DOSE: a lifestyle philosophy for dementia prevention informed by drug development and epidemiology

DOSE: uma filosofia de estilo de vida para a prevenção da demência informada pelo desenvolvimento de medicamentos e pela epidemiologia

ABSTRACT

This article aims to bridge the gap between drug development and lifestyle modification strategies for dementia prevention. First, it focuses on three lessons from drug development to inform lifestyle changes: dementia treatment-resistance, the importance of maximizing therapeutic dose, and obtaining actionable feedback from drug trials. Moreover, epidemiology reveals a mismatch between promising associations and later interventions, the specificity of different dementias, and the ethics of health promotion. The article will argue that lifestyle choices for dementia risk should be understood through the lens of a life philosophy rather than a testable scientific hypothesis. This philosophy known by "DOSE" has four components: Diet — Other life priorities — Stimulation — Exercise. Striking the balance between a healthy lifestyle and non-health priorities is a fundamentally personal question and challenge, particularly in resource-limited contexts. Finally, individual behaviors are only the tip of the iceberg of modifiable dementia risk, inviting collective action to ensure equitable prevention.

Keywords:
Philosophy; Dementia; Disease Prevention; Life Style; Science

RESUMO

Este artigo visa preencher a lacuna entre o desenvolvimento de medicamentos e as estratégias de modificação do estilo de vida para a prevenção da demência. Em primeiro lugar, ele se concentra em três lições do desenvolvimento de medicamentos para informar as mudanças no estilo de vida: resistência ao tratamento da demência, a importância de maximizar a dose terapêutica e a obtenção de informações acionáveis a partir de testes de medicamentos. Além disso, a epidemiologia revela um desacordo entre associações promissoras e intervenções posteriores, a especificidade de diferentes demências e a ética da promoção da saúde. O artigo argumentará que as escolhas de estilo de vida para o risco de demência devem ser entendidas pelas lentes de uma filosofia de vida em vez de uma hipótese científica testável. Essa filosofia conhecida como "DOSE" tem quatro componentes: Dieta — Outras prioridades da vida — Estimulação — Exercício. Alcançar o equilíbrio entre um estilo de vida saudável e as prioridades não relacionadas à saúde é uma questão e um desafio fundamentalmente pessoais, principalmente em contextos de recursos limitados. Finalmente, os comportamentos individuais são apenas a ponta do iceberg do risco de demência modificável, o que exige uma ação coletiva para garantir uma prevenção equitativa.

Palavras-chave:
Filosofia; Demência; Prevenção de Doenças; Estilo de Vida; Ciência

THREE LESSONS FROM DRUG DEVELOPMENT: THE TREATMENT-RESISTANCE OF DEMENTIA, THE IMPORTANCE OF THERAPEUTIC DOSE, AND GETTING FEEDBACK FROM DRUG TRIALS

Over 50 million people live with dementia worldwide, and this number may triple by 2050¹. The most common form of dementia is Alzheimer's disease, which may account for 60–70% of cases, and estimates suggest that 400 million people are on the "Alzheimer's continuum" that plots populations between a state of risk, mild cognitive decline, and actual diagnosis of Alzheimer's dementia².

Alzheimer is defined by the presence of the accumulation of brain proteins "amyloid" and "tau" which increase the risk of developing dementia, though they are not sufficient or necessary to cause it³. Nevertheless, most efforts to combat dementia have focused on targeting them⁴. The vast majority of these protein-lowering strategies, for Alzheimer's disease and other neurodegenerative diseases, have failed to improve outcomes for diagnosed or at-risk populations⁵. Nevertheless, recent drug trials with high-clearance amyloid-lowering antibodies suggest that these drugs offer a statistically significant⁶, although not clinically meaningful⁷, slowing effect on cognitive decline in patients in mild stages of cognitive decline due to Alzheimer's disease over a 12 to 18-month period. This paradoxical result — of "statistical significance" between treatment and control groups in a large trial population, with essentially unmeasurable effects at the individual level—has led to considerable debates around the relevance of these drugs and the hypotheses that motivate their testing⁸.

It is important to note the mismatch between the time course of Alzheimer's disease, which is expected to occur over a series of decades², and the relative shortness of trials that last no longer than a year and a half, even for well-funded trials of precision antibodies⁹. This incompatibility leads to at least two problems, both based on the low dose of exposure to the treatment. The first is therapeutic inadequacy, because if trials do not give the expected result, there is the possibility that longer trials with longer exposure to treatment conditions would improve outcomes¹⁰. Second, it does not give feedback on whether a small treatment effect is really due to the underlying disease course being modified in a curative or preventive way, or instead, is due to a symptomatic effect¹⁰.

In fact, getting feedback from trials — making sense of negative results — has been a major issue across clinical research into Alzheimer's, because of yet another paradox. While these randomized controlled trials (RCTs) represent the end product of years of drug development, they have historically been relatively poor tests of the theories they are based on⁵. Given the amount of failed trials, many amyloid-lowering RCTs have been akin to shooting in the dark because there are at least five questions to ask about designing the "right" trial for Alzheimer's drug development (or, conversely, about what went "wrong" in the case of failed trials): right target, right drug, right biomarkers, right participants, or right trial¹¹, or in a negative trial, "was it the wrong therapeutic target; or was there some problem with the drug; or were the right participants correctly included, etc?"⁹.

There have been calls to improve the feedback from therapeutic hypotheses of Alzheimer's during RCTs precisely because of the number of historical failed trials⁵. For all their flaws, one of the most important advantages of RCTs from the point of view of interpreting negative trial outcomes is the simplicity of their design: they involve changing one variable at a time to see what the effect is. Without these simple, one-variable tests, individual RCTs become opaque and essentially impossible to interpret due to treatment combination effects¹². If a trial works, it is impossible to establish the active mechanism or treatment ingredients; if a trial does not reach its outcomes, it is impossible to know which treatment ingredients or combinations may have been therapeutically useful or not.

These reflections on drug development lessons lead us to the next section, which deals with the issue of lifestyle changes and the need to move beyond the drug development model to maximize the impact of lifestyle modification for dementia prevention in ways that respect individual autonomy.

LIFESTYLE CHANGES AND DEMENTIA PREVENTION: THE ASSOCIATION-INTERVENTION MISMATCH, THE QUESTION OF SPECIFICITY, AND ETHICAL ISSUES

Against the backdrop of drug resistance to dementia, an emerging literature on the possibility of lifestyle prevention of the disease has shown that modifiable risk factors are associated with as many as 40% of cases³,¹³. Two expert groups commissioned by the medical journal are at the forefront of this literature, The Lancet, in 2017 and 2020³,¹³.

The factors identified in The Lancet commissions are relevant across lifetime, suggesting a large window of opportunity for interventions. These modifiable risk factors include early life (less education), midlife (hearing loss, brain injury, hypertension, alcohol consumption, obesity), and late life (smoking, depression, social isolation, physical inactivity, diabetes, air pollution)³,¹³. Thus, general aspects of physical, social, and mental health across lifetime are associated with the development of dementia at the level of populations. Moreover, results from population studies in China¹⁴,¹⁵, Brazil¹⁶, and Australia¹⁷ suggest that in certain contexts and populations, modifiable risk due to lifestyle behaviors may exceed 50%.

However, it must be stressed that this optimism is based on observational studies of association in large populations. The difficulty of turning promising associations from the epidemiology of populations into therapy for individuals is true across drug development and in lifestyle contributions to dementia¹⁸.

Population data show that rates of dementia in the United States and Europe are declining by 13% per decade across age groups¹⁹, independently of people developing less amyloid and tau brain proteins, a characteristic of Alzheimer's disease²⁰. Other factors, like healthier brain blood vessels, contribute to people being more "resilient" to brain pathology associated with cognitive decline²¹. Moreover, one recent study with a smaller population found that even when controlling for neuropathologies across different dementias, a healthy lifestyle score was associated with improved cognition²². There is, therefore, a good reason in favor of optimism about prevention from the point of view of epidemiological associations.

However, interventions or RCTs do not paint such an optimistic picture. The most promising trial was The Finnish Geriatric "FINGER" RCT, a two-year multi-domain physical and cognitive interventional trial in adults aged 60–77 years that is cited as a success in research into lifestyle prevention of dementia³,¹³. On the one hand, the treatment group received nutritional intervention, exercise, cognitive and social stimulation, and management of metabolic and vascular risk factors. Conversely, controls received regular health advice. The intervention group showed a minimal composite reduction in cognitive decline versus controls²³.

Given the absence of validated drug treatments and the need for action, the FINGER methodology was exported via the World-Wide FINGERS initiative²⁴. In the United States, the "US POINTER" prevention study has tested this methodology in diverse populations²⁵. However, the results of the World-Wide FINGERS initiative are still not available. The FINGER trial's positive findings of multi-domain intervention on cognition have found some support in the recent Systematic Multi-Domain Alzheimer's Risk Reduction Trial (SMARRT)²⁶. But other similar studies such as the French Multi-domain Alzheimer's Prevention Trial (MAPT) and the Dutch Prevention of Dementia by Intensive Vascular care (PreDIVA) did not find similar positive results²⁷,²⁸.

Certain aspects of these lifestyle interventions are reminiscent of drug development for Alzheimer's. In the methodological approach, although the treatment material of these interventions is very different from pharmacological trials — the FINGER, PreDIVA, and MAPT trials represent a set of complex behaviors rather than drugs — they are, nevertheless, based on a drug development-like process of translating promising data into therapy. The use of the RCT testing their therapeutic value, as well as dose-response and tolerability, show the influence of drug development on lifestyle studies²³,²⁹,³⁰.

While lifestyle interventions are a promising strategy based on the epidemiological trends in populations, and readily applicable without major technical hurdles, they also pose several problems. The first and arguably major problem relates to the need for one-variable tests of treatments for dementia via the RCT methodology to obtain actionable feedback¹², violated by these complex interventions. Secondly, the question of DOSE, raised in the first part of this article, is of vital importance here. There are promising trends for declining rates of dementia at the level of populations, with changes in society, behaviors, and public health policy measured over decades. However, a model of lifestyle intervention for individuals based on short trials lasting no more than two years is unlikely to deliver better results than those of the FINGER trial³¹. This led The Lancet commission of 2020 to recognize that there is no individual behavior that has been proven to lower the risk of developing dementia¹³.

Beyond complexity and dose, we saw that another problem with drug development for Alzheimer's was getting the right dose of the right drug to the right population. In this context, the specificity of dementia enters. Indeed, one of the defining features of The Lancet first commission on dementia in 2017 was its focus on "all the different" types of dementia rather than just Alzheimer's that is central to drug development³. By including all the different kinds of dementia, this meant that the net was cast wide to include as many possible cases and risk factors as possible. However, it ultimately leads to a lack of precision at the individual level because of all the different kinds and extents of exposure to different risk and protective factors at the level of populations. By analogy, as many as one in three patients diagnosed with Alzheimer's may not actually test positive for brain amyloid and, therefore, not actually have the disease according to the most recent definitions of what counts as Alzheimer's³² — how then would it be logical to test amyloid-lowering as a therapeutic strategy for dementia for this population? By extension, there are different kinds of dementia, many of which are "atypical" with a strong component of language dysfunction to whom it would seem to lack specificity to apply the methodology of multi-domain interventions for the sake of prevention³³.

Yet, despite the imperfect fit between dementia risk and lifestyle intervention, the need for dementia prevention in an aging society has motivated researchers and policymakers to advocate for widespread adoption of lifestyle modification across the aging population¹⁶,³⁴,³⁵. This can lead to many different kinds of ethical conflicts at the individual level, including a clash between health-related and non-health values, and also the possibility of blaming people if they live unhealthy lifestyles and develop dementia³⁵. But beyond individuals, ethical conflicts arguably extend into the whole of our capitalistic and individualistic society. Over the last few decades, the problem of "healthism" has emerged, in which health has become a "super value" that is an individual's property and problem, and should also be their priority to maintain³⁶,³⁷.

In light of the above lessons from drug development and research into lifestyle with its accompanying ethical conflicts, what follows is a positive vision of a lifestyle philosophy that is compatible with cutting-edge science on dementia prevention but that recognizes as well the personal and ethical dimension required for such lifestyle changes to be integrated into a coherent life philosophy.

THE DOSE PHILOSOPHY OF LIFESTYLE MODIFICATION FOR DEMENTIA PREVENTION: FINDING THE RIGHT BALANCE BETWEEN DIET, OTHER LIFE PRIORITIES, STIMULATION, AND EXERCISE

Although science grew out of natural philosophy, they are now very difficult intellectual domains (though there are calls for their reintegration³⁸). One important idea separating these two intellectual activities is the concept of falsification. In many scientific domains, ideas are understood as predictive hypotheses that are falsifiable by experimental investigations, whereas the same cannot be said of most philosophical theories³⁹. Even within Alzheimer's research, the idea of the falsifiability of theories is an important debate for discussion⁴⁰. Recent proposals to make hypotheses more prone to falsification have given strict and reproducible experimental conditions for this to happen⁵.

From the point of view of falsification, the kind of lifestyle changes that are proposed in "lifestyle programs" for Alzheimer's are essentially very uncontrolled experiments because of the sheer number of variables involved. There are already very problematic instances of the promotion of lifestyle protocols, like "metabolic enhancement protocols" for Alzheimer's disease, promoted as a silver bullet for dementia prevention for financial gain while actually being based on very weak data from uncontrolled studies⁴¹,⁴². Moreover, there is a widespread problem in research into dementia and brain health, more generally of clickbait communication and hype within scientific journalism⁴³, and pseudoscientific approaches based on lifestyle supplements and other unproven treatments⁴⁴.

The combination of hype and desperation means there are likely to be many inaccurate beliefs about realistic dementia prevention. Thus, this author believes that the last thing dementia research needs is another lifestyle program for prevention. What is offered here is, therefore, not offered as a fundamentally scientific object—though it is based on the latest science — but instead, a philosophical one. Thus, this philosophy of DOSE has two meanings: the scientific one, and the philosophical one.

The scientific meaning of DOSE is based on the fact that diet, stimulation, and exercise are three domains of life that are likely to lead to improved resilience to dementia⁴⁵. But, more philosophically, the letter "o" is deliberately interposed between the letters D, S and E to serve as a reminder that there are other priorities in life beyond health, without which we fall into healthism and end up medicalizing more and more aspects of our lives³⁶. This philosophy of finding the right dose between a healthy lifestyle and other priorities in life is based on the notion of moderation from Epicurus (341–271 BC) — "Be moderate in order to taste the joys of life in abundance."

Beyond its lack of immediate falsifiability, the other reason for which this philosophy is understood in terms of dose is because of the lesson learned from drug development and lifestyle interventions: the higher the "treatment dose" of exposure, the more likely it impacts a chronic condition like dementia. It must be repeated here: as of current expert understanding, dementia is not fundamentally a lifestyle condition, because the presence or absence of some behaviors does not have the specificity required to cause or cure it¹⁸. Paradoxically, the behaviors mentioned within this lifestyle vision have unknown preventive value. Still, if they have any, it will require decades of implementation to have any significant impact on dementia risk reduction. Anybody who undertakes lifestyle modification in the name of dementia prevention, therefore, does so with significant uncertainty about whether their hard work will "pay off"³⁵. From the perspective defended here, lifestyle changes should be implemented according to a long-term vision of behavior change. This makes it much more likely that the long-term DOSE of the changes will be higher, rather than a quick fix that individuals are unlikely to maintain throughout their life course. In other words, by lowering the dose of changes in the short term, there is greater scope for maintaining the overall dose of risk reduction in the long term. Lifestyle interventions that come late in life, when risk is already high, tend not to be effective for dementia prevention⁴⁶.

DIET AND DEMENTIA

One of the most important steps an individual can take regarding diet and dementia risk is the removal of ultra-processed foods — fast food, highly-refined cooking oils, and refined syrups — the consumption of which significantly increases the risk of different kinds of cognitive decline and dementia⁴⁷. However, beyond this "via negativa", i.e., the "negative path" of removing unhealthy foods, there is no diet proven to reduce dementia risk as a form of intervention⁴⁸.

The most promising associations exist between the Mediterranean diet and lower dementia risk. The Mediterranean diet is not easy to define but it emphasizes the intake of fresh fruit, vegetables, and legumes, some meat and fish, fats from sources like olive oil, and seasonal variations in food availability⁴⁹. Importantly, adherence to this diet can partly offset the genetic risk of developing dementia⁵⁰. Moreover, increased consumption of leafy greens as part of the Mediterranean diet is associated with reduced accumulation in the brain of Alzheimer's pathology proteins like amyloid⁵¹. There is also evidence in favor of a ketogenic diet, which involves reducing the consumption of carbohydrates from starch and sugars, thereby, favoring brain metabolism of ketones, an alternative energy source to glucose⁵²-⁵⁴.

However, once ultra-processed foods have been removed, provided there is a basic standard of food quality, arguably, the focus should be on reducing food quantity and avoiding over-eating. Once again, Epicurean reflections are beneficial in this context, as a philosophy of enjoying food in ways that maximize the mindful pleasure of eating⁵⁵. Indeed, simply reducing calories is one of the ways that regular periodic or "intermittent" fasting can exert its effects on weight loss⁵⁶. Thus, beyond the specific choice of diet, it would seem wise to emphasize enjoying foods and employing strategies that do not lead to overeating.

OTHER PRIORITIES BEYOND HEALTH

Health is a widely-held value across different societies and cultures. However, it is not the only value that people hold dear, because it is not the only reason why people make valued decisions. Living a healthy life is not enough to live a life of purpose, meaning, and enjoyment.

Diet is an important entry point into this conversation, because it shows the possibility of clashes between health and non-health values. For instance, there may be conflicts between healthy diets and environmentally sustainable diets, particularly with respect to meat consumption⁵⁷. Once more, however, the concept of DOSE is suitable, as many potential adherents to healthy diets who are wary of eating meat for environmental reasons may overestimate the amount of protein (and therefore meat) necessary in their diet if they are not particularly physically active⁵⁷. Vegetarian diets have a very long history, and while there may be certain health benefits, they have historically been motivated by ethical and religious beliefs rather than a focus on health⁵⁸. Moreover, beyond the discussion about ethics and religion, there is at least another essential part of ourselves that is not fundamentally health-related: esthetics, in other words, our tastes and pleasures, and enjoyment of life⁵⁹,⁶⁰. Esthetics includes art, nature, and activities that make us feel that our lives have transcendent meaning beyond our current state at any given time.

Indeed, these three dimensions — ethics, religion, and esthetics — are critical to what makes us human. So when the attitude of healthism is rife — when health is converted into a super value that becomes someone's individual property, problem, and moral priority to maintain³⁶ — it can lead to an overbearing pressure on older adults to be "superagers"⁶¹, and have unrealistic expectations about themselves and later life itself. Older people do value health, and therefore, we should look to promote and provide resources to support it as people age, but in ways that are not homogenizing or that deny the reality of aging³⁴,⁶².

STIMULATION AND DEMENTIA

Much expert and journalistic discourse with regards to modifiable dementia risk has understandably focused on the concept of lifestyle, a useful word to remind researchers and individuals that modifiable health behaviors play a significant role in dementia risk. But elsewhere, it has been proposed to instead talk about stimulation rather than lifestyle, which evidences the relationship between individuals and their environments⁴⁵. Some people grow, live, and work in safer and more stimulating environments, whereas others are exposed to impoverished environments, full of dangers, stressors, and pollution. Poor air quality, for example, is directly linked to dementia risk⁶³.

The concept of stimulation applies at different levels, from individual brain cells and circuits to entire populations of people⁴⁵. Stimulation can be enabling (leading to greater fortification of brain health), like early education, or disabling (worsening brain health)³⁴,⁴⁵. For instance, exposure to traffic noise in residential areas certainly stimulates the brain, but in ways that increase dementia risk⁶⁴. Moreover, there are forms of stimulation of the brain that are more specific than others, which stimulate the entire body, like exercise, which is reserved for the next section of this article. The focus of this section is on mental and social stimulation. The basic idea behind it concerning mental and social stimulation of the brain is "use it or lose it," though this useful phrase may not actually provide an adequate understanding of bodily or brain aging⁶⁵.

As with other considerations for dementia, the earlier the brain is stimulated, the better: early and longer access to schooling is protective against dementia¹³. Midlife hearing loss is a risk factor for dementia, and its correction through the use of hearing aids may therefore be protective, although interventional studies have not yet confirmed this hypothesis¹³. As with diet, correlation is not causation, and no activity has been proven to prevent the disease. That said, learning and speaking a foreign language may provide some years of resistance to dementia⁶⁶. Different forms of cognitively complex activities in later life may offer some protection against cognitive decline⁶⁷.

However, beyond specific activities that individuals can perform, the concept of stimulation reminds us that exposure to rich, green environments should be a priority. This is because richer, greener, and more complex living environments stimulate the brain and body across the entire lifetime, and may have important preventative roles against dementia⁶⁸. Moreover, beyond the physical environment, social stimulation is also important, as social connectedness strongly predicts cognitive health in older adults⁶⁹, and feelings of loneliness are associated with increased dementia risk⁷⁰ — though proving correlation or causation is difficult.

Nevertheless, the dose of mental and social stimulation is key: like the rest of the body, the brain needs rest, and therefore, stimulating physical and social activities should be offset by high-quality sleep, essential for brain health in general⁷¹. In particular, people who sleep less than seven hours at night during midlife have a higher risk of developing dementia later in life⁷². Research from mental health suggests that better sleep can be attained through plentiful natural light exposure during the day and less exposure to artificial light at night⁷³.

To close this section and move on to exercise, it is worth highlighting a recent study suggesting that exercising outdoors stimulates memory circuits within the brain more than exercising indoors⁷⁴. Thus, in this way, environmental stimulation and exercise may overlap to protect against dementia risk.

EXERCISE AND DEMENTIA

In the spirit of a philosophy about finding the right dose, it is important to warn against "too much" of a good thing. For instance, a recent review suggests that large doses of strenuous exercise across the lifespan can harm the nervous system and increase the risk of motor neuron disease⁷⁵. While it is unlikely that non-athletes will attain such high doses of strenuous exercise, it serves as a reminder of the need for prudence with any lifestyle recommendation, however intuitive it may seem.

That said, we should be ambitious about encouraging physical activity (PA) for dementia prevention. One notable study found that regular PA appears to be strongly protective against dementia⁷⁶. This particular study is unique because it involved studying families with an inherited aggressive and genetic form of Alzheimer's disease caused by very rare mutations. Researchers divided people with these aggressive mutations into two groups: those who reported doing more than 150 minutes per week of physical activity, as per World Health Organization guidelines ("high PA" group), and those who did less time ("low PA" group). These researchers found that, when controlling for age, on average, "high PA" mutation carriers developed very mild dementia an average of 15 years later than those in the "low PA" group. Though these data are derived from one observational study with the possibility of bias, they suggest the enormous individual and public health gains that could be derived from regular PA, even in those with a genetic risk or deterministic form of dementia. Another recent observational study suggested that approximately 10,000 steps of walking per day were the optimal dose for dementia risk reduction⁷⁷.

The fact that data from populations suggest that the decline in dementia rates in Europe and the USA does not depend on brain pathology²⁰, and may be due to improved cerebrovascular health²¹, suggests that the motto of prioritizing actions and activities that are "good for the heart and good for the brain" is important⁷⁸. Furthermore, PA can improve cerebrovascular health "even in those with a genetic predisposition to dementia"⁷⁹. Controlling high blood pressure, particularly at midlife through lifestyle modification and antihypertensive medication, appears to be protective against dementia as well⁸⁰.

Yet, as with other aspects of lifestyle and dementia, relatively short interventional studies do not paint such an optimistic picture about exercise's capacity to prevent dementia, and suggest that along with low intensity PA, resistance exercise that fatigues muscles more directly is another important component of maintaining cognitive health⁸¹. Exercise is no silver bullet, and the PA study of mutation carriers shows that as dementia progresses, exercise become harder without support⁷⁶.

Finally, as with stimulation, sufficient rest and recovery from exercise are as important as the exercise itself⁸², for PA to be healthy and sustainable in someone's life so as to keep the long-term dose as high as possible and maximize the preventive effects of PA.

Importantly, social support may be a key component of sticking to an exercise routine⁸³, suggesting another overlap between stimulation and exercise as part of a healthy life philosophy (Figure 1).

Figure 1
The DOSE philosophy for dementia prevention informed by drug development and epidemiology. Striking the balance between a healthy lifestyle (diet, exercise, and stimulation) and non-health priorities may be important in maximizing the long-term dose of risk reduction across the lifetime for individuals and leading to an enjoyable existence. This focus on individuals should not lead us to overlook the social health gradient and the need for collective action to make our society fairer and healthier.

In conclusion, this article argues for balance in lifestyle and brain health between health and non-health priorities, which aligns with a recent qualitative study showing that adults consider "balance in life as a prerequisite for … a sense of health and well-being"⁸⁴. But we have only discussed individuals and their lifestyle behaviors, whereas dementia risk within the population goes well beyond behaviors to structural, social, and commercial determinants of brain health⁸⁵-⁸⁷. Understood in this way, health behaviors are only the tip of the iceberg of modifiable risk in the population³⁰. Therefore, a major public health priority should be to change environments so as to improve structural access to healthy lifestyles across society and maximize health impact. These changes in society should happen in concert with citizens⁸⁸ with a focus on sharing responsibility for dementia prevention between citizens and governments rather than placing all of the onus on individuals to live healthily through coercive methods³⁷. In particular, there should be "no ought without support"³⁴, i.e., encouragement on the part of government health campaigns for individuals to change behaviors should be accompanied by steps to make them feasible, for example, by making healthy food more accessible and/or affordable. Moreover, dementia risk has a strong biological component and the need for targeted pharmacological solutions should not be underestimated nor undermined³³. If non-pharmacological preventive solutions are to be useful, they must be implemented with a long-term logic⁸⁹ and an eye on health justice and equity. Lifestyle medicine is not a silver bullet⁹⁰. As anthropologist Margaret Lock argued in 2013, a truly adequate societal response to dementia will require engaging with the "reality of aging" across the world⁹¹.

• This study was conducted by the Bioethics Program at Facultad Latinoamericana de Ciencias Sociales (Flacso) Argentina, Buenos Aires, Argentina, jointly with the Science Norms Democracy research team at Sorbonne Université, Paris, France.
• Funding: None.

REFERENCES

• ¹
  GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022;7(2):e105-25. https://doi.org/10.1016/S2468-2667(21)00249-8
  » https://doi.org/10.1016/S2468-2667(21)00249-8
• ²
  Gustavsson A, Norton N, Fast T, Frölich L, Georges J, Holzapfel D, et al. Global estimates on the number of persons across the Alzheimer's disease continuum. Alzheimers Dement. 2023;19(2):658-70. https://doi.org/10.1002/alz.12694
  » https://doi.org/10.1002/alz.12694
• ³
  Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673-734. https://doi.org/10.1016/S0140-6736(17)31363-6
  » https://doi.org/10.1016/S0140-6736(17)31363-6
• ⁴
  Liu PP, Xie Y, Meng XY, Kang JS. History and progress of hypotheses and clinical trials for Alzheimer's disease. Signal Transduct Target Ther. 2019;4:29. https://doi.org/10.1038/s41392-019-0063-8
  » https://doi.org/10.1038/s41392-019-0063-8
• ⁵
  Espay AJ, Herrup K, Daly T. Finding the falsification threshold of the toxic proteinopathy hypothesis in neurodegeneration. Handb Clin Neurol. 2023;192:143-54. https://doi.org/10.1016/B978-0-323-85538-9.00008-0
  » https://doi.org/10.1016/B978-0-323-85538-9.00008-0
• ⁶
  Villain N, Planche V, Levy R. High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 1: meta-analysis and review of efficacy and safety data, and medico-economical aspects. Rev Neurol (Paris). 2022;178(10):1011-30. https://doi.org/10.1016/j.neurol.2022.06.012
  » https://doi.org/10.1016/j.neurol.2022.06.012
• ⁷
  Howard R, Kales HC. New treatments for Alzheimer's disease. BMJ. 2023;382:1852. https://doi.org/10.1136/bmj.p1852
  » https://doi.org/10.1136/bmj.p1852
• ⁸
  Fedele E. Anti-amyloid therapies for alzheimer's disease and the amyloid cascade hypothesis. Int J Mol Sci. 2023;24(19):14499. https://doi.org/10.3390/ijms241914499
  » https://doi.org/10.3390/ijms241914499
• ⁹
  Daly T. Improving clinical trials of antioxidants in Alzheimer's disease. J Alzheimers Dis. 2024;99(s1):S171-S181. https://doi.org/10.3233/JAD-230308
  » https://doi.org/10.3233/JAD-230308
• ¹⁰
  Planche V, Villain N. Advocating for demonstration of disease modification-have we been approaching clinical trials in early Alzheimer disease incorrectly? JAMA Neurol. 2023;80(7):659-60. https://doi.org/10.1001/jamaneurol.2023.0815
  » https://doi.org/10.1001/jamaneurol.2023.0815
• ¹¹
  Cummings J, Feldman HH, Scheltens P. The "rights" of precision drug development for Alzheimer's disease. Alzheimers Res Ther. 2019;11(1):76. https://doi.org/10.1186/s13195-019-0529-5
  » https://doi.org/10.1186/s13195-019-0529-5
• ¹²
  Daly T, Mastroleo I, Henry V, Bourdenx M. An argument for simple tests of treatment of Alzheimer's disease. J Alzheimers Dis. 2022;86(1):49-52. https://doi.org/10.3233/JAD-215492
  » https://doi.org/10.3233/JAD-215492
• ¹³
  Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-46. https://doi.org/10.1016/S0140-6736(20)30367-6
  » https://doi.org/10.1016/S0140-6736(20)30367-6
• ¹⁴
  Liu Y, Zhang S, Tomata Y, Nurrika D, Sugawara Y, Tsuji I. The impact of risk factors for dementia in China. Age Ageing. 2020;49(5):850-5. https://doi.org/10.1093/ageing/afaa048
  » https://doi.org/10.1093/ageing/afaa048
• ¹⁵
  Wu Y, Zheng H, Xu F, Guo J, Liu Z, Wang S, et al. Population attributable fractions for risk factors and disability burden of dementia in Jiangxi Province, China: a cross-sectional study. BMC Geriatr. 2022;22(1):811. https://doi.org/10.1186/s12877-022-03507-4
  » https://doi.org/10.1186/s12877-022-03507-4
• ¹⁶
  Borelli WV, Leotti VB, Strelow MZ, Chaves MLF, Castilhos RM. Preventable risk factors of dementia: Population attributable fractions in a Brazilian population-based study. Lancet Reg Health Am. 2022;11:100256. https://doi.org/10.1016/j.lana.2022.100256
  » https://doi.org/10.1016/j.lana.2022.100256
• ¹⁷
  See RS, Thompson F, Russell S, Quigley R, Esterman A, Harriss LR, et al. Potentially modifiable dementia risk factors in all Australians and within population groups: an analysis using cross-sectional survey data. Lancet Public Health. 2023;8(9):e717-25. https://doi.org/10.1016/S2468-2667(23)00146-9
  » https://doi.org/10.1016/S2468-2667(23)00146-9
• ¹⁸
  Daly T, Henry V, Bourdenx M. From association to intervention: the Alzheimer's Disease-Associated Processes and Targets (ADAPT) ontology. J Alzheimers Dis. 2023;94(s1):S87-S96. https://doi.org/10.3233/JAD-221004
  » https://doi.org/10.3233/JAD-221004
• ¹⁹
  Wolters FJ, Chibnik LB, Waziry R, Anderson R, Berr C, Beiser A, et al. Twenty-seven-year time trends in dementia incidence in Europe and the United States: the Alzheimer cohorts consortium. Neurology. 2020;95(5):e519-31. https://doi.org/10.1212/WNL.0000000000010022
  » https://doi.org/10.1212/WNL.0000000000010022
• ²⁰
  Grodstein F, Leurgans SE, Capuano AW, Schneider JA, Bennett DA. Trends in postmortem neurodegenerative and cerebrovascular neuropathologies over 25 years. JAMA Neurol. 2023;80(4):370-6. https://doi.org/10.1001/jamaneurol.2022.5416
  » https://doi.org/10.1001/jamaneurol.2022.5416
• ²¹
  Arenaza-Urquijo EM, Vemuri P. Resistance vs resilience to Alzheimer disease: clarifying terminology for preclinical studies. Neurology. 2018;90(15):695-703. https://doi.org/10.1212/WNL.0000000000005303
  » https://doi.org/10.1212/WNL.0000000000005303
• ²²
  Dhana K, Agarwal P, James BD, Leurgans SE, Rajan KB, Aggarwal NT, et al. Healthy lifestyle and cognition in older adults with common neuropathologies of dementia. JAMA Neurol. 2024;81(3):233-9. https://doi.org/10.1001/jamaneurol.2023.5491
  » https://doi.org/10.1001/jamaneurol.2023.5491
• ²³
  Ngandu T, Lehtisalo J, Solomon A, Levälahti E, Ahtiluoto S, Antikainen R, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385(9984):2255-63. https://doi.org/10.1016/S0140-6736(15)60461-5
  » https://doi.org/10.1016/S0140-6736(15)60461-5
• ²⁴
  Rosenberg A, Mangialasche F, Ngandu T, Solomon A, Kivipelto M. Multidomain interventions to prevent cognitive impairment, Alzheimer's disease, and dementia: From FINGER to World-Wide FINGERS. J Prev Alzheimers Dis. 2020;7(1):29-36. https://doi.org/10.14283/jpad.2019.41
  » https://doi.org/10.14283/jpad.2019.41
• ²⁵
  Baker LD, Snyder HM, Espeland MA, Whitmer RA, Kivipelto M, Woolard N, et al. Study design and methods: U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER). Alzheimers Dement. 2024;20(2):769-82. https://doi.org/10.1002/alz.13365
  » https://doi.org/10.1002/alz.13365
• ²⁶
  Yaffe K, Vittinghoff E, Dublin S, Peltz CB, Fleckenstein LE, Rosenberg DE, et al. Effect of personalized risk-reduction strategies on cognition and dementia risk profile among older adults: the SMARRT randomized clinical trial. JAMA Intern Med. 2024;184(1):54-62. https://doi.org/10.1001/jamainternmed.2023.6279
  » https://doi.org/10.1001/jamainternmed.2023.6279
• ²⁷
  Andrieu S, Guyonnet S, Coley N, Cantet C, Bonnefoy M, Bordes S, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. 2017;16(5):377-89. https://doi.org/10.1016/S1474-4422(17)30040-6
  » https://doi.org/10.1016/S1474-4422(17)30040-6
• ²⁸
  van Charante EPM, Richard E, Eurelings LS, van Dalen JW, Ligthart SA, van Bussel EF, et al. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet. 2016;388(10046):797-805. https://doi.org/10.1016/S0140-6736(16)30950-3
  » https://doi.org/10.1016/S0140-6736(16)30950-3
• ²⁹
  Belleville S, Cloutier S, Mellah S, Willis S, Vellas B, Andrieu S, et al. Is more always better? Dose effect in a multidomain intervention in older adults at risk of dementia. Alzheimers Dement. 2022;18(11):2140-50. https://doi.org/10.1002/alz.12544
  » https://doi.org/10.1002/alz.12544
• ³⁰
  Daly T. The iceberg of dementia risk: empirical and conceptual arguments in favor of structural interventions for brain health. Cereb Circ Cogn Behav. 2024;6:100193. https://doi.org/10.1016/j.cccb.2023.100193
  » https://doi.org/10.1016/j.cccb.2023.100193
• ³¹
  Daly T. Upping the dose of dementia risk reduction. Alzheimers Dement. 2022;18(9):1699. https://doi.org/10.1002/alz.12692
  » https://doi.org/10.1002/alz.12692
• ³²
  Landau SM, Horng A, Fero A, Jagust WJ, Alzheimer's Disease Neuroimaging Initiative. Amyloid negativity in patients with clinically diagnosed Alzheimer disease and MCI. Neurology. 2016;86(15):1377-85. https://doi.org/10.1212/WNL.0000000000002576
  » https://doi.org/10.1212/WNL.0000000000002576
• ³³
  Daly T, Mastroleo I, Migliaccio R. Avoiding over-reliance on multi-domain interventions for dementia prevention. J Alzheimers Dis. 2022;90(3):989-92. https://doi.org/10.3233/JAD-215647
  » https://doi.org/10.3233/JAD-215647
• ³⁴
  Daly T. Dementia prevention guidelines should explicitly mention deprivation. AJOB Neurosci. 2024;15(1):73-6. https://doi.org/10.1080/21507740.2023.2225461
  » https://doi.org/10.1080/21507740.2023.2225461
• ³⁵
  Horstkötter D, Deckers K, Köhler S. Primary prevention of dementia: an ethical review. J Alzheimers Dis. 2021;79(2):467-76. https://doi.org/10.3233/JAD-201104
  » https://doi.org/10.3233/JAD-201104
• ³⁶
  Crawford R. Healthism and the medicalization of everyday life. Int J Health Serv. 1980;10(3):365-88. https://doi.org/10.2190/3H2H-3XJN-3KAY-G9NY
  » https://doi.org/10.2190/3H2H-3XJN-3KAY-G9NY
• ³⁷
  Daly T. Against healthism in dementia prevention: sharing responsibility. Aging Med (Milton). 2023;6(2):207-8. https://doi.org/10.1002/agm2.12252
  » https://doi.org/10.1002/agm2.12252
• ³⁸
  Laplane L, Mantovani P, Adolphs R, Chang H, Mantovani A, McFall-Ngai M, et al. Why science needs philosophy. Proc Natl Acad Sci U S A. 2019;116(10):3948-52. https://doi.org/10.1073/pnas.1900357116
  » https://doi.org/10.1073/pnas.1900357116
• ³⁹
  Popper K. Conjectures and refutations: the growth of scientific knowledge. Philadelphia: Routledge; 2014.
• ⁴⁰
  Hardy J. Has the amyloid cascade hypothesis for Alzheimer's disease been proved? Curr Alzheimer Res. 2006;3(1):71-3. https://doi.org/10.2174/156720506775697098
  » https://doi.org/10.2174/156720506775697098
• ⁴¹
  Daly T, Mastroleo I, Gorski D, Epelbaum S. The ethics of innovation for Alzheimer's disease: the risk of overstating evidence for metabolic enhancement protocols. Theor Med Bioeth. 2020;41(5-6):223-37. https://doi.org/10.1007/s11017-020-09536-7
  » https://doi.org/10.1007/s11017-020-09536-7
• ⁴²
  Daly T, Mastroleo I. The first survivors of Alzheimer's: how patients recovered life and hope in their own words by Dale Bredesen, Avery, 2021, 272 pp. J Alzheimers Dis. 2022;87(3):1413-4. https://doi.org/10.3233/JAD-220185
  » https://doi.org/10.3233/JAD-220185
• ⁴³
  Walsh S, Merrick R, Richard E, Nurock S, Brayne C. Lecanemab for Alzheimer's disease. BMJ. 2022;379:o3010. https://doi.org/10.1136/bmj.o3010
  » https://doi.org/10.1136/bmj.o3010
• ⁴⁴
  Hellmuth J, Rabinovici GD, Miller BL. The rise of pseudomedicine for dementia and brain health. JAMA. 2019;321(6):543-4. https://doi.org/10.1001/jama.2018.21560
  » https://doi.org/10.1001/jama.2018.21560
• ⁴⁵
  Daly T. If deprivation worsens dementia outcomes, stimulation should improve them. Curr Med Res Opin. 2023;39(10):1391-4. https://doi.org/10.1080/03007995.2023.2260741
  » https://doi.org/10.1080/03007995.2023.2260741
• ⁴⁶
  Harris E. Lifestyle intervention did not improve quality of life in dementia. JAMA. 2023;330(13):1218. https://doi.org/10.1001/jama.2023.17179
  » https://doi.org/10.1001/jama.2023.17179
• ⁴⁷
  Gonçalves NG, Ferreira NV, Khandpur N, Steele EM, Levy RB, Lotufo PA, et al. Association between consumption of ultraprocessed foods and cognitive decline. JAMA Neurol. 2023;80(2):142-50. https://doi.org/10.1001/jamaneurol.2022.4397
  » https://doi.org/10.1001/jamaneurol.2022.4397
• ⁴⁸
  Peters N, Nacmias B. The implications of dietary habits for dementia: does diet matter? Neurology. 2023;100(1):13-4. https://doi.org/10.1212/WNL.0000000000201420
  » https://doi.org/10.1212/WNL.0000000000201420
• ⁴⁹
  Rishor-Olney CR, Hinson MR. Mediterranean diet. In: StatPearls. Treasure Island: StatPearls Publishing; 2023. PMID: 32491665.
• ⁵⁰
  Shannon OM, Ranson JM, Gregory S, Macpherson H, Milte C, Lentjes M, et al. Mediterranean diet adherence is associated with lower dementia risk, independent of genetic predisposition: findings from the UK Biobank prospective cohort study. BMC Med. 2023;21(1):81. https://doi.org/10.1186/s12916-023-02772-3
  » https://doi.org/10.1186/s12916-023-02772-3
• ⁵¹
  Agarwal P, Leurgans SE, Agrawal S, Aggarwal NT, Cherian LJ, James BD, et al. Association of Mediterranean-DASH intervention for neurodegenerative delay and mediterranean diets with Alzheimer disease pathology. Neurology. 2023;100(22):e2259-68. https://doi.org/10.1212/WNL.0000000000207176
  » https://doi.org/10.1212/WNL.0000000000207176
• ⁵²
  Tabaie EA, Reddy AJ, Brahmbhatt H. A narrative review on the effects of a ketogenic diet on patients with Alzheimer's disease. AIMS Public Health. 2021;9(1):185-93. https://doi.org/10.3934/publichealth.2022014
  » https://doi.org/10.3934/publichealth.2022014
• ⁵³
  Phillips MCL, Deprez LM, Mortimer GMN, Murtagh DKJ, McCoy S, Mylchreest R, et al. Randomized crossover trial of a modified ketogenic diet in Alzheimer's disease. Alzheimers Res Ther. 2021;13(1):51. https://doi.org/10.1186/s13195-021-00783-x
  » https://doi.org/10.1186/s13195-021-00783-x
• ⁵⁴
  Xu Y, Zheng F, Zhong Q, Zhu Y. Ketogenic diet as a promising non-drug intervention for Alzheimer's disease: mechanisms and clinical implications. J Alzheimers Dis. 2023;92(4):1173-98. https://doi.org/10.3233/JAD-230002
  » https://doi.org/10.3233/JAD-230002
• ⁵⁵
  Cornil Y, Chandon P. Pleasure as an ally of healthy eating? Contrasting visceral and Epicurean eating pleasure and their association with portion size preferences and wellbeing. Appetite. 2016;104:52-9. https://doi.org/10.1016/j.appet.2015.08.045
  » https://doi.org/10.1016/j.appet.2015.08.045
• ⁵⁶
  Song DK, Kim YW. Beneficial effects of intermittent fasting: a narrative review. J Yeungnam Med Sci. 2023;40(1):4-11. https://doi.org/10.12701/jyms.2022.00010
  » https://doi.org/10.12701/jyms.2022.00010
• ⁵⁷
  Macdiarmid JI. Is a healthy diet an environmentally sustainable diet? Proc Nutr Soc. 2013;72(1):13-20. https://doi.org/10.1017/S0029665112002893
  » https://doi.org/10.1017/S0029665112002893
• ⁵⁸
  Leitzmann C. Vegetarian nutrition: past, present, future. Am J Clin Nutr. 2014;100 Suppl 1:496S-502S. https://doi.org/10.3945/ajcn.113.071365
  » https://doi.org/10.3945/ajcn.113.071365
• ⁵⁹
  Fingerhut J, Gomez-Lavin J, Winklmayr C, Prinz JJ. The aesthetic self. The importance of aesthetic taste in music and art for our perceived identity. Front Psychol. 2020;11:577703. https://doi.org/10.3389/fpsyg.2020.577703
  » https://doi.org/10.3389/fpsyg.2020.577703
• ⁶⁰
  Wikström BM. Older adults and the arts: the importance of aesthetic forms of expression in later life. J Gerontol Nurs. 2004;30(9):30-6. https://doi.org/10.3928/0098-9134-20040901-07
  » https://doi.org/10.3928/0098-9134-20040901-07
• ⁶¹
  Feldman S. Please don't call me "dear": older women's narratives of health care. Nurs Inq. 1999;6(4):269-76. https://doi.org/10.1046/j.1440-1800.1999.00041.x
  » https://doi.org/10.1046/j.1440-1800.1999.00041.x
• ⁶²
  Stephens C, Breheny M, Mansvelt J. Healthy ageing from the perspective of older people: a capability approach to resilience. Psychol Health. 2015;30(6):715-31. https://doi.org/10.1080/08870446.2014.904862
  » https://doi.org/10.1080/08870446.2014.904862
• ⁶³
  Wilker EH, Osman M, Weisskopf MG. Ambient air pollution and clinical dementia: systematic review and meta-analysis. BMJ. 2023;381:e071620. https://doi.org/10.1136/bmj-2022-071620
  » https://doi.org/10.1136/bmj-2022-071620
• ⁶⁴
  Cantuaria ML, Waldorff FB, Wermuth L, Pedersen ER, Poulsen AH, Thacher JD, et al. Residential exposure to transportation noise in Denmark and incidence of dementia: national cohort study. BMJ. 2021;374:n1954. https://doi.org/10.1136/bmj.n1954
  » https://doi.org/10.1136/bmj.n1954
• ⁶⁵
  Swaab DF. Brain aging and Alzheimer's disease, "wear and tear" versus "use it or lose it." Neurobiol Aging. 1991;12(4):317-24. https://doi.org/10.1016/0197-4580(91)90008-8
  » https://doi.org/10.1016/0197-4580(91)90008-8
• ⁶⁶
  Perani D, Abutalebi J. Bilingualism, dementia, cognitive and neural reserve. Curr Opin Neurol. 2015;28(6):618-25. https://doi.org/10.1097/WCO.0000000000000267
  » https://doi.org/10.1097/WCO.0000000000000267
• ⁶⁷
  Gómez-Soria I, Iguacel I, Aguilar-Latorre A, Peralta-Marrupe P, Latorre E, Zaldívar JNC, et al. Cognitive stimulation and cognitive results in older adults: a systematic review and meta-analysis. Arch Gerontol Geriatr. 2023;104:104807. https://doi.org/10.1016/j.archger.2022.104807
  » https://doi.org/10.1016/j.archger.2022.104807
• ⁶⁸
  Yuan M, Kennedy KM. Utility of environmental complexity as a predictor of alzheimer's disease diagnosis: a big-data machine learning approach. J Prev Alzheimers Dis. 2023;10(2):223-35. https://doi.org/10.14283/jpad.2023.18
  » https://doi.org/10.14283/jpad.2023.18
• ⁶⁹
  Samtani S, Mahalingam G, Lam BCP, Lipnicki DM, Lima-Costa MF, Blay SL, et al. Associations between social connections and cognition: a global collaborative individual participant data meta-analysis. Lancet Healthy Longev. 2022;3(11):e740-53. https://doi.org/10.1016/S2666-7568(22)00199-4
  » https://doi.org/10.1016/S2666-7568(22)00199-4
• ⁷⁰
  Qiao L, Wang G, Tang Z, Zhou S, Min J, Yin M, et al. Association between loneliness and dementia risk: a systematic review and meta-analysis of cohort studies. Front Hum Neurosci. 2022;16:899814. https://doi.org/10.3389/fnhum.2022.899814
  » https://doi.org/10.3389/fnhum.2022.899814
• ⁷¹
  Golombek DA, Booi L, Campbell D, Dawson WD, Eyre H, Lawlor B, et al. Sleep diplomacy: an approach to boosting global brain health. Lancet Healthy Longev. 2023;4(8):e368-70. https://doi.org/10.1016/S2666-7568(23)00109-5
  » https://doi.org/10.1016/S2666-7568(23)00109-5
• ⁷²
  Sabia S, Fayosse A, Dumurgier J, van Hees VT, Paquet C, Sommerlad A, et al. Association of sleep duration in middle and old age with incidence of dementia. Nat Commun. 2021;12(1):2289. https://doi.org/10.1038/s41467-021-22354-2
  » https://doi.org/10.1038/s41467-021-22354-2
• ⁷³
  Burns AC, Windred DP, Rutter MK, Olivier P, Vetter C, Saxena R, et al. Day and night light exposure are associated with psychiatric disorders: an objective light study in >85,000 people. Nat Ment Health. 2023;1:853-62. https://doi.org/10.1038/s44220-023-00135-8
  » https://doi.org/10.1038/s44220-023-00135-8
• ⁷⁴
  Boere K, Lloyd K, Binsted G, Krigolson OE. Exercising is good for the brain but exercising outside is potentially better. Sci Rep. 2023;13(1):1140. https://doi.org/10.1038/s41598-022-26093-2
  » https://doi.org/10.1038/s41598-022-26093-2
• ⁷⁵
  Chapman L, Cooper-Knock J, Shaw PJ. Physical activity as an exogenous risk factor for amyotrophic lateral sclerosis: a review of the evidence. Brain. 2023;146(5):1745-57. https://doi.org/10.1093/brain/awac470
  » https://doi.org/10.1093/brain/awac470
• ⁷⁶
  Müller S, Preische O, Sohrabi HR, Gräber S, Jucker M, Ringman JM, et al. Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer's disease. Alzheimers Dement. 2018;14(11):1427-37. https://doi.org/10.1016/j.jalz.2018.06.3059
  » https://doi.org/10.1016/j.jalz.2018.06.3059
• ⁷⁷
  Del Pozo Cruz B, Ahmadi M, Naismith SL, Stamatakis E. Association of daily step count and intensity with incident dementia in 78 430 adults living in the UK. JAMA Neurol. 2022;79(10):1059-63. https://doi.org/10.1001/jamaneurol.2022.2672
  » https://doi.org/10.1001/jamaneurol.2022.2672
• ⁷⁸
  Kivipelto M, Ngandu T. Good for the heart and good for the brain? Lancet Neurol. 2019;18(4):327-8. https://doi.org/10.1016/S1474-4422(19)30087-0
  » https://doi.org/10.1016/S1474-4422(19)30087-0
• ⁷⁹
  Low A, Prats-Sedano MA, McKiernan E, Carter SF, Stefaniak JD, Nannoni S, et al. Modifiable and non-modifiable risk factors of dementia on midlife cerebral small vessel disease in cognitively healthy middle-aged adults: the PREVENT-Dementia study. Alzheimers Res Ther. 2022;14(1):154. https://doi.org/10.1186/s13195-022-01095-4
  » https://doi.org/10.1186/s13195-022-01095-4
• ⁸⁰
  Lennon MJ, Lam BCP, Lipnicki DM, Crawford JD, Peters R, Schutte AE, et al. Use of antihypertensives, blood pressure, and estimated risk of dementia in late life: an individual participant data meta-analysis. JAMA Netw Open. 2023;6(9):e2333353. https://doi.org/10.1001/jamanetworkopen.2023.33353
  » https://doi.org/10.1001/jamanetworkopen.2023.33353
• ⁸¹
  Huang X, Zhao X, Li B, Cai Y, Zhang S, Wan Q, et al. Comparative efficacy of various exercise interventions on cognitive function in patients with mild cognitive impairment or dementia: a systematic review and network meta-analysis. J Sport Health Sci. 2022;11(2):212-23. https://doi.org/10.1016/j.jshs.2021.05.003
  » https://doi.org/10.1016/j.jshs.2021.05.003
• ⁸²
  Kellmann M, Bertollo M, Bosquet L, Brink M, Coutts AJ, Duffield R, et al. Recovery and performance in sport: consensus statement. Int J Sports Physiol Perform. 2018;13(2):240-5. https://doi.org/10.1123/ijspp.2017-0759
  » https://doi.org/10.1123/ijspp.2017-0759
• ⁸³
  Gjestvang C, Abrahamsen F, Stensrud T, Haakstad LAH. What makes individuals stick to their exercise regime? A one-year follow-up study among novice exercisers in a fitness club setting. Front Psychol. 2021;12:638928. https://doi.org/10.3389/fpsyg.2021.638928
  » https://doi.org/10.3389/fpsyg.2021.638928
• ⁸⁴
  Gillsjö C, Nyström M, Palmér L, Carlsson G, Dalheim-Englund AC, Eriksson I. Balance in life as a prerequisite for community-dwelling older adults' sense of health and well-being after retirement: an interview-based study. Int J Qual Stud Health Well-being. 2021;16(1):1984376. https://doi.org/10.1080/17482631.2021.1984376
  » https://doi.org/10.1080/17482631.2021.1984376
• ⁸⁵
  Walsh S, Merrick R, Brayne C. The relevance of social and commercial determinants for neurological health. Lancet Neurol. 2022;21(12):1151-60. https://doi.org/10.1016/S1474-4422(22)00428-8
  » https://doi.org/10.1016/S1474-4422(22)00428-8
• ⁸⁶
  Walsh S, Govia I, Wallace L, Richard E, Peters R, Anstey KJ, et al. A whole-population approach is required for dementia risk reduction. Lancet Healthy Longev. 2022;3(1):e6-8. https://doi.org/10.1016/S2666-7568(21)00301-9
  » https://doi.org/10.1016/S2666-7568(21)00301-9
• ⁸⁷
  Walsh S, Govia I, Peters R, Richard E, Stephan BCM, Wilson NA, et al. What would a population-level approach to dementia risk reduction look like, and how would it work? Alzheimers Dement. 2023;19(7):3203-9. https://doi.org/10.1002/alz.12985
  » https://doi.org/10.1002/alz.12985
• ⁸⁸
  Röhr S, Rodriguez FS, Siemensmeyer R, Müller F, Romero-Ortuno R, Riedel-Heller SG. How can urban environments support dementia risk reduction? A qualitative study. Int J Geriatr Psychiatry. 2022;37(1). https://doi.org/10.1002/gps.5626
  » https://doi.org/10.1002/gps.5626
• ⁸⁹
  Wu Z, Pandigama DH, Wrigglesworth J, Owen A, Woods RL, Chong TTJ, et al. Lifestyle enrichment in later life and its association with dementia risk. JAMA Netw Open. 2023;6(7):e2323690. https://doi.org/10.1001/jamanetworkopen.2023.23690
  » https://doi.org/10.1001/jamanetworkopen.2023.23690
• ⁹⁰
  Nunan D, Blane DN, McCartney M. Exemplary medical care or Trojan horse? An analysis of the "lifestyle medicine" movement. Br J Gen Pract. 2021;71(706):229-32. https://doi.org/10.3399/bjgp21X715721
  » https://doi.org/10.3399/bjgp21X715721
• ⁹¹
  Lock MM. The Alzheimer Conundrum: entanglements of dementia and aging. Princeton: Princeton University Press; 2013.

Publication Dates

• Publication in this collection
  22 July 2024
• Date of issue
  2024

History

• Received
  28 Nov 2023
• Reviewed
  06 Apr 2024
• Accepted
  27 Apr 2024