The investigation included 70 people with genetically confirmed 5q SMA recruited from centres in Germany and Belgium, together with comparison groups of 31 patients with ALS, 31 with Alzheimer’s disease and 31 disease controls who had no evidence of neurodegeneration based on clinical evaluation, cerebrospinal fluid analysis and neuroimaging. SMA participants underwent repeated blood sampling and clinical assessment. The main follow-up points were 9–16 months and 22–26 months after baseline, while an exploratory cohort of eight Halle patients was sampled at approximately 50–58 months but had no corresponding baseline data. All 70 patients with SMA received nusinersen or risdiplam at follow-up: 45 received nusinersen and 25 received risdiplam. Because the study was retrospective, relied on available observations at each time point and had incomplete sampling at some visits, its longitudinal findings were considered exploratory rather than confirmatory.

Serum p-tau181 and p-tau217 were quantified with single-molecule array immunoassays, while neurofilament light chain was measured with a separate automated assay. Group differences were evaluated with multiple linear regression adjusted for age and sex, using SMA as the reference category. Concentrations of p-tau181 differed across the diagnostic groups in the overall model, with p less than 0.001. The adjusted coefficient for disease controls was −0.48, with a 95% confidence interval of −0.81 to −0.15, indicating lower p-tau181 in controls than in SMA. Levels were higher in ALS, with a coefficient of 0.99 and 95% confidence interval of 0.58 to 1.39, and in Alzheimer’s disease, with a coefficient of 0.56 and 95% confidence interval of 0.11 to 1.00. For p-tau217, no difference was detected between SMA and disease controls: the coefficient was −0.09, with a 95% confidence interval of −0.22 to 0.05. Levels of p-tau217 were higher in both ALS and Alzheimer’s disease than in SMA. The results show that the two phosphorylated tau species did not behave as interchangeable measures across these conditions.

Centre-specific analyses added nuance to the pooled comparisons. In the Ulm cohort, p-tau181 was lower in disease controls than in SMA, with a coefficient of −0.52 and 95% confidence interval of −0.73 to −0.31, but no clear difference was detected between SMA and either ALS or Alzheimer’s disease. In Leuven, the SMA-control difference was not detected, with a coefficient of −0.20 and 95% confidence interval of −0.56 to 0.17, while p-tau181 was higher in ALS and Alzheimer’s disease than in SMA. The Halle baseline group contained only two patients and was not statistically tested. For p-tau217, neither Ulm nor Leuven showed a clear SMA-control difference, although both cohorts had higher concentrations in ALS and Alzheimer’s disease than in SMA. These variations mean the overall diagnostic-group pattern should not be interpreted as a uniform, validated threshold for distinguishing SMA from other conditions.

Within-person comparisons produced the clearest longitudinal result. Among 56 patients with measurements at both baseline and follow-up 2, p-tau181 decreased by a median of 1.80 pg/mL, with an interquartile range of −5.90 to 2.10 pg/mL; the paired Wilcoxon signed-rank test gave p = 0.017. No relevant change was detected between baseline and follow-up 1 among 29 paired patients, when the median difference was 0.17 pg/mL, or between follow-up 1 and follow-up 2 among 28 paired patients, when it was 0.00 pg/mL. P-tau217 showed no relevant change at any interval. An unpaired analysis using all available samples at each time point did not detect significant differences among baseline, follow-up 1 and follow-up 2, showing how the conclusion depended on which patients could be paired. The eight-patient exploratory group had p-tau values within the upper range of earlier observations, but its size and lack of baseline samples prevented statistical testing or paired analysis.

Linear mixed-effects models, with repeated observations accounted for and estimates adjusted for age, sex and other applicable variables, linked both p-tau species to several clinical measures. Higher p-tau181 and p-tau217 concentrations were associated with higher Hammersmith Functional Motor Scale Expanded scores, higher Revised Upper Limb Module scores and higher forced vital capacity as a percentage of the predicted value; all corresponding false-discovery-rate-adjusted p values were below 0.001. In the Leuven risdiplam-treated subgroup, where the Motor Function Measure 32 was available, both biomarkers were also positively associated with total and domain scores, although those analyses were exploratory because they were restricted to one centre and a limited sample. Concentrations were lower with longer disease duration, and ambulatory participants had higher levels than non-ambulatory patients. Thus, higher circulating p-tau was linked to better preserved motor and respiratory function, rather than simply indicating more severe impairment.

Creatine kinase was positively associated with both p-tau181 and p-tau217, with false-discovery-rate-adjusted p values below 0.001, whereas neither biomarker showed a significant association with neurofilament light chain after correction for multiple testing. The authors considered this pattern consistent with the possibility that peripheral p-tau in SMA is more closely related to denervated or remodelling muscle than to ongoing neuroaxonal injury. They also proposed that p-tau181 and p-tau217 may capture different aspects of motor-neuron and muscle pathology. These interpretations remain mechanistic hypotheses, however, because the study did not directly measure tau release from tissue, analyse p-tau in cerebrospinal fluid alongside serum, or use imaging and electrophysiology to locate its biological source. The absence of an association with neurofilament light chain should therefore be viewed as an observed result within this cohort, not direct proof of a peripheral origin.

Exploratory multivariable regression models suggested a possible prognostic association while showing substantial uncertainty. Higher baseline p-tau181 was associated with a greater decline in the Hammersmith Functional Motor Scale Expanded by follow-up 2, with a coefficient of 1.79 and 95% confidence interval of 0.59 to 2.99. The corresponding estimate for p-tau217 was 1.60, with a 95% confidence interval of −0.13 to 3.33, indicating a less certain association. Neither biomarker was clearly associated with change in the Revised Upper Limb Module; in those exploratory models, male sex and older age accounted for more of the observed variation. Motor scores remained broadly stable during follow-up, and ceiling effects in adult SMA may have limited the sensitivity of upper-limb analyses. The p-tau181 association was therefore characterized as preliminary and hypothesis-generating, and it requires independent confirmation before it can be regarded as a prognostic marker.

The findings also raise questions about the interpretation of blood p-tau measurements in people with motor neuron disorders. Because p-tau181 was higher in SMA and ALS than in non-neurodegenerative controls, elevated circulating p-tau may occur without concurrent Alzheimer-type pathology. The comparison is strengthened by the study’s exclusion of ALS participants with positive or unknown amyloid-tau-neurodegeneration status and by the cerebrospinal-fluid biomarker criteria used to define the Alzheimer’s disease group. At the same time, the retrospective design, modest sample size, few time points, advanced disease stage in many participants, missing body-mass-index data and absence of paired cerebrospinal-fluid measurements limit how broadly the results can be generalized. Future studies involving earlier-stage SMA, more consistent serial sampling, cerebrospinal fluid and serum collected together, and imaging or electrophysiological measures would be needed to determine whether p-tau181 adds reliable value to clinical assessment or whether it mainly provides information about muscle-related processes in adult SMA.

Subject of Research: Serum phosphorylated tau biomarkers and clinical measures in 5q spinal muscular atrophy

Article Title: Serum p-tau181 and p-tau217 levels in adolescents and adults with 5q spinal muscular atrophy

Article References: Stapf, C. D., Uzelac, Z., Iterbeke, L., Guthknecht, A., Barba, L., Strube, D., Kölsch, A., Kleeberg, K., Kendzierski, T., Roos, A., Steinacker, P., Abu-Rumeileh, S., Claeys, K. G., Weishaupt, J., Mensch, A., & Otto, M. (2026). Serum p-tau181 and p-tau217 levels in adolescents and adults with 5q spinal muscular atrophy. Journal of Neurology, 273(11), Article 672. https://doi.org/10.1007/s00415-026-14194-1

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14194-1

Keywords: spinal muscular atrophy, p-tau181, p-tau217, blood biomarkers, motor function, muscle turnover, denervation, creatine kinase, longitudinal study, tau protein, Serum, levels

The research, published in the Journal of Neurology, focused on a measurable feature of the brain’s outer mantle known as cortical thickness. The cerebral cortex, the wrinkled sheet of gray matter responsible for memory, language, and reasoning, gradually thins as neurons and their connections are lost in neurodegenerative disease. Previous large-scale studies, including work from the Longitudinal Early-Onset Alzheimer’s Disease Study consortium, had established that patients with dementia from early-onset Alzheimer’s show a characteristic pattern of thinning concentrated in the posterior parietal and lateral temporal regions of the brain, including the precuneus, the inferior and superior parietal lobules, and the supramarginal gyrus, while relatively sparing the medial temporal areas typically affected first in older-onset disease. What remained unknown was when this signature emerges along the clinical trajectory, particularly in people who do not carry rare genetic mutations but instead develop the disease sporadically.

To address this, the researchers studied 292 patients under the age of 65 who had been referred to the Karolinska memory clinic with cognitive concerns between April 2018 and May 2024. Every participant underwent a 3 Tesla structural MRI scan and a lumbar puncture to obtain cerebrospinal fluid, which was analyzed for two key Alzheimer’s biomarkers: the Aβ42/40 ratio, which signals the accumulation of amyloid-beta plaques in the brain, and phosphorylated tau 181, a protein released when tau pathology begins to damage neurons. Using these markers, the team stratified patients into three biologically defined groups: a reference group of 107 individuals negative for both markers, 76 patients with amyloid positivity alone, and 109 patients positive for both amyloid and p-tau181. Clinically, the cohort spanned the full spectrum of the disease, from subjective cognitive decline, in which patients report symptoms but perform normally on testing, through mild cognitive impairment, to frank dementia.

The first step was to define the early-onset Alzheimer’s cortical signature itself. Comparing patients with biomarker-confirmed Alzheimer’s dementia against the biomarker-negative reference group, using a vertex-wise analysis across the entire cortex, the researchers identified a robust and spatially coherent pattern of thinning. The most severely affected areas lay in the bilateral posterior parietal and lateral association cortices, particularly the precuneus, the inferior and superior parietal lobules, and the supramarginal gyrus. Additional atrophic clusters extended into the banks of the superior temporal sulcus, the superior frontal gyrus, the middle temporal gyrus, and the fusiform gyrus, with a notable predominance in the left hemisphere. This left-sided emphasis echoes earlier reports in younger populations and reinforces the idea that early-onset Alzheimer’s is not merely early-arriving late-onset disease, but a distinct neurodegenerative phenotype with its own spatial and possibly molecular underpinnings.

With the signature established, the team then traced it backward through the earlier clinical stages, and this is where the findings become striking. Among patients with mild cognitive impairment and Alzheimer’s biomarkers, cortical thinning was already present across most signature regions, accompanied by significant hippocampal atrophy. But when the researchers separated the amyloid-positive patients according to their tau status, a clear gradient emerged. Patients with amyloid positivity alone showed focal thinning confined to a handful of regions, including the signature composite, the banks of the superior temporal sulcus, the middle temporal gyrus, and the supramarginal gyrus, while their hippocampal volumes remained statistically intact. Patients with combined amyloid and p-tau181 positivity, by contrast, displayed far more extensive thinning that encompassed the precuneus, fusiform gyrus, inferior parietal lobule, superior parietal lobule, and superior frontal gyrus, together with marked hippocampal volume loss that was significantly greater than in the amyloid-only group.

Even more remarkable were the results at the earliest stage, subjective cognitive decline, when patients are aware something is wrong but still score normally on cognitive tests. Among these individuals, those with amyloid positivity alone showed no detectable structural brain changes whatsoever compared with the reference group. But those with both amyloid and p-tau181 positivity exhibited subtle yet statistically significant thinning in the early-onset signature regions, the precuneus, and the banks of the superior temporal sulcus. In other words, the structural footprint of Alzheimer’s disease is already present in the brains of some younger patients who appear, by every conventional clinical measure, to be functioning normally. This finding parallels evidence from studies of autosomal dominant Alzheimer’s, in which mutation carriers show cortical thinning years before expected symptom onset, but it extends that principle to the predominantly sporadic form of the disease seen in real-world memory clinics.

The study also connected these structural changes to actual cognitive performance, and here a threshold effect became apparent. In the dementia group, thinner cortex within the signature regions correlated with lower scores on global screening measures, the Mini-Mental State Examination and the Montreal Cognitive Assessment. At the mild cognitive impairment stage, the correlations became more specific: thinner inferior parietal cortex and precuneus were associated with poorer episodic memory on verbal learning tests, while thinning in the fusiform gyrus and the banks of the superior temporal sulcus tracked impaired visuospatial memory on complex figure recall tasks. Crucially, no such brain-behavior relationships were observed in the subjective cognitive decline group, suggesting that structural and cognitive changes become coupled only once neurodegeneration crosses a critical threshold, even though the structural changes themselves are already underway.

Why should amyloid positivity alone be so structurally silent? The authors offer two complementary interpretations. The first is temporal: amyloid accumulation precedes tau-related neurodegeneration, and patients with isolated amyloid positivity may simply be at an earlier point on the continuum, destined to convert to tau positivity later, a pattern supported by longitudinal biomarker studies. Consistent with this, amyloid-only patients were proportionally more represented in the earlier clinical stages of the cohort. The second interpretation is more provocative: amyloid-positive, tau-negative and amyloid-positive, tau-positive individuals may represent biologically distinct subtypes of Alzheimer’s disease, with the tau-negative group following a more indolent course and the tau-positive group facing a substantially higher risk of near-term progression. A further speculative possibility raised by the authors is that early amyloid-related processes may transiently increase cortical thickness, potentially masking subtle atrophy in the amyloid-only group, a phenomenon previously reported in presymptomatic carriers of PSEN1 mutations. Notably, the two biomarker groups did not differ in their frequency of the APOE ε4 allele, the major genetic risk factor for sporadic Alzheimer’s, indicating that the structural differences were not simply explained by genetic loading.

The translational implications are considerable. As disease-modifying therapies targeting amyloid move into clinical practice, identifying which patients have biologically active neurodegeneration, rather than amyloid deposition alone, becomes essential for timing intervention and selecting trial participants. The findings suggest that regional cortical thickness measured on a standard structural MRI could serve as a staging marker in biologically defined early-onset Alzheimer’s, complementing fluid biomarkers. Perhaps most importantly, the identification of focal cortical thinning in amyloid- and tau-positive patients who still have only subjective complaints defines a clinically silent but biologically progressive phase of the disease, a window in which closer surveillance and enrollment in secondary prevention trials could alter the trajectory before irreversible damage accumulates.

The authors are careful to note the limitations of their work. The cross-sectional design cannot establish individual disease trajectories, comprehensive neuropsychological testing was available for only a subset of participants, and the cohort lacked systematic genetic testing for monogenic Alzheimer’s genes such as PSEN1, PSEN2, and APP. The cortical signature was also derived and tested within the same clinical cohort, meaning that external replication in independent samples will be required before the pattern can be considered diagnostically applicable. Nevertheless, as one of the largest biomarker-stratified studies of early-onset Alzheimer’s conducted in a real-world memory clinic setting, the study provides a rigorous template for how imaging and fluid biomarkers can be combined to stage the disease in younger patients. It demonstrates that the atrophy signature of early-onset Alzheimer’s dementia is not a late-breaking phenomenon but a process that unfolds along a biomarker-defined gradient, becoming visible to the MRI scanner precisely when amyloid pathology is joined by the tau response that signals the brain’s descent into active neurodegeneration.

Subject of Research: Cortical thickness changes across clinical stages and amyloid/tau biomarker profiles in early-onset Alzheimer's disease

Article Title: Cortical thickness signature of early-onset Alzheimer’s disease across clinical stages and A/T1 biomarker profiles

Article References: Zilioli, A., Mohanty, R., Rosenberg, A., Matton, A., Granberg, T., Hagman, G., Spallazzi, M., Kivipelto, M., & Westman, E. (2026). Cortical thickness signature of early-onset Alzheimer’s disease across clinical stages and A/T1 biomarker profiles. Journal of Neurology, 273(10), Article 646. https://doi.org/10.1007/s00415-026-14187-0

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14187-0

Keywords: early-onset Alzheimer's disease, cortical thickness, p-tau181, amyloid biomarkers, cerebrospinal fluid, MRI, mild cognitive impairment, subjective cognitive decline, hippocampal atrophy, precuneus, biomarker staging, memory clinic

The study drew on the Island Study Linking Aging and Neurodegenerative Disease (ISLAND), a ten-year community-based initiative in Tasmania, Australia, that combines dementia education with large-scale data collection. From more than 1,300 potentially eligible participants, the researchers assembled a cross-sectional sample of 339 cognitively unimpaired adults with an average age of about 66 years, roughly 71 percent of them women. Of these, 238 reported no noticeable cognitive changes and served as asymptomatic controls, while 101 met criteria for subjective cognitive decline (SCD)—a self-perceived, persistent worsening of memory or mental function despite normal performance on cognitive tests. SCD matters because older adults with it progress to dementia at roughly twice the annual rate of those without it, and neuroimaging studies suggest it shares pathological features with mild cognitive impairment and Alzheimer’s dementia.

The participants completed the Tasmanian Test, a browser-based, self-administered battery of motor, cognitive, and speech tasks that they performed at home without supervision. For the speech component, they recorded four maximally paced DDK tasks in fixed order: rapid repetition of the monosyllables “pa,” “ta,” and “ka,” followed by the trisyllable sequence “pataka.” Each test lasted ten seconds, with up to two reattempts allowed. From the resulting audio recordings, the team extracted a rich set of features quantifying repetitions, speaking time, pauses, voice onset time—the interval between the release of a plosive consonant and the onset of vocal fold vibration—and variability measures. Crucially, they also computed derived “motor cost” measures by subtracting performance on one stimulus from another, capturing differences in articulatory control between bilabial, alveolar, and velar consonants, and between simple and complex sequences.

Why should rapid syllable repetition be sensitive to Alzheimer’s disease at all? The neurobiological rationale rests on the brain circuits that govern sub-second timing and sequential motor control. Functional MRI studies show that paced syllable repetition engages the putamen and cerebellum in a rate-dependent manner, and that rapid syllable-sequence production recruits the cerebellum in proportion to articulatory complexity. Cerebellar-basal ganglia circuits are central to internal timing and error correction, and Alzheimer’s-related alterations in cerebellar connectivity have been documented. Unlike connected speech tasks such as picture description, which confound motor control with language and memory demands, DDK tasks isolate the pure motor dimension of speech production—making them a potentially cleaner window onto preclinical brain changes.

The researchers tested whether these motor speech measures were associated with three established Alzheimer’s risk indicators: subjective cognitive decline, carriage of the apolipoprotein E ε4 allele, and plasma concentrations of phosphorylated tau 181 (p-tau181). Each carries weight. APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer’s, conferring roughly three- to fourfold increased risk with one allele and eight- to fifteenfold with two. Plasma p-tau181 rises during preclinical disease, performs comparably to tau PET for classifying amyloid positivity in people with SCD, and predicts progression to Alzheimer’s dementia in cognitively unimpaired individuals. Blood samples had been collected at in-person clinics across Tasmania in 2021, with p-tau181 measured using an ultrasensitive single-molecule array platform and APOE genotype determined by PCR.

The statistical approach was deliberately cautious. Bivariate, nonparametric analyses with Benjamini-Hochberg correction for multiple comparisons found that no associations with SCD or APOE ε4 survived adjustment—only one measure, a “pa”-“ta” cost of repetition duration variability, remained significantly linked to plasma p-tau181. The team then turned to LASSO-penalized regression, a machine learning technique that shrinks coefficients to prevent overfitting in high-dimensional data. To stabilize estimates against the randomness of cross-validation fold assignment, they used a percentile-LASSO procedure, running each tenfold cross-validation process one hundred times and fitting the final model at the 95th percentile of the regularization parameter. Logistic models predicted SCD and APOE ε4 status, while a linear model predicted natural log-transformed p-tau181, with age, sex, education, anxiety, and depression available as covariates.

The results were intriguingly patterned. In the main analysis of 315 participants with complete data, motor speech measures predicted SCD with an area under the curve of 0.700, APOE ε4 carriage with an AUC of 0.715, and log-transformed p-tau181 with a mean absolute error of 0.323. For SCD, the simple models selected only depression as a predictor, but the more complex “maximal” models—which allowed interaction terms—consistently outperformed them and selected several motor speech features, always in interaction with depression. For APOE ε4, the simple models prevailed, with voice onset time features and variability measures prominent among the selected predictors, alongside age. For p-tau181, age was the only non-speech covariate chosen, and one derived measure in particular—voice onset time variability cost for “ka”-“pataka”—appeared in the superior model of every analysis, sometimes standing alone and sometimes interacting with age, education, and depression.

Depression emerged as a recurring complication. Because depression can affect subjective cognition, speech, and motor function alike, the researchers ran sensitivity analyses excluding participants with Hospital Anxiety and Depression Scale scores of eight or above, and separately incorporating hearing loss and expanded samples of participants with incomplete biomarker data. These analyses revealed potentially mitigating effects of depression and hints of bias from the limited availability of blood biomarker data. In the expanded sample, APOE ε4 prediction fell to barely better than chance in the full group, yet improved markedly in the low-depression subset, where more motor speech predictors were selected. The authors interpret this as evidence that depression may modify or obscure genuine relationships between motor speech control and Alzheimer’s risk factors, and that even subclinical depression may need explicit adjustment in future studies.

The study has clear limitations that the authors acknowledge candidly. It was cross-sectional and exploratory, so temporal direction cannot be established and longitudinal follow-up will be essential. The sample was predominantly White, highly educated women of Northern European ancestry, limiting generalizability, and participants were health-motivated volunteers in a dementia risk reduction program. Exclusion of cognitive impairment relied on self-reported diagnoses, and blood biomarker data were available only for those who attended clinics, introducing potential selection bias that the expanded-sample analyses could only partially address. The authors also note that the differencing process used to compute motor costs may reduce intra-individual variability, complicating interpretation of those derived measures.

Even with those caveats, the findings broaden the Alzheimer’s motor phenotype—which already includes slower gait, reduced stride length linked to p-tau181, and faster motor decline in APOE ε4 carriers—into the domain of speech motor control. If replicated with counter-balanced task order and longitudinal designs, motor speech measures could become scalable, non-invasive behavioral indicators that complement gait analysis and blood biomarkers in population screening. The vision is compelling: a browser-based test that anyone can take at home, extracting subtle signatures of articulatory timing and consistency that reflect the earliest biological whispers of Alzheimer’s disease. For now, the study stands as careful, early-stage evidence that the voice may know something about the brain that standard cognitive tests do not yet reveal.

Subject of Research: Associations between motor speech performance in rapid syllable repetition tasks and Alzheimer's disease risk markers in cognitively unimpaired older adults

Article Title: Motor speech markers of Alzheimer’s risk

Article References: Giffard, J., Bindoff, A. D., Roccati, E., Li, R., Vogel, A. P., Goldberg, L. R., Bai, Q., King, A. E., Vickers, J. C., & Alty, J. (2026). Motor speech markers of Alzheimer’s risk. GeroScience. https://doi.org/10.1007/s11357-026-02560-w

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02560-w

Keywords: Alzheimer's disease, motor speech, diadochokinesis, subjective cognitive decline, APOE ε4, p-tau181, blood biomarkers, digital biomarkers, dementia screening, GeroScience, speech analysis, preclinical detection

The research team analyzed 202 people living with ALS, including some with comorbid frontotemporal dementia, alongside 94 healthy controls drawn from two multicenter cohorts. Every participant underwent standardized clinical assessment using the revised ALS Functional Rating Scale, diagnosis was confirmed according to the revised El Escorial Criteria, and disease severity was staged using the King’s staging system. Cognitive function was assessed with the German version of the Edinburgh Cognitive and Behavioural ALS Screen, a battery of fifteen subtests spanning five domains: verbal fluency, executive function including social cognition, language, memory, and visuospatial ability. Blood plasma concentrations of p-tau181 were measured using the ultrasensitive Quanterix SIMOA platform, with every sample run in technical duplicates and internal control aliquots monitoring consistency between runs. Neurofilament light chain, the established workhorse biomarker of axonal injury in ALS, was quantified in parallel, and a subset of patients also underwent cerebrospinal fluid analysis.

The cross-sectional results were striking in their asymmetry. At baseline, people with ALS showed significantly higher plasma concentrations of both p-tau181 and neurofilament light chain than healthy controls. Mean plasma p-tau181 in patients stood at 3.9 picograms per milliliter, more than double the control average of 1.7, while mean NfL soared to 73.2 picograms per milliliter against a control value of just 14.4. Yet when the researchers turned to cerebrospinal fluid, the picture changed dramatically: no significant difference in CSF p-tau181 emerged between patients and controls. This dissociation matters enormously. If the elevated blood signal were simply spilling over from tau pathology inside the brain, the fluid bathing that brain should carry a matching elevation. Its absence argues that the plasma p-tau181 in ALS is generated predominantly by peripheral processes rather than by cerebral disease.

The cognitive findings reinforced that conclusion. Cognitive impairment affects up to half of all ALS patients, typically eroding verbal fluency, executive function, language, and social cognition, with memory deficits sometimes appearing as well. If plasma p-tau181 were a marker of Alzheimer’s co-pathology, it should track those memory and visuospatial deficits. It did not. Biomarker levels at baseline did not differ significantly among cognitively unimpaired patients, cognitively impaired patients, and those with full frontotemporal dementia. Partial correlations between cognitive test scores and biomarker levels, controlled for age and corrected for multiple comparisons, reached statistical significance for no domain and no biomarker. The correlation between plasma p-tau181 and verbal fluency, for instance, was essentially zero. Even numerically, the strongest tendencies ran through CSF p-tau181 rather than its plasma counterpart, hinting that central tau relates to cognition in a way plasma tau simply does not.

Genetic analysis deepened the puzzle. Carriers of the APOE ε4 allele, the best-known genetic risk factor for late-onset Alzheimer’s disease, showed the expected elevations in cerebrospinal fluid Alzheimer’s markers, including altered amyloid beta ratios and higher p-tau181 in CSF, confirming that the assays were capturing genuine central pathology. But their plasma p-tau181 levels were indistinguishable from those of non-carriers. The same held true when patients were grouped by ATN status, the standard framework combining amyloid, tau, and neurodegeneration markers: patients with high-risk profiles showed clear CSF differences but no plasma tau differences whatsoever. ALS-associated gene mutations such as FUS and SOD1, meanwhile, had no measurable effect on any biomarker. Whatever is driving the blood tau signal in ALS, it is neither Alzheimer’s genetics nor ALS genetics.

Longitudinal monitoring over approximately one year revealed a dynamic that distinguishes the two blood proteins even more sharply. Plasma p-tau181 increased significantly over time in patients while remaining flat in controls, and a significant group-by-time interaction confirmed that disease status, not aging, was the engine of change. Neurofilament light chain, by contrast, remained statistically stable across the same interval, despite its much higher baseline concentrations. This divergence suggests the two markers capture fundamentally different biological processes, one rising steadily with ongoing disease activity and the other plateauing once a certain threshold of axonal damage has been reached.

Where the proteins parted ways most cleanly was in their relationship to clinical phenotype and prognosis. Neurofilament light chain behaved exactly as its reputation predicts: higher levels were associated with more advanced disease severity, faster progression rates, and shorter disease duration, and it clearly separated slow from fast progressors and discriminated across King’s disease stages. Plasma p-tau181, in contrast, showed no relationship with severity, progression, staging, or disease duration, and it failed to distinguish slow from fast progressors entirely. What it did do, and did clearly, was rise in patients with predominantly lower motor neuron involvement, the muscle-wasting form of the disease, reaching significantly higher concentrations than in patients whose upper motor neurons dominated the clinical picture. Combined with a positive correlation between plasma p-tau181 and NfL, but no correlation between plasma and CSF p-tau181, the data sketch a protein that accompanies peripheral neurodegenerative processes without measuring how sick a patient is or how fast they are declining.

The authors are careful to situate these results against a complicated literature. Previous studies have reported elevated serum p-tau181 in ALS with concentrations comparable to Alzheimer’s disease, and one recent investigation using the novel NULISA assay even reported robust associations between plasma p-tau181, clinical severity scores, and survival, with higher concentrations predicting poorer outcomes. That study, however, was a single-center pilot with a limited sample size and a different assay technology, factors that may explain the discrepancy. The present findings, converging with several independent cohorts across two large multicenter samples, suggest that p-tau181 in ALS is best understood as a marker with diagnostic relevance rather than prognostic power. One limitation the researchers acknowledge is that survival data were not available for analysis, leaving open whether the protein might yet relate to longevity in ways the current design could not detect.

The practical implications reach into the design of clinical trials, where biomarkers that respond to therapy are desperately needed. Because plasma p-tau181 rises over the course of the disease independently of progression rate, it could serve as a sensitive readout of biological response to experimental treatments, complementing rather than replacing neurofilament light chain, which remains the gold standard for tracking disease severity. The authors also point toward the future of the field: newer tau markers such as p-tau217 have largely superseded p-tau181 as indicators of Alzheimer’s pathology and may offer sharper discrimination between Alzheimer’s and non-Alzheimer’s biology. For now, the message of this study is a sober lesson in biomarker humility. A protein approved to diagnose a dementia of the brain can rise to dementia-like levels in a motor neuron disease without reflecting a single tangle in the brain or a single failed word on a cognitive test. In ALS, blood tau is a messenger from the periphery, and learning to read it on its own terms may prove as important as the excitement that first brought it to the clinic.

Subject of Research: Plasma p-tau181 as a peripheral biomarker in amyotrophic lateral sclerosis and its dissociation from cognitive impairment and disease severity

Article Title: Impact of Plasma p‐tau181 on Cognition, Motor Phenotypes, and Disease Course in ALS

Article References: Kasper, E., Lehto, A., Nordmann, N., Peters, O., Hellmann, J., Priller, J., Spruth, E. J., Petzold, G. C., Vogt, I., Weydt, P., Bernsen, S., Dinter, E., Falkenburger, B., Günther, R., Düzel, E., Glanz, W., Synofzik, M., Beichert, L., Spottke, A., … Hermann, A. (2026). Impact of Plasma p‐tau181 on Cognition, Motor Phenotypes, and Disease Course in ALS. Annals of Clinical and Translational Neurology, 13(8), 1711-1718. https://doi.org/10.1002/acn3.70423

Image Credits: AI Generated

DOI: 10.1002/acn3.70423

Keywords: ALS, p-tau181, biomarkers, neurofilament light chain, motor neuron disease, cognitive impairment, frontotemporal dementia, Alzheimer's disease, plasma biomarkers, lower motor neurons, disease progression, clinical trials

The research team, led by Andrea Mastrangelo, Simone Baiardi and Piero Parchi at the University of Bologna and the Institute of Neurological Sciences of Bologna, exploited a rare and powerful resource. Their cohort consisted of participants whose cerebrospinal fluid or plasma samples had been collected shortly before death, with a median sampling-to-death interval of just 1.5 months for cerebrospinal fluid and one month for plasma. This proximity matters enormously. Most neuropathological validation studies suffer from long gaps between the fluid measurement and the autopsy, during which the underlying disease may have progressed substantially, blurring the relationship between what the biomarker showed and what the brain actually contained. By anchoring the measurements to the final weeks of life, the Italian team effectively froze the correspondence between fluid chemistry and brain pathology.

The cohort included 230 participants with antemortem cerebrospinal fluid and 101 with plasma samples, the majority affected by prion disease, a group whose rapidly progressive syndromes prompt autopsy through the Italian surveillance program. The researchers measured five cerebrospinal fluid markers, namely the Aβ42/Aβ40 ratio, p-tau181, p-tau217, and the hybrid ratios Aβ42/p-tau181 and Aβ42/p-tau217, together with three plasma markers, p-tau217, p-tau217/Aβ42 and Aβ42/Aβ40. All assays were run on a single automated chemiluminescent platform, ensuring analytical consistency. Because prion disease itself can elevate tau biomarkers, analyses involving phosphorylated tau were restricted to the 88 participants with non-prion conditions.

On the pathology side, the team went beyond conventional categorical staging. In addition to Thal amyloid phases, Braak neurofibrillary stages and ABC scores of Alzheimer’s neuropathologic change, two blinded evaluators scored amyloid plaques and cerebral amyloid angiopathy across nine brain regions, from neocortex to cerebellum, yielding a cumulative amyloid score from 0 to 90. Tau pathology, including neuropil threads, neurofibrillary tangles and thick neurites, was graded across six cortical regions to produce a cumulative score from 0 to 54. This continuous, region-weighted approach captures the actual regional burden of disease in a way that categorical stages cannot, allowing the researchers to ask precisely how much pathology is required before each biomarker begins to move.

The results reveal a strikingly sequential pattern. The cerebrospinal fluid Aβ42/Aβ40 ratio was the earliest mover, declining significantly already at the second quartile of amyloid burden, corresponding to mild-to-moderate plaque deposition across neocortical and limbic regions, and falling progressively further in the third and fourth quartiles. By contrast, cerebrospinal fluid p-tau181 and p-tau217 rose significantly only from the third quartile of amyloid burden, indicating that tau phosphorylation in the fluid lags behind the initial phases of plaque accumulation. The hybrid ratios behaved like early amyloid markers in terms of onset, with Aβ42/p-tau217 decreasing significantly from the second amyloid quartile, yet their abnormalities in relation to standard staging emerged only at intermediate levels of Alzheimer’s neuropathologic change, unlike the Aβ42/Aβ40 ratio, which was already reduced at low levels.

Sequential receiver operating characteristic analyses sharpened this picture by testing how well each biomarker discriminated progressively higher pathology thresholds. The cerebrospinal fluid Aβ42/Aβ40 ratio achieved its peak accuracy at low-to-intermediate amyloid burden, with an area under the curve of 0.984 at a threshold above 16 in the non-prion subgroup, before showing a modest plateau at more advanced stages. The p-tau markers and their ratios performed best at higher amyloid thresholds, with areas under the curve ranging from 0.889 to 0.980, and at intermediate tau burden, where p-tau217 and Aβ42/p-tau217 reached extraordinary values of 0.994 and 0.995 respectively at a tau score above 15. Across both amyloid and tau continua, p-tau217 consistently outperformed its p-tau181 counterpart, reinforcing a growing consensus that phosphorylation at threonine 217 is the more informative tau epitope.

The plasma results told a more sobering story. Plasma p-tau217 and p-tau217/Aβ42 rose significantly only in the highest quartiles of both amyloid and tau burden, and their discriminatory power peaked at the most advanced thresholds, with areas under the curve between 0.893 and 0.928. Plasma Aβ42/Aβ40 showed only weak associations with pathology and poor discrimination across the entire amyloid continuum, a finding the authors attribute to possible peripheral contributions to circulating amyloid peptides, systemic confounders and blood-brain barrier effects. When both pathologies were modeled simultaneously, plasma p-tau217 remained independently associated only with tau burden, consistent with evidence that a marked surge in soluble p-tau217 release accompanies the spread of tau pathology into the neocortex.

These findings carry practical weight for the clinic and for drug development. The team showed that a cerebrospinal fluid Aβ42/Aβ40 cut-off below 0.074, slightly higher than values commonly used in clinical practice, achieved 95 percent specificity for identifying subjects with at least low Alzheimer’s neuropathologic change, supporting its use for early identification within the disease continuum. The staged behavior of the markers also aligns with therapeutic evidence suggesting that anti-amyloid antibodies such as donanemab and lecanemab exert greater clinical benefit at earlier pathological stages, and that plaque clearance proceeds faster in brains with lower amyloid load. Knowing which fluid marker corresponds to which pathological window could therefore help clinicians time interventions and interpret biomarker panels more rationally.

Equally important is what the study could not find. Even the best-performing cerebrospinal fluid marker, the Aβ42/Aβ40 ratio, showed limited accuracy at the very earliest phases of plaque formation, when only sparse neocortical deposits are present. This implies an initial window in the Alzheimer’s continuum that current fluid biomarkers do not fully capture, a gap that may matter for prevention trials aiming to intervene before substantial pathology accumulates. The authors also caution that their cohort, enriched for rapidly progressive syndromes and dominated by participants with no or low Alzheimer’s neuropathologic change, may limit generalizability, that kidney function data were largely unavailable, and that reliance on a single assay platform precludes direct comparison with other technologies.

Nevertheless, the study delivers a coherent and clinically actionable model of biomarker behavior across the Alzheimer’s pathological continuum. Cerebrospinal fluid Aβ42/Aβ40 emerges as the sentinel of early amyloid deposition, cerebrospinal fluid p-tau markers and hybrid ratios as indicators of advancing combined pathology, and plasma p-tau217 measures as signals of heavy, late-stage burden. As blood-based testing moves toward primary care and anti-amyloid therapies become routine, anchoring these tests to neuropathological ground truth, with sampling intervals measured in weeks rather than years, provides the kind of validation the field has long needed. The sequential model also sets a clear benchmark for the next generation of markers, which must reach further back into the disease process if the earliest, most treatable phases of Alzheimer’s pathology are to be caught in a tube of fluid.

Subject of Research: Neuropathological validation of cerebrospinal fluid and plasma Alzheimer's disease biomarkers across increasing brain amyloid-beta and tau pathology burden

Article Title: Changes in five cerebrospinal fluid and three plasma Alzheimer’s disease biomarkers across increasing brain amyloid-beta and tau pathology burden

Article References: Mastrangelo, A., Baiardi, S., Ruggeri, E., Bentivenga, G. M., Vargiu, C. M., Mammana, A., Sbriccoli, M., Polischi, B., Carlà, B., Capellari, S., & Parchi, P. (2026). Changes in five cerebrospinal fluid and three plasma Alzheimer’s disease biomarkers across increasing brain amyloid-beta and tau pathology burden. Acta Neuropathologica, 152(1), Article 28. https://doi.org/10.1007/s00401-026-03076-5

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03076-5

Keywords: Alzheimer's disease, biomarkers, amyloid-beta, tau pathology, cerebrospinal fluid, plasma p-tau217, neuropathology, autopsy validation, Aβ42/Aβ40 ratio, p-tau181, diagnostic accuracy, neurodegeneration