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Journal of Alzheimer’s Disease 42 (2014) 1151–1163 DOI 10.3233/JAD-140213 IOS Press

Hypothesis

Adapting to Dementia in Society: A Challenge for Our Lifetimes and a Charge for Public Health Simon D’Altona,∗ , Sally Hunterb , Peter Whitehousec , Carol Brayneb and Daniel Georged a Center

for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL, USA b Department of Public Health and Primary Care, Institute of Public Health, Forvie Site, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK c Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH, USA d Department of Humanities, Penn State Milton S Hershey Medical Center, Penn State College of Medicine, Hershey, PA, USA

Accepted 2 May 2014

Abstract. For the last several decades, Alzheimer’s disease (AD) has been widely regarded as a late life event, but is now being redefined as a chronic condition that develops over decades. Concurrently, a preponderance of evidence emerging from basic and clinical research in diverse fields such as cardiovascular, endocrine, and mental health has suggested that the environmental component of clinical AD is not only multifactorial in populations and in individuals, but is also modifiable across the lifecourse, from conception until death. Re-conceptualizing the environmental component of AD to account for these observations necessitates an approach to brain health that eschews singular, short- and medium-term methodology and instead reflects longterm complexity. Such thinking is consistent with the ecological models of public health, which emphasize the development of community infrastructure that can foster population and individual health over the life-course by minimizing risk through multifaceted, systemic approaches. Keywords: Alzheimer’s disease, amyloid, dementia, epidemiology, public heath, risk factors, social policy

INTRODUCTION The progression that humanity has made toward greater longevity over the last century is a testament to many civil improvements in urban infrastructure, public healthcare, protective social policies, and medical science. In an isolated few instances, such as immunizations for lethal viral or bacterial ∗ Correspondence

to: Simon D’Alton, Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, 1275 Center Drive, University of Florida, Gainesville, FL32610, USA. Tel.: +1 352 294 5160; Fax: +1 352 294 5060; E-mail: [email protected].

infection, science has produced a protective solution. However, in the cases of modern chronic and non-transmittable illnesses—the so-called “diseases of civilization”—our bodily dysfunction remains resistant to curative treatments. Furthermore, variable sociocultural-environmental influences such as diet, exercise, built environments, and other factors heavily influence the prevalence of such conditions. While the detrimental effects of poor lifelong diet and physical activity patterns on the cardiovascular and endocrine systems is now a medical truism, it is increasingly clear that less intuitive connections may also exist, such as that between obesity or dia-

ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

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betes and many forms of cancer [1–5]. There is now a growing body of epidemiological evidence and in vivo animal studies to suggest that these late-life disorders are impacted by early-life experience, including in utero development and childhood [6–14]. Given these emergent signals from research, such age-associated conditions have increasingly been viewed through the broad prism of public health [15]. Generally, the modifiable nature of chronic disease is espoused by physicians, and public and private organizations are invested in health education and outreach campaigns to highlight the benefits of regular exercise and a healthy and balanced diet. These initiatives target people across the life-course, and complement research in molecular biology aimed at producing pharmacological interventions. Governments and their policies, not to mention international, national, regional, and local history, belief, and practice shape the way cultures approach the treatment of chronic disease. Closely linked with the rise of chronic disorders is the emergence of complex, age-related neurodegenerative conditions that result in cognitive decline in old age. In contrast with the chronic conditions mentioned above, attempts to promote a risk-reducing lifestyle within supportive physical and natural environments to reduce the incidence of Alzheimer’s disease (AD) have been more restrained, as demonstrated by the absence of any such recommendations in the recent ‘National Plan’ in the United States [16]. Unlike other chronic conditions, AD is not widely accepted as modifiable [17], nor has it been unequivocally viewed as a condition that can be ameliorated by public health approaches. Instead, since the late 20th century, a molecular paradigm has dominated the field and shaped the way the condition is classified, studied, and culturally perceived. The cynosure of AD research has been the amyloid cascade hypothesis, which posits that the toxic aggregation of amyloid-␤ (A␤) is responsible for a cascade of detrimental molecular events leading to tau neurofibrillary tangle formation, synaptic failure, and progressive dementia [18–20]. Pharmacological efforts have largely attempted to reduce the levels of aggregated A␤ species, but unfortunately have not met with success to date. These disappointing results have been interpreted as a failure to intervene early enough, and at present, there are multiple presymptomatic prevention trials taking place to address this. As part of the “Alzheimer’s Prevention Initiative”, researchers are conducting a $100 million study with an extended family of 5,000 people living in the mountains around Medell´in, Columbia, one-third of whom carry a rare genetic predisposition to young-onset AD. The goal

is to administer crenezumab to asymptomatic participants between ages 30–60, and evaluate whether it prevents progression along the continuum of cognitive decline [21]. Meanwhile, a similar approach is being taken with solanezumab, which, while having failed to reverse symptoms in people with dementia in 2013, demonstrated some cognitive benefits for a subgroup with mild memory loss [22]. This antibody is being used in both individuals with familial AD (in the Dominantly Inherited Alzheimer Network Trial Unit) and intellectually ‘normal’ at-risk people (in the “A4” study). While it is hoped that these and other pharmacological approaches will ultimately produce tangible benefits to society, it is evident that AD is not as amenable to current molecular biological approaches as was once hoped, and that alternative approaches will also be required. Historically, these approaches have not included an emphasis on environmental contributions to AD, principally due to the inconclusive nature of epidemiological studies and intervention trials targeting environmental risk factors. However, there is now an abundance of epidemiological, biochemical, and neuropathological evidence supporting the notion that that the environmental component of AD is composed of multiple, modifiable factors acting across the life-course. Importantly, this emerging paradigm points strongly to the implication that multi-faceted public health initiatives to promote biopsychosocially healthy lives could reduce AD risk and, in combination with future pharmaceutical approaches, improve quality of life in aging populations. This article will endeavor to introduce a new conceptual model for AD that is informed by the broad ecological framework of public health, and unpack some of the practical and policy implications stemming from the growing body of evidence regarding the multifactorality of AD at the individual and population level.

GENETIC AND EPIDEMIOLOGICAL STUDIES REVEAL MUCH ABOUT ENVIRONMENTAL INFLUENCE ON COGNITIVE HEALTH Quantitation of risk contribution from genetic and environmental components of AD is often the aim of twin studies. Concordance rates in mono- and dizygotic twins conclusively demonstrate that genes affect the clinical outcome of AD, with studies estimating a heritability of liability of approximately 60% [23–25].

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These results support what is already highly intuitive: although a non-modifiable genetic contribution that influences clinical outcome is present from birth, AD is similar to other chronic conditions in that there is a malleable environmental input that may be altered to reduce total risk. An evidence-based example of this is found in ApoE4 positive individuals who, by remaining cognitively or physically active, may eliminate some of the additional risk derived from this allele [26–29]. It seems clear that long-term health is not merely determined by our genes, and we can partly define our cognitive health by modifying the environment. Epidemiological studies of this environmental component of clinical AD provide persuasive evidence that numerous, modifiable factors exist that can promote the development and maintenance of healthy brains, or contribute to neurodegeneration. The former category is principally the realm of what has been dubbed “cognitive and brain reserve”, a construct used to explain the apparently contradictory phenomenon that some individuals may present with a high burden of neuropathology but experience little clinical dementia. There are a range of inputs that may fall under the umbrella of ‘acquired reserve’ including larger brain size (which is itself comprised of genetic and environmental determinants) [30–33], years of formal education [34–36], a sense of purpose in life [37, 38], social engagement [39–44], and occupational complexity (reviewed in [45]). Meta-analyses of epidemiological studies further provide powerful evidence that numerous environmental/behavioral factors increase the relative risk of clinical AD by significant amounts [46–48]. Such factors include: midlife hypertension, obesity, diabetes, smoking, and physical inactivity, while psychosocial stress [49] and a late-life ‘hypoperfusive profile’ consisting of chronic heart failure and hypotension are more epidemiologically debatable [50, 51]. In concert, several of these factors are predictors of late-life dementia when present in midlife cohorts [52]. While many of these factors are correlated with clinical AD, fewer studies have attempted clinicopathological correlations, raising questions as to their true significance in the pathogenesis of AD.

NARROW BIOMEDICAL CLASSIFICATION OF AD STIFLES PROGRESS IN PUBLIC HEALTH APPROACHES Clinico-pathological studies have shown that the vast majority of individuals with any form of dementia

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have multiple, mixed pathologies [53, 54]. This heterogeneity presents a unique challenge for clinical and molecular science, as it prevents the simple categorization of individuals into singular neuropathologically confirmed diseases with simple linear mechanisms. This complexity is well chronicled in clinical AD, which is neuropathologically heterogeneous. It is now the rule rather than the exception to find concomitant pathologies such as hippocampal sclerosis, Lewy bodies, inclusions of TAR DNA binding protein of 43kDa (TDP-43), and vascular lesions, in addition to the classic A␤ plaque and neurofibrillary tangle pathology [55–59]. All of these pathological phenomena have been independently linked to neurodegeneration and neurological dysfunction. Indeed, as both vascular pathology and hippocampal sclerosis can generate the functional deficits commonly associated with plaques and tangles, A␤ and tau do not produce a unique AD symptomology [60–64]. Given the preponderance of vascular lesions and hippocampal sclerosis in AD, it seems reasonable to conclude that these lesions contribute to the difficulty in predicting underlying neuropathology in clinical AD and to the poor rate of concordance between clinical AD and plaque and tangle pathology [65]. Clearly, there are multiple pathways to neurodegeneration in individuals clinically diagnosed with AD, and these overlap frequently. Similarly, the classic neuropathological diagnosis of AD (i.e., the presence of plaques and tangles) is clinically heterogeneous. Although the cardinal clinical feature of AD is memory impairment, a primary neuropathological diagnosis of AD is frequently made in other syndromes such as posterior cortical atrophy and primary progressive aphasia [66, 67]. Furthermore, although AD is described as a slow, predictable decline in cognition [68, 69], the rate of conversion from preceding minor cognitive impairment phase to AD has yet to bear this out [70]. These observations demonstrate that AD is not explicitly definable as a singular entity, but rather is a catch-all term for a variety of pathologies and clinical manifestations occurring on a number of different trajectories. If the choice were made to label individuals with ‘Alzheimer’s disease’ only explicitly if they conformed to a narrow clinical phenotype purely involving mechanisms related to A␤ and tau, this would substantially reduce the prevalence of AD. Although there may be a connection between A␤- and tau-related pathologies, neurological dysfunction and memory impairment, this is not the same as saying that plaques and tangles are the sine qua non of AD. The borders delineating supposed singular categories have become blurred and inconsistent, perhaps

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rendering the application of distinct disease labels to populations and individuals an oversimplification. Adhering to the hitherto narrow biomedical definition of AD may have the unintended consequence of damaging public health. From a therapeutic standpoint, it suggests that all clinical AD can be effectively treated pharmacologically by focusing on pathways that converge on A␤, leaving a significant proportion of AD phenotype due to non-plaque and tangle pathology (e.g., vascular damage) untreated. Secondly, it may stifle the process of applying public health measures to reducing risk factors for AD. For instance, the notion that diabetes is not a risk factor for AD because it increases vascular pathology rather than traditional A␤ plaque pathology potentially discourages conversation regarding public health approaches and AD [71]. Similarly, individuals such as military servicemen exposed to head trauma are labeled with an entirely separate entity called chronic traumatic encephalopathy (CTE), even though CTE also results in increased abundance of A␤ plaques and tau tangles, and increased risk of clinical AD [72]. These examples demonstrate how the paradigmatic focus on creating clear-cut classificatory boundaries between the dementias can forestall conversation about commonsense preventive actions that might reduce risk for ‘AD’. Given the available evidence, choosing to link a narrow clinical term with the abundance of only one avenue of neurodegeneration is no longer an accurate reflection of the heterogeneity and complexity of ‘AD’, and mainly reflects historical convention and fealty to the dominant paradigmatic understandings rather than accumulated scientific progress.

ENVIRONMENTAL/BEHAVIORAL RISK FACTORS ARE SUPPORTED BY EPIDEMIOLOGICAL, NEUROPATHOLOGICAL, AND MOLECULAR EVIDENCE The neuropathology underlying clinical AD strongly supports a role for the cardiovascular risk factors mentioned above. Vascular pathology, which takes shape in the form of large infarcts, microinfarcts, lacunes, hemorrhages, atherosclerosis, arteriolosclerosis and cerebral amyloid angiopathy increases with age and is highly prevalent in neurodegenerative disease, but particularly in AD, where it contributes to clinical phenotype [55, 73–78]. Vascular abnormalities are driven by a combination of environmental risk factors that overlap with AD. Unequivocally, epidemiological

and supporting neuropathological evidence proves that the risk of manifesting AD symptomology is increased by these malleable risk factors that are heavily determined by physical activity and nutrition. A more contentious issue is: to what extent do modifiable factors relating to general health influence the dynamics of A␤ accumulation? Although the amyloid cascade hypothesis has attracted criticism—particularly in recent years following the consistent failure of anti-amyloid therapeutics—there is evidence that aggregated A␤ represents one source of neuronal toxicity in individuals with clinical AD. There is certainly a wealth of in vitro and in vivo data suggesting that conditions resulting from environmental insults such as hypoxia, metabolic disturbances, consequent oxidative stress, physical damage and chronic exposure to stress-related hormones cause alterations in A␤ processing [79–93]. Extrapolating these findings to the formation of human A␤ pathology is much harder. Although the endophenotypes that would be used as in situ evidence such as reduced brain perfusion, metabolic decline, and dysfunction of the stress pathways such as the hypothalamic-pituitary-adrenal axis all exist in AD, it is unclear whether these observations are causes or consequences of neuronal death or both [94–100]. It is possible that they are intertwined to such an extent that they are inseparable in human studies. However, it is unlikely that the rate of generation of A␤ is purely genetic, particularly in an age-related condition in which environmental factors and not an individual’s genetics change with time. Given their prevalence in the aged brain, and the in vitro and in vivo evidence for their ability to modulate A␤ metabolism, it is probable that environmental factors do play a role in highly complex amyloid-␤ protein precursor processing (A␤PP) and the rate of A␤ generation. Although in many instances the molecular pathways from external factor to A␤ have not been clearly delineated, A␤PP proteolysis is modulated by a multitude of molecular pathways which may be responsive individually or collectively as part of a coordinated, equilibrated system [101, 102]. What might be recognized, however, is that the significance of the connection between epidemiological risk and A␤ varies depending on the discipline. For the research communities that test the efficacy of either pharmaceutical or lifestyle interventions, A␤ burden may be a relevant outcome measure. However, from the vantage point of public health messaging and policy to promote the uptake of healthy activities across entire populations, the link between epidemiological risk fac-

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tors and A␤ is less important. Put otherwise, regardless of what specific lesion is consequently found, lack of physical exercise, as well as obesity, diabetes, hypertension and so forth are undeniably associated with worse brain health. We know that a measurable proportion of the clinical AD phenotype is independent of A␤ and is due to factors such as vascular damage. This raises the issue as to what cultural and social changes might be made as part of a focused, concerted effort to reduce risk factors that are an unequivocal part of AD.

RESHAPING CULTURAL BELIEFS AND PRACTICES ABOUT “ALZHEIMER’S” A key element of improving health is cultural beliefs, which are formed not just by the paradigmatic construction and classification of knowledge but also by the dominant language patterns of the time. The most effective language to mobilize a population to adopt healthier, risk-averse behavior or to change public policy that may improve brain health is coherent, simple, repetitive and consistent. As Frank Luntz, the highly successful language consultant to the Republican Party, attests: “You say it again, and you say it again, and you say it again, and you say it again, and you say it again, and then again and again and again and again, and about the time that you’re absolutely sick of saying it is about the time that your target audience has heard it for the first time” [103]. For decades, consistent, repetitive, and simple amyloidocentric, dread disease metaphors, and imagery about AD have become prevalent in our cultural scripts (e.g., ‘mind robber’ and ‘dread disease’) and have contributed to a culture of fear and stigmatization around brain aging [104–106]. Of equal concern is that this messaging has culturally diminished the notion that risk for AD dementia is in any way modifiable. More recently, progressive, humanistic messaging attempting to increase participation in healthy lifestyles (‘healthy heart, healthy brain’) or reduce stigmatization (‘person-centered care for individuals with dementia’) has been marketed alongside disease-centered messaging, creating a psychologically confusing dichotomy in which AD is both a disease for which there is no hope and yet also part of natural health. Further confusion in the media and thus the public comes in the form of a bewildering array of medical jargon and non-intuitive, overlapping terminologies (i.e., AD, mixed dementia, vascular dementia, etc.) that are conventionally treated as distinct cate-

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gories. This is partly a reflection of the heterogeneity of AD. However, as long as AD continues to be treated in a strictly amyloidocentric manner, there is the danger that truly effective public relations efforts to increase engagement in healthier lives will be postponed. Given the current epidemiological data, which overwhelmingly demonstrates that lifelong active lifestyle is associated with reduced risk of clinical AD, it would seem that an opportunity to improve brain health is not being fully realized. If healthier brains are truly the goal, a coherent, simple, repetitive and consistent message of modifiability may help to foster cultural norms and practices that can engender healthier bodies and brains. Clearly, the genetic component of brain degeneration and the inability to forestall environmental changes in the brain forever guarantee that there will always be some cognitive decline in old age. Promising complete prevention to the public is also neither an intellectually honest nor an ethical act. However, current cultural scripts about AD are likewise unreflective of the heterogeneity of brain aging, and may actively preempt efficacious public health approaches. It is perhaps na¨ıve to surmise that the AD label will be fully discarded in the near future since it is so firmly entrenched in our cultural lexicon. However, it is possible that by unsettling the meaning of ‘AD’ and promoting a dynamic and scientifically accurate biopsychosocial public understanding of brain aging that is neither reductive nor fear-inducing, progress could be made towards encouraging healthier lives.

AD IS DIFFERENT FOR EVERYONE: THE PROBLEM OF MULTIFACTORALITY Fixating on the potential role of a single, individual genetic or environmental factor in the etiology of AD can often result in focusing on equally ‘singular’ causes of AD, for example, hypoperfusion [107] or type 3 diabetes [108]. However, the environmental component of AD is multifactorial at the population level, as epidemiological studies have attested. This population-level heterogeneity means that there is no ‘one-type-fitsall’ method that can be targeted throughout the entire population. Advocates of these environmentally-based factors would logically suggest that only the unique population affected (e.g., hypertensive or diabetic individuals) be included in treatment plans. While this is perhaps more likely to yield success from a therapeutic standpoint, it would only do so for a subgroup of individuals, and probably only if they could be identified early. However, even in the event of a hypothetical

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success in treatment, would lowering the number of smokers reduce the ‘societal burden’ of AD if, for instance, the level of obesity continues to rise and thereby offset this achievement? More importantly, the environmental component of AD is multifactorial in every single person, and is different for everyone. In consideration of this, it is perhaps illuminating to first draw comparisons with the genetic component of AD, in which massive Genome Wide Association Studies (GWAS) have been instrumental in identifying risk alleles in the general population. Effective collaborative work in this field involving consortiums pooling massive amounts of data into hugely powerful studies is unveiling the heritable component of AD [109, 110]. With the exception of the aforementioned ApoE4 allele, the majority of GWAS hits add considerably little risk individually; yet, in combination, their sum effect is powerful in individuals and in populations and, in total, comprises the genetics of AD. Crucially, on an individual level, it is readily accepted that genetic risk profiles are multifactorial (i.e., polygenic) and different combinations of genes exist in each individual. By the same logic, the undeniable environmental component of AD is comprised of innumerable potentially brain-influencing agents that individually may add little risk, but which, in combination, are a powerful force. Sets of risk factors are likely to be different for each individual, just as sets of genetic risk alleles vary amongst individual people. For example, there is evidence that A␤ is increased following exposure to anesthetic agents or surgical procedures, and postoperative dementia in older people is a documented consideration in surgical practice [111–117]. Is the generally healthy elder with mild insulin insensitivity and an ‘old’ heart who is undergoing a hip replacement to be considered to have the same risk profile as the 40-something chronically hypertensive banker who smokes, or the poorly educated man who runs four times a week? What about individuals who are in generally poor vascular health, but do not meet clinical thresholds for any of the risk factors, or the war veteran or contact-sport athlete who received multiple head injuries but remains in excellent cardiovascular health? Accepting that there are likely many environmental pathways that influence cognitive health, and that the magnitude and preponderance of each will vary between individuals removes much of the mystery of the non-genetic component of AD. Combining this multifactorality with the polygenic nature of AD explains the stochastic nature of the condition—(i.e.,

why ‘some get it and some don’t’)—and also provides a framework to explain the heterogeneous nature and clinicopathological spectrum of AD, and the differing ages of onset and progression of the clinical condition amongst the population. Furthermore, it can perhaps also evoke a sense of solidarity: that we may all differ in our individual risk profiles but share a common susceptibility to brain aging that is, in part, driven by socio-cultural factors present in our shared built and natural environments. Developing a unifying ethos of collective vulnerability around our highly prized but vulnerable organ—the brain—could be used to justify increased funding for public health approaches and community education efforts, and create an impetus for local, state, and national action that actively addresses shared risk factors within modern communities.

A CHRONIC TONIC FOR AD For decades, AD has been paradigmatically viewed by many as a late-life ‘event’. Recently, however, a plethora of scientific evidence has confirmed it as another of the chronic disorders that potentially affects every human being to some degree across the life course. As a result of imaging compounds such a Pittsburgh compound B and Florbetapir, it has been demonstrated that A␤ fibril formation occurs decades prior to the onset of symptoms, and A␤ deposition has been detected in individuals in their 20s [118, 119]. As mentioned above, this evidence has suggested that tardy delivery of therapeutics aimed at A␤ is a potential reason for their failure in recent clinical trials, and has refocused researchers earlier in the life-course toward prodromal and presymptomatic individuals [120]. Imaging and cerebrospinal fluid biomarkers are being tested for their potential to diagnose individuals earlier in the life-course, and are presently changing the nomenclature for AD to place individuals along a spectrum of disease: presymptomatic AD, mild cognitive impairment, and AD (e.g., [121]). In addition to shifting the clinical trials ‘upstream’ to target asymptomatic individuals, researchers openly discuss the possibility of pharmacological management of A␤ metabolism throughout the life-course [122]. In parallel with these biomedical-based efforts, an almost identical refocusing has occurred in non-pharmacological paradigms. Historically, interventions using physical exercise, diet, cognitive activity, and so forth have resulted in inconsistent outcomes when deployed as singular interventions for older people. Citing again that these approaches are

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being employed too late in the disease process, work in this area has also moved upstream, and there are numerous trials being performed in cohorts of older people before any cognitive impairment [123, 124]. In acknowledgment of the multifactorality of the AD environmental component, some of these trials are also multidomain in nature, encompassing cardiovascular, cognitive, and social domains. This shift in approach raises the question of how far we might travel upstream in the life-course in our paradigmatic thinking about this chronic condition. From our perspective, it should invite further scientific and lay discussion of the consideration of how environmental factors affect the brain throughout life. Obesity, altered insulin sensitivity and cardiovascular factors are all modified by our experiences in utero, in childhood and beyond [6–10, 12, 13], and indeed our populations are entering a period in history in which we are seeing alarming rates of the relatively young developing these traditionally ‘age-associated’ chronic conditions. The quality of and access to education and healthcare resources is of deep concern to parents (and grandparents) who care passionately about the future of their children (and grandchildren). The natural extension of the logic guiding these multidomain interventions that are targeting cohorts earlier in the lifespan is to emphasize and create socially, physically, and cognitively stimulating environments in childhood and young adulthood and foster healthy prenatal environments. Indeed, there is already epidemiological evidence linking late-life cognitive function to our earliest experiences in the womb [125]. Thus, the prospect of “fixing” AD may not be achieved with any single intervention adopted temporarily or at end junctures of life. A complex, multifactorial, chronic condition like AD may require an equally ‘chronic tonic’. In other words, it may require societal policies and infrastructural investments that promote lifelong learning, enhanced educational opportunities for children and adults, more salutary built and natural environments, the establishment of patterns of lifelong healthy eating and exercise, greater social connectivity and cohesiveness, and the evolution of pharmacological and non-pharmacological caregiving approaches to help those who are more severely affected by brain changes that occur in later life. Relying on singular approaches in midlife or old age will always place a ceiling on the success of a given intervention. However, as evidenced by the heterogeneity of environmental risk factors and the chronic nature of AD, multiple approaches undertaken in combination and over long time periods, beginning early in life, will maximize

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one’s chances of avoiding insults to the brain and lowering susceptibility to the decrements of old age. Cognitive health, or factors that affect cognitive health in the elderly, are influenced throughout life; brain health does not begin at age 60, or at any other arbitrary starting point.

AD GETS AN MPH Faced with the looming crisis of a ‘silver tsunami’ as modern populations age, the World Health Organization has recently joined with Alzheimer’s Disease International to declare AD a “public health priority” [126]. Although this certainly brings immediacy to the current climate, it may also prompt us to ask not just how AD affects the public’s health, but how the public health field can affect AD. Making life-long changes to health is a complex challenge for a number of biological, behavioral, psychological, political, and economic reasons. For example, simple interventions to promote healthier lives through dietary education are likely to fail due to barriers that are economic (e.g., healthy foods are expensive), cultural (e.g., junk food advertising), biological (sugary, salty, and fatty foods are potentially more palatable and addictive), and structural (poor, economically disadvantaged, or badly structured neighborhoods can discourage exercise, play, and social interaction). To reflect this complexity, public health often employs ecological models that operate at individual, local, and broader cultural levels to minimize risk environments and positively reinforce salutary habits through many layered approaches [127]. Such methodology can mirror the high environmental complexity of AD, countering a complex population level and individual problem with an equally complex ‘chronic tonic’. Investing in safe walkable cities and play areas, modifying work environments to encourage less sedentary daily behavior, and improving sustained access to healthy foods across the socioeconomic spectrum benefits society as a whole and over long time frames. Given the robust evidence of its protective properties, education is itself a public health measure that could be tapped into by increasing access to stimulating learning environments for the young, the old and everyone in between, whether via provision of quality teachers or financial aid, university partnerships with nearby high schools or independent and assisted living communities, or online sharing of educational resources. Further, it has been established that such

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variables as social engagement, social connections, having a sense of purpose, and other interpersonal, community-based activities are, to some degree, cognitively protective for older people. Such a multifaceted approach moves away from the idea that cardiovascular fitness, highly simplistic ‘brain training games’ and so forth are sole interventions to be employed to singularly ‘stop AD’, and toward the notion that facilitating the creation of a physically healthier, cognitively stimulating, better society will have the additional, beneficial outcome of reduced incidence of AD and disease in general [128]. Such communities, bound by the recognition of shared vulnerability to brain aging, might also extend more compassion to the cognitively aged, and regard them with greater dignity, enabling older adults to remain purposefully interwoven into society rather than annexed in assisted living institutions with stigmatizing disease labels. Rather than being cultural shorthand for the fear, terror, and despair people feel about the aging process, finding solutions to “AD” could become a catalyst for improving many aspects of society. Combinations of these public health-oriented concepts are already operating synergistically in local communities around the world. One example is The Intergenerational School in Cleveland, Ohio, a public charter school in which elementary-aged children build relationships with elders who have been clinically diagnosed with dementia through reading together and making shared visits to cultural sites (i.e., art museums, nature centers, etc.), combining an educational environment with one that fosters greater social cohesiveness and protective social networks [129]. The model of the school is being replicated at other sites and in other countries, and similar learning environments forging intergenerational relationships are appearing more prevalently in many cultural settings [130, 131].

condition of aging can focus public and scientific attention upstream in the life-course. It is noticeable that medication and surgical techniques have improved greatly in the management and reduction in mortality of AD risk factors, although few if any can claim to be truly reversible. Thus, not only are our youngest generations accruing risk factors at earlier ages, but our brains are also being burdened by risk factors for longer periods as we age. These observations suggest that the instigation of multiple public health approaches that have impact on various risk factors throughout the lifespan may reduce the risk and progression of AD, but will perhaps only be successful if initiated as a part of a pattern of behavior over long time periods. In sum, AD is not just an issue for the times we live in, but is literally a challenge for each of our individual lifetimes. Although a challenge of immense proportions, it is no more so than the tremendous technical and economic difficulties that molecular biology is pressing hard to overcome. Adjusting paradigms to support a strong, integrated society that seeks and funds creative methods to promote physical and mental wellbeing of all may be a powerful approach to combating AD and enhancing quality of life in both the young and old. DISCLOSURE STATEMENT Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2322). REFERENCES [1]

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CONCLUSION For the last two decades, a predominantly molecular biological paradigm focused on a pharmaceutical approach to AD has instigated vast cultural changes in the perception of AD. Now, there is abundant evidence suggesting that the health of the brain is at least partially dependent on the rest of the body, interpersonal connections, and social structure. This evidence suggests that the environment’s contribution to AD risk is comprised of multiple factors, which are likely present to different degrees in different individuals. Furthermore, the reconceptualization of AD as a chronic

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