LongeCityNews Last Updated: 19 February 2026 - 04:53 AM

APOE is a component of the low density lipoprotein (LDL) particles that carry cholesterol from the liver to where it is needed in the body. Lowering circulating LDL-cholesterol levels to modestly slow the progression of atherosclerosis is the primary approach taken in cardiovascular medicine; in recent years, new forms of LDL-lowering therapy such as PCSK9 inhibitors have been used to dramatically reduce LDL-cholesterol to far below normal levels with no immediately apparent prohibitively negative effects on patients.

In today's open access paper, researchers show that elevated APOE levels are a feature of old age and negatively affect bone regeneration, likely by suppressing the creation of osteoblast cells responsible for producing bone extracellular matrix structures. A near complete elimination of APOE production in the liver (which will also have the consequence of dramatically reducing LDL-cholesterol in circulation) improves the regeneration of fractures in old mice. There is clearly still a sense of caution in making permanent changes of this nature, despite ongoing development such as Verve Therapeutics' gene-editing PCSK9 inhibition therapy.

Neutralizing hepatic apolipoprotein E enhances aged bone fracture healing

In our previously published study, we demonstrated that circulating ApoE levels increase with age in patients and in mice and that by using liver targeted AAV to deliver siRNA for ApoE we decreased circulating ApoE levels and increased bone deposition and mechanical stability of healed tissue. However, the potential negative impact on a patient's cardiovascular health resulting from the permanent lowering of ApoE precludes this therapeutic strategy. Therefore, in the current study we aimed to use a neutralizing antibody against ApoE which would be cleared from the body by immune cells.

In this study we identified the mechanism of action by which hepatic ApoE inhibits fracture healing and identified a translatable non-invasive therapeutic intervention to improve aged bone repair. We knocked out hepatic ApoE expression in mice - this decreased levels of circulating ApoE and increased bone deposition and tissue mineral density within the fracture callus. Using tissue culture models, we found ApoE inhibits bone marrow stem cell to osteoblast differentiation and activity by binding to the cell-surface receptor Lrp4 and inhibiting Wnt/β-catenin signaling. Moreover, the same mechanism of action was identified during ApoE-induced inhibition of human bone marrow stem cells.

Finally, aged wildtype mice underwent tibial fracture surgery and were treated with a neutralizing antibody for ApoE 3 days post-injury which decreased levels of circulating ApoE and significantly improved fracture healing.

A recent study suggests that cognitive enrichment throughout life is associated with reduced dementia risk, and it has the potential to delay the onset of dementia and mild cognitive impairment by five to seven years [1].

Cognitive stimulation

Engagement in cognitively stimulating activities has been linked to lower dementia incidence, better cognitive function, and a slower rate of cognitive decline [2-4]. However, previous studies have some limitations. First, they often examine engagement in cognitive activities at a single life stage. Second, they frequently focus on a single activity, such as solving crossword puzzles.

While it’s important to identify which activities and at what life stages contribute to maintaining cognitive function in older age, it’s also essential to recognize that these activities are part of broader lifestyles that individuals engage in throughout their lives, collectively affecting cognition.

To gain a more comprehensive picture, the current study examined the relationships between lifetime cognitive enrichment, access to various resources throughout life, Alzheimer’s disease-related dementia, and cognitive decline.

Measuring cognitive enrichment

This longitudinal study examined 1,939 older adults with a mean baseline age of 80 years, mostly female, from Northeastern Illinois who participated in the Rush Memory and Aging Project. The cohort consisted mostly of highly educated, non-Hispanic White people of European descent, which could limit generalizability. Participants were free of dementia at the beginning of the study and underwent annual clinical evaluations for almost 8 years. During that time, 551 persons developed Alzheimer’s disease-related dementia.

Based on lifetime-enrichment data collected through surveys, the researchers developed a composite measure of enrichment that captures each individual’s living environment.

“Our study looked at cognitive enrichment from childhood to later life, focusing on activities and resources that stimulate the mind,” said study author Andrea Zammit, Ph.D., of Rush University Medical Center in Chicago.

For early-life enrichment, the researchers took into account such factors as parental education; number of siblings; access to various cognitive resources at age 12, such as a newspaper subscription, encyclopedia, globe, or atlas; frequency of cognitively stimulating activities at age 6, for example, being read to; similar activities at age 12, such as reading books; and foreign language instruction before age 18.

For midlife and late life, the researchers considered income and frequency of engagement in cognitive activities; additionally, at the midlife time point, they assessed access to cognitive resources such as magazines, a dictionary, or a library card.

A lifetime enrichment composite score was computed as the average of the three composite scores and was moderately correlated with education and global cognition.

Higher enrichment, lower dementia risk

The analysis of the data showed that every point higher in lifetime enrichment was associated with a 38% reduced risk of dementia and a 36% reduced risk of mild cognitive impairment.

When scores were analyzed separately, the benefits of cognitive enrichment were evident as well, with the risk of Alzheimer’s disease-related dementia reduced by 20%, 21%, and 29%, and the risk of cognitive impairment lower by 17%, 20%, and 24% for early-, mid-, and late-life cognitive enrichment, respectively.

The researchers also calculated that for people at the 90th percentile of lifetime cognitive enrichment, compared with people at the 10th percentile, dementia onset was delayed by almost 5.5 years, with a mean age of 93.8 years (compared to 88.4 years); and for mild cognitive impairment by 7 years, with a mean age of 84.5 years (compared to 77.5 years). The delay was also present when each stage was analyzed separately, but it was smaller for early and mid-life enrichment.

The authors noted differences among study participants at baseline that they attributed to lifetime cognitive enrichment. The cognitive abilities of people at the 10th percentile declined 14% faster than those at the 50th percentile, and those at the 90th percentile declined 10% more slowly.

Among people who died during the follow-up period, the researchers didn’t observe meaningful associations between cognitive enrichment scores and neuropathological changes in the brain. However, they observed associations between higher cognitive enrichment scores and better cognitive function near death and slower cognitive decline.

Individual factors

While composite scores of cognitive enrichment are important for showing global trends, the researchers also conducted separate analyses of individual indicators, which showed a positive association with late-life cognition for all tested indicators except the availability of childhood resources.

The greatest effects were observed for midlife participation in cognitive activities and foreign language instruction, even after adjusting for socioeconomic status. It’s not the first time that learning a foreign language has appeared as a protective factor against cognitive decline or aging. We recently discussed a study linking multilingualism to delayed aging, which further supports the beneficial effects of speaking more than one language.

Lifelong consistency

The researchers conclude that “results suggest that cognitive health in late life is in part the product of lifetime exposure to cognitive enrichment,” and higher lifelong cognitive enrichment has the potential to reduce the risk of Alzheimer’s disease by nearly 40%. While the effect seems to be the strongest for mid- and late-life engagement, the researchers make an argument about the importance of creating intellectually stimulating environments in early life, as this helps to instill the love of lifelong learning in young individuals, which will help them to reap the benefits of intellectual engagement later in life. They also recommend public investment in creating spaces that provide free access to cognitively stimulating activities, such as libraries and other free services, so that these resources are readily available to those with limited financial resources.

“Our findings are encouraging, suggesting that consistently engaging in a variety of mentally stimulating activities throughout life may make a difference in cognition,” said Zammit. “Public investments that expand access to enriching environments, like libraries and early education programs designed to spark a lifelong love of learning, may help reduce the incidence of dementia.”

Literature

[1] Zammit, A. R., Yu, L., Poole, V. N., Kapasi, A., Wilson, R. S., & Bennett, D. A. (2026). Associations of Lifetime Cognitive Enrichment With Incident Alzheimer Disease Dementia, Cognitive Aging, and Cognitive Resilience. Neurology, 106(5), e214677.

[2] Wang, H. X., Karp, A., Winblad, B., & Fratiglioni, L. (2002). Late-life engagement in social and leisure activities is associated with a decreased risk of dementia: a longitudinal study from the Kungsholmen project. American journal of epidemiology, 155(12), 1081–1087.

[3] Gow, A. J., Pattie, A., & Deary, I. J. (2017). Lifecourse Activity Participation From Early, Mid, and Later Adulthood as Determinants of Cognitive Aging: The Lothian Birth Cohort 1921. The journals of gerontology. Series B, Psychological sciences and social sciences, 72(1), 25–37.

[4] Stern, C., & Munn, Z. (2010). Cognitive leisure activities and their role in preventing dementia: a systematic review. International journal of evidence-based healthcare, 8(1), 2–17.

The NUS Academy for Healthy Longevity invites you to the Geromedicine Conference, set to take place from February 26-27, 2026, at the National University of Singapore. This premier event will gather global experts in geroscience, researchers, clinicians and industry leaders to explore the translation of geroscience into real-world interventions aimed at optimizing health and extending healthspan.

Key Themes:

Clinical Translation: Focused on implementing practical, evidence-based interventions in personalized care, discussions will center around individual molecules like NAD+ precursors, bioactive compounds such as urolithin A and ergothioneine, and the gerotherapeutic potential of repurposed drugs.

Clinical Pathways: Sessions will delve into the growing interest in personalized care, foundational to precision geromedicine. Hear from healthcare professionals about how longevity clinics implement gerotherapeutic strategies into patient care.
Innovation and Collaboration: Experience the forefront of innovation with over 10 startup pitches, 50 scientific abstracts, industry showcases, and panels on uniting key players, reflecting the interdisciplinary nature of the geroscience.

Join us at this pivotal event to gain exclusive insights into the latest advancements in nutraceuticals and repurposed drugs. Register now to secure your place and connect with pioneers driving the future of precision geromedicine. Check out the programme for more information: Agenda

Venue Details:

Location: Shaw Foundation Alumni House, 11 Kent Ridge Drive, Singapore 119244
Time: Registration begins at 8:00 AM on Day 1, and 8:30 AM on Day 2.

The conference will be accessible to a virtual audience, ensuring that the discussions reach a global audience beyond the confines of the venue.

Atherosclerosis is the largest cause of human mortality, a growth of fatty plaques in blood vessel walls that narrow and weaken vessels. The structure and composition of plaques can vary considerably between people and within one individual. The most dangerous plaques are those with more fat and less structural material, as these are prone to rupture, leading to a downstream blockage and a heart attack or stroke. A plaque is a toxic environment that draws in macrophage cells that attempt to repair the lesion, but instead are overwhelmed, killed, and add their mass to the plaque. Initially, circulating monocyte cells arrive at a plaque and turn into macrophages, but in later stages an almost cancerous process causes smooth muscle cells in the vascular wall to turn into macrophages to further accelerate plaque growth and instability. Here, researchers find a way to potentially interfere in this process, and thus greatly reduce the formation of unstable plaques that are prone to rupture.

Smooth muscle cells (SMCs) exhibit remarkable plasticity, undergoing extensive phenotypic switching to generate a highly heterogeneous population within atherosclerotic plaques. While recent studies have highlighted the contribution of SMC-derived macrophage-like cells to plaque inflammation, the specific molecular drivers governing the transition to these pathogenic states remain poorly understood.

Here, we re-analyzed single-cell RNA sequencing data from lineage-traced mice to dissect SMC heterogeneity during atherogenesis. Trajectory analysis revealed that SMCs transdifferentiate into a distinct pro-inflammatory macrophage-like subpopulation via an intermediate "stem-endothelial-monocyte" cell state. Integrated gene regulatory network inference and in silico perturbation modeling identified interferon regulatory factor 7 (IRF7) as a master transcriptional regulator orchestrating this specific pathogenic transition.

Clinically, IRF7 expression was significantly upregulated in unstable and advanced human atherosclerotic plaques, correlating strongly with inflammatory macrophage burden. In vivo, ApoE knockout mice challenged with a high-fat diet exhibited robust upregulation of IRF7 in aortic plaques, which co-localized with macrophage markers. Crucially, SMC-specific knockdown of Irf7 significantly attenuated atherosclerotic plaque progression, reduced necrotic core formation, and enhanced fibrous cap stability. Mechanistically, Irf7 silencing preserved the contractile SMC phenotype and inhibited the accumulation of pro-inflammatory SMC-derived macrophage-like cells within the lesion.

Link: https://doi.org/10.1093/pcmedi/pbaf039