Lim TR, Suthiphosuwan S, Gaitán MI
… +10 more, Marrodán M, Horwath EA, Guenette M, Bharatha A, Sati P, Absinta M, Correale J, Shinohara RT, Reich DS, Oh J
JAMA Neurol
· 2026 Mar · PMID 41587044
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IMPORTANCE: Most people with radiologically isolated syndrome (RIS) have high proportions of white matter lesions (WMLs) demonstrating the central vein sign (ie, central vein sign-positive lesion [CVS+L]) and at least 1...IMPORTANCE: Most people with radiologically isolated syndrome (RIS) have high proportions of white matter lesions (WMLs) demonstrating the central vein sign (ie, central vein sign-positive lesion [CVS+L]) and at least 1 paramagnetic rim lesion (PRL), representing perivenular lesion development and chronic active demyelination, respectively. Whether these imaging measures predict developing clinical multiple sclerosis (MS) in people with RIS is not yet known. OBJECTIVE: To determine the prognostic value of various magnetic resonance imaging (MRI) measures, particularly PRLs and CVS+L, in predicting clinical MS in people with RIS. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter prospective cohort study conducted from 2011 and 2024. Participants older than 18 years and fulfilling published RIS criteria were consecutively recruited from 3 large academic MS centers. EXPOSURES: Participants underwent 3-T MRI including brain and spinal cord (SC) sequences and longitudinal clinical assessments. MRIs were evaluated for the total WML, PRL, and SC lesion (SCL) counts as well as the proportion of CVS+L. MAIN OUTCOMES AND MEASURES: The primary outcome was the development of clinical symptoms of MS. Time-varying Cox regression assessed the association between PRLs and symptom onset. Elastic net regression identified key predictors, incorporating PRLs, age, sex, and SCL. RESULTS: A total of 79 eligible people with RIS were included (36 [46%] in the discovery cohort [DC], 43 [54%] in the validation cohort [VC]). Of the initial 46 DC participants, 10 withdrew or were lost to follow-up, whereas all VC participants completed follow-up. In the DC (median [IQR] age, 40 [31-51] years; 25 female [70%]; median [IQR] follow-up, 6.4 [5.0-9.1] years), 9 of 36 people with RIS (25%) developed MS (median [IQR] time, 5.2 [5.0-6.8] years). In the VC (median [IQR] age, 43 [36-51] years; 23 female [53%]; median [IQR] follow-up, 4.4 [2.5-7.9] years), 9 of 43 people with RIS (21%) developed MS (median [IQR] time, 4.4 [2.5-4.7] years). Higher PRL count was associated with earlier symptom onset between 5 and 30 years after initial RIS diagnosis (hazard ratio [HR], 1.15; 95% CI, 1.05-1.26; P = .004) in the DC, replicated in the VC (HR, 1.51; 95% CI, 1.00-2.27; P = .04). In the DC, having 4 or more PRLs (odds ratio [OR], 14.64; 95% CI, 2.00-207.23; P = .02) and higher PRL count (OR, 1.15; 95% CI, 1.03-1.32; P = .02) predicted clinical MS. In the VC, having any PRL was significantly associated with developing clinical MS (OR, 20.90; 95% CI, 2.35-533.30; P = .02). CONCLUSIONS AND RELEVANCE: Study findings suggest that accrual of nonresolving chronic inflammation in WML portends development of clinical MS in people with RIS, which may have clinical utility in guiding treatment decisions across the MS spectrum and strengthens the case for including asymptomatic MS in the diagnostic criteria. There is growing recognition that early detection of most chronic neurological diseases is critical to prevent or diminish future disability, and these findings are a specific example of how this principle might operate in practice.
Tanaka H, Black LE, Forrest SL
… +8 more, Danics K, Sadia N, Khodadadi M, Tator C, Smith DH, Tartaglia MC, Stewart W, Kovacs GG
JAMA Neurol
· 2026 Mar · PMID 41587040
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IMPORTANCE: Exposure to repetitive head impacts (RHI) is associated with increased risk of a range of neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral sclerosis. However, while the protein...IMPORTANCE: Exposure to repetitive head impacts (RHI) is associated with increased risk of a range of neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral sclerosis. However, while the protein pathologies in the brains of individuals with the RHI-associated pathology of chronic traumatic encephalopathy (CTE) are well described, the spinal cord pathology in at-risk individuals remains poorly understood. OBJECTIVE: To evaluate spinal cord pathologies associated with RHI exposure or CTE neuropathologic change (CTE-NC) in the brain. DESIGN, SETTING, AND PARTICIPANTS: This case-control study of a retrospective autopsy series (June 2019 to August 2025) was performed among autopsied individuals who served as RHI-exposed cases or controls in a multicenter brain bank collaboration. Data analysis was performed from January 2024 to November 2025. EXPOSURES: RHI history and CTE-NC presence. MAIN OUTCOMES AND MEASURES: Informant-reported clinical history as well as symptoms and immunohistochemistry for phosphorylated tau (p-tau), phosphorylated TAR DNA-binding protein 43 (p-TDP-43), α-synuclein, and amyloid-β (Aβ), as well as amyloid precursor protein and human leukocyte antigen DR. RESULTS: Of 70 autopsied individuals (62 male, 8 female; mean [SD] age, 64.40 [13.94] years), 20 showed CTE-NC in the brain. All cases with CTE-NC exhibited spinal cord p-tau deposits, especially in cases aged 65 years or older with prior RHI (n = 14), often showing extensive spinal tau pathology as both neuronal (all 14 cases) and astrocytic (12 of 14 cases [86%]) p-tau deposits. Spinal p-tau pathology was associated with microglial activation and motor symptoms. Notably, among the individuals with CTE-NC and prior RHI who were aged 65 years or older, additional spinal protein pathologies were present, comprising p-TDP-43 inclusions (9 of 14 cases [64%]), Aβ deposits (13 of 14 cases [93%]), and α-synuclein deposits (7 of 14 cases [50%]), with all 4 of these pathologies present in 4 individuals (29%). In total, across all 20 CTE-NC cases, p-TDP-43 inclusions were confined to the spinal cord in 5 of the 10 individuals with spinal p-TDP-43 pathology. In contrast, among 50 individuals without CTE-NC, typically sparse p-tau deposits were seen in only 27 (54%). Among the 23 confirmed cases with a history of RHI, 16 (70%) exhibited CTE-NC, while 7 (30%) did not. Spinal tau pathology was more severe in those with CTE-NC; however, astrocytic tau pathology was also present in the group without CTE-NC, unlike in controls without RHI or CTE. CONCLUSIONS AND RELEVANCE: This case-control study provides autopsy evidence of a high prevalence of complex spinal pathology in individuals with CTE-NC, supporting the concept of trauma-related encephalomyelopathy. The frequent co-occurrence of p-TDP-43, Aβ, and α-synuclein pathologies in individuals aged 65 years or older with CTE-NC suggests that cumulative trauma might contribute to widespread misfolded protein aggregation.
Wu J, Pyko A, Chourpiliadis C
… +7 more, Hu Y, Hou C, Brauner S, Piehl F, Ljungman P, Ingre C, Fang F
JAMA Neurol
· 2026 Mar · PMID 41557441
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IMPORTANCE: Air pollution exposure has been associated with an increased risk of neurodegenerative diseases; however, evidence is limited for motor neuron disease (MND), especially regarding disease progression. OBJECTIV...IMPORTANCE: Air pollution exposure has been associated with an increased risk of neurodegenerative diseases; however, evidence is limited for motor neuron disease (MND), especially regarding disease progression. OBJECTIVE: To determine whether long-term exposure to air pollution is associated with the risk and prognosis of MND. DESIGN, SETTING, AND PARTICIPANTS: This population-based, nested case-control study used Swedish health register data of incident MND cases diagnosed between 2015 and 2023 with up to 8 years of follow-up. Participants included patients with MND, 5 age- and sex-matched population controls without MND per patient with MND, and full siblings of the patients with MND. Data were analyzed between November 6, 2024, and November 4, 2025. EXPOSURES: Mean yearly concentrations of particulate matters of 2.5 µm or less, 10 µm or less, or 2.5 to 10 µm in diameter (PM2.5, PM10, PM2.5-10) and nitrogen dioxide (NO2) were assessed at the residential address using a spatiotemporal model to approximate accumulated air pollution exposure. MAIN OUTCOME AND MEASURES: Association between air pollution and risk of MND was assessed by comparing cases to both population and sibling controls. Flexible parametric survival models estimated the association between air pollution exposure and the risk of mortality (or use of invasive ventilation) after MND diagnosis (case-only analyses). Based on the rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score and its subscores after diagnosis, patients were classified into fast (upper 25th percentile) or slow (lower 75th percentile) progression. Logistic regression was used to assess air pollution exposure and the risk of fast progression. RESULTS: The study included 1463 patients with MND, 7310 population controls, and 1768 sibling controls. The mean (SD) age for all patients with MND was 67.3 (11.7) years, and 814 (55.6) were male. In the population comparison, long-term air pollution was associated with an increased risk of MND; per IQR increase in the 10-year average level, the odds ratio was 1.21 (95% CI, 1.09-1.34) for PM2.5, 1.30 (95% CI, 1.19-1.42) for PM2.5-10, 1.29 (95% CI, 1.18-1.42) for PM10, and 1.20 (95% CI, 1.12-1.29) for NO2. A higher level of PM10 or NO2 was associated with a higher hazard of mortality, whereas a higher level of all PMs was associated with faster functional decline, particularly motor and respiratory functions, after MND diagnosis. CONCLUSIONS AND RELEVANCE: The findings of this case-control study suggest that air pollution, even at relatively low levels typical of Sweden, may contribute both to the risk of developing MND and disease prognosis after MND diagnosis.
Möhn N, Grote-Levi L, Bonifacius A
… +50 more, Tischer-Zimmermann S, Nay S, Jendretzky KF, Sassmann ML, Karacondi K, Zent M, Konen FF, Sühs KW, Meuth SG, Pawlitzki M, Warnke C, Ayzenberg I, Schneider R, Helmchen C, Brüggemann N, Klebe S, Hildner M, Grefkes C, Nitsch L, Hühnchen P, Böltz S, Alt L, Tumani H, Kleinschnitz C, Pul R, Grauer O, Clifford D, Gnanapavan S, Wicklein R, Perpoint T, Beudel M, Del Bello A, Rauer S, Wiendl H, Jelcic I, Gasnault J, Cimini E, Antinori A, Pinnetti C, Pourcher V, Weiss N, Lambert N, Maecker-Kolhoff B, Höglinger GU, Zahraeifard S, Cortese I, Eiz-Vesper B, Martin-Blondel G, Skripuletz T, Immunotherapy for PML Study Group
JAMA Neurol
· 2026 Mar · PMID 41557340
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IMPORTANCE: Progressive multifocal leukoencephalopathy (PML) is a life-threatening demyelinating disease caused by reactivation of the JC virus (JCV) in immunocompromised patients. While immune checkpoint inhibitors (ICI...IMPORTANCE: Progressive multifocal leukoencephalopathy (PML) is a life-threatening demyelinating disease caused by reactivation of the JC virus (JCV) in immunocompromised patients. While immune checkpoint inhibitors (ICIs) show therapeutic potential, responses vary and predictive biomarkers are lacking. OBJECTIVE: To determine whether pretreatment JCV- and/or BK virus-specific T cells in the blood are associated with treatment efficacy. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 111 patients with PML who were treated with ICIs stratified by peripheral virus-specific T cell presence (ELISpot/flow cytometry) between August 2021 and May 2024, with a median (IQR) follow-up of 7 (1-13) months. Of 112 patients with definite PML across 39 centers, 1 patient refused participation; 111 patients were included. EXPOSURE: Patients received pembrolizumab (n = 81), nivolumab (n = 28), or atezolizumab (n = 2) per availability and prescribing practices at participating centers. MAIN OUTCOME AND MEASURES: Clinical outcomes, diagnostic parameters, and immune-related adverse events were compared; association of virus-specific T-cell responses with survival was analyzed using the Kaplan-Meier method. RESULTS: The study cohort consisted of 111 patients (median [IQR] age, 61 [50-70] years; 74 male [66.6%]). Twenty-one patients had detectable virus-specific T cells prior to therapy, 22 were T cell-negative and 68 had an unknown T-cell status. T cell-positive patients showed significantly higher response rates and improved survival compared to both T cell-negative patients (18/21 [86%] vs 5/22 [23%]; P < .001; median survival time, none [95% CI, undefined] vs 136.5 days [95% CI, 19 to ∞]; P = .002) and those with unknown T-cell status (18/21 [86%] vs 29/68 [43%]; P = .001; median survival time, none vs 162 days [95% CI, 66 to ∞]; P = .004). They achieved better functional outcomes (median [IQR] modified Rankin Scale score, 3 [2-4] vs 4 [3-6]; P = .009) and lower JC viral load in cerebrospinal fluid (median [IQR], 0 copies/mL [0-502.5] vs 2500 copies/mL [0-6900]; P = .01) during follow-up compared to T cell-negative patients. Immune-related adverse events were most frequent in T cell-negative patients (10/20 [50%]), including the most severe events, and least frequent in T cell-positive patients (2/20 [10%]) (P = .02). CONCLUSIONS AND RELEVANCE: Preexisting functional virus-specific T cells were associated with better clinical response, longer survival, and lower toxicity in PML. These findings suggest the likely importance of preexisting antiviral immunity for successful ICI therapy.
Wolfova K, Engdahl BL, Horn J
… +4 more, Riley CS, Bello NA, Miller EC, Tom SE
JAMA Neurol
· 2026 Feb · PMID 41525064
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IMPORTANCE: Although concordance rates for multiple sclerosis (MS) are higher among dizygotic twins than among nontwin siblings-suggesting a potential influence of prenatal and perinatal factors-few large-scale studies h...IMPORTANCE: Although concordance rates for multiple sclerosis (MS) are higher among dizygotic twins than among nontwin siblings-suggesting a potential influence of prenatal and perinatal factors-few large-scale studies have systematically investigated the role of maternal adverse pregnancy outcomes in risk of MS in offspring. OBJECTIVE: To explore whether preterm birth, being born small or large for gestational age (SGA and LGA, respectively), maternal hypertensive disorders of pregnancy (HDP), placental abruption, and maternal diabetes are associated with the risk of adult-onset MS in offspring. DESIGN, SETTING, AND PARTICIPANTS: A closed cohort study with a follow-up beginning in January 2009 and continuing until the first event, death, emigration, or end of follow-up (December 2019). Data were derived from Norwegian national registers. All live births (N = 1 303 802) in the Medical Birth Registry of Norway from 1967 to 1989 were identified. MS cases were identified through the National Patient Register. Cox models were used to estimate the association between adverse pregnancy outcomes and MS among participants aged 18 years and older at the beginning of the follow-up and MS-free during the previous year. Data were analyzed from February to October 2025. EXPOSURES: Primary exposures included preterm birth (before gestational age of 37 completed weeks), SGA (birth weight <10th percentile), LGA (birth weight >90th percentile), HDP (preeclampsia, eclampsia, gestational hypertension, and chronic hypertension), placental abruption, and maternal diabetes (type 2, unspecified pregestational diabetes, gestational diabetes, and use of antidiabetic medication during pregnancy). MAIN OUTCOMES AND MEASURES: MS diagnosis defined by International Classification of Diseases and Related Health Problems, Tenth Revision, code G35. RESULTS: Among 1 166 731 infants (597 330 [51.2%] male), 4295 MS cases were identified in 2009 and onwards. Adjusting for confounders, the hazard ratio [HR] for LGA was 1.13 (95% CI, 1.03-1.25), while the HR for SGA was 0.88 (95% CI, 0.78-0.98). The HR for maternal diabetes was 2.15 (95% CI, 1.37-3.37). Preterm birth, placental abruption, and HDP were not associated with MS. CONCLUSIONS AND RELEVANCE: In this cohort study, being born LGA and being exposed to maternal diabetes were associated with a higher risk of adult-onset MS, whereas begin born SGA was associated with a lower risk. While high childhood body mass index and diabetes are known MS risk factors, these findings suggest susceptibility may begin as early as the prenatal period.
Lapidaire W, Kitt J, Krasner S
… +19 more, Bateman PA, Cutler HR, Barr L, Frost A, Tucker K, Suriano K, Kenworthy Y, Milner G, Lacharie M, Mills R, Roman C, Mackillop L, Aye C, Cairns A, Thilaganathan B, Chappell LC, Lewandowski AJ, McManus RJ, Leeson P
JAMA Neurol
· 2026 Feb · PMID 41490362
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IMPORTANCE: Hypertensive pregnancy increases risk of cognitive decline, stroke, and dementia, especially after preeclampsia. Women with prior hypertensive pregnancy show lower brain volumes, but it was unknown whether ea...IMPORTANCE: Hypertensive pregnancy increases risk of cognitive decline, stroke, and dementia, especially after preeclampsia. Women with prior hypertensive pregnancy show lower brain volumes, but it was unknown whether early postpartum blood pressure optimization could alter these outcomes. OBJECTIVE: To evaluate whether an intervention designed to achieve better postpartum blood pressure control after a hypertensive pregnancy is associated with differences in brain volumes around 9 months post partum compared with usual care. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial, the Physician Optimized Postpartum blood pressure self-management trial (POP-HT), was a prospective, open-label, blinded end-point study conducted at a single tertiary center in the UK. Participants were older than 18 years and had preeclampsia or gestational hypertension requiring antihypertensive treatment at hospital discharge. Enrollment began February 21, 2020; the last follow-up was on November 2, 2021; and the mean follow-up time was approximately 9 months. Secondary outcome analyses (primary results published 2022) were conducted May 2025. INTERVENTIONS: Telemonitored self-management with research physician-guided titration or usual postnatal care. MAIN OUTCOMES AND MEASURES: This substudy analyzed the secondary outcomes T1-weighted magnetic resonance imaging (MRI) brain volumes (gray matter, white matter, cerebrospinal fluid, subcortical structures) acquired approximately 9 months post partum. Analyses used linear regression models adjusted for total intracranial volume. RESULTS: Of 252 eligible participants, 32 declined, and 220 were randomized (mean [SD] age, 33.4 [5.1] years). The T1 brain MRI of 157 participants was available for analysis; 96 participants (63%) had preeclampsia, and 56 (37%) had gestational hypertension. The intervention group (n = 81) had larger total white matter volumes (adjusted mean difference, 11.50 cm3; 95% CI, 2.04 to 20.96; P = .02) compared with the usual care group (n = 71). In usual care, participants with preeclampsia had smaller putamen (adjusted mean difference, -0.83 cm3; 95% CI, -1.20 to -0.46; P < .001), accumbens (adjusted mean difference, -0.15 cm3; 95% CI, -0.24 to -0.05; P = .003), and pallidum (adjusted mean difference, -0.13 cm3; 95% CI, -0.26 to -0.01; P = .04) volumes compared with those with gestational hypertension. These differences were not observed in the intervention group. CONCLUSIONS AND RELEVANCE: This study found that short-term postpartum optimization of blood pressure control after hypertensive pregnancy was associated with larger brain volumes during the first year post partum. Because brain volume is a surrogate of brain health linked to tissue preservation and cognitive outcomes, these findings suggest potential neurovascular benefits that were most pronounced among women with preeclampsia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04273854.
Hu W, Tao C, Li R
… +28 more, Chen Z, Chen W, Yi T, Wang H, Zhou P, Cao Z, Zeng G, Cui T, Su J, Chen L, Wang G, Sun J, Zhu Y, Wang L, Zhang C, Liu T, Song J, Jing X, Wang A, Wang J, Xu P, Luo C, Qureshi AI, AbdalKader M, Nguyen TN, Saver JL, Nogueira RG, Liu X
JAMA Neurol
· 2026 Feb · PMID 41460644
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IMPORTANCE: Endovascular thrombectomy (EVT) has been established as an effective treatment for acute basilar artery occlusion (BAO) in the short term. However, the durability of these benefits over the long term has not...IMPORTANCE: Endovascular thrombectomy (EVT) has been established as an effective treatment for acute basilar artery occlusion (BAO) in the short term. However, the durability of these benefits over the long term has not been well characterized. OBJECTIVE: To determine whether the clinical benefits of EVT for acute BAO are sustained at 3 years, with a primary focus on functional outcomes and mortality compared with best medical management alone. DESIGN, SETTING, AND PARTICIPANTS: This study is a 3-year follow-up extension of a multicenter randomized clinical trial conducted between February 2021 and January 2022, with follow-up data collected through January 2025. The study was designed as an open-label, assessor-blinded trial to evaluate the long-term efficacy of EVT. The trial was conducted at 36 comprehensive stroke centers across China, representing a diverse, population-based setting that enhances the generalizability of the results. A total of 340 patients with acute BAO within 12 hours of estimated symptom onset were randomly assigned to the thrombectomy or control group. Eligible participants were adults with imaging-confirmed BAO and without contraindications to endovascular therapy. Of the randomized patients, 307 (90.3%) completed 3-year follow-up-203 in the thrombectomy group and 104 in the control group. INTERVENTIONS: Participants in the thrombectomy group received EVT in combination with best medical management, while the control group received best medical management alone. EVT procedures were performed according to institutional protocols using stent retrievers, aspiration devices, balloon angioplasty, stent deployment, intra-arterial thrombolysis, or combinations of these approaches that were left to the discretion of the treating team. MAIN OUTCOMES AND MEASURES: The primary outcome was a modified Rankin Scale (mRS) score of 0 to 3 at 3 years, representing the ability to walk and perform self-care. Secondary outcomes included a mRS score of 0 to 2, distribution across the mRS score categories, and quality of life. These outcomes were prespecified prior to data analysis. RESULTS: Among 307 patients (median [IQR] age, 68 [59-75]; 211 [69%] male) with available data, an mRS score of 0 to 3 at 3 years was observed in 78 patients (38.4%) in the thrombectomy group and in 19 patients (18.3%) in the control group (adjusted risk ratio, 2.05; 95% CI, 1.35-3.11; P = .001). The distribution of mRS scores favored the thrombectomy group over the control group (adjusted common odds ratio, 2.60; 95% CI, 1.53-4.43). The cumulative 3-year mortality increased from 36.7% (n = 83) at 90 days to 55.7% (n = 113) in the thrombectomy group and 55.3% (n = 63) to 73.1% (n = 76) in the control group (adjusted risk ratio, 0.76; 95% CI, 0.65-0.89). On prespecified subgroup analysis, benefit was observed in patients younger than 70 years; a treatment effect was not demonstrated in patients aged 70 years and older. CONCLUSIONS AND RELEVANCE: At 3 years, the clinical benefit of EVT in patients with acute BAO was durable, with substantially better functional outcomes and reduced mortality compared with medical management. These results reinforce EVT as the standard of care for BAO and support broader implementation and timely access to thrombectomy services. TRIAL REGISTRATION: ChiCTR.org.cn Identifier: ChiCTR2400082236.
Brown CA, Mundada NS, Cousins KAQ
… +17 more, Sadeghpour N, Lyu X, McGrew E, Korecka M, Chen-Plotkin A, Xie L, Wisse LEM, Detre JA, McMillan CT, Lee EB, Nasrallah IM, Das SR, Mechanic-Hamilton D, Yushkevich PA, Shaw LM, Wolk DA, Alzheimer’s Disease Neuroimaging Initiative
JAMA Neurol
· 2026 Feb · PMID 41396614
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IMPORTANCE: Even within individuals who are amyloid positive, clinical symptoms can be impacted by Alzheimer pathology, other pathologic proteins, and cognitive reserve or resilience. Understanding how each of these fact...IMPORTANCE: Even within individuals who are amyloid positive, clinical symptoms can be impacted by Alzheimer pathology, other pathologic proteins, and cognitive reserve or resilience. Understanding how each of these factors contributes to a patient's clinical presentation is crucial for prognosis and treatment decisions in the era of disease-modifying therapies. OBJECTIVE: To evaluate tau-clinical mismatch as a means to identify those more likely to harbor copathology and/or exhibit resilience to Alzheimer pathology. DESIGN, SETTING, AND PARTICIPANTS: This was a longitudinal, observational cohort study conducted from 2004 to 2024. The setting included multiple academic medical centers in the US participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI) or Penn Alzheimer's Disease Research Center (Penn-ADRC). Included in the analysis were individuals with clinical assessment and measures of either tau positron emission tomography (tau-PET) or phosphorylated tau 217 (p-tau217) who were selected from individuals positive for amyloid β (Aβ+) in the ADNI cohort (aged 55-95 years) and the Penn-ADRC cohort (aged 54-92 years). EXPOSURES: Clinical assessment (Clinical Dementia Rating Sum of Boxes [CDR-SB]) and tau burden (tau-PET or p-tau217) for mismatch group classification. MAIN OUTCOMES AND MEASURES: Cross-sectional measures of neurodegeneration (medial temporal lobe volume and thickness, cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature), α-synuclein cerebrospinal fluid seed-amplification assay, and longitudinal CDR-SB. RESULTS: A total of 365 participants (mean [SD] age, 75.4 [7.9] years; 192 female [52.6%]) in the ADNI tau-PET group and 524 participants (mean [SD] age, 77.1 [7.9] years; 268 male [51.1%]) in the ADNI p-tau217 group were selected from the 998 individuals who were Aβ+ in the ADNI cohort and used to generate tau-clinical mismatch models with 55.6% to 57.1% classified as canonical (CDR-SB commensurate to tau), 23.7% to 24.7% as resilient (CDR-SB < tau), and 19.3% to 19.7% as vulnerable (CDR-SB > tau). Vulnerable groups had evidence of greater likelihood of copathology, with TDP-43 neurodegeneration patterns and α-synuclein positivity. Mismatch groups showed diverging clinical trajectories with earlier cognitive impairment in vulnerable groups and later impairment in resilient individuals. Similar findings were seen when applied to an independent dataset of 244 individuals (mean [SD] age, 73.7 [6.8] years; 139 female [57.0%]) of the 248 who were Aβ+ in Penn-ADRC cohort. Finally, these models were applied to a cohort receiving antiamyloid therapy to show the utility of this method for predicting individual cognitive trajectories during therapy. CONCLUSION AND RELEVANCE: Results of this cohort study suggest that tau-clinical mismatch identified individuals more likely to have an accelerated disease course due to the presence of copathology and those exhibiting greater cognitive resilience to disease pathology. These models provide an important tool that can be implemented in clinical practice to provide improved individualized prognosis and, potentially, monitoring of response to disease-modifying therapy.