The imaging collection combines structural and functional magnetic resonance imaging with positron emission tomography using tracers for amyloid and tau pathology. Structural and functional MRI provide complementary views of the brain, while the PET scans target two pathological features associated with Alzheimer disease. The cohort also includes clinical, cognitive, genetic and biomarker data, allowing investigators to examine imaging measures alongside other participant-level information. The source does not present the dataset as a single test or diagnostic procedure; it is a collection designed to address questions that require multiple kinds of data.

A major feature of KARI is its longitudinal scope. Participants undergo extensive imaging over time, providing repeated acquisitions rather than a one-time snapshot of the cohort. That structure is intended to help researchers investigate how different measurements relate within individuals and how imaging and biomarker findings may evolve across the disease spectrum. The 6,217 acquisitions encompass 1,645 participants spanning a 55-year age range, from ages 42 to 97, and include people representing healthy aging, preclinical Alzheimer disease and symptomatic disease.

Alongside raw imaging data, KARI provides quality-controlled processed outputs, including anatomical segmentations and biomarker quantification. These derivatives give researchers standardized outputs for the kind of measurements described in the resource, while the raw data preserve the opportunity to apply other analytical approaches. The dataset is also described as open access, with the stated aim of making the material available to the wider scientific community for work on pathophysiology, biomarker identification and therapeutic development. Access to a combined collection, however, does not itself demonstrate that any particular biomarker, diagnostic method or intervention will improve clinical outcomes.

KARI should therefore be understood as a data resource and an invitation to conduct further analyses, not as the report of a completed trial or a demonstrated clinical advance. Its value lies in the scale, multimodal design, longitudinal coverage and processed outputs, while interpretation of any resulting association will depend on the specific question, sample, analysis and limitations of the data used. By linking MRI, PET, clinical, cognitive, genetic and biomarker information across the Alzheimer disease spectrum, the Knight ADRC aims to give researchers a foundation for studies of early detection and disease progression. The resource does not by itself resolve those questions, but it makes them testable with a common and broadly accessible dataset.

Subject of Research: A multimodal neuroimaging and biomarker dataset spanning the Alzheimer disease spectrum

Article Title: Exploring healthy aging through preclinical Alzheimer disease in the Knight Alzheimer Research Imaging dataset

Article References: Hoagey, D. A., McKay, N. S., Joseph-Mathurin, N., Flores, S., Doering, S., Keefe, S. J., Tiemann Powles, S., Hornbeck, R. C., Smith, T. H., Scott, J., Chen, G., Massoumzadeh, P., LaMontagne, P. J., Wang, Q., Hassenstab, J., Ponisio, M. R., Denny, A., Balls-Berry, J. E., Snider, B. J., … Benzinger, T. L. S. (2026). Exploring healthy aging through preclinical Alzheimer disease in the Knight Alzheimer Research Imaging dataset. Nature Communications. https://doi.org/10.1038/s41467-026-78439-3

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78439-3

Keywords: Alzheimer disease, brain imaging, MRI, PET, amyloid pathology, tau pathology, preclinical dementia, healthy aging, longitudinal imaging, biomarkers, Exploring, healthy

The study, published in Nature Communications, enrolled eighteen patients with suspected normal pressure hydrocephalus, a neurological condition that already requires neurosurgery. These patients were undergoing ventriculoperitoneal shunt placement, a procedure in which a tube is implanted to drain excess cerebrospinal fluid. Because the surgery already involves passing through the parieto-occipital cortex, the surgeons were able to take a tiny rice-grain-sized core of brain tissue at the same time, with the patients’ informed consent. Before the operation, each participant received an intravenous infusion of isotopically labelled leucine, an amino acid that crosses the blood-brain barrier and becomes incorporated into newly synthesized proteins. By measuring how much of this label appeared in tau and amyloid-beta proteins extracted from the biopsy, the researchers could determine when those molecules were made.

This technique, known as stable isotope labelling kinetics, has been used before to measure protein turnover in cerebrospinal fluid, but never before has it been combined with direct sampling of living human brain tissue in this way. The result is a kind of molecular timestamp. Proteins carrying the heavy carbon signature of the labelled leucine were manufactured during the hours or days before surgery; proteins without it are older. The approach gives researchers something that post-mortem studies fundamentally cannot: a snapshot of disease biology in real time, at the very earliest stages of the Alzheimer continuum, before symptoms have fully declared themselves.

What the team found in those tiny biopsies was striking. Half of the samples contained amyloid-beta pathology, visible as cored plaques, diffuse deposits and, in one case, cerebral amyloid angiopathy, where amyloid accumulates in blood vessel walls. Tau pathology, the second hallmark, was present but limited, appearing mostly as neuritic threads and tau associated with plaques rather than the mature neurofibrillary tangles seen in end-stage disease. Crucially, the researchers showed that phosphorylated tau, specifically the pTau217 form that has become one of the most accurate blood-based biomarkers for Alzheimer disease, was physically concentrated within and around the amyloid plaques themselves. The signal decreased progressively with distance from the plaque centre, providing direct visual evidence in living human tissue that tau phosphorylation and amyloid deposition are spatially coupled.

This co-localization matters because it speaks to one of the central unanswered questions in Alzheimer research: how amyloid and tau interact to drive neurodegeneration. Dystrophic neurites, the swollen and damaged neuronal processes that surround plaques, contain phosphorylated tau and are associated with synaptic dysfunction. The new findings suggest that this periplaque tau pool, rather than the aggregated tau inside mature tangles, may be the source of the pTau217 that appears in cerebrospinal fluid and blood. That would explain why fluid levels of this biomarker track so closely with plaque burden, and it offers a mechanistic explanation for why amyloid-targeting antibodies such as donanemab, which specifically clears pyroglutamate-modified amyloid-beta, also slow the accumulation of tau pathology even though they have no direct effect on tau metabolism.

The isotope labelling also yielded a remarkable measurement of tau biology. Labelled leucine was detectable in newly synthesized tau protein within just over three hours of the infusion starting, demonstrating that tau is translated rapidly in the human brain. By modelling the decay of the isotopic signal across the cohort, the researchers estimated that the half-life of tau in brain tissue is approximately thirty-four days, broadly consistent with the roughly twenty-three-day turnover previously measured in lumbar cerebrospinal fluid. When the researchers stratified their samples by plaque status, they found that tau labelling was significantly higher in biopsy samples that contained amyloid plaques compared to those that did not, providing ex vivo support for the idea that amyloid pathology drives increased tau production.

In sharp contrast to tau, the amyloid-beta peptides in the insoluble plaque fraction showed no detectable isotope labelling at all, despite the researchers using assays sensitive enough to detect enrichment as low as 1.87 percent and validating their findings across two independent mass spectrometry laboratories. This absence is not a technical failure but a biological finding in its own right. It suggests that amyloid plaques are remarkably stable structures, built up over years or decades, that do not dynamically incorporate significant amounts of new amyloid-beta within the few-hour window of the labelling period. The plaques in these early-stage samples were chemically immature, containing less than forty percent isomerised amyloid-beta species, compared with roughly ninety percent isomerisation in post-mortem Alzheimer tissue, where plaques have had years to accumulate molecular damage.

That isomerisation clock is one of the most conceptually powerful tools to emerge from this work. Aspartate residues in amyloid-beta spontaneously convert from their native L-form to non-native isomeric forms over time, at a rate that can be used to estimate the age of a plaque. Previous work has suggested that around fifty percent isomerisation corresponds to a mean plaque age of roughly eight months, while eighty-five percent indicates an age of about four years. By quantifying these isomers in living tissue, the researchers could distinguish freshly formed, immature plaques from older, more established deposits. This kind of molecular dating has never before been possible in living human brain, and it opens the door to staging the disease biochemically rather than relying on crude measures of plaque quantity, which notoriously correlate poorly with cognitive symptoms.

The team also used matrix-assisted laser desorption ionization mass spectrometry imaging to map the chemical architecture of individual plaques at ten-micrometre resolution. This revealed a striking degree of spatial organization within single deposits. Amyloid-beta 1-40 and pyroglutamate-modified amyloid-beta species were concentrated in the dense plaque core, while amyloid-beta 1-42 and related C-terminal species were distributed more homogeneously across both the core and the diffuse periphery. This peptide-specific spatial segregation, previously observed only in mouse models and post-mortem tissue, confirms that pyroglutamate-modified amyloid sits at the growing edge of plaques and may be a key driver of plaque expansion, making it a particularly relevant target for immunotherapies like donanemab that are designed to clear exactly this modified species.

One further finding carries practical implications for how Alzheimer biomarkers are interpreted. The researchers compared tau profiles in ventricular cerebrospinal fluid, collected during shunt surgery directly from the brain’s fluid spaces, with those in lumbar cerebrospinal fluid collected from the lower spine. Ventricular fluid closely mirrored the tau peptide profile seen in brain tissue itself, while lumbar fluid showed a distinctly different pattern with reduced C-terminal abundance. The team attributes this partly to iatrogenic contamination, as the shunt insertion procedure inevitably releases intracellular brain proteins into the ventricular fluid. Even so, the observation that ventricular cerebrospinal fluid can serve as a surrogate for brain tissue chemistry is significant, particularly for normal pressure hydrocephalus patients, in whom amyloid pathology is common and brain biopsy during shunt surgery is already practised as a diagnostic adjunct by many specialists.

The study is a proof of principle, and the authors are careful to acknowledge its limitations. The cohort is small, the participants were recruited for a hydrocephalus indication rather than Alzheimer disease itself, and the biopsies came from a single brain region that may not represent disease burden elsewhere. The tau half-life estimate rests on a statistical model with sparse timepoints around the peak of the labelling curve. Even so, the conceptual advance is hard to overstate. For the first time, researchers have captured the molecular birth of Alzheimer pathology in living human brains, dated plaques by their chemistry, watched tau being synthesized in real time, and visualized the physical interface between the disease’s two hallmark proteins. The methods developed here should be applicable to other neurodegenerative conditions, and they promise to reshape how clinical trials of the future are designed, allowing therapies to be matched to the specific molecular stage of disease rather than to symptoms alone.

Subject of Research: Molecular characterization of amyloid and tau pathology in living human brain tissue using stable isotope labelling and mass spectrometry imaging

Article Title: Spatiotemporal characterization of Alzheimer disease pathology in living human brain tissue

Article References: Aslanyan, A., Mukherjee, S., Moncur, E. M., Szadziewska, A., He, Y., Kac, P. R., Coyle, R., Camporesi, E., Sato, C., Ghoshal, N., Barthélemy, N. R., Wood, J., Ge, J., Dulewicz, M., Koutarapu, S., Schwetye, K., Roberts, K. F., Murphy, E. C., Carletti, F., … Paterson, R. W. (2026). Spatiotemporal characterization of Alzheimer disease pathology in living human brain tissue. Nature Communications, 17(1), Article 9878. https://doi.org/10.1038/s41467-026-76494-4

Image Credits: AI Generated

DOI: 10.1038/s41467-026-76494-4

Keywords: Alzheimer disease, amyloid-beta, tau, stable isotope labelling, mass spectrometry imaging, normal pressure hydrocephalus, pTau217, pyroglutamate, protein turnover, biomarkers, brain biopsy, neurodegeneration

The insulin receptor is a receptor tyrosine kinase, but it breaks the rules that govern many of its relatives. Rather than dimerizing upon ligand binding, IR exists as a preformed dimer at the cell surface, held in an autoinhibited conformation in which the ectodomain geometry keeps the intracellular kinase domains separated and poorly oriented for the trans-phosphorylation that ignites signaling. Insulin activates the receptor through a multistep trajectory involving two binding sites: site 1, formed by the leucine-rich repeat domain L1 of one protomer together with the alpha-chain C-terminal segment of the opposing protomer, and site 2, located on the lateral surface of the first fibronectin type III domain. When the receptor is fully liganded, up to four insulin molecules can engage it, stabilizing a T-shaped conformation that brings the kinase domains into productive proximity.

Once activated, the receptor autophosphorylates across its activation loop, juxtamembrane region, and C-terminal tail, creating a docking platform for adaptor proteins. The classical branches follow: insulin receptor substrate proteins recruit PI3K to drive the AKT pathway and metabolic regulation, while the adaptor Shc channels signaling into the MAPK cascade, more closely tied to mitogenic and proliferative outputs. Crucially, these are not simply parallel wires but competing engagement routes, and their relative utilization shapes the overall signaling balance. That balance, the review emphasizes, can be distorted in disease, most famously in selective insulin resistance, where the metabolic AKT arm fails while the mitogenic MAPK arm persists, a combination implicated in endothelial dysfunction and in the uncoupling of hepatic glucose production from lipogenesis in type 2 diabetes.

Beyond pathway choice, the review highlights two underappreciated dimensions of IR regulation: trafficking and spatial organization. Internalized receptors were long thought to be simply silenced and recycled, but accumulating evidence shows that endosomal IR can remain signaling-competent, and that insulin-stimulated AKT2 phosphorylation depends on specific endosomal compartments enriched in the protein WDFY2. Genetic mouse models drive the point home. Disrupting the interaction between IR and the spindle checkpoint protein MAD2 delays receptor endocytosis, reduces insulin clearance, elevates circulating insulin, and reshapes both membrane and intracellular signaling, with measurable consequences for lipid metabolism. Conversely, hepatic overexpression of EphB4 drives receptor degradation and insulin resistance, while loss of the beta-cell scavenger inceptor improves glucose tolerance. Precise control of receptor traffic, these studies show, is required for systemic metabolic homeostasis.

Super-resolution imaging adds yet another layer: IR dimers are organized into nanoclusters roughly 74 nanometers across, and insulin stimulation modestly enlarges these assemblies without fundamentally reorganizing them. To test whether ligand architecture matters, researchers built a DNA origami platform presenting insulin at defined valency and spacing. Multivalent insulin NanoRods bound the receptor more tightly, dissociated more slowly, and induced stronger autophosphorylation and downstream transcriptional responses than monovalent insulin. Receptor activation, in other words, is sensitive to nanoscale geometry, not merely to ligand identity, and even the temporal pattern of insulin exposure matters: pulsatile delivery elicits stronger hepatic signaling than constant infusion at an equivalent dose.

The most striking section of the review concerns engineered insulin mimetics, which the authors treat not as insulin substitutes but as molecular probes exposing signaling states inaccessible to the native hormone. Phage display screens originally identified the site 1 and site 2 hotspots, and fusing peptides targeting them in different orientations produced either agonists or antagonists. The 31-amino-acid peptide S597 activates the receptor through a non-native geometry, cross-linking site 1 and site 2 across protomers, and preferentially stimulates metabolic over mitogenic signaling, with in vivo data suggesting possible benefits in atherosclerosis. Reversing the fusion orientation yields antagonists such as S961, which cryo-electron microscopy reveals trap the receptor in an intermediate conformation between the inactive and active states. Fusion geometry, not binding affinity, determines whether a synthetic ligand stabilizes an active, biased, or antagonistic configuration.

Computational protein design has now made that principle fully explicit. De novo designed binders, roughly 7 kilodaltons each and directed against individual extracellular domains, were fused in defined orientations with tunable linker flexibility. Reversing the topology flipped the function: site 2 to site 1 constructs act as agonists, while site 1 to site 2 constructs act as antagonists. Linker rigidity further tunes the output. Rigid constructs such as RF-405 stabilize a compact, fully active conformation and signal in a balanced, insulin-like fashion, whereas flexible constructs such as S2-F1-S1 produce partial autophosphorylation, attenuated mitogenic signaling, and altered trafficking. In animals, these designer agonists lower glucose with slower onset but longer duration than insulin, bypass certain disease-causing IR mutations, and show reduced stimulation of cancer cell proliferation compared with the native hormone.

Aptamers and antibodies round out the modulator toolkit. The DNA aptamer IR-A43 does not activate the receptor alone but potentiates insulin signaling by stabilizing an asymmetric, singly occupied conformation, while IR-A62 behaves as a concentration-dependent allosteric modulator that can lower glucose even under insulin-deficient conditions. Monoclonal antibodies such as 83-7 and 83-14, and the engineered XMet series, demonstrate that epitope selection can tune the receptor from activation to inhibition: XMetA acts as a partial agonist with preferential AKT signaling, XMetS potentiates insulin action, and XMetD reverses hypoglycemia in hyperinsulinemic mouse models. Together these ligands show that IR activation can be synthetically programmed.

The disease implications are broad. In cancer, hyperinsulinemia is associated with increased risk and progression, tumors preferentially express the IR-A isoform that binds IGF2 and sustains mitogenic signaling, and the super-mitogenic analog Asp(B10), which induced mammary tumors in rodents, stands as a cautionary example of what mitogenic bias can do. In polycystic ovary syndrome, skeletal muscle shows post-receptor defects centered on the IRS-PI3K-AKT axis, while ovarian adaptor remodeling promotes androgen excess. In Alzheimer disease, postmortem tissue reveals brain insulin resistance with preserved signaling proteins but elevated inhibitory IRS1 serine phosphorylation, and the genetic risk factor APOE4 impairs neuronal signaling by trapping the receptor in endosomes. Severe insulin resistance syndromes caused by germline IR mutations, meanwhile, may one day be treated with mimetics that activate the receptor through mechanisms distinct from insulin.

The authors are candid about the challenges ahead: it remains unclear which signaling biases are beneficial versus pathological, how bias is maintained in complex physiological environments, and how trafficking, ligand geometry, and adaptor selection integrate in vivo. Translational hurdles, from peptide stability to CNS delivery, are substantial, though the engineering playbook proven by GLP-1 receptor agonists offers a template. Still, the conceptual shift is hard to miss. If insulin action is a programmable network rather than a simple switch, then the future of therapy may lie not in replacing insulin but in reprogramming its receptor, selectively and precisely, in the tissues and disease contexts where it matters most.

Subject of Research: Non-canonical insulin receptor signaling and the design of insulin mimetics

Article Title: Insulin mimetics and non-canonical insulin receptor signaling: mechanisms and disease relevance

Article References: Park, J., & Choi, E. (2026). Insulin mimetics and non-canonical insulin receptor signaling: mechanisms and disease relevance. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01862-5

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01862-5

Keywords: insulin receptor, insulin mimetics, biased agonism, receptor trafficking, endosomal signaling, protein design, type 2 diabetes, insulin resistance, cancer, PCOS, Alzheimer disease, receptor tyrosine kinase

Rapidly progressive dementia, defined by cognitive decline that unfolds over weeks to months rather than years, presents neurologists with one of the most urgent diagnostic challenges in medicine. The two leading causes are prion diseases, most commonly sporadic Creutzfeldt-Jakob disease, and rapidly progressive forms of Alzheimer disease. In typical presentations, the two can be separated with reasonable confidence: prion disease usually announces itself on magnetic resonance imaging with characteristic diffusion-weighted abnormalities, and cerebrospinal fluid tests for prion seeding activity can confirm suspicion. But as the new research demonstrates, a subset of patients slips through these diagnostic nets entirely, presenting with clinical pictures that faithfully reproduce the amnestic syndromes of Alzheimer disease.

The Mayo Clinic team, led by Anas Elgenidi and Gregory S. Day, examined a prospective cohort of 204 patients with rapidly progressive dementia evaluated between February 2020 and June 2026. Among these, five patients, or 2.5 percent, had been diagnosed with clinically probable Alzheimer disease but were ultimately determined to have prion disease. That figure may seem small, but its significance lies in what it reveals about the limits of current diagnostic algorithms. These were not obscure cases buried in ambiguity; they were patients who met accepted criteria for Alzheimer disease and behaved, at least initially, exactly as that diagnosis predicted.

To understand how widespread this phenomenon is, the researchers turned to a systematic review of MEDLINE and Embase, unearthing ten additional published cases. Together with the Mayo cohort, the analysis encompassed fifteen patients with a median age at onset of 59 years, roughly two-thirds of whom were male. The clinical phenotypes these patients displayed mapped remarkably well onto recognized Alzheimer disease variants: just over half presented with an amnestic syndrome dominated by memory loss, about a quarter with a dysexecutive pattern affecting planning and organization, and smaller proportions with primary progressive aphasia, a language-led deterioration, or posterior cortical atrophy, which disrupts visual processing and spatial abilities. In other words, these prion cases were not merely Alzheimer-like in a vague sense; they reproduced specific, named Alzheimer phenotypes with precision.

The technical details of the diagnostic workup reveal where the traditional tools faltered. Diffusion-weighted magnetic resonance imaging, widely regarded as a cornerstone of prion disease diagnosis, was absent in all of the Mayo Clinic cases. In the published cases, the characteristic imaging abnormalities were either absent or equivocal in two patients and, perhaps more troublingly, overlooked in eight. This pattern of missed radiological findings echoes earlier literature showing that MRI changes in Creutzfeldt-Jakob disease are frequently misread or underappreciated, particularly early in the disease course when cortical and basal ganglia changes may be subtle or confined to regions that are not scrutinized routinely.

Cerebrospinal fluid biomarkers added another layer of complexity. In six of nine tested patients, the CSF profile was actually consistent with Alzheimer disease, meaning the amyloid and tau signature that clinicians rely upon to confirm the diagnosis pointed in the wrong direction. Elevated total tau levels, however, emerged as a recurring signal: eleven of thirteen patients showed raised total tau, and in five of nine patients the ratio of total tau to phosphorylated tau 181 was disproportionately elevated. This distinction matters because total tau reflects neuronal injury in a relatively nonspecific fashion, whereas phosphorylated tau is more closely tied to Alzheimer-type pathology. When total tau climbs far out of proportion to phosphorylated tau, the brain is being injured faster and more destructively than Alzheimer disease alone typically explains, and prion disease should enter the differential.

The most definitive diagnostic tool in the study was the real-time quaking-induced conversion assay, or RT-QuIC, a laboratory technique that exploits the prion protein’s infectious misfolding behavior. In the assay, normal recombinant prion protein is exposed to a patient’s cerebrospinal fluid and agitated; if misfolded prions are present, they template the conversion of the normal protein into amyloid fibrils that can be detected with a fluorescent dye, providing a sensitive and specific readout of prion seeding activity. RT-QuIC was positive in the cerebrospinal fluid of nine of twelve patients tested. Across the full cohort, prion disease was ultimately confirmed by neuropathological examination in seven cases, by genetic testing in two, and by RT-QuIC in six, illustrating that no single modality sufficed in every patient.

The median interval between the initial Alzheimer diagnosis and the consideration of prion disease was two months, a delay that, while seemingly brief, is meaningful in a disease measured in months. The stakes are considerable. Prion diseases are uniformly fatal, typically causing death within a year of onset, and there is no established cure, although the field is stirring: an early-phase clinical trial of intrathecally administered prion protein siRNA, a gene-silencing therapy delivered into the spinal fluid, is now enrolling symptomatic patients. Accurate diagnosis also matters for infection control, since prions resist conventional sterilization and demand specialized decontamination protocols in surgical settings, and for genetic counseling, since a proportion of prion disease cases arise from mutations in the prion protein gene with implications for family members.

The timing of this research is particularly consequential given the transformation of Alzheimer therapeutics. With disease-modifying monoclonal antibodies such as lecanemab and donanemab now approved and increasingly deployed, the pressure to confirm an Alzheimer diagnosis early and confidently has never been greater. Blood-based biomarkers are being promoted as accessible confirmatory tests, and CSF profiles are routinely used to anchor clinical decisions. Yet this study demonstrates that a positive Alzheimer biomarker signature does not exclude prion disease, and that patients with rapidly progressive courses deserve scrutiny that goes beyond a single biomarker panel. A patient whose dementia gallops forward while their biomarkers say Alzheimer may, in rare instances, be harboring a prion.

The authors’ central recommendation is pragmatic and easily actionable: disproportionate elevations in cerebrospinal fluid total tau, or an abnormally high ratio of total tau to phosphorylated tau 181, should prompt clinicians to consider prion disease and pursue RT-QuIC testing. Combined with careful re-review of diffusion-weighted MRI, this biomarker-driven vigilance offers a path to catching these mimics earlier. For the vast majority of patients with rapidly progressive dementia, the diagnosis will not be prion disease, and Alzheimer disease itself remains a common and legitimate explanation for swift decline. But for the roughly one in forty patients in this cohort whose illness wore Alzheimer’s mask, the difference between a routine diagnosis and a searching second look was the difference between two entirely different diseases, and the study stands as a reminder that in neurology, the most convincing diagnosis sometimes deserves to be tested against its own biomarkers.

Subject of Research: Prion disease presenting as rapidly progressive Alzheimer disease, diagnosed through CSF tau biomarkers and RT-QuIC assays

Article Title: Prion disease mimicking rapidly progressive Alzheimer disease: case series and systematic review

Article References: Elgenidi, A., Shir, D., Piura, Y. D., Sokol, L. L., Duara, R., Lachner, C., & Day, G. S. (2026). Prion disease mimicking rapidly progressive Alzheimer disease: case series and systematic review. Journal of Neurology, 273(10), Article 565. https://doi.org/10.1007/s00415-026-14087-3

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14087-3

Keywords: prion disease, Creutzfeldt-Jakob disease, Alzheimer disease, rapidly progressive dementia, RT-QuIC, cerebrospinal fluid biomarkers, total tau, phosphorylated tau, diffusion-weighted MRI, differential diagnosis, neurodegeneration, Mayo Clinic

The research team, led by M. J. Dunnet and Tim Hore of the University of Otago in New Zealand, set out to find genomic regions that could cleanly separate leukocytes, the white blood cells that drive inflammation, from every other tissue in the body. Their starting point was a comprehensive human methylation atlas containing data for more than 423,000 CpG sites across blood cell preparations and nine other tissue types that were believed to be free of immune and vascular contamination. For each CpG site, the team calculated the difference between the average methylation level in leukocytes and the average across all non-leukocyte tissues. Sites with a difference of 0.8 or more on a scale from 0 to 1 were classified as leukocyte-specific differentially methylated positions, or ls-DMPs. The screen yielded 77 such sites, of which 19 were highly methylated in blood cells and 58 were essentially unmethylated.

From this list, the researchers focused on the only two CpG islands containing multiple leukocyte-specific sites. The first sits within the HOXA3 locus on chromosome 7, and the second lies within exon 26 of the MAP4K1 gene on chromosome 19. At both loci, the top CpG sites showed very high methylation in leukocytes, moderately low methylation in adipocytes, lung epithelial cells and vascular endothelial cells, and virtually no methylation in colonic epithelium, cortical neurons, hepatocytes and pancreatic cell types. When the team examined methylation across ten different immune cell populations, all mature leukocyte subpopulations were highly methylated at both markers. Intriguingly, the pattern appears to be laid down early in development: foetal liver CD34-positive haematopoietic stem cells showed significant demethylation compared with their adult counterparts, suggesting that methylation accumulates specifically in the foetal stem cells of the blood-forming lineage and is then maintained through every subsequent stage of differentiation and ageing.

Array-based methylation platforms, which measure thousands of CpG sites simultaneously, are powerful discovery tools but are expensive per sample and rely on single probes that risk under-sampling each region. To turn their discovery into something closer to a diagnostic test, the researchers adapted a rapid, cost-effective amplicon bisulphite sequencing assay. Bisulphite treatment converts unmethylated cytosines into uracils while leaving methylated cytosines untouched, so sequencing the treated DNA reveals the methylation state of every CpG within the amplified fragment. Because neighbouring CpGs in a CpG island tend to share the same methylation state, reading multiple sites per DNA molecule dramatically increases the discriminatory power of the test. The team amplified the HOXA3 and MAP4K1 regions using a dual-index, four-primer PCR strategy and sequenced the products on a benchtop instrument.

The validation strategy was elegantly simple. The researchers purified DNA from peripheral blood mononuclear cells, which represent the nucleated fraction of blood, and from cultured intestinal organoids, three-dimensional structures grown from rectal crypt stem cells that contain no blood or vascular contamination. Pure organoid DNA showed mean methylation of just 0.83 percent at HOXA3 and 1.02 percent at MAP4K1, while pure blood cell DNA showed 94.0 percent and 93.1 percent respectively. When the two DNA sources were mixed at seven precisely defined ratios and subjected to the assay, individual sequencing reads fell into two clean clusters with almost no intermediate methylation. A classification system that assigned reads as blood-derived or organoid-derived based on the number of methylated CpGs per fragment produced correlations with the input DNA ratios of R-squared 0.999 for HOXA3 and 0.9985 for MAP4K1, demonstrating near-perfect quantitative accuracy.

The team then moved to a genuinely heterogeneous, uncultured human sample: saliva. Saliva is attractive for epigenetic epidemiology because collection is non-invasive, but it contains an unpredictable mixture of leukocytes secreted from the oral gingiva and buccal epithelial cells sloughed from the cheek. Using flow cytometry and cellular filtration, the researchers purified buccal cells and salivary leukocytes to purities of 97.1 percent and 99.4 percent respectively, and confirmed that the two populations carried the expected opposite methylation patterns. In a mixed saliva sample that microscopic cell counting showed to be 38 percent leukocytes, the methylation-based test predicted leukocyte proportions of 38.1 percent using HOXA3 and 39.3 percent using MAP4K1, with linear regression R-squared values of 0.998 and 0.997. For researchers who use saliva in large epidemiological studies, this offers a way to correct for cellular composition that previously required complex bioinformatic deconvolution of whole-genome data.

Perhaps the most provocative part of the study is what the biomarkers reveal about published disease research. Because immune cells drive inflammation, genuine leukocyte-specific methylation markers should appear repeatedly in methylation studies of inflammatory diseases, even when the diseased tissue itself is not blood-derived. Searching the EWAS Atlas database, the team found 28 disease traits associated with their markers, with psoriasis, inflammatory bowel disease and Alzheimer disease topping the list. A deeper PubMed search of twelve publications found that seven of the eleven studies using the standard methylation array platform reported at least one differentially methylated position or region overlapping the leukocyte-specific sites. Strikingly, many of these studies never mentioned leukocyte infiltration as a possible confound, and only one investigated the proportion of leukocytes in its samples at all.

The Alzheimer disease connection is particularly striking. Several independent studies have reported that a 48-kilobase region spanning the HOXA gene cluster from HOXA2 to HOXA6 becomes progressively hypermethylated in the brain as disease severity increases, measured by Braak stage. When the Otago team overlaid that hypermethylation pattern with methylation data from purified leukocytes and cortical neurons, the genomic locations matched almost exactly: leukocytes are heavily methylated across the HOXA cluster, neurons are not. The authors hypothesise that the methylation signal in the Alzheimer brain comes from infiltrating leukocytes, a phenomenon known to occur as the ageing blood-brain barrier becomes leaky, rather than from any change in the methylation of the brain cells themselves. A simple calculation based on a single CpG site suggested that by Braak stage 6, an additional 13.9 percent of cells in the prefrontal cortex could be leukocyte-derived.

The biomarkers also performed well in cancer. Using more than 8,000 tumour samples from 30 cancer types in The Cancer Genome Atlas, the team compared methylation at the HOXA3 marker with published estimates of leukocyte content. Across all cancers combined the correlation was modest, because cancer cells frequently acquire their own hypermethylation at the HOXA cluster. But in six tumour types, including uveal melanoma, mesothelioma, thyroid carcinoma, testicular germ cell tumours, bladder urothelial carcinoma and ovarian serous cystadenocarcinoma, a single CpG site showed a strong linear relationship with the leukocyte estimate, meaning that in these cancers one methylation measurement may be enough to quantify immune infiltration without any complex deconvolution.

The implications reach well beyond a single laboratory technique. The study demonstrates that methylation differences attributed to diseased cells may sometimes simply reflect the immune cells living among them, and it offers a concrete remedy: researchers studying inflammatory diseases could sort pure cell populations, spike in known amounts of leukocyte DNA as controls, or compare their samples against reference methylation data from healthy tissues and blood. Looking forward, the authors suggest that because colonic epithelium is virtually unmethylated at both loci, a stool-based test for intestinal inflammation could one day complement or even replace invasive colonoscopy for diagnosing inflammatory bowel disease. What began as a search for molecular fingerprints of blood cells has ended up casting doubt on a whole class of disease methylation signals, and providing the tools to tell them apart.

Subject of Research: Leukocyte-specific DNA methylation biomarkers for detecting immune cell infiltration in tissue samples

Article Title: Leukocyte-specific DNA methylation biomarkers and their implication for pathological epigenetic analysis

Article References: Dunnet, M. J., Ortega-Recalde, O. J., Waters, S. A., Weeks, R. J., Morison, I. M., & Hore, T. A. (2022). Leukocyte-specific DNA methylation biomarkers and their implication for pathological epigenetic analysis. Epigenetics Communications, 2(1), Article 5. https://doi.org/10.1186/s43682-022-00011-z

Image Credits: AI Generated

DOI: 10.1186/s43682-022-00011-z

Keywords: DNA methylation, leukocytes, epigenetics, biomarkers, HOXA3, MAP4K1, inflammation, Alzheimer disease, inflammatory bowel disease, cancer immunology, bisulphite sequencing, saliva

The strongest case for this idea comes from genetics. Over the past twenty years, researchers hunting for genes that cause or raise the risk of neurodegenerative disorders have repeatedly landed on the endolysosomal system, the network of vesicles and organelles that ferries cargo to lysosomes for destruction. In Parkinson disease, the evidence is particularly compelling. A substantial proportion of genes linked to the condition encode proteins that are essential for lysosomal health, and the two most common genetic causes of Parkinson disease, mutations in GBA1 and LRRK2, both converge on lysosomal biology. Remarkably, both of these pathways are now being targeted in clinical trials, marking one of the first times that fundamental cell biology has been translated so directly into therapeutic strategies for a neurodegenerative illness.

The GBA1 story illustrates how a single gene can illuminate an entire disease mechanism. GBA1 encodes glucocerebrosidase, a lysosomal enzyme that breaks down fatty substances called glucosylceramides. People who carry one mutated copy of the gene are at markedly elevated risk of developing Parkinson disease, and studies have shown that reduced glucocerebrosidase activity in the substantia nigra, the brain region that degenerates in Parkinson disease, is associated with increased levels of alpha-synuclein, the protein that clumps into the Lewy bodies that define the disorder. Work from the Krainc laboratory and others has revealed a bidirectional loop: deficient glucocerebrosidase impairs the degradation of alpha-synuclein, while accumulating alpha-synuclein in turn blocks the delivery of fresh glucocerebrosidase to lysosomes, creating a vicious cycle of worsening protein aggregation and deepening lysosomal failure.

LRRK2, the other major Parkinson gene, tells a complementary story. This large kinase enzyme phosphorylates a family of Rab GTPases that regulate membrane trafficking throughout the cell. When lysosomes are damaged, LRRK2 is recruited to their surface through pathways involving the CASM machinery and GABARAP proteins, where it helps coordinate membrane repair and the removal of damaged lysosomal material. Pathogenic LRRK2 mutations boost kinase activity, producing enlarged lysosomes with reduced degradative capacity and impairing the clearance of alpha-synuclein. Because LRRK2 is also active in immune cells, its dysfunction extends to microglia, the brain’s resident immune cells, linking lysosomal failure to the neuroinflammation that accompanies neurodegeneration. LRRK2 kinase inhibitors, including the molecule BIIB122, have already been tested in patients, and a broad initiative called the LRRK2 investigative therapeutics exchange is working to overcome the remaining obstacles to translating this biology into disease-modifying therapies.

Beyond these headline genes, the review catalogues an expanding roster of lysosomal proteins implicated in Parkinson disease. Mutations in VPS35, a core component of the retromer complex that sorts cargo through endosomes, cause familial Parkinson disease and disrupt the retrieval of the chaperone-mediated autophagy receptor LAMP2A, which neurons use to deliver alpha-synuclein to lysosomes for destruction. ATP13A2, a lysosomal transporter whose loss causes an early-onset form of parkinsonism, exports polyamines from the lysosome, and its deficiency triggers lysosomal dysfunction and alpha-synuclein accumulation. The lysosomal ion channel TMEM175, identified through genome-wide association studies as a risk factor, regulates the proton balance that keeps lysosomes acidic enough for their digestive enzymes to function. Even the recently characterized Commander complex has emerged as a regulator of lysosomal function and Parkinson disease risk. Each of these discoveries reinforces the same message: many independent genetic insults funnel into a single vulnerable pathway.

In Alzheimer disease, the lysosomal connection takes a somewhat different form, centered on the endocytic trafficking machinery. Enlarged endosomes packed with amyloid-beta are among the earliest pathological changes detectable in neurons of people with Alzheimer disease, appearing before amyloid plaques form. The strongest genetic link is SORL1, which encodes the receptor SORLA, a key regulator of cargo trafficking through the endolysosomal system, including trafficking of the amyloid precursor protein. Loss-of-function variants in SORL1 substantially increase Alzheimer risk, and depletion of SORLA in human neurons impairs endosomal traffic even independently of amyloidogenic processing. Other risk genes, including BIN1, PICALM and CD2AP, all participate in endocytosis and endosomal sorting, and presenilin mutations that cause familial Alzheimer disease disrupt lysosomal acidification and autophagy, although the precise role of presenilins in this process remains debated.

The lipid-carrying protein APOE adds another layer to the Alzheimer picture. The APOE4 allele, the strongest common genetic risk factor for late-onset disease, promotes the accumulation of cholesterol in lysosomes of astrocytes, impairs mitochondrial function and dampens autophagy through multiple mechanisms, including direct binding of ApoE4 to gene regulatory elements that control autophagy genes. Meanwhile, TREM2, a receptor on microglia that depends on lysosomal processing for its function, shapes how immune cells respond to amyloid plaques, although a recent clinical trial targeting TREM2 failed, underscoring how much remains to be learned about translating lysosomal biology into treatments.

Frontotemporal dementia and amyotrophic lateral sclerosis, two clinically distinct disorders with heavily overlapping genetics, supply perhaps the most direct evidence that autophagy, the cellular self-eating process that delivers cargo to lysosomes, is essential for neuronal survival. Multiple ALS and FTD genes encode proteins that regulate autophagy at different steps: TBK1 and OPTN coordinate the selective removal of damaged mitochondria; VCP and UBQLN2 participate in extracting ubiquitinated proteins for degradation; SQSTM1, also known as p62, serves as a cargo receptor that tags aggregates for autophagic clearance; and C9ORF72, the most common genetic cause of both diseases, forms a complex that regulates Rab GTPases and mTORC1 signaling at the lysosome. Mutations in CHMP2B, part of the ESCRT-III machinery that repairs ruptured lysosomal membranes, cause a distinctive form of frontotemporal dementia characterized by lysosomal storage pathology, and recent work shows that the ALS-linked proteins annexin A11 and CHMP2B act sequentially in membrane repair.

Progranulin, encoded by the GRN gene, has become a focal point for therapeutic development in frontotemporal dementia. Haploinsufficiency, meaning that carriers of a single mutated GRN copy produce only half the normal amount of the protein, causes familial FTD and produces features resembling neuronal ceroid lipofuscinosis, a classic lysosomal storage disease. Progranulin supports lysosomal homeostasis through multiple mechanisms: it promotes lysosomal acidification, acts as a chaperone for the enzyme cathepsin D, facilitates the processing of prosaposin into saposins that activate lipid-degrading enzymes, and supports glucocerebrosidase activity. The risk gene TMEM106B, which regulates lysosomal size, motility and stress responses, modifies disease penetrance in GRN mutation carriers, and strikingly, TMEM106B itself was recently discovered to form amyloid fibrils in aged brains across multiple neurodegenerative diseases. Progranulin augmentation strategies, including an antibody called latozinemab that raises progranulin levels and AAV gene therapy, are already in clinical trials, with interim results reported for the gene therapy approach.

What emerges from this synthesis is a view of neurodegeneration as, at its core, a failure of cellular housekeeping that unfolds over decades. Neurons are uniquely vulnerable because they live as long as the organism, rely heavily on long-range transport of lysosomes along axons, and generate toxic metabolic byproducts such as oxidized dopamine that further damage lysosomes. The convergence of genetic evidence from four major disease families onto the endolysosomal system suggests that therapies aimed at restoring lysosomal health, whether by enhancing enzyme activity, improving acidification, boosting autophagic flux or repairing damaged lysosomal membranes, could offer benefits that span diagnostic boundaries. With GBA1 and LRRK2 trials underway in Parkinson disease, progranulin augmentation advancing in frontotemporal dementia and lysosome-targeting small molecules in preclinical development, the humble lysosome has moved from the margins of neuroscience to the center of the search for disease-modifying treatments.

Subject of Research: Lysosomal dysfunction as a mechanism of neurodegenerative disease

Article Title: Lysosomal dysfunction in neurodegenerative disease

Article References: Brooker, S. M., Coukos, R., & Krainc, D. (2026). Lysosomal dysfunction in neurodegenerative disease. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01262-3

Image Credits: AI Generated

DOI: 10.1038/s41582-026-01262-3

Keywords: lysosome, neurodegeneration, Parkinson disease, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, GBA1, LRRK2, autophagy, progranulin, alpha-synuclein, endolysosomal trafficking

The review begins with the established drug classes. Cholinesterase inhibitors such as donepezil, rivastigmine and galantamine, together with the N-methyl-D-aspartate receptor antagonist memantine, continue to deliver small but statistically significant and clinically meaningful improvements in cognition and function. A meta-analysis of 43 randomized clinical trials encompassing more than 16,000 patients, cited in the review, quantifies both the efficacy and the substantial discontinuation rates that complicate real-world use. What is new, however, is the emerging biomarker dimension. Stratified analyses now suggest that individuals with biochemically confirmed Alzheimer pathology, verified through amyloid positron emission tomography or cerebrospinal fluid markers, respond more robustly to these agents than patients whose cognitive impairment arises from other mechanisms. Studies of amyloid PET-negative mild cognitive impairment show markedly attenuated cognitive responses to cholinesterase inhibitors, and positron emission tomography work even hints that these drugs may influence tau pathology within the Alzheimer disease continuum. The implication is profound: the era of prescribing cognitive enhancers on clinical impression alone may be drawing to a close, replaced by biomarker-informed precision symptomatic therapeutics.

Beyond the cholinergic and glutamatergic mainstream, the review charts a strikingly diverse pipeline of next-generation symptomatic agents. Selective muscarinic receptor agonism, a strategy first explored with xanomeline in the 1990s, has returned to prominence with modern M1-selective compounds such as HTL0018318, which showed preliminary pharmacodynamic activity in mild-to-moderate Alzheimer disease, and with xanomeline-based programs now being tested for Alzheimer-related psychosis in the ADEPT-5 trial. Multitarget agents are advancing in parallel: blarcamesine, which modulates the sigma-1 receptor and other pathways, reported phase IIB/III results in early Alzheimer disease, while masupirdine, a selective serotonergic 5-HT6 antagonist, showed exploratory signals on agitation, aggression and psychosis in moderate disease. Neurotrophic modulation represents another frontier, with positive allosteric modulators of neurotrophin receptors under development to support synaptic resilience, and brain-derived neurotrophic factor gene therapy being explored as a longer-term strategy for neurodegeneration.

Drug repurposing has emerged as a particularly pragmatic route to broader symptomatic benefit. The review highlights a Delphi consensus process and stakeholder consultation that prioritized existing medicines with plausible mechanisms and safety profiles for Alzheimer disease, alongside work identifying synergistic combinations of repurposed treatments. The logic is compelling: established drugs with decades of safety data can be recombined rationally to hit multiple neurotransmitter and circuit-level systems simultaneously, potentially achieving additive or synergistic effects that single agents cannot. Combination therapy itself is gaining formal traction, with the EU/US Clinical Trials on Alzheimer’s Disease task force articulating frameworks for testing cholinesterase inhibitor plus memantine regimens and, ultimately, pairing symptomatic agents with disease-modifying antibodies such as lecanemab and donanemab, whose approvals have changed the therapeutic context in which symptomatic care is delivered.

On the non-pharmacological side, the evidence base has matured considerably. Cognitive training, structured physical exercise, cognitive stimulation therapy and multimodal lifestyle programmes all show small-to-moderate benefits, with the strongest and most consistent effects observed in people with mild cognitive impairment. Computerized cognitive training meta-analyses demonstrate measurable gains in memory and general cognition, and comparative trials have even suggested that crossword puzzles may outperform computerized games on some outcomes. Exercise research, synthesized through network meta-analyses, points to benefits for executive function, activities of daily living and potentially the capacity for independent living, with aerobic, resistance and multicomponent regimens each contributing. The landmark FINGER trial, which combined diet, exercise, cognitive training and vascular risk monitoring, and its American counterpart US POINTER, which compared structured against self-guided multidomain lifestyle intervention, have established that comprehensive lifestyle programmes can protect global cognition in at-risk older adults, findings now being translated into public health policy.

Cognitive stimulation therapy deserves particular attention as one of the few non-drug interventions with evidence at the level of established dementia, not merely its prodrome. Systematic reviews and meta-analyses of randomized controlled trials using the original protocol show benefits for cognition and quality of life in mild-to-moderate disease, and emerging work extends the approach to mild cognitive impairment. Yet the review is candid about the implementation gap. Scalability, workforce training, delivery fidelity and real-world adherence remain formidable barriers, particularly in residential aged care settings where systematic reviews document persistent obstacles to embedding evidence-based non-pharmacological therapies. Non-invasive brain stimulation, including repetitive transcranial magnetic stimulation and transcranial direct current stimulation, is profiled as an adjunctive technology with encouraging meta-analytic signals for cognition and daily functioning, though heterogeneity across protocols tempers enthusiasm.

The most clinically burdensome domain, the review argues, is neuropsychiatric symptomatology. Agitation, depression, apathy, psychosis and sleep disturbance affect the substantial majority of people with Alzheimer disease over the course of illness, driving caregiver distress, institutionalization and reduced quality of life more powerfully than cognitive decline itself. Here the evidence favours personalized psychosocial interventions. The WHELD programme, a factorial cluster-randomized trial combining person-centred care training, tailored social interaction and exercise, and antipsychotic review, reduced agitation and antipsychotic prescribing in nursing homes, and its digital adaptation has since been tested in a randomized controlled trial. Brief operationalized psychosocial interventions for agitation and psychosis, systematic individualized approaches that identify the unmet needs driving behavioural symptoms, and structured strategies such as the DICE framework for caregiver training all demonstrate meaningful reductions in agitation and depression without pharmacological risk. Even treating pain, as a cluster-randomized trial showed, substantially reduces behavioural disturbance in nursing home residents with dementia.

Where drugs are required, the safety calculus is unfavourable for older agents. Atypical antipsychotics offer only modest efficacy against agitation and psychosis while carrying elevated risks of stroke, mortality, cognitive worsening and sedation, findings documented across the CATIE-AD trial, Cochrane reviews and the long-term DART-AD follow-up, which showed sustained excess mortality associated with continued antipsychotic exposure. Against this backdrop, newer agents represent genuine, if incremental, progress. Brexpiprazole, now approved for agitation associated with dementia due to Alzheimer disease, demonstrated significant benefit in two 12-week phase trials and in post hoc analyses of clinically relevant subgroups, with a more favourable metabolic and motor safety profile than predecessors. The dextromethorphan-quinidine combination AXS-05 showed relapse-prevention efficacy in the phase 3 ACCORD trial and became the first non-antipsychotic approved in the United States for dementia-related agitation. Pimavanserin, an inverse agonist at serotonin 5-HT2A receptors, showed significant benefit for dementia-related psychosis in a pivotal trial and phase 2 data in Alzheimer disease psychosis, while escitalopram achieved a positive phase 3 result for agitation, contrasting with the negative mirtazapine findings from the SYMBAD trial. Methylphenidate, meanwhile, offers a modestly effective option for apathy in the ADMET 2 trial.

The review’s forward-looking synthesis is unambiguous about what must change. Future progress will depend on biomarker-informed patient selection, increasingly enabled by blood-based biomarkers now moving into clinical implementation; on the integration of circuit-level measures that connect molecular mechanisms to network dysfunction; on rational combination strategies that span pharmacological and non-pharmacological modalities rather than testing interventions in isolation; and on the adoption of patient-centred outcomes such as goal attainment, quality of life and independence rather than narrow rating-scale endpoints. Symptomatic therapies, the authors conclude, will remain essential for improving quality of life in people with Alzheimer disease even as disease-targeted therapies gradually reshape disease trajectories. In an era captivated by amyloid clearance, the humble work of relieving symptoms, sharpening cognition, preserving function and calming distress is being reimagined with a precision and ambition that may ultimately matter just as much to patients and the families who love them.

Subject of Research: Current evidence and future directions for pharmacological and non-pharmacological symptomatic treatment of Alzheimer disease

Article Title: Symptomatic treatment for Alzheimer disease: current evidence and future directions

Article References: Ballard, C., Doherty, P., Ismail, Z., Corbett, A., & Cummings, J. L. (2026). Symptomatic treatment for Alzheimer disease: current evidence and future directions. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01260-5

Image Credits: AI Generated

DOI: 10.1038/s41582-026-01260-5

Keywords: Alzheimer disease, symptomatic treatment, cholinesterase inhibitors, memantine, neuropsychiatric symptoms, cognitive stimulation therapy, physical exercise, brexpiprazole, pimavanserin, biomarkers, drug repurposing, combination therapy

At its core, the complement cascade is a proteolytic amplification machine. It can be triggered through three converging routes: the classical pathway, initiated when the C1 complex binds antibody-antigen complexes or other target structures; the lectin pathway, ignited when pattern-recognition molecules such as mannose-binding lectin and ficolins detect carbohydrate motifs on pathogens or damaged cells; and the alternative pathway, which samples surfaces continuously through spontaneous hydrolysis and is stabilized by properdin. All three routes converge on C3, whose cleavage generates the opsonin C3b that tags targets for phagocytosis and the anaphylatoxin C3a that recruits and activates inflammatory cells. Further cleavage of C5 releases the potent anaphylatoxin C5a and assembles the C5b-9 membrane attack complex, a pore-forming structure that can lyse susceptible cells. In host defence, this is a marvel of efficiency. In the nervous system, where many cell types are exquisitely vulnerable to lysis and inflammation, the same machinery can become an instrument of destruction.

What makes complement particularly fascinating in a neurological context is that it is not merely a circulating defence system but an active participant in normal brain physiology. Seminal experimental work has shown that classical pathway components, including C1q and C3, physically tag synapses during postnatal development, allowing microglia to prune weak or inactive connections in an activity-dependent manner. This complement-dependent synaptic sculpting is essential for wiring the developing brain, and related mechanisms continue to influence adult neural circuit plasticity, including microglia-mediated elimination of synapses linked to forgetting. The complement system also contributes to the clearance of apoptotic cells and cellular debris, processes fundamental to maintaining tissue health. These physiological roles carry a sobering implication: any therapeutic strategy that blanketly suppresses complement risks interfering with brain development, synaptic maintenance, and debris clearance, a concern that hangs over much of the current drug pipeline.

In autoimmune neurological disease, aberrant complement activation is now documented with striking consistency. In myasthenia gravis, autoantibodies against the acetylcholine receptor recruit complement to the neuromuscular junction, where the membrane attack complex destroys the postsynaptic membrane, a mechanism established experimentally decades ago and confirmed ultrastructurally by localization of the lytic component C9 at the motor end-plate. Complement activation profiles correlate with disease severity, and eculizumab, a monoclonal antibody that blocks cleavage of C5, demonstrated efficacy in refractory generalized disease in the pivotal REGAIN trial, earning regulatory approval and opening the floodgates for a broader class of anti-C5 agents, including the longer-acting ravulizumab and the subcutaneous peptide zilucoplan, alongside newer C5-targeting candidates such as gefurulimab now in phase 3 testing.

The antibody-mediated demyelinating diseases of the central nervous system tell a similarly compelling story. In neuromyelitis optica spectrum disorder, aquaporin-4-specific IgG1 antibodies bind astrocytic endfeet, fix complement, and generate astrogliotic, necrotic lesions; passive transfer experiments show that immunoglobulin G plus complement reproduces the pathology in animals. Blocking C5 with eculizumab dramatically reduced relapse rates in aquaporin-4-positive patients, and ravulizumab has since replicated these results with a more convenient dosing schedule. The related condition, myelin oligodendrocyte glycoprotein antibody-associated disease, displays its own distinctive complement activation signatures, with recent work showing that activation patterns downstream of C5 cleavage differ between MOGAD and aquaporin-4 antibody-positive neuromyelitis optica, and that complement profiles can predict clinical outcomes. In multiple sclerosis, complement deposition is a prominent feature of lesions, oligodendrocytes are peculiarly susceptible to complement lysis even in the absence of antibody, and growing clinical evidence links circulating complement activation products to structural brain damage, disease severity, and disability progression, including in primary progressive disease. Notably, animal studies reveal that some complement components, such as C5-derived signals, may actually facilitate remyelination, reinforcing the argument for nuanced, pathway-selective modulation rather than indiscriminate shutdown.

In disorders of the peripheral nervous system, complement has moved from suspected accomplice to validated therapeutic target. In Guillain-Barré syndrome, autoantibodies against gangliosides on motor nerve terminals and perisynaptic Schwann cells recruit the membrane attack complex, and complement inhibition protects nerve terminals in murine models. Eculizumab was tested in a large phase 3 trial and, although the primary endpoint was not met, encouraging signals and real-world comparative data for the proximal inhibitor ANX005, which blocks C1q, suggest that early, pathway-targeted intervention may still prove valuable. Chronic inflammatory demyelinating polyneuropathy has emerged as a particularly fertile field: recent complement profiling of sural nerves, together with the demonstration that terminal pathway activation tracks with disease severity, has set the stage for phase 2 studies of the C1s inhibitor riliprubart, with promising early efficacy and safety findings. Multifocal motor neuropathy and IgM anti-MAG antibody neuropathies are likewise being reinterpreted through a complement lens, with the C2-blocking antibody empasiprubart, derived from the ARGX-117 program, advancing through clinical development on the logic that IgM-driven complement activation depends critically on the classical pathway component C2.

Perhaps the most provocative frontier is neurodegeneration. In Alzheimer disease, genetic association studies first implicated complement genes as susceptibility loci, and mechanistic work then showed that C1q and C3 drive early synapse loss in mouse models, with microglia engulfing complement-tagged synapses. Complement C3 deficiency protects aged, plaque-laden mice from neurodegeneration, yet other data indicate that specific complement components exert tissue-protective effects, promoting clearance of amyloid debris and supporting repair. Similarly, in amyotrophic lateral sclerosis, elevations of C5a and the membrane attack complex in patient blood and dysregulation of the cascade in the hSOD1G93A mouse model motivated a randomized trial of ravulizumab, which did not slow disease progression but provided dose-finding and safety data that will inform future, more precisely targeted efforts. These mixed results crystallize the central dilemma of the field: complement is both arsonist and firefighter, and the therapeutic challenge is to extinguish the destructive arm of the cascade while preserving its reparative functions.

The authors of the review emphasize that the existing complement drug arsenal, which includes C5 inhibitors such as eculizumab, ravulizumab, and crovalimab; the C1s inhibitor sutimlimab; the C3-targeting peptide pegcetacoplan; factor B and factor D blockers such as iptacopan and danicopan; C1-esterase inhibitor concentrates; and the C2-blocking antibody empasiprubart, was largely forged in hematology, ophthalmology, and nephrology before being imported into neurology. Expanding these agents to the brain raises distinctive pharmacological hurdles, including the blood-brain barrier, the need for sustained pathway suppression in a compartment with limited drug access, and the infection risks inherent in disabling a key arm of host defence, particularly meningococcal disease in patients receiving terminal pathway inhibitors. Proximal inhibitors that block C1 or C2 confer broader cascade suppression and may better preserve certain distal functions, but they carry their own trade-offs in infection susceptibility and disruption of physiological opsonization and debris clearance.

Looking ahead, Dalakas and Lünemann argue that the future of complement-targeted neurology will depend on systematic, biomarker-guided patient selection. Reliable, disease-specific measures of complement activation, whether from cerebrospinal fluid, blood, or tissue, will be essential to identify which patients are most likely to benefit from proximal versus distal inhibition, and to time intervention before irreversible tissue injury has occurred. As biologics targeting other axes of autoimmunity, from FcRn antagonists and neonatal Fc receptor blockers to B-cell-depleting agents and, increasingly, CAR T-cell therapies, crowd the neurological treatment landscape, complement inhibitors will need to demonstrate not just efficacy but a rational, mechanistically defined place in therapeutic algorithms. What is no longer in doubt is the direction of travel: from a system once studied almost exclusively by immunologists, complement has become a frontier of clinical neurology, and the coming decade will determine how precisely medicine can wield its power without extinguishing its gifts.

Subject of Research: The role of the complement system and complement-targeted therapeutics in autoimmune and neurodegenerative neurological diseases

Article Title: Role of complement and complement-targeted therapeutics in neurological diseases

Article References: Dalakas, M. C., & Lünemann, J. D. (2026). Role of complement and complement-targeted therapeutics in neurological diseases. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01261-4

Image Credits: AI Generated

DOI: 10.1038/s41582-026-01261-4

Keywords: complement system, neuroimmunology, myasthenia gravis, neuromyelitis optica, multiple sclerosis, Guillain-Barré syndrome, Alzheimer disease, amyotrophic lateral sclerosis, eculizumab, ravulizumab, membrane attack complex, complement inhibitors