The impact of sex on memory during aging and Alzheimer's disease progression: Epigenetic mechanisms

Abstract

Alzheimer's disease (AD) is a leading cause of dementia, disability, and death in the elderly. While the etiology of AD is unknown, there are several established risk factors for the disease including, aging, female sex, and genetics. However, specific genetic mutations only account for a small percentage (1–5%) of AD cases and the much more common sporadic form of the disease has no causative genetic basis, although certain risk factor genes have been identified. While the genetic code remains static throughout the lifetime, the activation and expression levels of genes change dynamically over time via epigenetics. Recent evidence has emerged linking changes in epigenetics to the pathogenesis of AD, and epigenetic alterations also modulate cognitive changes during physiological aging. Aging is the greatest risk factor for the development of AD and two-thirds of all AD patients are women, who experience an increased rate of symptom progression compared to men of the same age. In humans and other mammalian species, males and females experience aging differently, raising the important question of whether sex differences in epigenetic regulation during aging could provide an explanation for sex differences in neurodegenerative diseases such as AD. This review explores distinct epigenetic changes that impact memory function during aging and AD, with a specific focus on sexually divergent epigenetic alterations (in particular, histone modifications) as a potential mechanistic explanation for sex differences in AD.

Keywords

aging Alzheimer's disease epigenetics histone modifications sex

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily effects the elderly and is characterized by irreversible memory loss and neuropathological changes in the brain. AD is currently one of the most pervasive age-related public health concerns and is projected to impact 152 million people aged 65 or older by 2050.¹ While aging does not cause AD directly, the rate of AD cases is positively correlated with aging with a prevalence of 5% at age 65 and over 30% by age 85.^1–3 Aging is a complex process characterized by a time-dependent deterioration in physiological and cognitive functions, and encompasses a wide range of biological changes, many of which can become risk factors for neurodegenerative disorders.^2,4–6 The progression of aging can be attributed to both intrinsic factors such as cellular damage and loss,^7,8 as well as extrinsic factors such as environmental pollutants and lifestyle.^9–11 Many mechanistic hypotheses for aging and age-related neurodegenerative disorders have been proposed, and one of these potential mechanisms is epigenetic modifications.

Epigenetics refers to a collection of dynamic modifications that affect gene expression levels and activation states. While essential genetic information is established at birth and remains static throughout the lifetime, epigenetic modifications are malleable and change in accordance with various behavioral, physiological, and environmental stimuli/processes, including aging.^10,12,13 In fact, recent evidence has emerged suggesting that mammalian aging is driven largely by erosion of the epigenetic landscape, leading to cellular ex-differentiation, senescence, and a loss of transcriptional networks.¹⁴ Specifically, experimental acceleration of epigenetic aging in mice disrupts developmental genes, alters spatial chromatin contacts, and impairs short- and long-term memory.¹⁴ Age-related epigenetic changes translate to substantial alterations in gene expression patterns corresponding with a gradual decline in physical and cognitive functioning.^10,12,13 For example, within the brain, decreased expression levels of genes related to synaptic function and GTPase activity contribute to a loss in cognitive flexibility¹⁵ and impairments in long-term potentiation, the cellular underpinning of memory formation.¹⁶ However, while a general, time-related senescent phenotype is characteristic of all eukaryotic species, aging is not a universally experienced process and varies greatly within a population.^17–20 Interestingly, studies of aging monozygotic twins have demonstrated that epigenetic modifications, including DNA methylation and histone acetylation, can vary significantly between older identical twins, but are similar at younger ages,²¹ suggesting that novel experiences and exposures impact the trajectory of aging at the epigenetic level.

Additionally, in humans and many other mammalian species, males and females age differently.²² For example, women tend to live longer than men in most populations^19,23,24 and experience a slower overall rate of molecular,^25–27 metabolic,²⁸ and cognitive²⁹ aging. Sex differences in aging trajectories, including lifespan, may be related to fundamental differences in age-related epigenetic modifications.^23,30,31 Specifically, epigenetic divergences between the sexes include telomere attrition, progressive skewing of X chromosome inactivation, and maternally inherited mirochondrial inheritance patterns.^19,23,32,33 Understanding these epigenetic mechanisms and how they regulate gene expression and function during aging could provide a framework for evaluating sex-biased suseptability to a broad range of aging-related brain disorders. This review will focus on evaluating the epigenetic mechanims of aging and AD, with a specific focus on histone modifications, as the previous literature on this topic mostly focuses on DNA methylation.^26,34–36 The concept of a sexually divergent epigenetic aging process will also be discussed and this potiential novel mechanism may help to explain sex differences in the suceptibility to AD.

Epigenetics and histone modifications

Consisting of approximately 20,000 genes that encode for as many as 100,000 proteins, the human genome is vast, but it is also dynamic. While every cell in the human body contains all 3.2 billion base pairs of DNA, cellular fate is determined through the selective expression and repression of various genes through epigenetics, first described in 1942 by Conrad Waddington.³⁷ Within each cell, nearly 2 meters of chromosomal DNA is packaged inside nuclei by wrapping around histones, positively charged proteins that strongly adhere to the negative charge of DNA. While the raw genetic information contained within DNA does not change, how tightly DNA is packaged around histones determines the relative accessibility of genes: highly condensed DNA, known as heterochromatin, largely contains silent genes, while loosely packaged DNA, or euchromatin, generally consists of active/open genetic material that can be easily transcribed. There are three primary epigenetic mechanisms that impact chromatin structure and genetic activity: DNA methylation, histone modifications, and non-coding RNA. DNA methylation is a mechanism by which a methyl group is covalently transferred onto DNA strands by DNA methyltransferases, which can either silence or activate a given gene depending on the type and location of the methylation.^38,39 Another well-studied epigenetic mechanism is histone modification, in which the addition or removal of a chemical group (e.g., methyl, acetyl) to histone tails determines the transcriptional state of the local genomic region by altering nucleosome positioning, histone-DNA interactions, and access to DNA for gene transcription. Lastly, non-coding RNA are RNA molecules transcribed from the genome that do not encode proteins, but rather control gene expression by interacting with protein-coding RNA directly and/or by recruiting proteins that modify histones.^40–42 The primary focus of this review will be histone modifications in mammalian species.

A typical nucleosome consists of two identical subunits, each consisting of four histone proteins: H2A, H2B, H3, and H4, while the H1 protein acts to stabilize internucleosomal DNA. Each of these histones is susceptible to a unique series of post-translational modifications including acetylation, methylation, phosphorylation, and ubiquitination. Chemical groups are added or removed from histone tails at specific amino acid residues (primarily lysine and arginine) by enzymes. Broadly, enzymes that introduce various chemical modifications to histones such as histone acetyl transferases (HATs) and methyltransferases, are referred to as “writers”, while those that remove chemical tags such as histone deacetylases (HDACs) and demethylases, are known as “erasers.”⁴³ In general, certain histone modifications are associated more with gene transcription/activation, while others are more closely linked to transcriptional repression and gene silencing.^44,45 Currently, well over 1000 different histone modifications have been identified and the functional complexity of these modifications as well as how they interact with each other, have yet to be fully understood.⁴⁵ Nonetheless, a tightly regulated balance of both active and repressive histone markers at specific amino acid residues on histone tails is essential for the homeostatic regulation of gene expression which impacts a wide range of biological processes, including cell cycle regulation,^46,47 embryogenesis,⁴⁸ and learning and memory.

Histone modifications in learning and memory

The dynamic nature of histone modifications allows for the fine-tuning of gene expression in response to neural activity and is thus essential in learning and memory.^49–52 In vivo pharmacological and genetic studies indicate that enzymatic writers, readers, and erasers facilitate the formation and stabilization of memory by regulating activity-triggered gene expression and maintaining molecular changes induced by memory-related events.^53,54 For instance, modifications to chromatin structure that promote active gene transcription are necessary for processes such as long-term potentiation (LTP), the cellular basis for memory formation. Indeed, genetic knockout of the acetyltransferase CREB-binding protein (CBP) in hippocampal neurons of the CA1 results in significant cognitive changes in rodents including impairment of LTP, contextual fear conditioning, object recognition, spatial navigation, and long-term memory.^55–57 Similarly, mutant CBP knock-in mice exhibit impaired long-term memory, while short-term memory remained intact, indicating that CBP HAT activity is needed for memory consolidation.⁵⁸ Brain-specific knockouts of other HATs including P300,⁵⁹ P300/CBP-associated factor (PCAF),⁶⁰ and Kat2A⁶¹ also resulted in short-term and working memory deficits along with increased stress responses and altered hippocampal neuronal organization. Conversely, HDACs generally act to repress gene expression and activity. For example, overexpression of HDAC1 in the hippocampus impairs memory recall, spatial learning, and mediates transcriptional repression during learning.⁶² Similarly, knockout models of HDAC2 demonstrate improvements in associative learning, concurrent with an increase in synapse number⁶³ and dendritic spine density.⁶⁴ Conditional knockout of HDAC3 in the hippocampus enhances long-term memory related to object location, however elimination of HDAC4⁶⁵ and/or SIRT1⁶⁶ results in impairment in hippocampal dependent learning, memory, and long-term synaptic plasticity, as well as altered dendritic architecture. Histone methylation also influences memory processes. Pharmacological inhibition of the dimethyltransferase complex G9a/GLP in the hippocampus regulates hippocampal LTP and differentially regulates gene transcription, while brain-specific knockout of histone methyltransferase MLL2 (KMT2B) impairs short-term working memory, object recognition, and associative learning.^67,68 Spatially and temporally specific histone modifications dictate alterations in the expression levels of plasticity-related genes, corresponding with the synthesis of proteins involved in the formation and persistence of memory. For instance, in the hippocampus, the abundancy of the transcriptionally repressive marker H3K9me2, was increased 1 h and decreased 24 h following fear conditioning in mice, whereas the transcriptionally permissive H3K4me3 marker was increased 1 h and decreased 24 h following conditioning in the entorhinal cortex⁶⁷ suggesting that distinct epigenetic mechanisms underly memory formation and consolidation. Other histone alterations such as ubiquitination,^69,70 serotonylation,^71,72 and dopamylation^73,74 may also play a role in the modulation of genes involved in synaptic plasticity and behavior, although the exact mechanisms behind these modifications are less clear. These data collectively indicate that epigenetic regulation is crucial in synaptic plasticity and memory-relevant behavior, supporting the idea that dysregulated histone modifications may enhance memory deficits and accelerate cognitive decline. A summary of the existing literature supporting the regulation of histone modifications in learning and memory can be found in Table 1.

Table 1.

Histone modifications involved in learning and memory.

Histone modifications in age-related cognitive decline

Age-related cognitive decline refers to a gradual decrease in cognitive capabilities that occurs as a normal part of the aging process. While there is a great deal of individual variability in the extent and rate of age-related cognitive decline, it is generally characterized by a decline in functions such as memory, attention, language, executive function, spatial reasoning, and processing speed.^75–77 Importantly, normal (i.e., non-pathological) age-related cognitive decline does not interfere with daily functioning and is less severe than dementia. Factors influencing age-related cognitive decline include overall physical health, lifestyle factors (i.e., diet, exercise), genetics, and epigenetics. In general, patterns of histone acetylation tend to change in response to learning and memory tasks and have been implicated in memory decline in aged rodents.^10,78–80 However, aging does not seem to be linked to global changes in histone acetylation in the brain, as both age-related increases^53,81 and decreases^7,81,82 have been reported. Rather, age-related alterations in histone modifications and the effect of these alterations on gene expression and behavioral phenotypes depends on the type of modification, the location along the histone tail and within the genome, and interactions with transcription factors.^80,83,84 There are also some data to suggest that activity levels of HATs and HDACs are altered in the aging brain. For example, HDAC2 levels have been reported to be elevated in the hippocampus of aged mice⁸⁵ and the binding of HDAC2 to the promoters of immediate early genes (molecular markers of synaptic plasticity) such as Arc, EGR1, Homer1, and Narp, increases with age.⁸⁶ Similarly, HDAC3 deletion or disruption in a mouse model ameliorated age-related deficits in hippocampal LTP and long-term memory.⁸⁷ P300/CBP-associated factor is thought to play a role in vascular aging which may impact brain structure and function via the cerebrovasculature, as dysfunction of the blood brain barrier has been linked to cognitive impairment in normal aging and dementia.^88,89 There is also an age-related increase in levels of H3K9 methyltransferase euchromatic histone methyltransferase 1 (EHMT1) and the epigenetic-related recognition factor, bromodomain adjacent to the zinc finger 2B gene (BAZ2B) in the human prefrontal cortex⁹⁰ and levels of the Lysine Methyltransferase (KMT), SUV39H1, are elevated in the hippocampus of aged mice.⁹¹ Recent evidence has also revealed that the H3K27ac, a gene activation marker, is reduced on the promoters of brain-derived neurotrophic factor (BDNF) exons in the hippocampus of aged mice as compared to adult mice, a process that is mediated by the recruitment of HATs CBP.^92,93 In conjunction with this finding, the inhibitory marker, H3K9me3, was found to be enriched at BDNF and IEG promoters in the hippocampus of aged mice, which may contribute to the downregulation of corresponding protein expression and age-related deficits in hippocampal memory function.^91,94

Overall, certain epigenetic alterations that occur during aging induce transcriptional patterns that lead to abnormal chromatin states and subsequent dysregulation of gene expression patterns in the brain that contribute to cognitive dysfunction.^14,95,96 Specifically, this is thought to occur through the transcriptional repression of genes important to learning, memory, and cognition.^14,20,97 A study in senescence-accelerated prone 8 (SAMP8) mice found that markers of heterochromatin (H4K20me and H3K26me3) were reduced in the brains of aged mice as compared to young adults, while there were increases in the abundancies of H3K27me3, H3K79me, and H3K79me2.⁹⁸ In keeping with this finding, cultured cells from patients with Hutchinson-Gilford Progeria Syndrome, an autosomal-dominant premature aging syndrome, exhibit a reduction in heterochromatic makers H3K27me3 and H3K9me3.⁹⁹ Dysregulation of chromatin architecture at the promoter regions of genes encoding for AMPA and NMDA receptors have also been implicated in age-related alterations in synaptic plasticity and cognitive decline.^78,100,101 Moreover, during learning, aged mice display a specific dysregulation in histone acetylation patterns and fail to initiate a gene expression program conducive to memory consolidation.^78,100 Importantly, age-related alterations in histone modifications in the brain is region- and cell-type-specific. For example, H3K9ac and H3K14ac abundancy was reduced in the CA1, but not CA3, of aged rats, while H3K4me3 abundancy was enhanced in both the CA1 and CA3.^79,102 Additionally, reductions in H3K27me3 abundancy were concentrated primarily on interneurons in aged wild type and AD transgenic mice,^79,103–105 while H3K27me3 abundancy was increased in aged microglia.¹⁰⁶ Finally, there is some indication of an age-related reduction in histone biosynthesis,¹⁰⁷ and histone loss and nucleosomal reorganization are considered key markers of cellular aging, particularly in the brain.¹⁰ Indeed, loss of histones during cellular aging has been observed across multiple eukaryotic species and reduced histone deposition/expression is mediated by anti-silencing factor 1 (ASF1), a histone chaperone important in nucleosome assembly pathways.^108,109 Taken together, findings from these studies support that epigenetic mechanisms, including alterations in histone acetylation, methylation, and chromatin structure, play significant roles in shaping gene expression patterns that underlie changes in cognitive function in the aging brain. A summary of histone modifications that occur during aging can be found in Table 2.

Table 2.

Histone modifications in aging and Alzheimer's disease with sex differences.

Histone modifications in memory deficits and neuropathology of Alzheimer's disease

While certain histone modifications modulate age-related cognitive decline, a distinct set of epigenetic alterations underlies AD pathogenesis. Changes in DNA methylation patterns have been observed with age and AD, and data suggest that methylation patterns are dysregulated in AD neurons, specifically at enhancers associated with amyloid plaques and neurofibrillary tangles.^110,111 Additionally, studies using next generation sequencing techniques to map histone modification patterns support a redistribution of histone modifying post-transcriptional processes in AD brains as compared to those that occur during normal aging.^112–114 However, the mechanism(s) through which histone modifications impact disease progression is not yet known and further research is needed. Moreover, the redistribution in histone modifications that occurs in AD demonstrates the complexity of AD pathogenesis because while some histone markers decline during disease progression, others become more abundant, depending on the genetic loci and stage of disease.¹¹⁵ For instance, higher levels of gene activating histone acetylation markers H3K27ac^113,116 and H3K9ac,¹¹³ have been identified in the temporal cortex of AD postmortem brains, concurrent with lower levels of HDACs^117,118 and higher global levels of H3 acetylation.¹¹⁹ H3K27ac was also enriched in genes related to Aβ (APP, PS1, PS2), Tau (MAPT) processing,^116,120 and transcriptional regulation (CREBBP, EP300, and TRRAP), supporting the epigenetic regulation of pathways involved in AD pathology.¹¹³ Conversely, decreased genome-wide abundancy of H4K16ac has been reported in the brains of AD patients compared to younger and elderly cognitively normal controls.¹²¹ With regards to histone methylation, higher abundancies of H3K9me2¹²² and H3K27me3,¹²³ both repressive markers, have been observed in the PFC and entorhinal cortex, respectively, of AD patient brain tissue compared to healthy controls, along with higher levels of methyltransferases.^122,124 Additionally, reduction in H3K4me3 abundancy, an activating marker, was found to be concentrated on promoters of genes involved in glutamate receptor signaling, providing evidence for chromatin remodeling in neurons that impacts synaptic function in AD.¹²³ These data highlight that AD is not simply due to accelerated aging, but rather dysregulated aging involving chromatin structural changes and epigenetically regulated transcriptional reprograming.

Transgenic rodent models of AD also demonstrate a dysregulation of epigenetic processes linked to AD pathology. For example, levels of methyltransferases were elevated in the PFC of 5xFAD and P301 mice compared to wild type controls^122,124 indicating higher overall methylation activity. The H3K9me2 repressive marker was also enriched at NMDA-related genes Grin2a and Grin2b, corresponding with lower transcription and expression of AMPA and NMDA receptors in 5xFAD mice.¹²² In keeping with this, a separate report found that H3K9ac and H4K12ac abundancy was reduced at genes encoding for NMDA receptors, along with Gria2, and Gria3 (genes encoding for AMPA receptor subunits).¹²⁵ This could indicate that neuronal dysfunction at both the structural and functional levels in AD may be due to epigenetic repression of glutamate receptor transcription leading to impaired synaptic transmission. Since these data indicate that global dysregulation of histone acetylation plays a role in AD pathology,^{116,117,119,126} pharmacological studies have been conducted examining the effect of histone deacetylase (HDAC) inhibitors in AD rodent models. These preclinical studies indicate that both broad-acting and specific HDAC inhibitors could improve memory and decrease AD pathogenesis.^127–129 In particular, HDAC inhibitors have been shown to reduce Aβ deposition and tau phosphorylation, improve performance on learning and spatial memory tasks, and increase synaptic plasticity in various AD rodent models.^127–129 However, conclusions that can be drawn from these studies are limited due to the broad acting nature of these drugs and the fact that they act not only on nuclear histones, but also cytoplasmic proteins. Additional studies examining the effects of histone acetylation/deacetylation at specific genes are needed to fully evaluate the efficacy of HDAC inhibitors as a potential treatment for AD. A brief summary of histone modifications in AD can be found in Table 2.

Sex differences in histone modifications

In addition to age, female sex is considered a significant risk factor for the development of AD. In fact, two-thirds of all AD patients are female, and women exhibit an earlier emergence of AD pathology and higher rates of neurological decline following diagnosis as compared to men.¹³⁰ Though the progression of AD is more rapid among elderly women, studies conducted in the United States and United Kingdom suggest that males with AD have a shorter survival time, suggesting a fundamental difference in disease pathogenesis between the sexes in addition to a discrepancy in lifetime risk.¹³¹ There are many theories regarding this discrepancy, and some of them center around the notion that males and females age differently.^30,132–134 For instance, women have longer life expectancies than men, a discrepancy that has fundamental genetic and epigenetic associations.^19,23,24 To this end, it is important to note that the relatively early death of males (compared to females) following AD diagnosis may not be attributed to AD, but to a relative lack of physical robustness with age in conjunction with a different set of genes regulating longevity. Longevity differences between the sexes may also be derived from X-linked inactivation,^33,135,136 sex differences in the prevalence of age-related diseases such as diabetes, heart disease, and high cholesterol, and/or lifestyle differences such as stress, alcohol consumption, or exposure to environmental toxins and violence.¹³⁷ Additionally, the most robust age-related modification that occurs in women is the drastic change in sex hormone levels during menopause. Estrogen and progesterone in the brain act as neuromodulators¹³⁸ and rapidly changing hormone levels in the brain, both up and down, beginning during perimenopause contributes to changes in neurocircuitry, brain volume, and cognitive function, and is proposed to accelerate the accumulation of DNA methylation in women.^139,140 At the genetic level, both somatic mutation rate and total mutation load are higher in men than in women, indicating that sex influences the extent and type of genomic instability that occurs during aging.¹⁹ DNA methylation patterns also differ in a locus-specific manner between males and females throughout autosomes, with a trend toward higher global methylation levels in males.^141–143 Further, a recent meta-analysis reported that women have longer mean telomere lengths than men regardless of cell type, and the trajectory of telomere attrition is sex-specific.^144,145 Gene expression changes during normal brain aging are also sexually divergent. The brains of males undergo an almost 2-fold greater global gene change with age as compared to females, with the most robust changes occurring between 60–79 years of age.¹⁴⁶ More specifically, according to analysis from the Gene Ontology database, males experience a larger decrease in expression levels of genes related to energy production and protein synthesis/ transport with age as compared to females.¹⁴⁶ A separate transcriptomic analysis in younger brains also revealed a sexually divergent pattern of gene expression beginning at the prenatal stage and peaking during puberty, indicating sex biased gene expression patterns occur throughout the life span.¹⁴⁷ There is also some indication of sex-specific targeting of transcription factors for genes associated with synapse structure, neuronal activity, and neurotransmitter transport.¹⁴⁸

Alterations in gene expression levels is caused by a shift in chromatin architecture from heterochromatin to euchromatin (or vice versa) through histone modifications. Human and animal studies indicate that within the brain, there are variations in the abundancy of different histone modifications between females and males throughout the lifespan. In animals, these differences appear to begin early on, with lower global abundancies of the activating markers H3K9ac, H3K14ac, and H3K9me3 in the cortex and hippocampus in female as compared to male mouse pups.¹⁴⁹ In young adult mice (∼2 months old), females have a higher abundancy of H3K9ac, along with H3K9me2 and H3K27me3 in the hippocampus as compared to males.¹⁵⁰ Female mice of a similar age (∼4 months old), also have higher global cortical abundancies of H3K9me3 and H3K4me3 as compared to males, and lower abundancies of H3K4me3 and H3K9ac within the dentate gyrus.¹⁵¹ Interestingly, a genome wide comparison study of H3K4me3, a histone mark organized around the transcription start sites of active genes, found that 71% of differentially abundant loci were higher in adult female than male mice and many of the sites were genes associated with synaptic function.¹⁵² Finally, limited evidence suggests that there may be sex differences in epigenetic regulation during learning and memory formation. For example, sex differences in fear memory and stress have been linked to alterations in post-translational histone modifications in the frontal cortex and hippocampus.^136,153 Histone variants may also be sex-specific epigenetic regulators of memory. Specifically, H2A.Z, a variant of histone H2A that acts as a negative regulator of fear memory,¹⁵⁴ is more abundant in the brains of female mice as compared to males, and the conditional knockout of H2A.Z enhanced fear memory only in males.¹⁵⁵ H2B ubiquitination is also a crucial element in learning-dependent synaptic plasticity and memory formation for both sexes.⁷⁰ A summary of sex-specific histone modifications can be found in Table 2. Ultimately, it is likely that a complex interplay between genetic, hormonal, psychosocial,^156–159 and environmental factors gives rise to physiological sex differences, modulated by epigenetic alterations that, in turn, dynamically regulate gene expression and function throughout the lifetime, particularly during aging.

Sex differences in epigenetic regulation during aging and AD

Sex differences in epigenetic regulation during aging may contribute to sex differences in age-related neurodegenerative disease susceptibility. Understanding how epigenetic modification patterns diverge between sexes at older ages and to what extent these differences correspond with sex-biased AD risk, may reveal new biomarkers and/or treatment targets for the disease. We hypothesize that aging and female sex interact at the epigenetic level to impact AD etiology (Figure 1). Various genome-wide studies have begun to establish a specific epigenomic signature of AD that differs substantially from epigenetic modifications that occur during normal aging.^13,103,160 Dysregulation of the normal epigenetic aging process, specifically dysregulation of homeostasis between active and repressive histone markers, may trigger and/or promote abnormal gene expression patterns, neuronal dysfunction, and ultimately, the development of AD pathology. In addition to specific histone variants and modifications, gene expression is regulated through the synergistic actions of multiple epigenetic factors including transcriptional machinery and chromatin remodelers.⁴⁵ Due to the dynamic crosstalk between chromatin writers and histone markers at active and repressed genes, along with the dynamic and complex feedback loops that regulate chromatin states,⁴⁵ the processes involved in normal epigenetic aging that become dysregulated in AD cannot be pinpointed to a single event at a single point in time. Rather, this dysregulation is a gradual process that likely begins years, if not decades before symptom onset and females may be more susceptible than males. Aging is the greatest risk factor for the development of AD^2,161–163 and 2/3 of all AD patients are female.^{130,164–166} Women have longer life expectancies than men,¹³³ however the risk of developing AD may be higher for women at any given age due to hormonal or genetic variations, independent of lifespan. Epigenetics plays an important role in regulating the aging process for both sexes as evidenced by twin studies²¹ and changes in gene expression levels throughout the lifespan.^13,147 Sex-specific patterns of histone modifications have been observed at gene promoters of hormone receptors and sex hormones regulate the activity of histone-modifying enzymes.^24,167–169 Finally, unique histone modifications and DNA methylation patterns are present in AD postmortem brains that are distinct from those that occur during normal aging.^{112,114,116,119,170–172} Genome-wide studies evaluating the effect of age, sex, and AD on histone modifications in the brain are needed in order to identify the epigenetic mechanisms involved in converting normal aging to pathological aging. This type of basic and preclinical therapeutic research may ultimately lead to the identification of epigenetic patterns that predict and/or prevent AD development and progression in both men and women.

Figure 1.

The connection between aging, sex, Alzheimer's disease, and epigenetics.

Conclusions and recommendations for future study

Based on the existing literature and our research, we propose that specific dysregulations in epigenetic processes that underly normal aging may tip the scales toward the development of AD pathology, and that women may be more vulnerable to age-related epigenetic dysfunctions than men. An important caveat to this idea is that the timing and progression of aging depends on a complex interplay between internal and external environmental stimuli which have the potential to produce a wide variety of epigenetic effects and is the reason behind the heterogeneous nature of aging itself. Nevertheless, epigenetics represents a promising new field of study that has the potential to provide a novel mechanistic link between aging, sex, and AD that may ultimately lead to the development of new treatment targets to prevent or treat AD. Further research is needed to evaluate to extent to which 1) epigenetic modifications, specifically at genes linked to memory and neuronal function, are differentially regulated in males and females during aging, particularly before and after menopause in women, and 2) dysregulation of these modifications during normal aging initiates and/or accelerates the pathogenesis of AD to a greater extent in females than males.

Footnotes

Acknowledgments

The authors have no acknowledgments to report.

ORCID iD

Sarah B Scheinman

Author contributions

Sarah Scheinman, PhD (Conceptualization; Writing – original draft); Hongxin Dong, MD, PhD (Conceptualization; Writing – review & editing).

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the National Institute of Health grant R01AG079989-01 and the Mechanisms in Aging and Dementia T32 Training Grant (T32AG020506-22).

Declaration of conflicting interests

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

References

2022 Alzheimer's disease facts and figures. Alzheimers Dement 2022; 18: 700–789.

Guerreiro

Bras

. The age factor in Alzheimer's disease. Genome Med 2015; 7: 106.

Lane

Hardy

Schott

. Alzheimer's disease. Eur J Neurol 2018; 25: 59–70.

Liu

. Aging, cellular senescence, and Alzheimer's disease. Int J Mol Sci 2022; 23: 1989.

Tucker-Drob

. Cognitive aging and dementia: a life span perspective. Annu Rev Dev Psychol 2019; 1: 177–196.

Hou

Dan

Babbar

, et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 2019; 15: 565–581.

Sidler

Kovalchuk

. Epigenetic regulation of cellular senescence and aging. Front Genet 2017; 8: 138.

Gladyshev

Kritchevsky

Clarke

, et al. Molecular damage in aging. Nat Aging 2021; 1: 1096–1106.

Ottinger

. A comparative approach to metabolic aspects of aging: conserved mechanisms and effects of calorie restriction and environment. Prog Mol Biol Transl Sci 2018; 155: 109–127.

10.

Saul

Kosinsky

. Epigenetics of aging and aging-associated diseases. Int J Mol Sci 2021; 22: 401.

11.

Lopez-Otin

Blasco

Partridge

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

12.

Benayoun

Pollina

Brunet

. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 2015; 16: 593–610.

13.

Morris

Willcox

Donlon

. Genetic and epigenetic regulation of human aging and longevity. Biochim Biophys Acta Mol Basis Dis 2019; 1865: 1718–1744.

14.

Yang

Hayano

Griffin

, et al. Loss of epigenetic information as a cause of mammalian aging. Cell 2023; 186: 305–326 e327.

15.

Ianov

Riva

Kumar

, et al. DNA Methylation of synaptic genes in the prefrontal cortex is associated with aging and age-related cognitive impairment. Front Aging Neurosci 2017; 9: 249.

16.

Guan

Haggarty

Giacometti

, et al. HDAC2 Negatively regulates memory formation and synaptic plasticity. Nature 2009; 459: 55–60.

17.

Jylhava

Pedersen

Hagg

. Biological age predictors. EBioMedicine 2017; 21: 29–36.

18.

Hertel

Friedrich

Wittfeld

, et al. Measuring biological age via metabonomics: the metabolic age score. J Proteome Res 2016; 15: 400–410.

19.

Fischer

Riddle

. Sex differences in aging: genomic instability. J Gerontol A Biol Sci Med Sci 2018; 73: 166–174.

20.

Bacon

Brinton

. Epigenetics of the developing and aging brain: mechanisms that regulate onset and outcomes of brain reorganization. Neurosci Biobehav Rev 2021; 125: 503–516.

21.

Fraga

Ballestar

Paz

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

22.

Ploner

Wang

, et al. Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up. Elife 2020; 9: e51507.

23.

Engelbrecht

Merrill

Gladish

, et al. Sex differences in epigenetic age in Mediterranean high longevity regions. Front Aging 2022; 3: 1007098.

24.

Hagg

Jylhava

. Sex differences in biological aging with a focus on human studies. Elife 2021; 10: e63425.

25.

Horvath

Gurven

Levine

, et al. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol 2016; 17: 171.

26.

Yusipov

Bacalini

Kalyakulina

, et al. Age-related DNA methylation changes are sex-specific: a comprehensive assessment. Aging (Albany NY) 2020; 12: 24057–24080.

27.

Dela Justina

Miguez

JSG

Priviero

, et al. Sex differences in molecular mechanisms of cardiovascular aging. Front Aging 2021; 2: 725884.

28.

Goyal

Blazey

, et al. Persistent metabolic youth in the aging female brain. Proc Natl Acad Sci U S A 2019; 116: 3251–3255.

29.

McCarrey

Kitner-Triolo

, et al. Sex differences in cognitive trajectories in clinically normal older adults. Psychol Aging 2016; 31: 166–175.

30.

Nakamura

Miyao

. Sex differences in human biological aging. J Gerontol A Biol Sci Med Sci 2008; 63: 936–944.

31.

Gegenhuber

Tollkuhn

. Sex differences in the epigenome: a cause or consequence of sexual differentiation of the brain? Genes (Basel) 2019; 10: 432.

32.

Kankaanpaa

Tolvanen

Saikkonen

, et al. Do epigenetic clocks provide explanations for sex differences in life span? A cross-sectional twin study. J Gerontol A Biol Sci Med Sci 2022; 77: 1898–1906.

33.

Chow

Heard

. X inactivation and the complexities of silencing a sex chromosome. Curr Opin Cell Biol 2009; 21: 359–366.

34.

Semick

Bharadwaj

Collado-Torres

, et al. Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer's disease. Acta Neuropathol 2019; 137: 557–569.

35.

Duan

Sun

, et al. Epigenetic clock: a promising biomarker and practical tool in aging. Ageing Res Rev 2022; 81: 101743.

36.

Rakyan

Down

Maslau

, et al. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 2010; 20: 434–439.

37.

Noble

. Conrad waddington and the origin of epigenetics. J Exp Biol 2015; 218: 816–818.

38.

Jin

Robertson

. DNA Methylation: superior or subordinate in the epigenetic hierarchy? Genes Cancer 2011; 2: 607–617.

39.

Unnikrishnan

Freeman

Jackson

, et al. The role of DNA methylation in epigenetics of aging. Pharmacol Ther 2019; 195: 172–185.

40.

Herman

Tsitsipatis

Gorospe

. Integrated lncRNA function upon genomic and epigenomic regulation. Mol Cell 2022; 82: 2252–2266.

41.

Henshall

. Epigenetics and noncoding RNA: recent developments and future therapeutic opportunities. Eur J Paediatr Neurol 2020; 24: 30–34.

42.

Blount

Coursey

Kocerha

. MicroRNA networks in cognition and dementia. Cells 2022; 11: 1882.

43.

Biswas

Rao

. Epigenetic tools (the writers, the readers and the erasers) and their implications in cancer therapy. Eur J Pharmacol 2018; 837: 8–24.

44.

Gates

. Foulds CE and O'Malley BW. Histone marks in the ‘driver's seat': functional roles in steering the transcription cycle. Trends Biochem Sci 2017; 42: 977–989.

45.

Zhang

Cooper

Brockdorff

. The interplay of histone modifications - writers that read. EMBO Rep 2015; 16: 1467–1481.

46.

Zaib

Rana

Khan

. Histone modifications and their role in epigenetics of cancer. Curr Med Chem 2022; 29: 2399–2411.

47.

Zhang

Chang

. Epigenetics in health and disease. Adv Exp Med Biol 2020; 1253: 3–55.

48.

Kiefer

. Epigenetics in development. Dev Dyn 2007; 236: 1144–1156.

49.

Zovkic

. Epigenetics and memory: an expanded role for chromatin dynamics. Curr Opin Neurobiol 2021; 67: 58–65.

50.

Guan

Xie

Ding

. The role of epigenetic regulation in learning and memory. Exp Neurol 2015; 268: 30–36.

51.

Geng

Chen

Wang

, et al. The histone modifications of neuronal plasticity. Neural Plast 2021; 2021: 6690523.

52.

Pao

Tsai

. Histone deacetylases 1 and 2 in memory function. ACS Chem Neurosci 2022; 13: 848–858.

53.

Castellano

Fletcher

Kelley-Bell

, et al. Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus. PLoS One 2012; 7: e33249.

54.

Zovkic

Guzman-Karlsson

Sweatt

. Epigenetic regulation of memory formation and maintenance. Learn Mem 2013; 20: 61–74.

55.

Barrett

Malvaez

Kramar

, et al. Hippocampal focal knockout of CBP affects specific histone modifications, long-term potentiation, and long-term memory. Neuropsychopharmacology 2011; 36: 1545–1556.

56.

Alarcon

Malleret

Touzani

, et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 2004; 42: 947–959.

57.

Lopez-Atalaya

Ciccarelli

Viosca

, et al. CBP Is required for environmental enrichment-induced neurogenesis and cognitive enhancement. EMBO J 2011; 30: 4287–4298.

58.

Korzus

Rosenfeld

Mayford

. CBP Histone acetyltransferase activity is a critical component of memory consolidation. Neuron 2004; 42: 961–972.

59.

Oliveira

Estevez

Hawk

, et al. Subregion-specific p300 conditional knock-out mice exhibit long-term memory impairments. Learn Mem 2011; 18: 161–169.

60.

Maurice

Duclot

Meunier

, et al. Altered memory capacities and response to stress in p300/CBP-associated factor (PCAF) histone acetylase knockout mice. Neuropsychopharmacology 2008; 33: 1584–1602.

61.

Stilling

Ronicke

Benito

, et al. K-Lysine acetyltransferase 2a regulates a hippocampal gene expression network linked to memory formation. EMBO J 2014; 33: 1912–1927.

62.

Bahari-Javan

Maddalena

Kerimoglu

, et al. HDAC1 Regulates fear extinction in mice. J Neurosci 2012; 32: 5062–5073.

63.

Morris

Mahgoub

, et al. Loss of histone deacetylase 2 improves working memory and accelerates extinction learning. J Neurosci 2013; 33: 6401–6411.

64.

Moonat

Sakharkar

Zhang

, et al. Aberrant histone deacetylase2-mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism. Biol Psychiatry 2013; 73: 763–773.

65.

Kim

Akhtar

Adachi

, et al. An essential role for histone deacetylase 4 in synaptic plasticity and memory formation. J Neurosci 2012; 32: 10879–10886.

66.

Michan

Chou

, et al. SIRT1 Is essential for normal cognitive function and synaptic plasticity. J Neurosci 2010; 30: 9695–9707.

67.

Gupta-Agarwal

Franklin

Deramus

, et al. G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. J Neurosci 2012; 32: 5440–5453.

68.

Kerimoglu

Agis-Balboa

Kranz

, et al. Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. J Neurosci 2013; 33: 3452–3464.

69.

Navabpour

Farrell

Kincaid

, et al. Monoubiquitination of histone H2B is a crucial regulator of the transcriptome during memory formation. Learn Mem 2024; 31: a053912.

70.

Jarome

Perez

Webb

, et al. Ubiquitination of histone H2B by proteasome subunit RPT6 controls histone methylation chromatin dynamics during memory formation. Biol Psychiatry 2021; 89: 1176–1187.

71.

Farrelly

Thompson

Zhao

, et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 2019; 567: 535–539.

72.

Zhao

Chuh

Zhang

, et al. Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout. Proc Natl Acad Sci U S A 2021; 118: e2016742118.

73.

Fulton

Mitra

Lepack

, et al. Histone H3 dopaminylation in ventral tegmental area underlies heroin-induced transcriptional and behavioral plasticity in male rats. Neuropsychopharmacology 2022; 47: 1776–1783.

74.

Lepack

Werner

Stewart

, et al. Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking. Science 2020; 368: 197–201.

75.

Harada

Natelson Love

Triebel

. Normal cognitive aging. Clin Geriatr Med 2013; 29: 737–752.

76.

Salthouse

. Neuroanatomical substrates of age-related cognitive decline. Psychol Bull 2011; 137: 753–784.

77.

Kennedy

Raz

. Aging white matter and cognition: differential effects of regional variations in diffusion properties on memory, executive functions, and speed. Neuropsychologia 2009; 47: 916–927.

78.

Peleg

Sananbenesi

Zovoilis

, et al. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 2010; 328: 753–756.

79.

Gong

Qian

Ertl

, et al. Histone modifications change with age, dietary restriction and rapamycin treatment in mouse brain. Oncotarget 2015; 6: 15882–15890.

80.

Ding

Liu

Zhang

. Aging-related histone modification changes in brain function. Ibrain 2023; 9: 205–213.

81.

Dagnas

Mons

. Region- and age-specific patterns of histone acetylation related to spatial and cued learning in the water maze. Hippocampus 2013; 23: 581–591.

82.

Lovatel

Elsner

Bertoldi

, et al. Treadmill exercise induces age-related changes in aversive memory, neuroinflammatory and epigenetic processes in the rat hippocampus. Neurobiol Learn Mem 2013; 101: 94–102.

83.

Barter

Foster

. Aging in the brain: new roles of epigenetics in cognitive decline. Neuroscientist 2018; 24: 516–525.

84.

Harman

Martin

. Epigenetic mechanisms related to cognitive decline during aging. J Neurosci Res 2020; 98: 234–246.

85.

Chouliaras

van den Hove

Kenis

, et al. Histone deacetylase 2 in the mouse hippocampus: attenuation of age-related increase by caloric restriction. Curr Alzheimer Res 2013; 10: 868–876.

86.

Singh

Thakur

. Histone deacetylase 2 inhibition attenuates downregulation of hippocampal plasticity gene expression during aging. Mol Neurobiol 2018; 55: 2432–2442.

87.

Kwapis

Alaghband

Kramar

, et al. Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory. Nat Commun 2018; 9: 3323.

88.

Qiu

Liu

Xia

, et al. Downregulation of P300/CBP-associated factor protects from vascular aging via Nrf2 signal pathway activation. Int J Mol Sci 2022; 23: 12574.

89.

Hussain

Fang

Chang

. Blood-brain barrier breakdown: an emerging biomarker of cognitive impairment in normal aging and dementia. Front Neurosci 2021; 15: 688090.

90.

Yuan

Chang

Yin

, et al. Two conserved epigenetic regulators prevent healthy ageing. Nature 2020; 579: 118–122.

91.

Kushwaha

Thakur

. Increase in hippocampal histone H3K9me3 is negatively correlated with memory in old male mice. Biogerontology 2020; 21: 175–189.

92.

Palomer

Martin-Segura

Baliyan

, et al. Aging triggers a repressive chromatin state at Bdnf promoters in hippocampal neurons. Cell Rep 2016; 16: 2889–2900.

93.

Palomer

Carretero

Benvegnu

, et al. Neuronal activity controls Bdnf expression via Polycomb de-repression and CREB/CBP/JMJD3 activation in mature neurons. Nat Commun 2016; 7: 11081.

94.

Snigdha

Prieto

Petrosyan

, et al. H3k9me3 inhibition improves memory, promotes spine formation, and increases BDNF levels in the aged hippocampus. J Neurosci 2016; 36: 3611–3622.

95.

Pal

Tyler

. Epigenetics and aging. Sci Adv 2016; 2: e1600584.

96.

Tsurumi

. Global heterochromatin loss: a unifying theory of aging? Epigenetics 2012; 7: 680–688.

97.

Duke

Kennedy

Gavin

, et al. Experience-dependent epigenomic reorganization in the hippocampus. Learn Mem 2017; 24: 278–288.

98.

Wang

Tsai

Yew

, et al. Identification of histone methylation multiplicities patterns in the brain of senescence-accelerated prone mouse 8. Biogerontology 2010; 11: 87–102.

99.

Chojnowski

Ong

Foo

MXR

, et al. Heterochromatin loss as a determinant of progerin-induced DNA damage in Hutchinson-Gilford Progeria. Aging Cell 2020; 19: e13108.

100.

Montalvo-Ortiz

Fisher

Rodriguez

, et al. Histone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice. Psychopharmacology (Berl) 2017; 234: 2385–2398.

101.

Azpurua

Eaton

. Neuronal epigenetics and the aging synapse. Front Cell Neurosci 2015; 9: 208.

102.

Morse

Butler

Davis

, et al. Environmental enrichment reverses histone methylation changes in the aged hippocampus and restores age-related memory deficits. Biology (Basel) 2015; 4: 298–313.

103.

Dyer

Phipps

Mitew

, et al. Age, but not amyloidosis, induced changes in global levels of histone modifications in susceptible and disease-resistant neurons in Alzheimer's disease model mice. Front Aging Neurosci 2019; 11: 68.

104.

Hijazi

Heistek

Scheltens

, et al. Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer's disease. Mol Psychiatry 2020; 25: 3380–3398.

105.

Nagarajan

Lyu

Kambali

, et al. Genetic ablation of dentate hilar somatostatin-positive GABAergic interneurons is sufficient to induce cognitive impairment. Mol Neurobiol 2024; 61: 567–580.

106.

Tang

, et al. Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson's disease. Cell Death Differ 2014; 21: 369–380.

107.

O'Sullivan

Kubicek

Schreiber

, et al. Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. Nat Struct Mol Biol 2010; 17: 1218–1225.

108.

Horard

Sapey-Triomphe

Bonnefoy

, et al. ASF1 Is required to load histones on the HIRA complex in preparation of paternal chromatin assembly at fertilization. Epigenetics Chromatin 2018; 11: 19.

109.

Henikoff

Smith

. Histone variants and epigenetics. Cold Spring Harb Perspect Biol 2015; 7: a019364.

110.

Marshall

, et al. Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer's disease pathology and cognitive symptoms. Nat Commun 2019; 10: 2246.

111.

De Jager

Srivastava

Lunnon

, et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 2014; 17: 1156–1163.

112.

Stoccoro

Coppede

. Role of epigenetics in Alzheimer's disease pathogenesis. Neurodegener Dis Manag 2018; 8: 181–193.

113.

Nativio

Lan

Donahue

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

114.

Xia

Jiang

McDermott

, et al. Aging and Alzheimer's disease: comparison and associations from molecular to system level. Aging Cell 2018; 17: e12802.

115.

Santana

Smith

MAC

Chen

. Histone modifications in Alzheimer's disease. Genes (Basel) 2023; 14: 347.

116.

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.

117.

Schueller

Paiva

Blanc

, et al. Dysregulation of histone acetylation pathways in hippocampus and frontal cortex of Alzheimer's disease patients. Eur Neuropsychopharmacol 2020; 33: 101–116.

118.

Pascoal

Chamoun

Lax

, et al. [(11)C]martinostat PET analysis reveals reduced HDAC I availability in Alzheimer's disease. Nat Commun 2022; 13: 4171.

119.

Narayan

Lill

Faull

, et al. Increased acetyl and total histone levels in post-mortem Alzheimer's disease brain. Neurobiol Dis 2015; 74: 281–294.

120.

Klein

McCabe

Gjoneska

, et al. Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer's human brains. Nat Neurosci 2019; 22: 37–46.

121.

Nativio

Donahue

Berson

, et al. Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease. Nat Neurosci 2018; 21: 497–505.

122.

Zheng

Liu

Wang

, et al. Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer's disease. Brain 2019; 142: 787–807.

123.

Persico

Casciaro

Amatori

, et al. Histone H3 lysine 4 and 27 trimethylation landscape of human Alzheimer's disease. Cells 2022; 11: 734.

124.

Cao

Wang

Williams

, et al. Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer's disease. Sci Adv 2020; 6: eabc8096.

125.

Lin

Cai

, et al. ACSS2-dependent Histone acetylation improves cognition in mouse model of Alzheimer's disease. Mol Neurodegener 2023; 18: 47.

126.

Walker

LaFerla

Oddo

, et al. Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer's disease. Age (Dordr) 2013; 35: 519–531.

127.

Francis

Ashraf

, et al. Dysregulation of histone acetylation in the APP/PS1 mouse model of Alzheimer's disease. J Alzheimers Dis 2009; 18: 131–139.

128.

Kilgore

Miller

Fass

, et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology 2010; 35: 870–880.

129.

Sung

Lee

Yoon

, et al. Mercaptoacetamide-based class II HDAC inhibitor lowers Abeta levels and improves learning and memory in a mouse model of Alzheimer's disease. Exp Neurol 2013; 239: 192–201.

130.

Barnes

Wilson

Bienias

, et al. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry 2005; 62: 685–691.

131.

Podcasy

Epperson

. Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin Neurosci 2016; 18: 437–446.

132.

Zhang

Tian

Wang

, et al. The epidemiology of Alzheimer's disease modifiable risk factors and prevention. J Prev Alzheimers Dis 2021; 8: 313–321.

133.

Yan

Arias

Geller

, et al. Widening gender gap in life expectancy in the US, 2010–2021. JAMA Intern Med 2024; 184: 108–110.

134.

Maccora

Peters

Anstey

. Gender differences in superior-memory superagers and associated factors in an Australian cohort. J Appl Gerontol 2021; 40: 433–442.

135.

Carrel

Willard

. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005; 434: 400–404.

136.

Ratnu

Emami

Bredy

. Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain. J Neurosci Res 2017; 95: 301–310.

137.

Ostan

Monti

Gueresi

, et al. Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine. Clin Sci (Lond) 2016; 130: 1711–1725.

138.

Bortz

Klatt

Wallace

. Perspective: estrogen and the risk of cognitive decline: a missing choline(rgic) link? Adv Nutr 2022; 13: 376–387.

139.

Levine

Chen

, et al. Menopause accelerates biological aging. Proc Natl Acad Sci U S A 2016; 113: 9327–9332.

140.

Guo

Zhong

Zhang

, et al. Sex differences in Alzheimer's disease: insights from the multiomics landscape. Biol Psychiatry 2022; 91: 61–71.

141.

El-Maarri

Becker

Junen

, et al. Gender specific differences in levels of DNA methylation at selected loci from human total blood: a tendency toward higher methylation levels in males. Hum Genet 2007; 122: 505–514.

142.

Singmann

Shem-Tov

Wahl

, et al. Characterization of whole-genome autosomal differences of DNA methylation between men and women. Epigenetics Chromatin 2015; 8: 43.

143.

Perzel Mandell

Price

Wilton

, et al. Characterizing the dynamic and functional DNA methylation landscape in the developing human cortex. Epigenetics 2021; 16: 1–13.

144.

Frenck Jr

Blackburn

Shannon

. The rate of telomere sequence loss in human leukocytes varies with age. Proc Natl Acad Sci U S A 1998; 95: 5607–5610.

145.

Gardner

Bann

Wiley

, et al. Gender and telomere length: systematic review and meta-analysis. Exp Gerontol 2014; 51: 15–27.

146.

Berchtold

Cribbs

Coleman

, et al. Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc Natl Acad Sci U S A 2008; 105: 15605–15610.

147.

Shi

Zhang

. Sex biased gene expression profiling of human brains at major developmental stages. Sci Rep 2016; 6: 21181.

148.

Lopes-Ramos

Chen

Kuijjer

, et al. Sex differences in gene expression and regulatory networks across 29 human tissues. Cell Rep 2020; 31: 107795.

149.

Tsai

Grant

Rissman

. Sex differences in histone modifications in the neonatal mouse brain. Epigenetics 2009; 4: 47–53.

150.

Sobolewski

Singh

Schneider

, et al. Different behavioral experiences produce distinctive parallel changes in, and correlate with, frontal cortex and hippocampal global post-translational histone levels. Front Integr Neurosci 2018; 12: 29.

151.

Tyler

Hafez

Solomon

, et al. Developmental exposure to 50 parts-per-billion arsenic influences histone modifications and associated epigenetic machinery in a region- and sex-specific manner in the adult mouse brain. Toxicol Appl Pharmacol 2015; 288: 40–51.

152.

Shen

Ahern

Cheung

, et al. Epigenetics and sex differences in the brain: a genome-wide comparison of histone-3 lysine-4 trimethylation (H3K4me3) in male and female mice. Exp Neurol 2015; 268: 21–29.

153.

Schneider

Anderson

Kidd

, et al. Sex-dependent effects of lead and prenatal stress on post-translational histone modifications in frontal cortex and hippocampus in the early postnatal brain. Neurotoxicology 2016; 54: 65–71.

154.

Stefanelli

Azam

Walters

, et al. Learning and age-related changes in genome-wide H2A.Z binding in the mouse hippocampus. Cell Rep 2018; 22: 1124–1131.

155.

Ramzan

Creighton

Hall

, et al. Sex-specific effects of the histone variant H2A.Z on fear memory, stress-enhanced fear learning and hypersensitivity to pain. Sci Rep 2020; 10: 14331.

156.

Ebstein

Israel

Chew

, et al. Genetics of human social behavior. Neuron 2010; 65: 831–844.

157.

Ngun

Ghahramani

Sanchez

, et al. The genetics of sex differences in brain and behavior. Front Neuroendocrinol 2011; 32: 227–246.

158.

Ivan

Daniela

Jaroslava

. Sex differences matter: males and females are equal but not the same. Physiol Behav 2023; 259: 114038.

159.

Chen

Van Horn

and GENDAAR Research Consortium. Developmental neurogenetics and multimodal neuroimaging of sex differences in autism. Brain Imaging Behav 2017; 11: 38–61.

160.

Levine

Bennett

, et al. Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer's disease related cognitive functioning. Aging (Albany NY) 2015; 7: 1198–1211.

161.

Trevisan

Cristina-Pereira

Silva-Amaral

, et al. Theories of aging and the prevalence of Alzheimer's disease. Biomed Res Int 2019; 2019: 9171424.

162.

R AA. Risk factors for Alzheimer's disease. Folia Neuropathol 2019; 57: 87–105.

163.

Kramer

Hahn

Cohen

, et al. Ageing, fitness and neurocognitive function. Nature 1999; 400: 418–419.

164.

Feng

, et al. Sex differences between APPswePS1dE9 mice in A-beta accumulation and pancreatic islet function during the development of Alzheimer's disease. Lab Anim 2016; 50: 275–285.

165.

Rahman

Jackson

Hristov

, et al. Sex and gender driven modifiers of Alzheimer's: the role for estrogenic control across age, race, medical, and lifestyle risks. Front Aging Neurosci 2019; 11: 315.

166.

Pike

. Sex and the development of Alzheimer's disease. J Neurosci Res 2017; 95: 671–680.

167.

Lee

Richard

de Leon

, et al. Sex differences in cognition across aging. Curr Top Behav Neurosci 2023; 62: 235–284.

168.

Qureshi

Mehler

. Genetic and epigenetic underpinnings of sex differences in the brain and in neurological and psychiatric disease susceptibility. Prog Brain Res 2010; 186: 77–95.

169.

Gurvich

Thomas

Kulkarni

. Sex differences in cognition and aging and the influence of sex hormones. Handb Clin Neurol 2020; 175: 103–115.

170.

Nikolac Perkovic

Videtic Paska

Konjevod

, et al. Epigenetics of Alzheimer's disease. Biomolecules 2021; 11: 195.

171.

Patel

Ren

Yan

. Epigenomic analysis of Alzheimer's disease brains reveals diminished CTCF binding on genes involved in synaptic organization. Neurobiol Dis 2023; 184: 106192.

172.

Maity

Farrell

Navabpour

, et al. Epigenetic mechanisms in memory and cognitive decline associated with aging and Alzheimer's disease. Int J Mol Sci 2021; 22: 12280.

173.

Maddox

Watts

Schafe

. P300/CBP histone acetyltransferase activity is required for newly acquired and reactivated fear memories in the lateral amygdala. Learn Mem 2013; 20: 109–119.

174.

Pao

Patnaik

Watson

, et al. HDAC1 Modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer's disease. Nat Commun 2020; 11: 2484.

175.

McQuown

Barrett

Matheos

, et al. HDAC3 Is a critical negative regulator of long-term memory formation. J Neurosci 2011; 31: 764–774.

176.

Gilbert

Zurcher

Catanese

, et al. Neuroepigenetic signatures of age and sex in the living human brain. Nat Commun 2019; 10: 2945.

177.

Auzmendi-Iriarte

Moreno-Cugnon

Saenz-Antonanzas

, et al. High levels of HDAC expression correlate with microglial aging. Expert Opin Ther Targets 2022; 26: 911–922.

178.

Singh

Thakur

. Reduced recognition memory is correlated with decrease in DNA methyltransferase1 and increase in histone deacetylase2 protein expression in old male mice. Biogerontology 2014; 15: 339–346.

179.

Kawabata

Kamio

Jincho

, et al. Sex-specific histone modifications in mouse fetal and neonatal germ cells. Epigenomics 2019; 11: 543–561.

180.

Kawakami

Nakamura

Ishigami

, et al. Age-related difference of site-specific histone modifications in rat liver. Biogerontology 2009; 10: 415–421.

181.

Price

Manjegowda

Kain

, et al. Hdac3, Setdb1, and Kap1 mark H3K9me3/H3K14ac bivalent regions in young and aged liver. Aging Cell 2020; 19: e13092.

182.

Han

Yan

, et al. Stress-associated H3K4 methylation accumulates during postnatal development and aging of rhesus macaque brain. Aging Cell 2012; 11: 1055–1064.

183.

Shumaker

Dechat

Kohlmaier

, et al. Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci U S A 2006; 103: 8703–8708.

184.

Varma

Sobolewski

Cory-Slechta

, et al. Sex- and brain region- specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood. Neurotoxicology 2017; 62: 207–217.

185.

Gjoneska

Pfenning

Mathys

, et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease. Nature 2015; 518: 365–369.

186.

Cheung

Shulha

Jiang

, et al. Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex. Proc Natl Acad Sci U S A 2010; 107: 8824–8829.

187.

Suo

Meng

Pei

, et al. Changes in acetylation on lysine 12 of histone H4 (acH4K12) of murine oocytes during maternal aging may affect fertilization and subsequent embryo development. Fertil Steril 2010; 93: 945–951.

188.

Benito

Urbanke

Ramachandran

, et al. HDAC inhibitor-dependent transcriptome and memory reinstatement in cognitive decline models. J Clin Invest 2015; 125: 3572–3584.