SAN DIEGO – A new AI model applied to routine pathology slides accurately predicts outcomes and response to immunotherapy in patients with metastatic non-small cell lung cancer (NSCLC). The study was study presented at the American Association for Cancer Research (AACR) Annual Meeting.
“Immunotherapy has transformed cancer treatment, but only a subset of patients benefit from it, and predicting who will respond remains challenging,” said Rukhmini Bandyopadhyay, PhD, a postdoctoral fellow at The University of Texas (UT) MD Anderson Cancer Center.
“This study represents, to our knowledge, the first deep learning-based pathomics biomarker rigorously validated across international real-world cohorts and a Phase III randomized clinical trial, directly addressing one of the most urgent unmet needs in precision oncology: reliable patient selection and stratification for immunotherapy,” he continued.
Pathomics applies computational and machine learning methods for high-throughput analysis of digital pathology images to extract large-scale data related to cell and tissue architecture linked to disease outcomes.
Bandyopadhyay and colleagues developed a deep learning survival prediction model called Pathology-driven Immunotherapy Optimization (Path-IO), which can study patterns across tissue to identify patients most likely to benefit from immunotherapy. The model then combines imaging and clinical data to estimate whether a patient may have a higher or lower risk of poor outcomes from immunotherapy.
The researchers tested the platform in a study that included 797 immune checkpoint inhibitor-treated NSCLC patients from UT MD Anderson, with external validation in 280 additional patients from Mayo Clinic, Gustave Roussy, and the Phase III Lung-MAP S1400I trial in which immunotherapy-naïve patients with lung squamous cell carcinoma, a subtype of NSCLC, were treated with immune checkpoint inhibitors.
The model reliably stratified patients into higher and lower risk groups. In the UT MD Anderson cohort, patients in the high‑risk group had more than double the risk of death or disease progression compared with patients in the low‑risk group.
Model performance was evaluated using the concordance index (C-index), which measures how well each biomarker distinguishes between patients with different outcomes. Notably, Path-IO consistently outperformed PD-L1, the U.S. Food and Drug Administration-validated standard-of-care biomarker for guiding immunotherapy use in NSCLC patients, across both discovery and test cohorts.
PD-L1 alone showed limited prognostic performance, with C-indices of 0.58 for overall survival (OS) and 0.57 for progression-free survival (PFS) in the discovery cohort, declining to 0.50 and 0.51, respectively, in the test cohort. In contrast, Path-IO demonstrated stronger discriminative ability, achieving C-indices of 0.69 for OS and 0.65 for PFS in the discovery cohort and 0.63 for OS and 0.58 for PFS in the test cohort.
Combining pathology-based predictions with radiomics and clinical data further improved the model’s performance, with the C-index increasing from 0.58 to 0.70 for PFS and from 0.63 to 0.75 for OS.
Given that the approach was designed to be applied to routine pathology slides, the platform can be incorporated into existing clinical workflows without significant expense compared to other emerging data-based technologies.
As the study is retrospective, further investigation is needed to go beyond the identification of patients who would benefit from immunotherapy and help predict what type of immunotherapy they can benefit from. Future directions include prospective validation and the integration of paired, more comprehensive molecular profiling to enhance predictive performance.
The mood at the recent 2026 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders in Copenhagen was notably different from the mood that has hung over much of neurodegeneration research for the past decade.
There was still plenty of caution, and plenty of unanswered questions, and certainly no shortage of technical nuance. But there was also something more concrete than hope: a growing sense that the field now has enough tools, biological insight, and clinical momentum to start probing more deeply and stratifying pathologies of neurodegenerative diseases in patients, at varying stages of progression.
That shift was visible across the meeting. It was there in conversations about co-pathologies, the increasingly central role of inflammation and the rapid maturation of blood-based biomarkers. It also featured in the way industry and academia alike talked about therapy: not as a search for a single silver bullet, but as a move toward combination treatment strategies more familiar from the fields of oncology, cardiology, and other complex chronic diseases.
Henrik Zetterberg, PhD, Gothenburg University
Henrik Zetterberg, PhD, Gothenburg University, University College London, and a guest professor at University of Wisconsin-Madison, one of the field’s most influential biomarker researchers, put the central theme plainly: “I think disease heterogeneity will be the mantra in the coming years, to dissect the molecular underpinnings of this heterogeneity.”
Heterogeneity moves from caveat to core concept
Zetterberg described how biomarker-enabled phenotyping is exposing just how different patient trajectories can be once amyloid begins to accumulate. Some people decline quickly. Others remain resilient for a decade or longer. Some cases that appear clinically similar may in fact be driven by very different molecular constellations.
Geoff Kerchner, MD, PhD, vice president, global head of neurodegeneration at Roche
Geoff Kerchner, MD, PhD, vice president, global head of neurodegeneration at Roche, made a similar point from the therapeutic side. In Alzheimer’s disease, he said, some features remain strikingly consistent across patients.
But once one moves beyond core pathology, “the rate at which that happens varies from person to person,” and that variance is shaped in part by co-pathologies, including alpha-synuclein, TDP-43, and vascular disease.
Steve Williams, MD, PhD, chief scientific officer at Alamar Biosciences, pushed the same logic further, arguing that mixed biology is not the exception but the rule. “Everyone with neurodegeneration is carrying around some combination of other pathologies,” he said. “It’s almost inevitable because it’s a feature of aging.”
Steve Williams, MD, PhD, chief scientific officer at Alamar Biosciences
That view has major consequences. It means the field is increasingly moving away from asking whether a patient is amyloid-positive or tau-positive in a binary sense and toward asking what additional pathological burden may be present, what that burden means for progression, and how it should influence treatment choice.
Betty M. Tijms, PhD, head of science Alzheimer Center Amsterdam
Betty M. Tijms, PhD, head of science Alzheimer Center Amsterdam at Amsterdam UMC, offered a useful example from discovery research. In her work integrating CSF proteomics and lipidomics, she described signals that shift depending on tau status and amyloid background. At one point, she noted that these patterns “will inform which type of patients may require their own, personalized therapies.” It captures the direction of travel: from broad molecular mapping to biologically meaningful subtyping.
Inflammation is no longer a side story
Andréa Lessa Benedet, PhD, University of Gothenburg
Andréa Lessa Benedet, PhD, University of Gothenburg, discussed findings showing that people with faster progression in tau-related pathology had “higher expression of many inflammatory markers in plasma and in CSF.” That observation alone is not enough to settle the longstanding question of whether inflammation is driving disease, responding to it, or doing both. But it adds to a growing body of work suggesting that immune biology is closely tied to the pace of progression.
What made Benedet’s description especially interesting was that the signal was not identical across biofluids. The proteins elevated in CSF were not the same as those elevated in plasma. Yet when her group mapped those proteins to cell types and pathways, the two compartments converged on similar biology. In other words, the field may not always be looking for one-to-one molecular matches between brain-adjacent and peripheral compartments. It may instead be learning to recognize pathway-level concordance.
Benedet pointed to evidence suggesting that amyloid pathology together with inflammation may influence how tau spreads through the brain. That “bit of both” view—driver and response, cause and consequence—may be unsatisfying if one wants a simple mechanism. It may also be closer to biological reality.
The therapeutic implication is obvious. If inflammatory processes help define faster-progressing biology, then they are not merely descriptive. They become candidates for stratification and, eventually, intervention.
Blood-based biomarkers as research infrastructure
Jacob Vogel, PhD, Lund University and SciLifeLab
Few topics drew more sustained attention in Copenhagen than blood-based biomarkers. Kerchner called blood-based biomarkers one of the biggest themes of the meeting saying they could “really democratize the diagnosis of Alzheimer’s disease.”
Democratization here is about health equity—geography, trial access, earlier identification, and the possibility of shifting neurodegeneration research beyond the relatively narrow populations that have historically been easiest to recruit and deeply phenotype. That broader perspective surfaced in a session on sex differences in neurodegeneration, where Jacob Vogel, PhD, assistant professor at Lund University and SciLifeLab, presented findings suggesting that brain cells responding to Alzheimer’s pathology have different expression patterns in men and women. Seen that way, the field needs tools that are sophisticated enough to capture the true biological complexity of disease across different patients.
However, one excellent blood-based biomarker, such as brain-derived p-tau217, does not solve the co-pathology problem. As Niranjan Bose, PhD, managing director at Gates Ventures put it, there is a growing “need to do better when it comes to co-pathologies so we can stratify participants better.” A strong single analyte may be enough to identify one core process very well; it is not enough to capture the layered biology of aging brains. That is why the discussion is shifting from singleplex to multiplex, from favorite markers to models.
Zetterberg spoke about the new NULISA Neuro 220 panel from Alamar Biosciences, as a research tool that can help the field probe lysosomal and synaptic biology, alpha-synuclein-related processes, and other pathways relevant to co-pathology. He also highlighted the importance of brain-derived tau readouts, arguing that they may reduce confounding from peripheral tau expression and make blood results easier to interpret in diseases where peripheral neuropathy or other non-CNS biology could muddy the picture.
Zetterberg said, “Those broader panels will be the engines for discovery.” In other words, the value of broad biomarker panels is not that every protein measured will someday be run routinely in a clinical lab. It is that broad panels can reveal reproducible patterns, identify hub biology, and narrow the search toward robust clinical assays.
Combination treatment is becoming the default future
The conference’s other major shift was therapeutically focused. Even where amyloid remained central, the discussion increasingly assumed that amyloid-directed therapy alone will not be the endpoint.
Michael Irizarry, MD, senior vice president and deputy chief clinical officer at Eisai US
Michael Irizarry, MD, senior vice president and deputy chief clinical officer at Eisai US, put it bluntly: “Alzheimer’s is being used as the example of precision medicine.” That is a striking statement, because for years Alzheimer’s was more often framed as the place where precision medicine had failed to arrive. What changed is that biomarkers, imaging, and fluid measures have advanced enough to stage disease more accurately and begin matching interventions to biology and timing.
Irizarry also described an emerging combination logic already being tested clinically. “The hope is that by targeting multiple processes we can get a greater treatment effect,” he said, referring to efforts to combine anti-amyloid therapy with a tau-directed antibody strategy. The reasoning is straightforward: if amyloid clearance slows disease but does not stop it, then other mechanisms—including tau propagation—remain actionable targets.
Kerchner made the same point in even broader terms. “The combination of therapies attacking different aspects of Alzheimer’s disease and Parkinson’s disease is almost surely going to be needed,” he said. He compared the situation to hypertension, diabetes, and cardiovascular disease—complex chronic illnesses that are almost never controlled with one intervention alone.
If the field is moving toward a wider therapeutic lens, with multiple mechanisms and intervention points in play, then there is value in creating space for a broader range of emerging approaches. That was visible in the Startup Hub, now in its second year, where early-stage companies gave short five-minute pitches that often echoed the meeting’s main scientific themes. ScandBio was one example: its Phase III clinical trial of a combined metabolic drug targeting mitochondrial dysfunction in Alzheimer’s disease connected to the conference session on mitochondrial pathways in neurodegeneration and therapy.
Taken together, these developments pointed to the same conclusion: as the biology becomes more layered, the response from the field is becoming more layered too. Combination therapy only becomes rational if disease heterogeneity is measurable. It only becomes practical if blood-based biomarkers can help define stage, likely response, and co-pathology burden without requiring every patient to undergo repeated PET imaging. And it only becomes truly precise if inflammation, synaptic injury, lysosomal dysfunction, vascular change, can be integrated into the treatment model rather than treated as background noise.
As presented at the 2026 AACR Annual Meeting: in a phase 1b trial, patients with microsatellite-stable colorectal cancer received a FAP-4-1BB ligand together with the CEA-directed T cell engager cibisatamab; the treatment was safe, and biomarker analysis showed induction of immunity in line with the biological rationale.
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Older adults with anemia have significantly higher levels of blood biomarkers for Alzheimer’s disease and a significantly increased risk for the disease itself, particularly when anemia is combined with the presence of the biomarkers, Swedish study data show.
The findings “suggest that anemia may interact with neuropathologic processes, potentially accelerating dementia development,” write Martina Valletta, MD, from Karolinska Institutet and Stockholm University in Sweden, and co-authors in JAMA Network Open.
Their analysis included data for 2282 dementia-free participants (median age, 72 years, 62% women) of the population-based Swedish National Study on Aging and Care in Kungsholmen. Of these, 8.7% had anemia at baseline.
The researchers report that participants with anemia had significantly higher baseline levels of the Alzheimer’s disease blood biomarkers phosphorylated tau 217 (p-tau217; 0.2 vs 0.1 pg/mL), neurofilament light chain (NfL; 36.6 vs 17.0 pg/mL), and glial fibrillary acidic protein (GFAP; 187.8 vs 117.4 pg/mL) relative to individuals with normal hemoglobin levels.
During a mean follow-up of 9.3 years, 362 (15.9%) participants developed dementia, with the incidence significantly higher among those with versus without anemia, at 4.4 and 1.7 cases per 100 person–years, respectively.
After adjustment for multiple potential confounding factors, like age, sex, education level, chronic kidney disease, heart disease, cerebrovascular disease, cancer, weight, iron and vitamin supplementation, and interleukin-6 level, the difference between the two groups corresponded to a significant 1.7-fold higher risk for developing dementia during follow-up among the participants with anemia relative to those with normal hemoglobin levels.
Valletta and colleagues note that the relationship between baseline hemoglobin levels and incident dementia was nonlinear. Specifically, below hemoglobin levels of approximately 14 g/dL dementia risk was inversely associated with hemoglobin level. Above this cutoff, the association plateaued.
In addition, the team found that co-occurrence of low hemoglobin and elevated Alzheimer’s disease blood biomarkers further amplified dementia risk.
For example, compared with participants without anemia and with low NfL, the risk for dementia was a non-significant 1.1-fold higher among those with anemia only, a significant 2.2-fold higher among those with high NfL only, and a significant 3.6-fold higher among participants with both anemia and high NfL.
Elevated dementia risk also occurred when anemia was combined with high p-tau217 or GFAP levels, but no additive interaction was detected for these biomarkers.
In general, the risk associations were stronger in men than women and among participants not carrying APOE ε4 compared with carriers.
The researchers say there are several potential interpretations for their findings, including the possibility that “anemia may reduce brain resilience, thereby lowering the threshold at which neuropathology manifests clinically as dementia.”
They conclude that the study data “suggest anemia is a clinically relevant factor in the context of dementia risk stratification and is possibly a modifiable target in dementia prevention strategies.”
“Future studies should further investigate this possibility and formally assess whether—and which—blood biomarkers mediate the relationship between anemia and dementia development.”
BackgroundGastrointestinal adverse events (GI AEs) are the main dose-limiting side effects of metformin in type 2 diabetes mellitus (T2DM), reducing adherence and compromising long-term glycaemic control. Current strategies (dose adjustment or combination therapy) seldom address both tolerability and sustained metabolic efficacy. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that may modulate gut–brain–metabolic pathways—vagal reflexes, inflammation, intestinal barrier function, and enteroendocrine signaling—and thus improve drug tolerance while preserving glycaemic control.MethodsThis single-center, randomized, sham-controlled pilot trial will enroll 60 T2DM patients with metformin-associated GI AEs, randomized 1:1 to either the taVNS group or the sham control group. The intervention lasts 2 weeks with a follow-up at week 4. Assessments at baseline and follow-up include a validated Metformin Symptom Severity Score (total score 0–50; primary outcome), Bristol Stool Form Scale, bowel urgency, glycaemic/metabolic indices [fasting blood glucose (FBG), 2-h postprandial glucose (PG2h), glycated albumin (GA), fasting C-peptide, fasting insulin, HOMA-IR, ISI], and mechanistic biomarkers (GLP-1, 5-HT, IL-6, IL-10, TNF-α, D-lactate, DAO, bile acids). Safety monitoring includes routine hematology, liver and renal function tests.DiscussionBy combining clinical outcomes with targeted biomarker analyses in a randomized design, this pilot study will assess whether taVNS alleviates metformin-associated GI intolerance without impairing glycaemic efficacy, and will provide feasibility data, effect-size estimates, and biomarker selection for future confirmatory trials.Clinical trial registrationTrial registration International Traditional Medicine Clinical Trial Registry (ITMCTR) http://itmctr.ccebtcm.org.cn/, Identifier: ITMCTR2025001086.
ObjectiveConventionally, blood oxygen level-dependent (BOLD) signals derived from resting-state functional magnetic resonance imaging (rs-fMRI) are attributed to gray matter, but recent evidence confirms stable low-frequency oscillations within white matter. While structure–function coupling is pivotal in neuropsychiatry, it remains underexplored in HIV-associated neurocognitive disorders (HAND). Focusing on Asymptomatic Neurocognitive Impairment (ANI), the earliest stage of HAND, this study establishes a white matter skeleton-based fusion framework integrating diffusion tensor imaging (DTI) and rs-fMRI to investigate underlying mechanisms.MethodsWe enrolled 47 patients with ANI and 48 matched healthy controls. Fractional anisotropy (FA) images from DTI and BOLD signals derived from rs-fMRI were projected onto a unified white matter skeleton to achieve structure–function spatial alignment. FA, skeleton-based white matter amplitude of low-frequency fluctuations (SWALFF), and its dynamic variability (dSWALFF) were calculated. Group differences in white matter structure and function were assessed, with structure–function coupling examined in regions showing overlapping FA-SWALFF and FA-dSWALFF alterations. Additionally, a novel White Matter Dys-coupling Index (WDI) was proposed to quantify the deviation between structural integrity and functional activity and evaluate its clinical relevance.ResultsCompared to controls, ANI patients exhibited widespread FA reductions and increased mean diffusivity (MD) and radial diffusivity (RD), indicating diffuse demyelination. Functionally, a spatial dissociation emerged: SWALFF was reduced in posterior occipital pathways (left vertical occipital fasciculus, forceps major), whereas SWALFF and dSWALFF were elevated in prefrontal pathways (forceps minor). Overlapping regions revealed complex coupling patterns, ranging from concordant decline to compensatory upregulation and decoupling. The interaction between FA and dSWALFF further highlighted instability in dynamic regulation. The WDI was significantly correlated with infection duration, immune status, and cognitive domain scores.ConclusionThis study identifies a characteristic “coupling imbalance” in the white matter of ANI patients, defined by the coexistence of structural degeneration and functional reorganization. We propose the WDI as a quantitative metric for this deviation. Its significant associations with clinical and cognitive metrics suggest its potential as a neuroimaging biomarker for the early identification and mechanistic understanding of HAND.
PrecisionLife and Ovation.io have signed a commercialization agreement to bring GLP-1 response genetic tests to the market. Today, the partners announced plans to launch both direct-to-consumer and laboratory developed tests later this year.
The companies had entered a collaboration at the end of last year, leveraging Ovation’s multi-omics and longitudinal clinical data and PrecisionLife’s advanced analytics platform to uncover genetic mechanisms of response to GLP-1 medication. Earlier this year, they reported the identification of a series of biomarker signatures that can quantitatively predict which patients are most likely to respond to GLP-1 therapies and sustain that response over time.
The partners are now actively working on translating this discovery into noninvasive genetic tests for patients to make informed decisions about the likely risks and benefits of these increasingly popular drugs, as well as for drug developers to stratify patients in clinical trials.
“Our teams have generated the world’s most detailed insights into why patients respond differently to these medicines,” said Steve Gardner, chief executive officer of PrecisionLife. “We will make these insights clinically actionable via noninvasive DNA tests supported by our results reporting platform and CLIA lab partners.”
PrecisionLife stressed that their findings go beyond the GLP-1 genetic predictors reported last week by 23andMe. “While that study highlighted a handful of variants associated with modest differences in outcomes, this work identifies combinatorial biomarker signatures that stratify patients and quantitatively predict response—and is already being translated into tests designed for use in real treatment decisions,” a company representative told Inside Precision Medicine.
Over the course of the next six months, PrecisionLife will reproduce, refine, and validate their findings using additional datasets provided by Ovation, including studies to confirm the predicted response to GLP-1 drugs including semaglutide and tirzepatide in a real-world context.
The launch of a consumer DNA test is expected to enable patients to understand their individual safety, efficacy, and tolerability profile for GLP-1 drugs before starting treatment. This could also offer providers a clearer basis for selecting therapies and help payors make more sustainable coverage decisions. The collaborators have stated they will evaluate the opportunity of using these tests to inform reimbursement decisions and expand coverage of certain health plans based on an individual’s predicted response.
For drug developers, laboratory developed tests (LDT) could open up opportunities for more precise patient stratification, improving the probability of success in clinical trials evaluating the expansion of GLP-1 drugs into new indications. The companies are currently in discussions with various stakeholders and sponsors to deploy the LDTs as stratification tools in a clinical setting.
“We’re confident that together we can translate those insights into commercial outcomes and products in GLP-1s and other diseases with huge clinical impact,” said Curt Medeiros, chief executive officer of Ovation.io.
Going forward, the partners will continue to validate their findings and expand the scope of the studies, including identifying additional markers of safety and tolerability to GLP-1 drugs as well as pinpointing further efficacy and safety signals for individual molecules.
A new cerebrospinal fluid biomarker, AcTau174, was elevated in frontotemporal lobar degeneration with TAR DNA-binding protein (FTLD-TDP), distinguishing this pathology from FTLD-Tau, and was associated with disease severity and progression in FTLD-TDP.
