👤 Jean-Laurent Casanova

There is limited research on the long-term associations of plasma phosphorylated tau 217 (p-tau217) with mild cognitive impairment (MCI) and dementia. No study has evaluated whether such associations vary by race or hormone therapy (HT) use. To examine associations of baseline plasma p-tau217 with incident MCI and dementia and determine whether associations vary by age, race, APOE ε4 carrier status, or HT use. This cohort study examined women recruited from 39 US clinical sites between 1996 and 1999 into the Women's Health Initiative Memory Study who were randomized to either estrogen alone vs placebo or estrogen plus progestin vs placebo. Women were assessed for up to 25 years through 2021. Baseline plasma p-tau217 was measured in 2024 and analyzed between February and August 2025. Women aged 65 to 79 years who were cognitively unimpaired at baseline were included for this analysis. Plasma p-tau217, quantified using the ALZpath Simoa assay. The primary outcome was the combined end point of incident MCI or probable dementia. Secondary outcomes included MCI and dementia examined separately. Cause-specific hazard ratios (HRs) and 95% CIs for the association of p-tau217 with MCI or dementia were estimated using Cox proportional hazards regression models. Among 2766 participants (mean [SD] age, 69.9 [3.8] years; 486 [17.9%] Black, 196 [7.1%] Hispanic, and 2007 [73.9%] White), 1311 developed the combined end point of MCI or dementia (849 participants with MCI and 752 participants with dementia). Every 1-SD increase in log2-transformed p-tau217 was associated with incident MCI or dementia (HR, 2.43; 95% CI, 2.18-2.71) and each individual outcome (MCI: HR, 1.94; 95% CI, 1.72-2.20; dementia: HR, 3.17; 95% CI, 2.79-3.61). Associations of p-tau217 with dementia were larger in magnitude for women randomized to estrogen plus progestin (HR, 4.18; 95% CI, 3.41-5.13) vs placebo (HR, 3.07; 95% CI, 2.41-3.91) (P for interaction = .04) but did not significantly vary by estrogen alone vs placebo. P-tau217 associations with MCI or dementia were larger in magnitude for women older than 70 years (P for interaction = .04), APOE ε4 carriers (P for interaction = .02), and White women compared with Black women (P for interaction < .001). However, the combination of p-tau217 and age performed similarly in White women (area under the curve = 72.0%; 95% CI, 70.3%-73.6%) and Black women (area under the curve = 70.4%; 95% CI, 64.0%-78.0%). P-tau217 was not associated with incident MCI in Black women. In this cohort study of cognitively unimpaired older women, p-tau217 was associated with incident MCI or dementia up to 25 years later. These findings suggest that age, race, APOE ε4, and HT use should be considered when examining associations of p-tau217 with cognitive outcomes. Show less

Identifying proteomic signatures in treatment-naïve individuals newly diagnosed with inflammatory bowel disease (IBD) may provide insights into the underlying pathophysiological mechanisms of the disease and aid in distinguishing Crohn's disease (CD) from ulcerative colitis (UC). In the discovery phase, label-free quantitative proteomics was performed to analyze proteomic profiles in serum extracellular vesicles (EVs), serum, urine, and intestinal tissue from 100 newly diagnosed IBD patients (50 CD and 50 UC), and 51 healthy controls (HC). Serum candidate biomarkers were validated using ELISA in a separate subset cohort (87 CD, 134 UC, and 99 HC), and immunohistochemistry was performed on biopsies from the discovery cohort to confirm findings. We identified 419 proteins in serum EVs, 468 in serum, 683 in urine, and 2603 in intestinal tissue. ELISA results showed lower levels of TTR and APOC3 and higher levels of ATRN in UC patients compared to HC. Similarly, CD patients showed lower TTR and higher ATRN levels compared to HC. Moreover, serum protein S10A9 was differentially upregulated in CD vs UC. Immunohistochemistry revealed increased PRDX4 and AZU1 expression in the ileum of CD patients, whereas AOFB expression was lower in the ileum of CD and in the left colon of both CD and UC compared to HC. This comprehensive proteomic study has identified a set of proteins differentially expressed in IBD, which may contribute to a better understanding of its mechanisms and hold promise as candidate biomarkers. Although these findings are preliminary, they warrant further investigation to evaluate their diagnostic and therapeutic relevance. Show less

Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood. APOEε4 carriers and APOEε3 homozygotes enrolled in the Women's Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß We identified and replicated a plasma proteomic signature associated with cognitive resilience among APOEε4 carriers. These proteins implicate specific immune processes in the preservation of cognitive status despite elevated genetic risk for AD. Future studies in diverse cohorts will be needed to assess the generalizability of these results. Show less

Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Show less

Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1-dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors. Show less

Neuronal ceroid lipofuscinoses (NCL) are lysosomal storage disorders characterized by the accumulation of lipofuscin within lysosomes. Late infantile (LINCL) and juvenile (JNCL) are their most common forms and are caused by loss-of-function mutations in tripeptidyl peptidase 1 (TPP1), a lysosomal endopeptidase, and CLN3 protein (CLN3p), whose location and function is still controversial. LINCL patients suffer more severely from NCL consequences than JNCL patients, in spite of having in common an abnormal accumulation of material with a similar composition in the lysosomes. To identify distinctive characteristics that could explain the differences in the severity of LINCL and JNCL pathologies, we compared the protein degradation mechanisms in patientś fibroblasts. Pulse-chase experiments show a significant decrease in protein degradation by macroautophagy in fibroblasts bearing TPP1 (CLN2) and CLN3p (CLN3) mutations. In CLN2 fibroblasts, LC3-II levels and other procedures indicate an impaired formation of autophagosomes, which confirms the pulse-chase experiments. This defect is linked to an accumulation of reactive oxygen species (ROS), an upregulation of the Akt-mTOR signalling pathway and increased activities of the p38α and ERK1/2 MAPKs. In CLN3 fibroblasts, LC3-II analysis indicates impairment in autophagosome maturation and there is also a defect in fluid phase endocytosis, two alterations that can be related to an observed increase of 0.5 units in lysosomal pH. CLN3 fibroblasts also accumulate ROS but to a lower extent than CLN2. TPP1 activity is completely abrogated in CLN2 and partially diminished in CLN3 fibroblasts. TPP1 cleaves small hydrophobic proteins like subunit c of mitochondrial ATP synthase and the lack or a lower activity of this enzyme can contribute to lipofuscin accumulation. These alterations in TPP1 activity lead to an increased ROS production, especially in CLN2 in which it is aggravated by a decrease in catalase activity. This could explain the earlier appearance of the symptoms in the LINCL form. Show less

Cbx1 is a dominant mutation of the bithorax complex (BX-C) of Drosophila partially transforming the second thoracic (T2) segment towards the third one (T3). Molecular analysis has shown that Cbx1 arose from a transposition within the BX-C of a DNA fragment of 17 kb containing pbx+ inserted into the Ubx area. In addition to the dominant phenotype, the Cbx1 mutation produces a set of recessive homeotic transformations that we show are characteristic of the Ubx mutations. We present evidence that the dominant and the recessive transformations arise from different mechanisms and suggest the dominant transformation is caused by an alteration of the normal regulatory role of pbx+ resulting in an adventitious expression of some Ubx+ products in T2, while the Ubx phenotype is caused by the breakpoint of the insertion. Show less