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Abstract

Dementia encompasses a broad spectrum of neuropsychiatric disease states marked by cognitive impairments that interfere with day-to-day functioning. Most dementias are complex phenotypes that result from a genome-environment interplay. Epigenetic regulation has emerged as a candidate mechanism for studying this interplay. In this narrative review, we discuss state-of-the-art evidence on environmental exposures relevant to dementia, including nutrition, physical exercise, psychosocial stress, and environmental toxins, and highlight epigenetic mechanisms that have been reported as a putative link between each exposure and dementia risk. We then discuss the clinical implications and future directions of this line of research. An improved understanding of the epigenetic mechanisms involved in dementia pathogenesis can promote the development of novel biomarkers for predicting outcomes but also targeted therapies to intervene early in the course of the disease.

Keywords

Alzheimer's disease dementia epigenetics exercise nutrition psychosocial stress toxins

Introduction

The term dementia refers to a broad spectrum of neuropsychiatric disease states marked by cognitive impairments that interfere with day-to-day functioning. The leading cause of dementia is Alzheimer's disease (AD), which leads to impaired visuospatial skills, aberrant conduct, and ultimately death.¹ AD is characterized pathologically by twisted beta-pleated sheet (amyloid) fibrils, including intraneuronal neurofibrillary tangles, extracellular amyloid-containing neuritic plaques, and cerebrovascular amyloid fibril deposits.² Alzheimer's disease neuropathologic changes are further defined by the accumulation of amyloid-β (Aβ) in the form of neuritic plaques and abnormally phosphorylated microtubule-associated protein tau in the form of neuronal neurofibrillary tangles. One of the most abundant proteins in the central nervous system, the amyloid-β protein precursor (AβPP), is crucial in the development of neuritic plaques,³ The remaining cases of dementia include a variety of conditions with distinct neurodegenerative pathologies, such as vascular dementia, frontotemporal dementia, and dementia with Lewy bodies. In patients with dementia, a spectrum of neuropathologies may contribute to neurodegeneration, and some of the major neuropathology hallmarks may overlap.⁴ Most dementias are complex disease entities thought to result from an intricate interplay between genetic and environmental factors.⁵

AD and related dementias exhibit significant heterogeneity in clinical presentation, even among patients with similar genetic backgrounds. This variability is marked by genetic, demographic, neuropathological, cognitive, functional, neuropsychiatric, and biomarker factors. Genetic heterogeneity can arise from differences in mutations, such as those affecting AβPP processing, which influence Aβ deposition and disease course. Demographic factors like age, sex, education, and socioeconomic status also contribute to this heterogeneity, affecting disease progression and cognitive resilience. Neuropathological differences include the distribution and density of neurofibrillary tangles and Aβ plaques in various brain regions. Cognitive and functional heterogeneity is evident in the variability of cognitive profiles, daily living activities, and progression rates. Additionally, neuropsychiatric symptoms such as depression and apathy further diversify clinical presentations. These complexities necessitate tailored clinical and research approaches in AD to address the wide range of patient experiences and disease trajectories.⁶

Among key mechanisms integrating environmental stimuli into the genome, epigenetic regulation has been studied as a possible hallmark of the aging process and a potential therapeutic target for age-related diseases.⁷ López-Otín et al.⁸ made this statement more specific by proposing the molecular hallmarks of aging. It has further been proposed that epigenetics may play a role in dementia pathogenesis.⁹

The purpose of this review is to discuss state-of-the-art evidence on epigenetic mechanisms linking environmental exposure with dementia risk. To this end, the article presents an overview of environmental exposures associated with increased risk for developing dementia and highlights the epigenetic mechanisms reported as a link between environmental exposures and dementia. We then discuss the clinical implications and future directions of this line of research.

Brief primer on epigenetics

The term “epigenetics” was originally coined by Conrad Waddington in the 1940s to refer to the study of the way through which genes and their products bring the phenotype into being.¹⁰ However, nowadays the term usually encompasses the heritable chemical modifications that regulate gene expression without changing the underlying DNA sequence. Epigenetic mechanisms include DNA methylation, histone modifications, and microRNAs (miRNAs).¹¹ DNA methylation is a widely researched epigenetic alteration, most commonly occurring in the context of cytosine-guanine dinucleotides (CpG) that tend to cluster in regions called CpG islands.¹² DNA methylation regulates gene expression by changing the access that transcription factors have to the genomic region it occurs.¹³ DNA methyltransferases (DNMTs), including DNMT1, DNMT3a and DNMT3b, catalyze the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the C5 position of cytosine.¹⁴ 5-hydroxymethylcytosine (5-hmC) should be distinguished from 5-methylcytosine (5-mC), as it is the first oxidative product in the active demethylation of 5-mC, an important molecule in switching genes on and off.¹⁵ Ten-eleven translocation methylcytosine dioxygenases, such as TET1 and TET2,^16,17 hydroxylate the methyl group of 5-mC, converting it to 5-hmC. Regarding histone modifications, several post-transcriptional modifications occur in histone tails.¹⁸ Histone acetylation, catalyzed by histone acetyltransferases (HATs), is associated with transcriptional activation, whereas histone deacetylation, regulated by histone deacetylases (HDACs), is involved in transcriptional repression.¹⁹ MicroRNAs (miRNAs) are small noncoding RNAs that act after gene transcription to influence the protein levels of target mRNAs.²⁰

Several epigenetic modifications have been implicated in dementia, including DNA methylation²¹; histone acetylation,²² methylation,²³ and phosphorylation²⁴; and miRNAs.²⁵ Epigenome-wide association studies have further attempted to identify exact genomic locations where relative epigenetic differences are found.^26,27 Below we highlight epigenetic studies linking specific environmental risk factors with dementia phenotypes. Among candidate epigenetic mechanisms, emphasis is placed on chromatin modifications, namely DNA methylation and histone modifications, which have the most evidence to date for their involvement in dementia phenotypes.

Epigenetic mechanisms linking environment and dementia

Even though certain modifiable risk factors have been associated with dementia, a significant amount of risk remains unexplained.²⁸ At the same time, the field of epigenetics has significantly evolved since the early 1940s, when the British embryologist Conrad Waddington introduced this concept.¹⁰ Since then, progress has been made in identifying the role that epigenetic mechanisms play in various diseases. Below are presented some of the most important risk factors that have been linked with dementia and the epigenetic modifications underlying this relationship.

Nutrition

One of the most established environmental manipulations influencing age-related diseases is caloric restriction (CR). It has been reported that a CR dietary regimen attenuates Aβ neuropathology, prevents the generation of Aβ peptides, and reduces neuritic plaque deposition in a mouse model of AD.²⁹ These effects are associated with the promotion of anti-amyloidogenic α-secretase activity, which plays a role in reducing the pathological accumulation of Aβ peptides. CR has also been found to ameliorate age-related behavioral deficits in mouse models of AD, while also demonstrating neuroprotective effects by enhancing neurogenesis, improving synaptic plasticity, and reducing oxidative stress.³⁰ Corroborating findings have been observed in other animal models, including squirrel monkeys³¹ and C. elegans.³²

CR has been shown to exert neuroprotective effects against AD through mechanisms involving histone deacetylases (HDACs), particularly sirtuins like SIRT1 and histone acetyltransferases. SIRT1 induction via CR or pharmacological activators has been demonstrated to protect against neuronal loss and impairment in models of AD and Parkinson's disease by reducing oxidative stress and improving mitochondrial function.³³ CR's beneficial effects in AD models include the reduction of Aβ production and stabilization of tau protein, achieved through the modulation of chromatin structure and gene expression by HDACs and SIRT1.³⁴ Additionally, the ketone body β-hydroxybutyrate, a known HDAC inhibitor, extends lifespan and enhances stress response pathways,³⁵ which are protective against Aβ toxicity and neurodegeneration in AD models.

Histone acetyltransferases (HATs), such as CREB-binding protein (CBP), also mediate the neuroprotective effects of CR. CBP has been shown to mediate the beneficial effects of CR by enhancing histone acetylation, delaying age-related pathologies, and extending lifespan.³⁶ In transgenic models of AD, the reduction of CBP activity due to presenilin mutations leads to decreased acetylation at specific histone sites, contributing to cognitive deficits. This suggests that maintaining normal CBP levels and histone acetylation is critical for neuronal health.³⁷ Furthermore, drugs that facilitate histone acetylation, such as 4-phenylbutyrate, have been shown to improve cognitive function and reduce tau pathology in AD mouse models,³⁸ highlighting the potential therapeutic role of HAT activation.

Numerous studies have looked at the effect of nutrients and diets in the prevention of cognitive decline, which eventually results in dementia. Individual nutrients or food groups, however, might not accurately represent the inherently complicated human eating habits or a composite dietary pattern. Dietary patterns incorporate potential synergistic or interactive effects between multiple nutrients and foods, thus more accurately reflecting real-life conditions.³⁹ The dietary pattern most strongly associated with protection against dementia and cognitive decline is the Mediterranean diet (MeDi). Measured across various memory and executive function domains, MeDi, a diet based on fruits, vegetables, and fish, has been shown to delay cognitive decline and lower risk for AD.^40,41 In a large prospective cohort study, MeDi was found to be inversely associated with dementia incidence after accounting for major cardiovascular risk factors. These results differed by dementia sub-type, sex, and education.⁴² In a systematic review, however, the association between MeDi adherence and dementia risk has not been consistent, with lower risk of AD and all-cause dementia found, respectively, in four out of seven and zero out of five studies (with the other studies reporting null findings).⁴³ Notably, when the MeDi is combined with the Dietary Approach to Systolic Hypertension (DASH) diet, its positive effects on cognition may be increased. This hybrid diet—based on high intakes of fruits, vegetables, low-fat dairy products, whole grains, poultry, fish, and nuts and low intakes of fats, red meat, sweets, and sugar-containing beverages—has been shown to lower blood pressure that contributes to vascular pathologies, enhance cognitive functioning, and reduce the likelihood of developing AD.^44,45 The MIND diet, also based on plant-based foods, is a combination of the Mediterranean diet and the DASH diet and has been associated with better cognitive function and reduced risk of cognitive decline.^44–46

While cellular and molecular mechanisms underlying the interaction between nutrition and its effects on brain function have been widely investigated,^47,48 we still know little about the epigenetic mechanisms underlying these phenomena. Early-life nutrition can induce long-lasting alterations in DNA methylation that influence a person's health and possible development of aging-related diseases throughout their lifetime.⁴⁹ Nutrients can exert their effects either by directly suppressing epigenetic enzymes like DNMTs, HDACs, or HATs, or by changing the availability of the substrate required for certain enzymatic activities. The expression of critical genes is in turn altered, affecting general health and longevity.

DNA methylation is mediated by the DNMTs and the methyl donor SAM. Vitamins B6, B12, choline, methionine, and folate regulate this process. One-carbon pathways donate and regenerate one-carbon units, including the methyl group that is essential for DNA methylation. When this process is altered, aberrant DNA methylation occurs, which is linked to several autoimmune diseases and neurological disorders. For example, folate, which is a water-soluble B vitamin, is a source of one carbon for the synthesis of SAM, which is required for DNA methylation, establishing a connection between folate metabolism and phenotypic alterations through DNA methylation.⁵⁰ Choline is another methyl donor nutrient that can influence the DNA methylation status and hence affect gene expression.⁵¹

Histone modifications and miRNAs are also affected by diet. For example, dietary fibers derived from vegetable consumption and the polyphenol kaempferol, mainly found in vegetables but also in some fruits, can induce histone post-translational modifications by inhibiting HDAC activity.⁵²

Early-life nutrient exposures that can occur through pregnancy and breastfeeding have also been linked with cognition and dementia. Obesity is considered an important risk factor for cognitive decline. Parental obesity is associated with altered DNA methylation at multiple genes. Maternal obesity can influence the expression of multiple genes in the fetal brain, possibly altering the developmental program of key fetal brain regions involved in neurological disorders in later life.⁵³ Paternal obesity is associated with hypomethylation of the gene encoding insulin-like growth factor 2 (IGF2) in newborns.⁵⁴ IGF2 is a growth factor with effects on fetal skeletal muscle growth and development, while it also has a known insulin-like action that can contribute to obesity risk in adults.⁵⁵ Imbalanced maternal intake of specific nutrients, such as folate and vitamin B12, has been associated with global DNA hypomethylation in the offspring that is normalized by omega-3 fatty acid supplementation delivered 3 months postnatally.⁵⁶ This also highlights the importance of the interactions between different nutrients in modulating the expression of multiple genes linked with long-term neuroprotection and cognition.

Physical exercise

Both in human populations and animal models, exercise has been found to positively influence brain function, improving memory and learning and promoting healthy brain aging.⁵⁷ In a large meta-analysis that included several cohorts and 33,816 individuals, higher levels of physical activity were associated with a significant reduction in dementia risk.⁵⁸ Although the level of possible activity is more limited for older adults with osteoarthritis or other motor disabilities, even minimal amounts of exercise have been shown to help prevent dementia in this population, supporting the role of exercise in at-risk groups.⁵⁹ However, randomized controlled trials revealed conflicting results regarding the impact of exercise on cognition and the brain, raising some concerns about the effectiveness of exercise in preventing dementia.⁶⁰ It should also be noted that exercising in the setting of high air pollution in urban environments and cities might not be beneficial because air pollution intake increases considerably due to an increased ventilation rate and particle deposition fraction that can negatively influence brain function.⁶¹

Physical exercise can induce DNA methylation changes by regulating DNMTs and demethylases. It has been shown that DNMT1 and DNMT3b levels in the hippocampus of young adult rats can be decreased by a single exercise session. This, however, does not apply to aged rats, even when a longer exercise protocol is followed.⁶² In contrast to DNMTs, enzymes involved in DNA demethylation are regulated by physical exercise in aged animals. A 2-week voluntary wheel training in sedentary rats increased the level of hippocampal Tet1,⁶³ while a 4-week physical exercise increased the hippocampal 5-hmC content, counteracting the decreased Tet1 and Tet2 expression induced by aging and, in turn, promoting cognitive functions of aged mice.¹⁷ Additionally, physical exercise has been reported to increase the level of activated MeCP2 (Methyl-CpG binding protein 2), a protein binding to methylated DNA (i.e., a DNA methylation reader).⁶⁴ Wheel-running exercise increased activated MeCP2 and the expression levels of the brain-derived neurotrophic factor (BDNF) in the rat hippocampus.⁶⁵

Increased BDNF expression induced by physical exercise was also a common mediator of enhanced cognitive ability in other rodent studies.⁶⁶ More specifically, studies have reported reduced HDAC2 and HDAC3 expression⁶⁷ as well as increased global H3 acetylation and reduced DNMT and HDAC levels,⁶⁸ resulting in increased BDNF expression. Finally, voluntary wheel running upregulated 20 miRNAs and downregulated 12 miRNAs in the hippocampus of adult mice, enhancing cognitive function.⁶⁹

Psychosocial stress

Studies on stress and health show that cumulative or severe adverse childhood experiences are significantly associated with increased risk for dementia.^70–72 The association between stress exposure and cognitive impairment has been supported by preclinical studies. Maternal separation in mice has been reported to dysregulate microglia function, facilitate Aβ plaque formation, and worsen cognitive function.⁷³ In line with these preclinical observations, childhood maltreatment and loss of a parent or other relatives during early life have been linked to higher dementia risk.^74,75 Exposure to chronic stress and lifetime trauma during adulthood has also been associated with a decline in cognitive functioning assessed in both midlife and later life.⁷⁶

Life adversity can have epigenetic effects relevant to human health that can last throughout life and could even be passed on to future generations. Psychosocial stress has been shown to induce changes in DNA methylation and gene expression that are relevant to aging-related and other disease states.⁷⁷ For example, a number of studies have found associations between psychosocial stressors and promoter methylation of the gene encoding the glucocorticoid receptor.^78–80 Stress has also been found to synergize with aging to alter DNA methylation across the epigenome and at specific genomic sites, such as the gene encoding the stress-responsive molecule FK506-binding protein 5 (FKBP5/FKBP51).^81,82 FKBP5 hypomethylation was associated with enhanced FKBP5 expression in immune cells, heightened peripheral inflammation, and cardiovascular risk.⁸¹ Notably, the FKBP5 protein has also been shown to influence other aging-related processes and disease phenotypes relevant to dementia, including tau degradation and neurodegeneration.^83,84 Life adversity has been further associated with epigenetic regulation of BDNF.⁸⁵ Maternal separation in rats resulted in biphasic changes in histone 3-lysine 9 dimethylation (H3K9me2) at the Bdnf IV promoter. H3K9me2 initially decreased into young adulthood before reversing into a significantly increased histone demethylation in midlife. These changes in H3K9me2 inversely correlated with BDNF exon IV transcription and hippocampal neurogenesis.⁸⁶ In conclusion, evidence supports epigenetic regulation as a highly plausible link between psychosocial stress and cognitive decline, but the underlying mechanisms have not been adequately examined.

Strengths and limitations should be kept in mind when translating the findings on psychosocial stress from rodents and other model organisms. Human psychosocial environments are far more intricate and multifaceted, making phenotypes such as stress and dementia also more complex to understand. By enabling controlled experimental manipulation, studies in model organisms can yield mechanistic insights about certain biological processes conserved in humans, but their findings and potential implications should be interpreted with caution.

Environmental toxins

Environmental toxins can come in various forms, such as air pollutants, persistent organic pollutants, toxic metals like arsenic, mercury, lead, cadmium, nickel and manganese, polycyclic aromatic hydrocarbons, tobacco smoke, and aflatoxin B1.⁸⁷ Killin et al. provided a systematic review of environmental toxins linked with dementia risk.²⁸ Air quality measured by levels of nitrogen dioxide and carbon monoxide was shown to have a dose-response relationship with dementia risk.⁸⁸ Second-hand tobacco exposure was also found to be associated with severe dementia syndromes.⁸⁹ Accordingly, long-term improvements in ambient air quality has been associated with lower dementia risk in older women.⁹⁰ Toxic metals have also been associated with dementia risk.²⁸ Furthermore, exposure to fine particulate matter and ozone levels above standards in megacities like Metropolitan Mexico City is linked to increased AD risk, likely as a result of increased neuroinflammation and neurodegeneration.⁹¹ Notably, air pollution, particularly exposure to ultrafine particulate matter and industrial nanoparticles, poses significant early risks for neurodegeneration.

Little is known about the epigenetic and other molecular mechanisms through which environmental toxins may contribute to dementia risk. Studies in both cultured cells and human cohorts suggest that metals such as mercury and manganese are associated with increased AβPP expression, circulating Aβ peptides, and AD risk.^92,93 Convergent findings across rodents and humans also suggest that prenatal particulate matter exposure is linked to dysregulation of biological pathways relevant to neuronal survival and neurodegeneration, infant neurodevelopmental delays, and changes in miRNA levels found in placental extracellular vesicles.^94,95 While these early findings suggest that environmental toxins can epigenetically regulate the expression of molecules involved in dementia pathology,⁹⁶ further research is needed to understand the underlying mechanisms.

Clinical implications and interventions

Acetylcholinesterase inhibitors such as donepezil, rivastigmine, galantamine, and tacrine as well as the N-methyl-D-aspartate receptor antagonist memantine are medications currently approved by the FDA for the treatment of AD, but they can only improve symptoms rather than modifying disease progression. An improved understanding of the epigenetic underpinnings of dementias may open opportunities for developing new treatment strategies for these devastating diseases. Experiments in model organisms have provided early support for the potential role of targeting DNA methylation and histone modifications in dementia.⁹⁷ Increases in the methyl donor S-adenosyl-L-methionine have been demonstrated to reduce the production of AβPP and Aβ through hypermethylation of genes involved in relevant biological pathways.^98,99 Small molecules acting as HDAC inhibitors can pass the blood-brain barrier, delaying the onset and progression of symptoms and enhancing cognitive performance in animal models of AD.¹⁰⁰ Several drugs known to act as HDAC inhibitors, including trichostatin A, sodium 4-phenylbutyrate, and valproic acid, have shown benefits across both cell and rodent models of AD, collectively contributing to decreased Aβ production and tau pathology, enhanced neuroprotection and synaptic plasticity, and improved cognitive functioning.^38,101–104 Targeting these epigenetic modifications could pave the way for new, personalized therapies for neurodegenerative disorders. However, there is much research needed to be done before such therapeutic modalities become clinically applicable.

Conclusions/ future directions

As schematically summarized in Figure 1, epigenetic regulation is a key candidate for understanding how environmental factors contribute to dementia risk, but much evidence is still needed before reaching conclusive evidence on specific mechanisms. An improved understanding of the epigenetic mechanisms involved in dementia pathogenesis has the potential to promote the development of novel biomarkers for predicting outcomes but also targeted therapies to intervene early in the course of the disease. We thus hope that this narrative review will spur future studies on this important line of research.

Figure 1.

Simplified scheme summarizing evidence to date and model of epigenetic regulation as a link between environmental factors and dementia risk. APP: amyloid precursor protein; BDNF: brain-derived neurotrophic factor; DNMTs: DNA methyltransferases; HATs: histone acetyltranferases; HDACs: histone deacetylases; TETs: Ten-eleven translocation methylcytosine dioxygenases.

Footnotes

Acknowledgments

The authors have no acknowledgments to report.

Author contributions

Adamantia Koulouri (Writing – original draft; Writing – review & editing); Anthony S Zannas (Conceptualization; Supervision; Writing – original draft; Writing – review & editing).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Arvanitakis

Shah

Bennett

. Diagnosis and management of dementia: review. JAMA 2019; 322: 1589–1599.

Glenner

Wong

. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885–890.

Tsering

Prokop

. Neuritic plaques - Gateways to understanding Alzheimer's disease. Mol Neurobiol 2024; 61: 2808–2821.

Mehta

Schneider

. Neuropathology of the common forms of dementia. Clin Geriatr Med 2023; 39: 91–107.

Ferrari

Sorbi

. The complexity of Alzheimer's disease: an evolving puzzle. Physiol Rev 2021; 101: 1047–1081.

Duara

Barker

. Heterogeneity in Alzheimer's disease diagnosis and progression rates: implications for therapeutic trials. Neurotherapeutics 2022; 19: 8–25.

Fraga

Ballestar

Paz

, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 2005; 102: 10604–10609.

López-Otín

Blasco

Partridge

, et al. Hallmarks of aging: an expanding universe. Cell 2023; 186: 243–278.

Nativio

Lan

Donahue

, et al. An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease. Nat Genet 2020; 52: 1024–1035.

10.

Nicoglou

. Waddington's epigenetics or the pictorial meetings of development and genetics. Hist Philos Life Sci 2018; 40: 61.

11.

Cavalli

Heard

. Advances in epigenetics link genetics to the environment and disease. Nature 2019; 571: 489–499.

12.

Moore

Fan

. DNA Methylation and its basic function. Neuropsychopharmacology 2013; 38: 23–38.

13.

Szyf

Tang

Hill

, et al. The dynamic epigenome and its implications for behavioral interventions: a role for epigenetics to inform disorder prevention and health promotion. Transl Behav Med 2016; 6: 55–62.

14.

Valente

Liu

Schnekenburger

, et al. Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells. J Med Chem 2014; 57: 701–713.

15.

Liu

. Distribution of 5-hydroxymethylcytosine in different human tissues. J Nucleic Acids 2011; 2011: 870726.

16.

Williams

Christensen

Pedersen

, et al. TET1 And hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 2011; 473: 343–348.

17.

Jessop

Toledo-Rodriguez

. Hippocampal TET1 and TET2 expression and DNA hydroxymethylation are affected by physical exercise in aged mice. Front Cell Dev Biol 2018; 6: 45.

18.

Portela

Esteller

. Epigenetic modifications and human disease. Nat Biotechnol 2010; 28: 1057–1068.

19.

Marmorstein

Zhou

. Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb Perspect Biol 2014; 6: a018762.

20.

Yao

Chen

Zhou

. The roles of microRNAs in epigenetic regulation. Curr Opin Chem Biol 2019; 51: 11–17.

21.

Villela

Ramalho

Silva

, et al. Differential DNA methylation of microRNA genes in temporal cortex from Alzheimer's disease individuals. Neural Plast 2016; 2016: 2584940.

22.

Schneider

Chatterjee

Bousiges

, et al. Acetyltransferases (HATs) as targets for neurological therapeutics. Neurotherapeutics 2013; 10: 568–588.

23.

Basavarajappa

Subbanna

. Histone methylation regulation in neurodegenerative disorders. Int J Mol Sci 2021; 22: 4654.

24.

Santana

Smith

MAC

Chen

. Histone modifications in Alzheimer's disease. Genes (Basel) 2023; 14: 47.

25.

Abdelmaksoud

Sallam

Abulsoud

, et al. Unraveling the role of miRNAs in the diagnosis, progression, and therapeutic intervention of Alzheimer's disease. Pathol Res Pract 2024; 253: 155007.

26.

Marzi

Leung

Ribarska

, et al. A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nat Neurosci 2018; 21: 1618–1627.

27.

Vacher

Canovas

Laws

, et al. A comprehensive multi-omics analysis reveals unique signatures to predict Alzheimer's disease. Front Bioinform 2024; 4: 1390607.

28.

Killin

Starr

Shiue

, et al. Environmental risk factors for dementia: a systematic review. BMC Geriatr 2016; 16: 75.

29.

Wang

Qin

, et al. Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer's disease. FASEB J 2005; 19: 659–661.

30.

Schroeder

Richardson

Virley

. Dietary manipulation and caloric restriction in the development of mouse models relevant to neurological diseases. Biochim Biophys Acta 2010; 1802: 840–846.

31.

Qin

Chachich

Lane

, et al. Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). J Alzheimers Dis 2006; 10: 417–422.

32.

Steinkraus

Smith

Davis

, et al. Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell 2008; 7: 394–404.

33.

Srivastava

Haigis

. Role of sirtuins and calorie restriction in neuroprotection: implications in Alzheimer's and Parkinson's diseases. Curr Pharm Des 2011; 17: 3418–3433.

34.

Karagiannis

Ververis

. Potential of chromatin modifying compounds for the treatment of Alzheimer's disease. Pathobiol Aging Age Relat Dis 2012; 2: 10.3402/pba.v2i0.14980.

35.

Edwards

Canfield

Copes

, et al. D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging (Albany NY) 2014; 6: 621–644.

36.

Zhang

Poplawski

Yen

, et al. Role of CBP and SATB-1 in aging, dietary restriction, and insulin-like signaling. PLoS Biol 2009; 7: e1000245.

37.

Boyles

Lantz

Poertner

, et al. Presenilin controls CBP levels in the adult Drosophila central nervous system. PLoS One 2010; 5: e14332.

38.

Ricobaraza

Cuadrado-Tejedor

Pérez-Mediavilla

, et al. Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model. Neuropsychopharmacology 2009; 34: 1721–1732.

39.

Scarmeas

Anastasiou

Yannakoulia

. Nutrition and prevention of cognitive impairment. Lancet Neurol 2018; 17: 1006–1015.

40.

Hardman

Kennedy

Macpherson

, et al. Adherence to a Mediterranean-style diet and effects on cognition in adults: a qualitative evaluation and systematic review of longitudinal and prospective trials. Front Nutr 2016; 3: 22.

41.

van den Brink

Brouwer-Brolsma

Berendsen

AAM

, et al. The Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets are associated with less cognitive decline and a lower risk of Alzheimer's disease-A review. Adv Nutr 2019; 10: 1040–1065.

42.

Andreu-Reinón

Chirlaque

Gavrila

, et al. Mediterranean Diet and risk of dementia and Alzheimer's disease in the EPIC-Spain Dementia Cohort Study. Nutrients 2021; 13: 00.

43.

Limongi

Siviero

Bozanic

, et al. The effect of adherence to the Mediterranean diet on late-life cognitive disorders: a systematic review. J Am Med Dir Assoc 2020; 21: 1402–1409.

44.

Morris

Tangney

Wang

, et al. MIND Diet associated with reduced incidence of Alzheimer's disease. Alzheimers Dement 2015; 11: 1007–1014.

45.

Stefaniak

Dobrzyńska

Drzymała-Czyż

, et al. Diet in the prevention of Alzheimer's disease: current knowledge and future research requirements. Nutrients 2022; 14: 4564.

46.

McEvoy

Guyer

Langa

, et al. Neuroprotective diets are associated with better cognitive function: the Health and Retirement Study. J Am Geriatr Soc 2017; 65: 1857–1862.

47.

Businaro

Ippoliti

Ricci

, et al. Alzheimer's disease promotion by obesity: induced mechanisms-molecular links and perspectives. Curr Gerontol Geriatr Res 2012; 2012: 986823.

48.

Tosti

Bertozzi

Fontana

. Health benefits of the Mediterranean diet: metabolic and molecular mechanisms. J Gerontol A Biol Sci Med Sci 2018; 73: 318–326.

49.

Dauncey

. Nutrition, the brain and cognitive decline: insights from epigenetics. Eur J Clin Nutr 2014; 68: 1179–1185.

50.

Mischoulon

Raab

. The role of folate in depression and dementia. J Clin Psychiatry 2007; 68: 28–33.

51.

Tiffon

. The impact of nutrition and environmental epigenetics on human health and disease. Int J Mol Sci 2018; 19: 3425.

52.

Berger

Venturelli

Kallnischkies

, et al. Kaempferol, a new nutrition-derived pan-inhibitor of human histone deacetylases. J Nutr Biochem 2013; 24: 977–985.

53.

Stachowiak

Oommen

Vasu

, et al. Maternal obesity affects gene expression and cellular development in fetal brains. Nutr Neurosci 2013; 16: 96–103.

54.

Soubry

Schildkraut

Murtha

, et al. Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med 2013; 11: 29.

55.

Roth

Schrager

Metter

, et al. IGF2 Genotype and obesity in men and women across the adult age span. Int J Obes Relat Metab Disord 2002; 26: 585–587.

56.

Kulkarni

Dangat

Kale

, et al. Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats. PLoS One 2011; 6: e17706.

57.

Rolland

Abellan van Kan

Vellas

. Healthy brain aging: role of exercise and physical activity. Clin Geriatr Med 2010; 26: 75–87.

58.

Sofi

Valecchi

Bacci

, et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med 2011; 269: 107–117.

59.

Chung

Wei

Tzeng

, et al. Minimal amount of exercise prevents incident dementia in cognitively normal older adults with osteoarthritis: a retrospective longitudinal follow-up study. Sci Rep 2023; 13: 16568.

60.

Demurtas

Schoene

Torbahn

, et al. Physical activity and exercise in mild cognitive impairment and dementia: an umbrella review of intervention and observational studies. J Am Med Dir Assoc 2020; 21: 1415–1422.e1416.

61.

Bos

De Boever

Int Panis

, et al. Physical activity, air pollution and the brain. Sports Med 2014; 44: 1505–1518.

62.

Elsner

Lovatel

Moysés

, et al. Exercise induces age-dependent changes on epigenetic parameters in rat hippocampus: a preliminary study. Exp Gerontol 2013; 48: 136–139.

63.

Sølvsten

CAE

de Paoli

Christensen

, et al. Voluntary physical exercise induces expression and epigenetic remodeling of VegfA in the rat hippocampus. Mol Neurobiol 2018; 55: 567–582.

64.

Guy

Cheval

Selfridge

, et al. The role of MeCP2 in the brain. Annu Rev Cell Dev Biol 2011; 27: 631–652.

65.

Gomez-Pinilla

Zhuang

Feng

, et al. Exercise impacts brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation. Eur J Neurosci 2011; 33: 383–390.

66.

Pietrelli

Matković

Vacotto

, et al. Aerobic exercise upregulates the BDNF-Serotonin systems and improves the cognitive function in rats. Neurobiol Learn Mem 2018; 155: 528–542.

67.

Sleiman

Henry

Al-Haddad

, et al. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Elife 2016; 5: e15092.

68.

Abel

Rissman

. Running-induced epigenetic and gene expression changes in the adolescent brain. Int J Dev Neurosci 2013; 31: 382–390.

69.

Bao

Miao

Han

, et al. Spontaneous running wheel improves cognitive functions of mouse associated with miRNA expressional alteration in hippocampus following traumatic brain injury. J Mol Neurosci 2014; 54: 622–629.

70.

Grande

Qiu

Fratiglioni

. Prevention of dementia in an ageing world: evidence and biological rationale. Ageing Res Rev 2020; 64: 101045.

71.

Luo

Beam

Gatz

. Is stress an overlooked risk factor for dementia? A systematic review from a lifespan developmental perspective. Prev Sci 2023; 24: 936–949.

72.

Rakesh

Szabo

Alexopoulos

, et al. Strategies for dementia prevention: latest evidence and implications. Ther Adv Chronic Dis 2017; 8: 121–136.

73.

Tanaka

Hirai

Hosokawa

, et al. Early-life stress induces the development of Alzheimer's disease pathology via angiopathy. Exp Neurol 2021; 337: 113552.

74.

Conde-Sala

Garre-Olmo

. Early parental death and psychosocial risk factors for dementia: a case-control study in Europe. Int J Geriatr Psychiatry 2020; 35: 1051–1059.

75.

Widom

Lynch

, et al. Childhood maltreatment and dementia risk factors in midlife: a prospective investigation. Curr Alzheimer Res 2023; 20: 636–647.

76.

Lynch

Lachman

. The effects of lifetime trauma exposure on cognitive functioning in midlife. J Trauma Stress 2020; 33: 773–782.

77.

Gassen

Chrousos

Binder

, et al. Life stress, glucocorticoid signaling, and the aging epigenome: implications for aging-related diseases. Neurosci Biobehav Rev 2017; 74: 356–365.

78.

McGowan

Sasaki

D'Alessio

, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009; 12: 342–348.

79.

Shields

Wise

Ruiz-Narvaez

, et al. Childhood abuse, promoter methylation of leukocyte NR3C1 and the potential modifying effect of emotional support. Epigenomics 2016; 8: 1507–1517.

80.

Tyrka

Price

Marsit

, et al. Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults. PLoS One 2012; 7: e30148.

81.

Zannas

Jia

Hafner

, et al. Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappaB-driven inflammation and cardiovascular risk. Proc Natl Acad Sci U S A 2019; 116: 11370–11379.

82.

Zannas

. Epigenetics as a key link between psychosocial stress and aging: concepts, evidence, mechanisms. Dialogues Clin Neurosci 2019; 21: 389–396.

83.

Blair

Nordhues

Hill

, et al. Accelerated neurodegeneration through chaperone-mediated oligomerization of tau. J Clin Invest 2013; 123: 4158–4169.

84.

Zannas

Wiechmann

Gassen

, et al. Gene-stress-epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology 2016; 41: 261–274.

85.

Daskalakis

De Kloet

Yehuda

, et al. Early life stress effects on glucocorticoid-BDNF interplay in the hippocampus. Front Mol Neurosci 2015; 8: 68.

86.

Suri

Veenit

Sarkar

, et al. Early stress evokes age-dependent biphasic changes in hippocampal neurogenesis, BDNF expression, and cognition. Biol Psychiatry 2013; 73: 658–666.

87.

Sokan-Adeaga

, et al. Environmental toxicants and health adversities: a review on interventions of phytochemicals. J Public Health Res 2023; 12: 22799036231181226.

88.

Chang

Muo

, et al. Increased risk of dementia in patients exposed to nitrogen dioxide and carbon monoxide: a population-based retrospective cohort study. PLoS One 2014; 9: e103078.

89.

Chen

Wilson

Chen

, et al. Association between environmental tobacco smoke exposure and dementia syndromes. Occup Environ Med 2013; 70: 63–69.

90.

Wang

Younan

Millstein

, et al. Association of improved air quality with lower dementia risk in older women. Proc Natl Acad Sci U S A 2022; 119: e2107833119.

91.

Calderón-Garcidueñas

Torres-Jardón

Kulesza

, et al. Alzheimer disease starts in childhood in polluted Metropolitan Mexico City. A major health crisis in progress. Environ Res 2020; 183: 109137.

92.

Song

Choi

. Mercury induced the accumulation of amyloid beta (Aβ) in PC12 cells: the role of production and degradation of Aβ. Toxicol Res 2013; 29: 235–240.

93.

Tong

Yang

Tian

, et al. High manganese, a risk for Alzheimer's disease: high manganese induces amyloid-β related cognitive impairment. J Alzheimers Dis 2014; 42: 865–878.

94.

Wang

Zhou

Zhao

, et al. Prenatal fine particulate matter exposure associated with placental small extracellular vesicle derived microRNA and child neurodevelopmental delays. Sci Total Environ 2022; 841: 156747.

95.

Liu

, et al. Maternal urban particulate matter exposure and signaling pathways in fetal brains and neurobehavioral development in offspring. Toxicology 2022; 474: 153225.

96.

Ijomone

Iroegbu

, et al. Epigenetic influence of environmentally neurotoxic metals. Neurotoxicology 2020; 81: 51–65.

97.

Adwan

Zawia

. Epigenetics: a novel therapeutic approach for the treatment of Alzheimer's disease. Pharmacol Ther 2013; 139: 41–50.

98.

Fuso

Seminara

Cavallaro

, et al. S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci 2005; 28: 195–204.

99.

Chan

Shea

. Folate deprivation increases presenilin expression, gamma-secretase activity, and Abeta levels in murine brain: potentiation by ApoE deficiency and alleviation by dietary S-adenosyl methionine. J Neurochem 2007; 102: 753–760.

100.

Coppedè

. The potential of epigenetic therapies in neurodegenerative diseases. Front Genet 2014; 5: 220.

101.

Hsing

Hung

Chen

, et al. Histone deacetylase inhibitor trichostatin A ameliorated endotoxin-induced neuroinflammation and cognitive dysfunction. Mediators Inflamm 2015; 2015: 163140.

102.

Peng

Deng

, et al. Action of trichostatin A on Alzheimer's disease-like pathological changes in SH-SY5Y neuroblastoma cells. Neural Regen Res 2020; 15: 293–301.

103.

Ricobaraza

Cuadrado-Tejedor

Marco

, et al. Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus 2012; 22: 1040–1050.

104.

Qing

, et al. Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. J Exp Med 2008; 205: 2781–2789.

Epigenetics as a link between environmental factors and dementia risk

Abstract

Keywords

Introduction

Brief primer on epigenetics

Epigenetic mechanisms linking environment and dementia

Nutrition

Physical exercise

Psychosocial stress

Environmental toxins

Clinical implications and interventions

Conclusions/ future directions

Footnotes

Acknowledgments

Author contributions

Declaration of conflicting interests

Funding

References