{"id":658669,"date":"2026-08-27T05:01:27","date_gmt":"2026-08-27T05:01:27","guid":{"rendered":"https:\/\/www.europesays.com\/ie\/658669\/"},"modified":"2026-08-27T05:01:27","modified_gmt":"2026-08-27T05:01:27","slug":"faulty-myelin-making-brain-cells-may-help-drive-cognitive-decline-with-age","status":"publish","type":"post","link":"https:\/\/www.europesays.com\/ie\/658669\/","title":{"rendered":"Faulty myelin-making brain cells may help drive cognitive decline with age"},"content":{"rendered":"

A rare combination of lifelong cognitive tracking, postmortem brain analysis, and targeted mouse experiments reveals unexpected changes in the cells that maintain the brain\u2019s white matter.<\/strong><\/p>\n

\"Study:<\/a><\/p>\n

Study: Oligodendrocyte dysfunction in human age-related cognitive decline<\/a>. Image Credit: Lightspring \/ Shutterstock<\/p>\n

A recent study published in the journal\u00a0Nature Medicine<\/strong><\/a> suggests that dysfunction of oligodendrocytes, or brain cells that form myelin, may contribute to age-related cognitive decline in humans. The researchers observed smaller, degenerating axons with thicker myelin sheaths in individuals with greater cognitive decline, whereas larger mitochondria were more strongly associated with aging than with the severity of cognitive decline. They then performed animal experiments to test whether reduced oligodendrocyte NRF2 could reproduce aspects of the human pathology. In mice, conditionally deleting the gene encoding nuclear factor erythroid 2-related factor 2 (NRF2) from oligodendrocytes also produced comparable alterations in axon size and myelin thickness and reduced cognitive improvement over time.<\/p>\n

Together with the human data, these observations suggest that increased oligodendrocyte density, reduced NRF2 expression, and damage to myelinated axons may offer valuable clues to the cellular changes underlying cognitive impairment. If confirmed in larger, more diverse human studies, these findings could help identify new ways to protect brain health during aging.<\/p>\n

Cognitive processes deteriorate gradually with age, which may lead to memory-related difficulties and limit older individuals’ ability to perform everyday tasks. Intervention strategies designed to alter molecular pathways associated with biological aging could potentially help slow or mitigate cognitive decline. While magnetic resonance imaging (MRI) scans have demonstrated abnormalities in the white matter of older individuals with cognitive impairment, corresponding changes occurring at the cellular level remain poorly understood.<\/p>\n

About the study<\/p>\n

In this study, an international team of researchers investigated transcriptomic and neuropathological changes in human white matter associated with age-related cognitive decline by analyzing brain samples from participants in the Lothian Birth Cohort 1936 (LBC1936). Members of the cohort underwent intelligence testing at age 11, and those participating in later-life assessments were followed from age 70 approximately every three years thereafter.<\/p>\n

Using standardized tests of cognitive ability and memory, such as the Wechsler Adult Intelligence Scale-III (WAIS-III) and the Wechsler Memory Scale-III (WMS-III), the team assessed cognition in participants aged 70-82\u2009years. Using latent cognitive growth curve models, they assessed cognitive decline among participants.<\/p>\n

The corpus callosum was examined to investigate the vulnerability of white matter to age-related pathology. The team performed spectral confocal reflectance (SCoRe) microscopy to investigate changes in compacted myelin and transmission electron microscopy (TEM) to assess ultrastructural changes in myelinated axonal health and myelin integrity. Single-nucleus RNA sequencing (snRNA-seq) provided detailed molecular-level information that helped characterize the observed changes.<\/p>\n

Fluorescence-activated nuclei sorting (FANS) improved nuclei yield, and immunofluorescence validated changes in NRF2 and cell proportions. The team also performed Ingenuity Pathway Analysis (IPA) on differentially expressed genes (DEGs) in oligodendrocyte subclusters to assess alterations in these cells associated with cognitive decline. In addition, the NRF2-encoding gene Nfe2l2 was conditionally deleted specifically in oligodendrocytes in mice. Recombination was induced at 6 months, and findings were assessed at 12-15 months using RNAscope and behavioral tests, including the open field test and Morris water maze (MWM). Female knockout mice were excluded from the cognitive analysis because they showed altered anxiety-like behavior.<\/p>\n

Results<\/p>\n

Nearly all participants (865 of 866 with follow-up cognitive testing beyond age 70) demonstrated cognitive decline. Although compacted myelin signal decreased among individuals with severe cognitive decline, myelin thickness was greater around larger axons exceeding 1.0 \u03bcm in diameter, which also showed increased myelin decompaction.<\/p>\n

The researchers noted smaller myelinated axons and thicker myelin sheaths among participants with greater cognitive decline. The proportion of oligodendrocytes expressing NRF2 was also lower in this group. The findings suggest that NRF2 could be explored in further studies to develop therapeutic strategies. In addition, mitochondrial size, known to increase with axonal stress in large-diameter myelinated axons, increased with aging but was not associated with the severity of cognitive decline. Among the human participants, smaller axons were also associated with more advanced Braak stages, suggesting that smaller axons may be a shared pathological feature of age-related cognitive decline and Alzheimer\u2019s disease (AD)-related pathology.<\/p>\n

In NRF2 gene knockout studies, aged mice with poorer cognitive performance showed white matter abnormalities, including smaller axons and thicker myelin, but not higher oligodendrocyte density. Their cognitive performance also improved less over time.<\/p>\n

As cognitive decline worsened, genes associated with neurodevelopment, demyelination, deoxyribonucleic acid (DNA) damage and oxidative stress, such as neurexin 3 (NRXN3) and oxidation resistance 1 (OXR1), were upregulated in one oligodendrocyte subcluster, while another showed increased expression of genes linked to mitochondrial function and oligodendrocyte differentiation. Within the latter oligodendrocyte subcluster, expression of ceramide synthase 6 (CERS6), Hsp70 member 4 like (HSPA4L), heat shock protein family E (Hsp10) member 1 (HSPE1), and sequestosome 1 (SQSTM1) decreased as cognitive decline became more severe.<\/p>\n

However, the postmortem analyses involved small subsets of participants, focused on the corpus callosum, and came from a predominantly white European Scottish cohort, limiting the generalizability of the findings.<\/p>\n

Conclusions<\/p>\n

The study findings suggest that an increased abundance of dysfunctional oligodendrocytes, together with smaller axons, thicker myelin,n and reduced NRF2 expression in the white matter, is associated with more severe cognitive decline in older individuals. Based on the study’s observations, oligodendrocytes may become actively detrimental with age, while abnormally thick or pathological myelin may make myelinated axons more vulnerable to neurodegenerative changes, ultimately contributing to reduced cognitive ability.<\/p>\n

While NRF2 is known to regulate genes involved in cellular functions such as autophagy, proliferation, differentiation, and antioxidant responses, the study identifies a potential role for oligodendrocyte NRF2 in maintaining myelin thickness and supporting the integrity of myelinated axons. In further studies, researchers could explore how NRF2 activity changes in aging oligodendrocytes and whether preserving this pathway could help protect myelin and cognitive function later in life.<\/p>\n","protected":false},"excerpt":{"rendered":"A rare combination of lifelong cognitive tracking, postmortem brain analysis, and targeted mouse experiments reveals unexpected changes in…\n","protected":false},"author":2,"featured_media":658670,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":"","_share_on_mastodon":"0"},"categories":[78],"tags":[2429,159,18,3288,5506,135,19,17,55825,96,11692,7818,19339,7345,173],"class_list":["post-658669","post","type-post","status-publish","format-standard","has-post-thumbnail","category-health","tag-aging","tag-brain","tag-eire","tag-gene","tag-genes","tag-health","tag-ie","tag-ireland","tag-knockout","tag-medicine","tag-microscopy","tag-mitochondria","tag-myelin","tag-pathology","tag-stress"],"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@ie\/117165719396085454","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts\/658669","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/comments?post=658669"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts\/658669\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/media\/658670"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/media?parent=658669"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/categories?post=658669"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/tags?post=658669"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}