{"id":196083,"date":"2025-09-03T06:07:12","date_gmt":"2025-09-03T06:07:12","guid":{"rendered":"https:\/\/www.europesays.com\/us\/196083\/"},"modified":"2025-09-03T06:07:12","modified_gmt":"2025-09-03T06:07:12","slug":"alzheimers-linked-to-epigenomic-breakdown-not-just-plaques","status":"publish","type":"post","link":"https:\/\/www.europesays.com\/us\/196083\/","title":{"rendered":"Alzheimer\u2019s Linked to Epigenomic Breakdown, Not Just Plaques"},"content":{"rendered":"<p><strong>Summary: <\/strong>A new large-scale study shows that Alzheimer\u2019s disease is marked by the erosion of epigenomic control, where brain cells lose the ability to maintain stable gene expression. Using a multi-region atlas of 3.5 million cells, researchers found that vulnerable cells in key memory regions such as the hippocampus suffer breakdowns in nuclear compartmentalization and lose their \u201cepigenomic information.\u201d<\/p>\n<p>This decline makes disease-related genes more active, linking the collapse of gene regulation directly to cognitive loss. The findings suggest that Alzheimer\u2019s is not just about plaques and tangles, but about fundamental breakdowns in genome regulation that may open new doors for treatment.<\/p>\n<p><strong>Key Facts<\/strong><\/p>\n<ul class=\"wp-block-list\">\n<li><strong>Massive Cell Atlas:<\/strong> Researchers mapped gene expression and regulation in 3.5 million brain cells across six brain regions.<\/li>\n<li><strong>Epigenomic Erosion:<\/strong> Cognitive decline correlated with cells losing nuclear order and epigenomic information, not just plaque buildup.<\/li>\n<li><strong>Therapeutic Potential:<\/strong> Findings point to targeting epigenomic stability as a path to preserving brain function.<\/li>\n<\/ul>\n<p><strong>Source: <\/strong>Picower Institute at MIT<\/p>\n<p><strong>Most people recognize Alzheimer\u2019s from its devastating symptoms such as memory loss, while new drugs target pathological aspects of disease manifestations, such as plaques of amyloid proteins.<\/strong><\/p>\n<p>Now, a sweeping new study in the Sept. 4 edition of\u00a0Cell\u00a0by MIT researchers shows the importance of understanding the disease as a battle over how well brain cells control the expression of their genes.<\/p>\n<p>  <img fetchpriority=\"high\" decoding=\"async\" width=\"1200\" height=\"800\" src=\"https:\/\/www.europesays.com\/us\/wp-content\/uploads\/2025\/09\/epigenome-alzheimers-neuroscience.jpg\" alt=\"This shows a brain and DNA.\"  \/>  The new study sheds new light on their fate by demonstrating that they exhibit early and severe epigenomic information loss as disease advances, but that in people who remained cognitively resilient the neurons maintained epigenomic information. Credit: Neuroscience News<\/p>\n<p>The study paints a high-resolution picture of a desperate struggle to maintain healthy gene expression and gene regulation where the consequences of failure or success are nothing less than the loss or preservation of cell function and cognition.<\/p>\n<p>The study presents a first-of-its-kind, multimodal atlas of combined gene expression and gene regulation spanning 3.5 million cells from six brain regions, obtained by profiling 384 post-mortem brain samples across 111 donors.<\/p>\n<p>The researchers profiled both the \u201ctranscriptome,\u201d showing which genes are expressed into RNA, and the \u201cepigenome,\u201d the set of chromosomal modifications that establish which DNA regions are accessible and thus utilized between different cell types.<\/p>\n<p>The resulting atlas revealed many insights, described in a paper that appears in the September 4th\u00a0issue of\u00a0Cell, and shows that the progression of Alzheimer\u2019s is characterized by two major epigenomic trends.<\/p>\n<p>The first is that vulnerable cells in key brain regions suffer a breakdown of the rigorous nuclear \u201ccompartments\u201d they normally maintain to ensure some parts of the genome are open for expression but others remain locked away.<\/p>\n<p>The second major finding is that susceptible cells experience a loss of \u201cepigenomic information,\u201d meaning they lose their grip on the unique pattern of gene regulation and expression that gives them their specific identity and enables their healthy function.<\/p>\n<p>Accompanying the evidence of compromised compartmentalization and the erosion of epigenomic information are many specific findings pinpointing molecular circuitry that breaks down by cell type, by region, and gene network.<\/p>\n<p>They found, for instance, that when epigenomic conditions deteriorate, that opens the door to expression of many genes associated with disease, whereas if cells manage to keep their epigenomic house in order, they can keep disease-associated genes in check.<\/p>\n<p>Moreover, the researchers clearly saw that when the epigenomic breakdowns were occurring people lost cognitive ability but where epigenomic stability remained, so did cognition.<\/p>\n<p>\u201cTo understand the circuitry, the logic responsible for gene expression changes in Alzheimer\u2019s disease, we needed to understand the regulation and upstream control of all the changes that are happening, and that\u2019s where the epigenome comes in,\u201d said senior author\u00a0Manolis Kellis, a professor in the Computer Science and Artificial Intelligence Lab and head of MIT\u2019s\u00a0Computational Biology Group.<\/p>\n<p>\u201cThis is the first large-scale single-cell multi-region gene-regulatory atlas of AD, systematically dissecting the dynamics of epigenomic and transcriptomic programs across disease progression and resilience.\u201d<\/p>\n<p>By providing that detailed examination of the epigenomic mechanisms of Alzheimer\u2019s progression, the study provides a blueprint for devising new Alzheimer\u2019s treatments that can target factors underlying the broad erosion of epigenomic control or the specific manifestations that affect key cell types such as neurons and supporting glial cells.<\/p>\n<p>\u201cThe key to developing new and more effective treatments for Alzheimer\u2019s disease depends on deepening our understanding of the mechanisms that contribute to the breakdowns of cellular and network function in the brain,\u201d said Picower Professor and co-corresponding author\u00a0Li-Huei Tsai, director of The Picower Institute for Learning and Memory and a founding member of\u00a0MIT\u2019s Aging Brain Initiative, along with Kellis.<\/p>\n<p>\u201cThis new data advances our understanding of how epigenomic factors drive disease.\u201d<\/p>\n<p>Kellis Lab members Zunpeng Liu and Shanshan Zhang are the study\u2019s co-lead authors.<\/p>\n<p><strong>Compromised compartments and eroded information<\/strong><\/p>\n<p>Among the post-mortem brain samples in the study, 57 came from donors to the Religious Orders Study or the Rush Memory and Aging Project (collectively known as \u201cROSMAP\u201d) who did not have AD pathology or symptoms, while 33 came from donors with early-stage pathology and 21 came from donors at a late stage. The samples therefore provided rich information about the symptoms and pathology each donor was experiencing before death.<\/p>\n<p>In the new study, Liu and Zhang combined analyses of single cell RNA sequencing of the samples, which measures which genes are being expressed in each cell, and ATACseq, which measures whether chromosomal regions are accessible for gene expression.<\/p>\n<p>Considered together, these transcriptomic and epigenomic measures enabled the researchers to understand the molecular details of how gene expression is regulated across seven broad classes of brain cells (e.g. neurons or other glial cell types) and 67 subtypes of cells types (e.g. 17 kinds of excitatory neurons or 6 kinds of inhibitory ones).<\/p>\n<p>The researchers annotated more than 1 million gene-regulatory control regions that different cells employ to establish their specific identities and functionality using epigenomic marking.<\/p>\n<p>Then, by comparing the cells from Alzheimer\u2019s brains to the ones without, and accounting for stage of pathology and cognitive symptoms, they could produce rigorous associations between the erosion of these epigenomic markings and ultimately loss of function.<\/p>\n<p>For instance, they saw that among people who advanced to late-stage AD, normally repressive compartments opened up for more expression and compartments that were normally more open during health became more repressed. Worryingly, when the normally repressive compartments of brain cells opened up, they became more afflicted with disease.<\/p>\n<p>\u201cFor Alzheimer\u2019s patients, repressive compartments opened up, and gene expression levels increased, which was associated with decreased cognitive function,\u201d explained first author Zunpeng Liu.<\/p>\n<p>But when cells managed to keep their compartments in order such that they expressed the genes they were supposed to, people remained cognitively intact.<\/p>\n<p>Meanwhile, based on the cells\u2019 expression of their regulatory elements, the researchers created an epigenomic information score for each cell. Generally, information declined as pathology progressed but that was particularly notable among cells in the two brain regions affected earliest in Alzheimer\u2019s: the entorhinal cortex and the hippocampus.<\/p>\n<p>The analyses also highlighted specific cell types that were especially vulnerable including microglia that play immune and other roles, oligodendrocytes that produce myelin insulation for neurons, and particular kinds of excitatory neurons.<\/p>\n<p><strong>Risk genes and \u2018chromatin guardians\u2019<\/strong><\/p>\n<p>Detailed analyses in the paper highlighted how epigenomic regulation tracked with disease-related problems, Liu noted.<\/p>\n<p>The e4 variant of the APOE gene, for instance, is widely understood to be the single biggest genetic risk factor for Alzheimer\u2019s. In APOE4 brains, microglia initially responded to the emerging disease pathology with an increase in their epigenomic information, suggesting that they were stepping up to their unique responsibility to fight off disease. But as the disease progressed the cells exhibited a sharp drop off in information, a sign of deterioration and degeneration.<\/p>\n<p>This turnabout was strongest in people who had two copies of APOE4, rather than just one. The findings, Kellis said, suggest that APOE4 might destabilize the genome of microglia, causing them to burn out.<\/p>\n<p>Another example is the fate of neurons expressing the gene RELN and its protein Reelin. Prior studies, including by\u00a0Kellis and Tsai, have shown that RELN- expressing neurons in the entorhinal cortex and hippocampus are especially vulnerable in Alzheimer\u2019s, but promote resilience if they survive.<\/p>\n<p>The new study sheds new light on their fate by demonstrating that they exhibit early and severe epigenomic information loss as disease advances, but that in people who remained cognitively resilient the neurons maintained epigenomic information.<\/p>\n<p>In yet another example, the researchers tracked what they colloquially call \u201cchromatin guardians\u201d because their expression sustains and regulates cells\u2019 epigenomic programs.<\/p>\n<p>For instance, cells with greater epigenomic erosion and advanced AD progression displayed increased chromatin accessibility in areas that were supposed to be locked down by Polycomb repression genes or other gene expression silencers.<\/p>\n<p>While resilient cells expressed genes promoting neural connectivity, epigenomically eroded cells expressed genes linked to inflammation and oxidative stress.<\/p>\n<p>\u201cThe message is clear: Alzheimer\u2019s is not only about plaques and tangles, but about the erosion of nuclear order itself,\u201d Kellis said.<\/p>\n<p>\u201cCognitive decline emerges when chromatin guardians lose ground to the forces of erosion, switching from resilience to vulnerability at the most fundamental level of genome regulation.<\/p>\n<p>\u201cAnd when our brain cells lose their epigenomic memory marks and epigenomic information at the lowest level deep inside our neurons and microglia, it seems that Alheimer\u2019s patients also lose their memory and cognition at the highest level.\u201d<\/p>\n<p>Other authors of the paper are Benjamin T. James, Kyriaki Galani, Riley J. Mangan, Stuart Benjamin Fass, Chuqian Liang, Manoj M. Wagle, Carles A. Boix, Yosuke Tanigawa, Sukwon Yun, Yena Sung, Xushen Xiong, Na Sun, Lei Hou, Martin Wohlwend, Mufan Qiu, Xikun Han, Lei Xiong, Efthalia Preka, Lei Huang, William F. Li, Li-Lun Ho, Amy Grayson, Julio Mantero, Alexey Kozlenkov, Hansruedi Mathys, Tianlong Chen, Stella Dracheva, and David A. Bennett.<\/p>\n<p><strong>Funding: <\/strong>Funding for the research came from The National Institutes of Health, The National Science Foundation, the Cure Alzheimer\u2019s Fund, the Freedom Together Foundation, the Robert A. and Renee E. Belfer Family Foundation, Eduardo Eurnekian, and Joseph P. DiSabato.<\/p>\n<p>About this genetics and Alzheimer\u2019s disease research news<\/p>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Author: <\/strong><a href=\"http:\/\/neurosciencenews.com\/cdn-cgi\/l\/email-protection#ec888d9a85888683ac818598c2898899\" target=\"_blank\" rel=\"noreferrer noopener\">David Orenstein<\/a><br \/><strong>Source: <\/strong><a href=\"https:\/\/mit.edu\" target=\"_blank\" rel=\"noreferrer noopener\">Picower Institute at MIT<\/a><br \/><strong>Contact: <\/strong>David Orenstein \u2013 Picower Institute at MIT<br \/><strong>Image: <\/strong>The image is credited to Neuroscience News<\/p>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Original Research: <\/strong>Open access.<br \/>\u201c<a href=\"https:\/\/dx.doi.org\/10.1016\/j.cell.2025.06.031\" target=\"_blank\" rel=\"noreferrer noopener\">Single-cell multiregion epigenomic rewiring in Alzheimer\u2019s disease progression and cognitive resilience<\/a>\u201d by Manolis Kellis et al. Cell<\/p>\n<p><strong>Abstract<\/strong><\/p>\n<p><strong>Single-cell multiregion epigenomic rewiring in Alzheimer\u2019s disease progression and cognitive resilience<\/strong><\/p>\n<p>Alzheimer\u2019s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, yet its epigenetic underpinnings remain elusive.<\/p>\n<p>Here, we generate and integrate single-cell epigenomic and transcriptomic profiles of 3.5 million cells from 384 postmortem brain samples across 6 regions in 111 AD and control individuals.<\/p>\n<p>We identify over 1 million candidate\u00a0cis-regulatory elements (cCREs), organized into 123 regulatory modules across 67 cell subtypes.<\/p>\n<p>We define large-scale epigenomic compartments and single-cell epigenomic information and delineate their dynamics in AD, revealing widespread epigenome relaxation and brain-region-specific and cell-type-specific epigenomic erosion signatures during AD progression.<\/p>\n<p>These epigenomic stability dynamics are closely associated with cell-type proportion changes, glial cell-state transitions, and coordinated epigenomic and transcriptomic dysregulation linked to AD pathology, cognitive impairment, and cognitive resilience.<\/p>\n<p>This study provides critical insights into AD progression and cognitive resilience, presenting a comprehensive single-cell multiomic atlas to advance the understanding of AD.<\/p>\n","protected":false},"excerpt":{"rendered":"Summary: A new large-scale study shows that Alzheimer\u2019s disease is marked by the erosion of epigenomic control, where&hellip;\n","protected":false},"author":3,"featured_media":196084,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[8],"tags":[10263,827,45516,815,829,912,831,64339,159,67,132,68],"class_list":{"0":"post-196083","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-science","8":"tag-alzheimers-disease","9":"tag-brain-research","10":"tag-epigenetics","11":"tag-genetics","12":"tag-neurobiology","13":"tag-neurology","14":"tag-neuroscience","15":"tag-picower-institute-at-mit","16":"tag-science","17":"tag-united-states","18":"tag-unitedstates","19":"tag-us"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@us\/115138870923280047","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/196083","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/comments?post=196083"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/196083\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media\/196084"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media?parent=196083"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/categories?post=196083"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/tags?post=196083"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}