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Neurodegeneration risk variants promote lysosomal TMEM106B fibril accumulation.

John Michael Replogle·Jordan D Marks·Martin G Fernandez·Hebao Yuan·Dahyun Yu·Elizabeth Winters·Vidhya Maheswari Jawahar·Rishi Deshmukh·Renaldo Sutanto·Isabelle Kowal·Ashley Frankenfield·Rachel Shi·Yari Carlomagno·Karen Jansen-West·Tiffany W Todd·Andrii Kopach·Iradukunda Sandra Ndayambaje·Yue A Qi·Ananth Shantaraman·Ignacio Pozo-Cabanell·Udit Sheth·Mei Yue·Duc Duong·Shawn M Ferguson·David A Bennett·Markus Damme·Brad F Boeve·Gregory S Day·Benjamin Kellman·William C Skarnes·Ronald C Petersen·Keith A Josephs·Neill R Graff-Radford·Justin A McDonough·Mercedes Prudencio·Sami J Barmada·Yongjie Zhang·Ling Hao·Michael DeTure·Bailey Rawlinson·Erica Engelberg-Cook·Monica Castanedes Casey·Nathan Perez·Dennis W Dickson·Aliza Wingo·Yue Liu·Nicholas T Seyfried·Thomas S Wingo·Shyamal Mosalaganti·Leonard Petrucelli·Michael E Ward
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Abstract

Variants in TMEM106B and GRN, which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN-mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

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John Michael Replogle, Jordan D Marks, Martin G Fernandez, Hebao Yuan, Dahyun Yu, Elizabeth Winters, Vidhya Maheswari Jawahar, Rishi Deshmukh, Renaldo Sutanto, Isabelle Kowal, Ashley Frankenfield, Rachel Shi, Yari Carlomagno, Karen Jansen-West, Tiffany W Todd, Andrii Kopach, Iradukunda Sandra Ndayambaje, Yue A Qi, Ananth Shantaraman, Ignacio Pozo-Cabanell, Udit Sheth, Mei Yue, Duc Duong, Shawn M Ferguson, David A Bennett, Markus Damme, Brad F Boeve, Gregory S Day, Benjamin Kellman, William C Skarnes, Ronald C Petersen, Keith A Josephs, Neill R Graff-Radford, Justin A McDonough, Mercedes Prudencio, Sami J Barmada, Yongjie Zhang, Ling Hao, Michael DeTure, Bailey Rawlinson, Erica Engelberg-Cook, Monica Castanedes Casey, Nathan Perez, Dennis W Dickson, Aliza Wingo, Yue Liu, Nicholas T Seyfried, Thomas S Wingo, Shyamal Mosalaganti, Leonard Petrucelli, Michael E Ward. 2026-03-28. Neurodegeneration risk variants promote lysosomal TMEM106B fibril accumulation.. https://doi.org/10.64898/2026.03.26.714634

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Effectiveness of high-dose versus standard-dose influenza vaccines against hospitalisation according to frailty risk: a prespecified analysis of the randomised trial DANFLU-2.

BACKGROUND: Frailty is a major risk factor for influenza-related complications and can influence vaccine effectiveness. We aimed to assess the relative vaccine effectiveness (rVE) of high-dose (HD-IIV) versus standard-dose inactivated influenza vaccine (SD-IIV) in older adults aged 65 years or older according to frailty risk. METHODS: This study was a prespecified analysis of DANFLU-2, an open-label, individually randomised trial, conducted in Denmark during three consecutive influenza seasons (2022-23, 2023-24, and 2024-25). Adults aged 65 years or older were randomised (1:1) to the HD-IIV or SD-IIV group. The primary endpoint was hospitalisation for influenza or pneumonia. Frailty was defined according to the validated Hospital Frailty Risk Score (HFRS) based on ICD-10 codes within 10 years before randomisation. Participants were stratified into three HFRS categories, namely low (<5 points), intermediate (5-15 points), and high (>15 points) frailty risk. The rVE of HD-IIV versus SD-IIV against the primary endpoint was assessed across prespecified HFRS categories and treating HFRS as a continuous variable. Pearson's chi-square test was used to compare safety events across frailty risk groups and randomisation groups. FINDINGS: Among 332&#x2009;438 randomised participants (mean age 73&#xb7;7 years [SD 5&#xb7;8]; 161&#x2009;538 [48&#xb7;6%] were female), 276&#x2009;173 (83&#xb7;1%) had low frailty risk, 52&#x2009;395 (15&#xb7;8%) had intermediate frailty risk, and 3861 (1&#xb7;2%) had high frailty risk. The primary endpoint of hospitalisation for influenza or pneumonia occurred in 1424 (0&#xb7;5%) of 276&#x2009;173 participants with low frailty risk, 761 (1&#xb7;5%) of 52&#x2009;395 with intermediate frailty risk, and 163 (4&#xb7;2%) of 3861 with high frailty risk (relative risk [RR] for intermediate vs low frailty risk 2&#xb7;8 [95% CI 2&#xb7;6-3&#xb7;1]; RR for high vs low frailty risk 8&#xb7;2 [7&#xb7;0-9&#xb7;6]). HFRS as a continuous variable significantly modified the effect of HD-IIV versus SD-IIV against the primary endpoint with higher rVE estimates with increasing HFRS (pinteraction=0&#xb7;020). The rVE was 0&#xb7;2% (95% CI -10&#xb7;8 to 10&#xb7;2) among those with low frailty risk, 13&#xb7;1% (-0&#xb7;4 to 24&#xb7;8) among those with intermediate frailty risk, and 19&#xb7;9% (-10&#xb7;3 to 42&#xb7;1) among those with high frailty risk. No significant interaction was observed when HFRS was assessed according to the prespecified categorical frailty groups (pinteraction=0&#xb7;17). The proportion of participants with at least one serious adverse event increased across frailty risk groups (13&#x2009;366 [4&#xb7;8%] of 275&#x2009;795 for low frailty risk, 5475 [10&#xb7;5%] of 52&#x2009;315 for intermediate frailty risk, and 777 [20&#xb7;2%] of 3850 for high frailty risk; p<0&#xb7;0001), with similar proportions of serious adverse events in the HD-IIV and SD-IIV groups for each frailty risk group. INTERPRETATION: Among adults aged 65 years or older in Denmark, frailty risk might modify the effects of HD-IIV versus SD-IIV against hospitalisation for influenza or pneumonia, with higher rVE estimates with increasing frailty risk. These findings might support considering high-dose influenza vaccines for frail older adults. However, effect modification was not evident when frailty was assessed using prespecified categorical subgroups, and subgroup-specific estimates were imprecise, with 95% CIs crossing the null. These results should be considered exploratory, warranting further investigation. FUNDING: The DANFLU-2 trial was funded by Sanofi.

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