Dementia is a major health issue in Latin America and the Caribbean (LAC), with a prevalence of 9.5% and an incidence of 26.0 per 1000 among people over 60 years. With cases expected to triple by 2050, there is an urgent need for more extensive local research in this field.¹ Despite advancements in neuroimaging and protein biomarkers, significant gaps remain in understanding how biological mechanisms that interact with LAC-specific environmental exposures influence dementia risk, presentation, and treatment. Interactions between genetic and environmental factors, mainly through epigenetic changes including DNA methylation (DNAm), noncoding RNA, and histone modifications, can modulate gene expression, altering molecular traits and health outcomes.² Adverse environmental exposures in LAC, including socioeconomic disparities, pollutants, unhealthy habits, and comorbidities, have been associated with higher dementia risk,¹ potentially through epigenetic mechanisms. Most existing knowledge on epigenetics is derived from studies conducted in Europe and the United States, which limits the generalization of these findings to underrepresented regions,³ including LAC. To understand state-of-the-art epigenetic studies on dementia in LAC, we conducted a systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) protocols. Our search focused on chemical modifications of the DNA or histones able to regulate chromatin's structure. We reviewed the literature up to May 2024 in MEDLINE, Web of Science, PubMed, and Scopus databases (research strategy and findings in Table 1). Surprisingly, we found only five case-control studies comparing late-onset Alzheimer's disease (LOAD)^4-6 or mild cognitive impairment (MCI)^{7, 8} versus healthy controls, revealing a disparity in published studies on epigenetics and dementia in LAC. Further epigenetics research is needed in the region, including the use of cutting-edge methods, target tissues, and systematic approaches. Studies have investigated global DNAm (LINE-1).⁴ DNAm in candidate genes.^{5, 6} or genome-wide DNAm^{7, 8} assessed in peripheral blood. Two studies were conducted in Colombian,^{4, 5} two in Mexican-American (MA),^{7, 8} and one in Costa Rican populations.⁶ Three studies addressed sex^{4, 5} or ethnic⁸ differences in DNAm. The study conducted by Hernández et al. found no significant differences in LINE-1 methylation across LOAD patients and controls, even after stratification by sex or APOE4 genotypes.⁴ Further, Salcedo-Tacuma et al. identified significantly lower DNAm levels at three CpGs at BIN1 gene in LOAD patients.⁵ In 2019, Pathak et al. reported differentially methylated CpGs in MCI individuals in an Epigenome-Wide Association Study (EWAS). These findings were linked to neuronal death, metabolic dysfunction, and inflammation.⁷ In 2021, Coto-Vílchez et al. compared Horvath's epigenetic clock DNAm profiles to measure biological aging. Both LOAD patients and control group exhibited an average epigenetic age 20 years younger than their chronological age. Additionally, they identified differentially methylated regions at PM20D1 across study groups.⁶ Finally, Abraham Daniel et al. analyzed ethnicity-specific DNAm profiles in non-Hispanic whites and MA, identifying significant differential methylation at CREBBP gene associated with MCI and AD in MA participants.⁸ These findings generally agree with previous evidence from other populations, suggesting distinctive DNAm patterns associated with dementia or impaired cognition, although some contradictions remain regarding differential epigenetic aging. Also, they provide evidence showing that genetic ancestry influences DNAm patterns. Overall, limitations of these studies include restricted sample size,^4-7 limited follow-up data for functional interpretation like gene expression, and the use of peripheral blood-derived methylation biomarkers while they may not reflect brain-specific alterations in dementia. Unfortunately, none of the reviewed articles investigated histone modifications.

Despite the limited number of identified studies, their positive quality assessment by the Newcastle-Ottawa scale (6 to 8 points) suggests considerable potential for conducting meaningful research and providing valuable insights into the epigenetic landscape of dementia within the region. Given the scarce but encouraging evidence, it is imperative to promote further efforts to unravel LAC-specific epigenetic biomarkers of dementia. We advocate for coordinated and systematic joint efforts to guide future studies relevant to the context of the region.

We believe these efforts are essential for understanding the role of gene-environment interplay in dementia development in LAC.

痴呆症是拉丁美洲和加勒比地区 （LAC） 的一个主要健康问题，在 60 岁以上的人群中，痴呆症的患病率为 9.5%，发病率为 26.0/1000。预计到 2050 年，病例将增加两倍，因此迫切需要在该领域进行更广泛的本地研究。¹ 尽管神经影像学和蛋白质生物标志物取得了进步，但在理解与 LAC 特异性环境暴露相互作用的生物机制如何影响痴呆风险、表现和治疗方面仍然存在重大差距。遗传和环境因素之间的相互作用，主要通过包括 DNA 甲基化 （DNAm）、非编码 RNA 和组蛋白修饰在内的表观遗传变化，可以调节基因表达，改变分子性状和健康结果。² LAC 的不利环境暴露，包括社会经济差异、污染物、不健康的习惯和合并症，与较高的痴呆风险有关，¹ 可能通过表观遗传机制。大多数现有的表观遗传学知识都来自在欧洲和美国进行的研究，这限制了这些发现对代表性不足的地区3的推广，^包括 LAC。为了了解 LAC 中痴呆的最新表观遗传学研究，我们按照系统评价和荟萃分析的首选报告项目 （PRISMA） 方案进行了系统评价。我们的检索集中在能够调节染色质结构的 DNA 或组蛋白的化学修饰上。我们回顾了截至 2024 年 5 月的 MEDLINE、Web of Science、PubMed 和 Scopus 数据库中的文献（研究策略和结果见表 1）。 令人惊讶的是，我们发现只有五项病例对照研究比较了迟发性阿尔茨海默病 （LOAD）^4-6 或轻度认知障碍 （MCI）^{7， 8} 与健康对照，揭示了已发表的关于 LAC 表观遗传学和痴呆的研究存在差异。该地区需要进一步的表观遗传学研究，包括使用尖端方法、靶组织和系统方法。研究调查了全球 DNAm （LINE-1）。^候选基因中的 4 个 DNAm。^5、6 或全基因组 DNAm^7、8 在外周血中评估。2 项研究在哥伦比亚进行^{，4， 5,2} 在墨西哥裔美国人 （MA） 进行^{，7， 8} 和 1 在哥斯达黎加人群中进行。⁶ 三项研究解决了 DNA 中的性别^4、5 或种族⁸ 差异。Hernández 等人进行的研究发现，即使在按性别或 APOE4 基因型分层后，LOAD 患者和对照组的 LINE-1 甲基化也没有显著差异。⁴ 此外，Salcedo-Tacuma 等人在 LOAD 患者的 BIN1 基因处发现 3 个 CpG 的 DNAm 水平显著降低。⁵ 2019 年，Pathak 等人在表观全基因组关联研究 （EWAS） 中报道了 MCI 个体的差异甲基化 CpG。这些发现与神经元死亡、代谢功能障碍和炎症有关。⁷ 2021 年，Coto-Vílchez 等人比较了 Horvath 的表观遗传时钟 DNAm 图谱以测量生物衰老。LOAD 患者和对照组的平均表观遗传年龄均比实际年龄小 20 岁。 此外，他们还在研究组中确定了 PM20D1 的差异甲基化区域。⁶ 最后，Abraham Daniel 等人分析了非西班牙裔白人和 MA 的种族特异性 DNAm 谱，确定了 MA 参与者中与 MCI 和 AD 相关的 CREBBP 基因的显着差异甲基化。⁸ 这些发现与先前来自其他人群的证据基本一致，表明与痴呆或认知受损相关的独特 DNAm 模式，尽管在差异表观遗传衰老方面仍然存在一些矛盾。此外，它们还提供证据表明遗传祖先会影响 DNAm 模式。总体而言，这些研究的局限性包括样本量有限，^4-7 功能解释（如基因表达）的随访数据有限，以及使用外周血来源的甲基化生物标志物，而它们可能无法反映痴呆的大脑特异性改变。不幸的是，没有一篇综述文章研究组蛋白修饰。

尽管已确定的研究数量有限，但纽卡斯尔-渥太华量表（6 至 8 分）对它们的积极质量评估表明，在进行有意义的研究和为该地区痴呆的表观遗传景观提供有价值的见解方面具有相当大的潜力。鉴于稀缺但令人鼓舞的证据，必须进一步努力解开痴呆的 LAC 特异性表观遗传生物标志物。我们倡导协调和系统的共同努力，以指导与该地区背景相关的未来研究。

我们相信这些努力对于理解基因 - 环境相互作用在 LAC 痴呆发展中的作用至关重要。