¹⁶ Studies of epigenetic modifications find these changes associated with chronological age and with poorer cognitive function but more research is needed in humans as far as specific epigenetic changes and consequent pathophysiology.¹⁷ Neuroinflammation appears to be an important part of accelerated brain structural changes and Alzheimer’s pathology, likely through multiple pathways. In addition, high levels of some markers of systemic inflammation (i.e. IL-6) predict cognitive decline in longitudinal studies but causality remains to be established.¹⁸ Taken together, there is no consistent radiographic or biologic predictor of clinical brain ageing. Similarly, the association between presence of neuropathology and clinical cognitive function is variable.¹⁹ This brings us to the concept of cognitive reserve. This is a “theoretical construct used to describe individual differences in susceptibility to cognitive, functional or clinical decline due to ageing or brain disease”.²⁰ Other terms used for this concept are brain-age gap, compensation, or resilience.^16,21 As the presence of structural or molecular pathology is not inevitable to cause brain dysfunction, we conceptualize brain health as a process and an outcome. The outcome of brain health is age-appropriate brain function over the life span. Maintenance of brain health leads to preservation of thought processing, executive planning, sensory and motor function, and memory and emotional connection, which all positively influence the quality of lives and well-being of individuals, families, and communities.⁷

Damage (risk factor exposure), resistance to damage (active repair) and inherent resilience to function despite damage are the fundamental forces driving brain health. Centering the focus on brain health mandates an emphasis on protecting the brain from reaching a critical point where damage overwhelms healing mechanisms, and consequent morphologic and physiologic changes lead to overt clinical symptoms and irreversible progression of brain dysfunction. The difference between various trajectories of brain health is visualised in Figure 1. Some common factors that injure the brain over time are hypertension, smoking, sedentarism, and poor sleep.²² The resulting stress from these factors build up and overwhelm the compensatory repair mechanisms of the brain. There may be some degree of resilience but quickly, this can be overcome to result in dysfunction. Put another way, allostasis exhausts earlier in life with frequent and numerous metabolic and environmental stressors, tipping the system into allostatic load earlier. In the alternative trajectory, the number, duration, and intensity of exposure to risk factors is less. This leads to slower accumulation of damage, slower brain ageing, and a longer preserved brain function over life span. With fewer risk factors and boosted repair mechanisms, the capacity for allostasis is prolonged and does not tip into allostatic load, dysregulation, and irreversible brain damage. This model simply underscores the significance of a life-course preventive approach before permanent impairment in brain structural and functional integrity occurs.

Figure 1.

Trajectories of accelerated versus delayed brain ageing in relationship with chronological age and brain health. Accelerated brain ageing due to accumulation of damage, in the absence or failure of compensatory mechanisms, results in impaired brain functional and structural integrity. This impairment, when surpasses a certain threshold, can manifest with decrease in cognitive function and neurologic diseases.

Is neuroscience prepared to welcome a preventive approach?

Neuroscience community is primed to welcome a preventive care approach for several reasons. First, modifiable risk factors (e.g., hypertension, smoking, sedentarism) increase the risk of several neurologic conditions from stroke to epilepsy to neurodegenerative diseases, like Alzheimer’s disease and Parkinson disease.^23–26 The high prevalence of these risk factors has a substantial impact on the prevalence of neurological diseases: current data indicate that more than 40% of dementia and 70% of stroke cases are attributable to modifiable risk factors.^26,27 In addition to conventional vascular disease risk factors, evidence linking modifiable lifestyle, metabolic, environmental, and infectious exposures to other high morbidity and high-cost neurologic diseases (e.g. multiple sclerosis and amyotrophic lateral sclerosis) is growing, although risk factors such as Epstein-Barr virus for multiple sclerosis are ubiquitous as compared to conventional risk factors such as smoking which can be readily targeted.^28,29

Second, prevention is possible. Vaccination against infectious diseases, better water sanitation and food safety practices, improved workplace safety, social marketing around drunk driving and smoking, and—in high income countries—better control of hypertension and hyperlipidemia are all major public health achievements of the 20^th century.³⁰ These population level interventions have led to a decrease in preventable deaths from infectious, toxic, and traumatic causes as well as vascular diseases.³⁰ Specific to neurological conditions, the incidence of stroke and dementia has decreased over the last decades in certain parts of the world, likely attributable to public education and better medical management of modifiable risk factors.²⁶ (26)

Third, research points to a long preclinical phase for most neurological diseases.³¹ Aggressive risk factor management can occur in this preclinical phase. By identifying “high risk” patients earlier, a neurologist with a preventive focus can contribute to changing risk factor exposure intensity and frequency. Mild cognitive impairment (MCI), minor traumatic brain injuries (TBI) and transient ischemic attack (TIA) are examples of such transitional states where neurologists with preventive approach can make a major difference in long term brain health. Most neurologic conditions do not have modifying or reversing therapies; thus, prevention is currently the only form of effective intervention.

It is of great importance to highlight that the promotion of brain health cannot be achieved with efforts in the neuroscience community alone. This requires advancing partnership among various stakeholders and close collaborations between primary care physicians, neurologists and preventive cardiologists given the well-established links between midlife conventional cardiovascular risk factors and features of impaired brain health (such as cognitive decline and abnormal brain structural changes) later in life. In addition to this collaborative effort, the neuroscience community can serve several important purposes in order to advance brain health at the individual and population levels. The unique features of brain physiology (privileged immune system, neurovascular unit, neuroplasticity, unapparelled waste metabolic product clearance pathway with glymphatic system,…) ^32,33 require focused research activities to develop novel and life course preventive targets and measures to preserve brain network connectivity and function beyond the control of traditional cardiovascular risk factors. In terms of implementation research, neurologists can play significant roles to translate data from clinical trials to daily practice. The complexity of brain function and structure requires expertise of the neuroscience community in defining brain health phenotypes, identification of intermediate adverse outcomes and discovering specific neuroprotective measures. In addition, the neuroscience community, and in particular neurologists, can provide major contributions in advocacy for policies and population-level interventions that promote brain health. Examples are workers protection around sleep or environmental health to reduce exposure to air pollution and pesticides, safe sport and physical activity practices to avoid concussion and designing cognitively stimulating educational environments to safeguard optimal early life brain development.

How to maintain brain health?

The three pillars of brain health preservation include: 1) altering the life course trajectory of risk exposure (risk factor identification, management, and monitoring), 2) boosting healthy habits and behaviours that promote repair mechanisms and 3) risk stratification and early life interventions combined with maintaining brain functional connectivity to promote resilience against age-related pathologies.

What can we do to alter the life course trajectory of risk exposure?

Several longitudinal epidemiologic studies have identified modifiable risk factors over the life course for vascular diseases and cognitive decline. In an analysis of data from the Framingham Heart study, the lifetime risk for cardiovascular diseases was markedly lower in middle-aged adults who did not have any known vascular risk factor (i.e. normal blood pressure, cholesterol, non-smoking status) relative to adults who had even just one risk factor, like diabetes.³⁴ Other large epidemiologic studies similarly observed this relationship.³⁵ With this collective evidence, the American Heart Association (AHA) introduced the concept of “Life’s Simple 7.” Life’s Simple 7 are modifiable health conditions or health behaviours which, when optimal, are associated with lower risk of cardiovascular disease incidence and mortality.³⁶ The “Life’s Simple 7” include healthy diet, regular physical activity, non-smoking status, healthy weight, normal lipids, normoglycemia, and normal blood pressure. Recently, this list was updated to “Life’s Essential 8” to incorporate the critical role of regular and adequate sleep in vascular, metabolic, and cognitive health.³⁷ We prefer the “Essential 8” over “Life’s Simple 7” not just for the inclusion of sleep but because the revised language acknowledges that lifestyle factors are not necessarily “simple” measures to achieve. Lifestyle changes at the individual level, whether promoted through a primary care intervention or health awareness campaign, can be extremely difficult to achieve and sustain. Truly rewiring our health system to support brain health cannot ‘simply’ rely on individual behaviour change. System change must accompany these efforts so that the healthy choice can be an easy choice. Hence, the preventive plan and a systems-level framework for tackling each factor can assist in overall and targeted risk exposure reduction. Figure 2 demonstrates the “ABC” framework for systematic risk exposure evaluation, monitoring, and management. As we proposed previously, the ABC framework can be individualised for primary prevention in specific neurological conditions, such as ischemic stroke, to factor in individuals’ unique susceptibility to various conditions.³⁸

Figure 2.

The ABC framework for systematic risk exposure evaluation. This proposed systematic approach proposes addessing and monitoring the following items in middle age and young adult individuals in order to decrease the damge load to the brain and modifying the trajectory of brain ageing at an individual level: Awareness (education about factors that can affect brain function and structure and paying attention to early signs of neurological diseases), Blood Pressure (early diagnosis and treatment of hypertension), Community engagement (increase the sense of belonging and participating in meaningful social activities), Drugs and smokings (avoiding and cessation of recreational drugs, alcohol and tobacco), Enviromental hazards (avoiding chemical exposures and air and water polutant), Food (balanced diet with low sodium and sugar and enriched with fruits and vegtables), Glyecmic control (early diagnosis and treatment of diabetes), Hyperlipdemia (early diagnosis and treatment of hyperlipidemia), Inactivity/Insomnia (physical activity and mobility with focus on aerobic excercises and walking/improving regular and adequate sleep and early diagnosis of sleep disorders such as sleep apnea). The figure was created by BioRender.

What can we do to boost resistance to brain damage?

Several lines of evidence indicate that cardiovascular fitness is a key factor to advance the repair capacity and recovery from risk factor exposure.^22,37 Cardiovascular fitness is a broad term and generally reflects the efficiency to meet the metabolic needs of tissues.³⁷ While the heart-brain axis is the gateway for nutrient, oxygen, and energy to the brain, the neurovascular unit is the main target and manifestation of systemic vascular health and fitness within the brain. The neurovascular unit is the functional unit within the brain where neurons, glial cells and vasculature act in concert to maintain brain homeostasis. This unit serves as the interface between the brain and outside world. The functional capacity of this unit reflects the readiness of the brain to encounter insults and recover from injuries to prevent long term deficits.³² The neurovascular unit is not only of importance in cerebrovascular function but also maintains homeostasis of the microenvironment to ensure optimal metabolic functioning.²² Maintaining homeostasis requires efficient distribution of oxygen, energy, and nutrient delivery in brain regions with the greatest need, also termed neurovascular coupling.³² Metabolic waste clearance is another fundamental process under the influence of the neurovascular unit.³⁹ Of note, some authors have called to expand this term to be the neuro-glial-vascular unit, acknowledging the role of glial cells in signaling, maintenance of the microenvironment, and waste clearance.³³

Current data indicate that consistent physical exercise and adequate sleep induce physiologic or metabolic processes that promote brain health and protect the brain from damage. Many studies observe better cognitive function in individuals who engage in physical exercise.⁴⁰ There are several hypotheses regarding the putative mechanisms and research is still largely limited to experimental models. Physical exercise likely exerts its effect directly through neurogenesis, improved mitochondrial function, improved metabolism and autophagy, decreased neuroinflammation, proliferation of astrocytes, higher myelin content, and white matter microstructural integrity.^40–42 The metabolic cascade induced by physical exercise leads to an increase in brain derived neurotrophic factor (BDNF), which has been shown to increase mitochondrial biogenesis in the brain.⁴³ Due to energetic demands, neurons are highly dependent on oxidative metabolism. It follows that impaired mitochondrial function and the reduced ability to manage reactive oxygen species are one of the mechanistic hypotheses of brain ageing. Abnormal mitochondrial function can also lead to dysregulated hippocampal neurogenesis.⁴¹ BDNF also improves autophagy by lysosomes in the brain thereby improving clearance of toxic metabolites and misfolded proteins. Exercise also increases levels of insulin growth-like factor-1 (IGF-1) which improves neuron insulin sensitivity and, consequently, intraneuronal metabolism.⁴⁴ Impaired neuronal insulin signaling in the brain is one possible driving mechanism of neurodegenerative diseases like Alzheimer’s disease.⁴⁵

Evidence is also growing for the importance of sleep for maintaining brain health and resisting damage. Consistent lack of sleep (e.g., insomnia) or poor-quality sleep (i.e., untreated obstructive sleep apnea) particularly in midlife are closely linked with cognitive decline and dementia.^46,47 Like exercise, most research regarding the mechanisms of sleep quality and quantity on the function and health of the brain were conducted in experimental models. The dominant way by which sleep impacts brain health and metabolism is likely through clearance of metabolic waste.⁴⁸ How the brain clears metabolic waste has been a major area of study in the last two decades. A major mechanism of clearance is via the glymphatic system, which is a perivascular conduit for cerebrospinal fluid flow through the brain parenchyma and into the dural venous sinuses.⁴⁹ The glymphatic system is much more active during sleep (particularly slow wave sleep) than wake time.⁵⁰ Several studies observe increased clearance of toxic proteins like amyloid beta, hyperphosphorylated tau, and alpha synuclein during sleep and elevations of those proteins during periods of short sleep or disrupted sleep.^39,48,50 Radiographic studies observe that disrupted sleep leads to increased deposition of amyloid beta in the hippocampus and thalamus.³⁹ Enhanced function or dysfunction of the glymphatic system likely link known protective factors or risk factors to brain health. Physical exercise also increases the glymphatic flow.⁵¹ Small vessel disease and traumatic brain injury may disrupt the architecture necessary (i.e., organization of astrocyte foot processes) for efficient glymphatic system function and thus impaired waste clearance may be a key mechanism linking these known epidemiologic risk factors with cognitive impairment and dementia.^15,50 Dysfunction of the glymphatic system may in part drive the link between diabetes and dementia.⁵² Aside from increased activity of the glymphatic system, adequate sleep and a normal circadian rhythm are related to normal mitochondrial function, which is foundational for normal neuron function and repair.⁵³ Overall, available evidence shows that targeted and multi-modal life style and cerebrovascular risk factor modifications can boost resistance to damage and promote repair. The Systolic Blood Pressure Intervention Trial-Memory and Cognition in Decreased Hypertension (SPRINT-MIND) trial demonstrated that blood pressure control in midlife decreases incidence of cognitive impairment and dementia.⁵⁴ The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study also provides randomized control trial evidence that a lifestyle program involving regular exercise, cognitive training and a diet high in fruits, vegetables, grains and fish leads to maintenance—and even improvement in some domains—of cognitive function over the long term.⁵⁵ Currently, this study is being replicated at multiple sites worldwide.⁵⁶ In addition, as presented in Table 1, population-wide policies can advance brain health by promoting factors such as physical activity and sleep hygiene which are known to boost brain resistance and repair.

Table 1.

Proposed life-course population-wide strategies to promote brain health

Life-stage	Population-wide interventions
Fetal/perinatal	- Monitoring for maternal mental and nutritional needs throughout pregnancy - Global access to prenatal care and safe delivery - Protected parental leave after delivery
Childhood and adolescence	- Early childhood neurodevelopmental, cognitive and language screening - Secure a global access to formal education in childhood and adolescence - Concussion prevention programs integrated into school educational activities - Regulating social media and digital ecosystems to safeguard adolescents’ mental health
Young adulthood/midlife	- Screening for cerebrovascular risk factors (e.g., hypertension, diabetes, hyperlipidemia) from early adulthood - Legislations and incentives to encourage employers to adjust work schedules to ensure all their workers have time to get enough sleep.
Older age	- Screening for early signs of sensory impairment including hearing loss and vision changes - Public health campaigns to increase awareness about maintaining physical and cognitive activities in older age
Lifespan	- Elimination of poverty and providing affordable healthcare systems and insurance coverage - Improving access to primary health care particularly in underserved regions - Promote the designs of healthy cities and urban structures to promote mobility and physical activity - Addressing global environmental changes and air pollution

What can be done to boost resilience despite brain damage?

We define resilience as maintenance of good brain function despite clinical or subclinical damage. Resilience is a phenomenon that clinicians face frequently in practice, but the specific mechanisms of resilience are far less defined. A familiar example is older patients who have moderate to severe degree of cerebral small vessel disease as well as atrophy on MRI, but they have preserved cognitive function and can live independently despite such structural brain changes. Current hypotheses and studies center on the connectivity of the brain or the connectome. Studies using functional imaging and neurophysiology techniques observe that over the life course, the human brain has less connectivity within networks and greater connectivity between networks, and this changing connectivity is thought to maintain cognitive function and is a normal adaptation.⁵⁷ The ability of the brain to adapt its connections may be influenced by the degree of proper cortical network structure and connectivity in early life. Early trauma and disrupted attachment may affect this early network connectivity and, thus, later network adaptability.⁵⁸ Neuroplasticity is another way to conceptualise the brain’s adaptability. Allostatic load—i.e., the rapid or overwhelming accumulation of stressors—impairs neuroplasticity and neurogenesis likely through epigenetic mechanisms.¹⁷ Rapid overwhelm of allostasis to allostatic load and altered neurogenesis and plasticity may explain the epidemiologic observation that children from families with low socioeconomic status or disadvantaged neighborhoods have lower brain volumes and higher risk of dementia.^59,60 Other studies have looked at changes in network connectivity in diseased versus normal brains. Having multiple vascular risk factors is associated with a loss of long axonal fibers in the white matter and decreased network efficiency.⁶¹ Thus, the ability to maintain connectivity between networks may protect the brain despite damage and a loss of connectivity may be mechanism by which several risk factors damage brain health. Preserved connectivity—i.e., fewer life course insults (in particular, during the brain development) to prevent damage to neuronal network connectivity—as a resilience mechanism is illustrated in a recent study of cognitive outcomes for patients with mild traumatic brain injury. Patients who had fewer risk factors for poor brain function or dementia pre-injury had better cognitive outcomes one year later.⁶² Another related concept is ‘cognitive reserve’ which is a general model for the observed association between greater educational attainment in early life and a lower risk of dementia in later life.^21,26 Similarly, cognitive training and engagement in social activities can potentially promote brain network connectivity and activation as strategies to boost brain resilience.²⁰ Recent post-mortem pathology data shows that across birth cohorts over 25 years the degree of brain neurodegenerative changes have remained unchanged despite a decrease in burden of dementia. The same cohort had a decrease in burden of brain vessel pathologies indicating that the observed improvement in clinical dementia is likely due to improved resilience to such neurodegeneration injuries with improved brain vascular health.⁶³ Figure 3 reviews the concept of brain resilience in the framework of brain network function and demonstrates strategies that can influence brain resilience over the life course. Avoidance of early life adverse events and providing a nurturing care, enriched childhood living environment and vascular health from young adulthood can contribute to boosting and maintaining brain network function, underscoring the importance of life-span interventions.⁶⁴

Figure 3.

The brain connectivity as a proxy for brain resilence. Adverse events in early life, lack of formal education and deprevied living enviroment and exposure to cerebrovascular risk factors can prevent the brain from reaching its maximum network capacity. Addressing those factors will boost the brain connectome and changes the baseline functional levels and the slope of decline overtime. The figure was created by BioRender.

Preventive versus disease-based approach in brain health

The two main strategies for primary prevention of neurological conditions include population-wide approaches and high-risk group approaches. The so-called high-risk approach puts emphasis on recognition of high-risk individuals by healthcare professionals and implementing interventions that aim to address each risk factor separately. Addressing elevated blood pressure, treating depression and anxiety, treating sleep apnea, and improving glycemic control in a patient with diabetes are some examples of this approach. Population-wide interventions, on the other hand, aim to lower the average levels of exposures to risk factors, and thereby lower the incidence of a disease in the whole population.^4,65 High-risk group interventions are effective measures and can cut the risk of developing an adverse outcome in individuals. Examples related to brain health include early diagnosis and treatment of TIA, minor TBI and MCI. While the role of high-risk interventions is well-established, the magnitude of their impacts can be limited as the available evidence suggests that a significant portion of chronic medical conditions arise from individuals at low risk or those who were not identified as high-risk groups earlier.⁶⁵ In this setting, population-wide interventions are necessary to change the average duration of exposure to causal risk factors throughout the population. The combination of both approaches is shown to lead to higher benefits.⁶⁶ For instance, an epidemiologic modeling suggests that a high-risk approach alone can reduce the risk of stroke about 11%, but when combined with motivational mass prevention strategy via eHealth technologies, they can lead to primary stroke prevention in up to 50% of events.²⁷ Despite higher magnitude of impacts, population-wide interventions are difficult to design, slow to implement, and challenging to implement and evaluate given that they require major nationwide policy changes and lifestyle modifications. Over the last decades and with further medicalization of the primary prevention, the focus of primary preventive approaches has shifted to high-risk group detection and initiation of pharmacological treatments. The impact of this high-risk approach, which usually starts in late middle adulthood, might be limited if it is not combined with population-wide strategies that include younger adults. Preventive care ideas, such as brain health service clinics, are of importance to address the clinical demands from at risk but neurologically intact individuals concerned about their risk of dementia and other neurological conditions.⁶⁷ Recent advancement in developing a disease modifying treatment for mild cognitive impairment and dementia, Iecanemab, highlights the importance of such high-risk approaches.⁶⁸ With a rapidly growing older population, a high-risk approach is likely limited in its ability to impact the epidemic of unhealthy brain ageing at a wide scale, hence, major resources need to be directed towards activities that target a larger portion of the population.

Current and Future Directions

Over the last years, several international health and neurologic associations have identified brain health as a critical area for clinical work, research, and policy. In 2017, the American Heart Association (AHA) published a position statement on brain health. AHA emphasized a life course approach, acknowledging that the brain can slowly and usually silently accumulate damage over the life span before clinically manifesting compromised function.²² In 2022, the European Academy of Neurology published its “Brain Health Strategy”. This strategy outlines individual factors contributing to brain health, while also explicitly including the role of population level interventions to promote and protect brain health. These policies include education, environmental health, and social conditions.⁶⁹ Other organizations like the World Federation of Neurology and the American Academy of Neurology have published editorials and statements on the need to shift focus to brain health.^70,71 Universally, each organization observes that most brain health research has been on factors at the individual level (i.e., blood pressure, smoking) and less has been on population-wide factors like physical environment, social and psychological factors.

Understanding brain ageing is of major importance in defining and addressing brain health. In this paper, we highlighted that ageing is a fundamental driver of brain health and factors that influence brain ageing can serve as targets in maintaining brain health. Strategies that can change the presence, frequency and course of cerebrovascular risk exposure, for instance, are essential to slow the pace of biological damage build up in the brain, and protect it from reaching an irreversible stage when biological derangements have been already translated to impaired function. While a high-risk approach is necessary to address brain health at individual levels, the age-appropriate population-wide interventions have the highest impact to promote the brain for successful ageing from early childhood and protect its structural and functional integrity throughout the life course. Table 1 proposes population-wide interventions to promote brain health at each stage of life in the framework of World Health Organization (WHO) guidance on brain health optimization with focus on physical health, healthy environments, safety and security, learning and social connection, and access to quality services.⁷² While the proposed items are all important in safeguarding brain health throughout life course, it is unclear how much each item will contribute in brain health of the population. Future comprehensive studies are needed to quantify the effect estimates for individual interventions to be able to set national and international priorities and allocate resources in areas with the highest impact.

While there have been great efforts to advocate for brain health, the concept is still evolving. Currently a global and easily-assessed measure of brain health is not available. This mainly stems from the fact that major gaps in our knowledge about determinants and features of brain health exist. Public health, clinical and translational studies, in diverse populations, are all needed to develop a better understanding of factors contributing to deviation from brain health to brain diseases.

Search Strategy.

This narrative literature review was conducted using PubMed on English language literature published between 2002 to 2023. Initial search terms were outlined based on the collective specialty expertise of this author panel (neurology, vascular neurology, preventive medicine, epidemiology, and public health).

For background, our first search was to describe epidemiology and modifiable risk factors for dementia and stroke, two neurologic diseases of high prevalence, morbidity and mortality. Dementia AND stroke AND incidence (182 results) for which titles and abstracts were reviewed for relevance. Related searches were Alzheimer’s disease AND incidence (731 results). Subsequently, search was done for modifiable risk factors iteratively searching Dementia AND stroke AND Risk Factors (660 results), Alzheimer’s disease AND risk factors and prevention & control (506 results). Following review of epidemiology, we reviewed basic science of ageing and mechanisms of neurodegenerative disease. Searches included: dementia AND aging AND physiological stress (352 results), dementia AND aging AND inflammation (186 results), allostasis AND dementia (8 results), epigenomics AND aging AND neurodegenerative disease (20 results), sleep AND dementia AND aging (241 results), glymphatic system AND dementia (80 results), brain reserve and dementia (280 results), exercise AND dementia AND aging (499 results). For interventions, we searched health promotion AND dementia (236 results), health policy and dementia (447 results), primary prevention AND dementia (441 results). Finally, as the term ‘brain health’ is a new concept to both research and clinical work, this was a keyword search. To review current work, research and thought leadership in this area, the following searches were done: “brain health” AND “cognitive reserve” (67 results), brain health AND longitudinal studies (245 results), brain health and primary prevention (31 results).