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Pitfalls and Potential of Dementia Prevention Trials

💬 Editorial by Holly Elser, MD, PhD, and Jonathan Graff-Radford, MD:

Recent randomized clinical trials on dementia prevention highlight several challenges in interpreting lifestyle intervention studies, including practice and Hawthorne effects, modest changes in cognitive outcomes, and heterogeneity in both trial design and participant baseline risk.

The trial by Zhang et al—evaluating aerobic exercise and intensive vascular risk reduction—showed no significant cognitive benefit over 2 years in older adults at elevated risk, underscoring the potential influence of midlife vs late-life intervention timing and the need for longer trials or biomarker-enriched cohorts to better assess dementia prevention strategies.

Dementia prevention is a global public health priority,1,2 with up to 45% of cases potentially attributable to modifiable risk factors over the life course.3 While recent landmark trials, including FINGER, SPRINT MIND, and POINTER, suggest either single-or multidomain lifestyle interventions can improve cognitive outcomes,4-6 others have shown no clear benefit,7,8 thus highlighting ongoing uncertainty in the field.

In this issue of JAMA Neurol ogy, Zhang and colleagues9 report the results of a single-blind, multicenter randomized clinical trial of the effects of exercise and intensive vascular risk reduction on cognitive function. Eligible study participants were between the ages of 60 and 85 years at baseline with a history of hypertension, family history of dementia, or self-reported cognitive decline. The study used a 2 × 2 factorial design wherein participants were randomized to aerobic exercise training alone, intensive pharmacological reduction of cardiovascular risk factors (IRVR) alone, both aerobic exercise and IRVR, or usual care for a 24-month period. The IRVR protocol lowered systolic blood pressure to less than 130 mm Hg, and participants with baseline serum low-density lipoprotein cholesterol (LDL-C) of 70 mg/dL or higher were also treated with a high-intensity statin.

Studying 2 distinct human cohorts with recent exposure to TB

https://doi.org/10.1172/jci.insight.202134 Paul Ogongo & team find different individual Mycobacterium tuberculosis antigens induce distinct T cell responses, with important implications for TB vaccine development.

5Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.

6Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, California, USA.

7Department of Infectious Disease and Immunology, Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark.

Long-term inflammatory memory driver identified!

The researchers first gave a bout of psoriasis to mice when they were young. They discovered that about 10–15% of the memories that persisted a month later stuck around even to the end of the mouse’s life (~2 years). To see why these long-term memories lingered while their short-term counterparts faded within six months, they analyzed the DNA sequence characteristics within each of the memories by using a deep learning model customized by the third co-first author.

“When we compared the DNA sequences of short and long-term memory domains, they looked very similar in terms of the numbers and kinds of transcription factor binding sites,” says the author. “We realized we needed to develop a new metric that specifically captures memory persistence across time, not just total accessibility at any one point.”

Soto-Ugaldi’s adaptation, called PersistNet, quickly identified a telling trait: The longest lasting memory domains had an unusually high frequency of CpG dinucleotides—short DNA sequences of cytosine followed by guanine, which are known to play a key role in gene regulation. In fact, the model predicted that CpG density hardwires a timer into every memory domain: The more CpG’s, the longer the memory.

When they tested the prediction, that’s exactly what they found. “Looking across all 1,000 memory domains, we discovered that these nucleotide densities alone, and no other DNA sequence pattern, could distinguish how long each memory would linger,” says the author.

Back in the lab, the team discovered that these genetically wired densities enabled a host of epigenetic changes in memory domains, including DNA demethylation (the removal of a methyl group specifically found on CpG dinucleotides); the binding of transcription factors that prefer demethylated states; and the recruitment of a histone variant called H2A.Z, which preferentially seeks out demethylated sites and boosts chromatin accessibility while staving off future re-methylation. Together, these changes stabilized the open chromatin formation and its gene-priming activity. As the authors discovered, this structure could crucially be passed down across cellular generations, essentially keeping the doors open for life. Science Mission sciencenewshighlights.

One of the most puzzling aspects of common chronic inflammatory skin diseases such as psoriasis is how they become chronic. What allows an ongoing condition to stay dormant for months or even years, then seemingly spring back out of nowhere?

Continue reading “Long-term inflammatory memory driver identified!” | >

Fragmented phone use—not total screen time—is the main driver of information overload, study finds

Amid hot discussion on screen time, social media use and the impact of digital devices on our well-being, a seven-month study from Aalto University in Finland sheds new light on what overwhelms users the most—and the results aren’t what you might think.

“Screen time does matter, but the heaviest users aren’t the most overloaded,” says doctoral researcher Henrik Lassila. “Those who feel most overwhelmed are the ones who return to their phone again and again for brief moments and then put it down shortly after.”

The seven-month study followed the digital behavior of nearly 300 adults in Germany across smartphones and computers. Participants completed repeated surveys about information overload, while all apps and websites used were logged, creating a rich longitudinal dataset of real world device use.

Induced Hypertension Shows Promise for Managing Early Neurological Deterioration in Stroke Care

In this BloggingStroke post, Romil Singh discusses Stroke article by Kim et al.

Kim H, Kim JT, Lee JS, Kim BJ, Kang J, Kim DY, Lee KJ, Kim CK, Park JM, Kang K, et al. Management Strategies for Early Neurological Deterioration in Noncardioembolic Ischemic Stroke. Stroke. 2025.

Early neurological deterioration (END) remains one of the most challenging and feared complications during the acute phase of ischemic stroke. Affecting up to 40% of patients, END often signals the expansion of infarction, worsening hypoperfusion, or thrombus propagation. Despite its prevalence and its strong association with long-term disability, we lack clear evidence-based guidance on treatment strategies for inducing hypertension to improve perfusion and escalating antithrombotic therapy in hopes of stabilizing the patient.

A new nationwide study from South Korea, published in Stroke, now offers some much-needed clarity. Kim et al. analyzed data for more than 3,000 patients with no cardioembolic ischemic stroke who developed END due to stroke progression. They compared the real-world effectiveness of three treatment approaches: conservative treatment, change in antithrombotic therapy, and iHTN, and looked at associations with early neurological improvement (NI) during hospitalization and functional outcomes at 3 months. Because END was confirmed with imaging and standardized assessments, the cohort offers a clear view of how clinicians manage stroke progression in the absence of hemorrhage or metabolic causes.

What makes a good proton conductor?

A number of advanced energy technologies — including fuel cells, electrolyzers, and an emerging class of low-power electronics — use protons as the key charge carrier. Whether or not these devices will be widely adopted hinges, in part, on how efficiently they can move protons.

One class of materials known as metal oxides has shown promise in conducting protons at temperatures above 400 degrees Celsius. But researchers have struggled to find the best materials to increase the proton conductivity at lower temperatures and improve efficiency.

Now, MIT researchers have developed a physical model to predict proton mobility across a wide range of metal oxides. In a new paper, the researchers ranked the most important features of metal oxides for facilitating proton conduction, and demonstrated for the first time how much the flexibility of the materials’ oxide ions improves their ability to transfer protons.

Spatial profiling of patient-matched HER2 positive gastric cancer reveals resistance mechanisms to targeted therapy

Sheng et al. present “” via https://bit.ly/4spB5XM (Original research, GI cancer section).

Why do targeted therapies stop working? Using spatial transcriptomics, this study reveals how tumour heterogeneity, immune escape and metabolic shifts drive resistance in HER2-positive gastric cancer. A must-read for anyone interested in precision oncology and treatment optimisation.

Background Human epidermal growth factor receptor 2 (HER2; ERBB2) is overexpressed or amplified in 15–20% of gastric cancers (HER2+ GC). Within individual HER2+ GCs, HER2/ ERBB2 expression is often variable. Although HER2 therapeutic targeting improves outcomes for HER2+ GC patients, acquired resistance is frequent.

Objective To spatially interrogate HER2+ GC interpatient and intrapatient heterogeneity and resistance mechanisms associated with HER2-targeting agents (trastuzumab, trastuzumab deruxtecan (T-DXd)).

Design Spatial transcriptomic analysis (GeoMx Digital Spatial Profiler) was applied to 1,500 regions of interest in 30 GCs—these contained 15 HER2+ GCs treated with trastuzumab and T-DXd subsequently. Analysis of patient-matched samples with acquired trastuzumab or T-DXd resistance revealed escape mechanisms.

Symmetry Keeps Fermions Pure in a Noisy World

A theoretical study reveals how to control and drive a quantum system without causing its decoherence.

Quantumness is famously fragile. Decoherence, particle loss, and other dissipative processes typically destroy delicate quantum superpositions, causing open quantum systems to behave classically. This universal, inevitable fate suggests that, even when a system’s constituents are fully quantum, its nonequilibrium critical points could be described by classical universality classes. That is, the system could belong to a group whose behavior near a critical point is identical and scale invariant regardless of microscopic details. In a new theoretical study, Rohan Mittal and his collaborators at the University of Cologne in Germany have overturned this expectation for open systems of fermions [1]. They identified a particular symmetry, which, if present, blocks most of the noise channels that would ordinarily wash out quantum behavior at large scales.

Liquids can fracture like solids—researchers discover the breaking point

In a development that could shift our basic understanding of fluid mechanics, researchers from Drexel University have reported that, given the right circumstances, it is possible to induce a simple liquid to fracture like a solid object. Recently published in the journal Physical Review Letters, the research shows how viscous liquids can suddenly break if stretched with enough force.

The fracturing behavior suggests that viscosity—a liquid’s resistance to flowing—may play a more prominent role in its mechanical properties than previously understood. It also raises new possibilities for how liquids might be manipulated in everything from hydraulics to 3D printers to blood vessels.

“Our findings show that if pulled apart with enough force per area, a simple liquid—a liquid that flows—will reach what we call a point of ‘critical stress,” when it will actually fracture like a solid. And this is likely true for all simple liquids, including common examples, such as water and oil,” said Thamires Lima, Ph.D., an assistant research professor in Drexel’s College of Engineering, who helped to lead the research. “This fundamentally changes our understanding of fluid dynamics.”

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