👤 Anna-Maria Mielke

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

Depressive symptoms are common in older adults and have been associated with the risk of Alzheimer's disease/Alzheimer's disease and related dementias (AD/ADRD), but the mechanisms and biomarkers underlying this association remain unclear. We included baseline data from 11,947 non-demented adults aged ≥ 70 years at enrollment in the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial. Linear regressions were used to examine cross-sectional associations between AD/ADRD blood-based biomarkers (BBMs) and baseline depressive symptoms. Interactions between sex or apolipoprotein E (APOE) ε4 carrier status and BBMs were examined. Higher glial fibrillary acidic protein (GFAP) was associated with higher depressive symptoms. We did not observe an association between amyloid beta 42/40 ratio, phosphorylated tau181, or neurofilament light chain with depressive symptoms; interactions between sex or APOE ε4 with depressive symptoms were not significant. In this large, community-based cohort of older adults, plasma GFAP was associated with greater depressive symptoms. Plasma glial fibrillary acidic protein was associated with depressive symptoms. Neuroinflammation may underlie depressive symptoms in this group. Future research is needed to examine sex differences in this association. Show less

Study DesignRetrospective Single-center propensity score-matched cohort study.ObjectiveAdjacent segment disease remains a major cause of revision surgery after multilevel lumbosacral fusion, and muscle-preserving approaches may help reduce this risk. This study compared clinical and radiographic outcomes between a muscle-preserving fusion combining standalone anterior plus lateral lumbar interbody fusion (A + LLIF) vs circumferential lateral plus posterior lumbar interbody fusion (L + PLIF).MethodsPatients who underwent multilevel lumbosacral fusion (2016-2023) with either A + LLIF or L + PLIF were included. L + PLIF patients with contraindications to standalone A + LLIF were excluded. Propensity score matching, based on age, BMI, PI-LL mismatch and stenosis severity, yielded 90 1:1-matched patients. The primary outcome was revision surgery. Secondary outcomes included spinopelvic alignment, cage subsidence, and perioperative metrics.ResultsBaseline characteristics were comparable between groups (mean age 57 ± 10 years; median fusion levels: 2 [range 2-4]). The 5-year cumulative incidence of revision surgery was significantly lower with A + LLIF (1/45 events; 2.2%) than with L + PLIF (14/45 events; 31.1%; Show less

Neuroprotective properties of estrogen have poorly translated to reduced neurodegeneration in clinical trials of systemic estrogen replacement therapy. To more directly assess biological processes associated with brain estrogen (estrone, estradiol) levels, we recruited 81 women (42 non-white) and 28 men (13 non-white) for cerebrospinal fluid (CSF) hormone, targeted proteomic, and volumetric brain analysis. In the mostly post-menopausal women, we found CSF estrogen levels to only modestly correlate with their corresponding plasma levels, and were additionally influenced by body mass index or age. CSF estrone was also correlated with a marker of Alzheimer’s disease (AD) neuropathologic change (CSF Aβ42/Aβ40), but this was not the case for the more biologically active CSF estradiol. Aptamer-based proteomic analysis of 1,075 CSF markers for inflammation, proteolysis, signaling, and DNA/RNA regulation revealed CSF estrogen levels to associate with alternative complement pathway proteins, and shifts observed in AD (apoE, RAGE). Parallel MRI analysis correlated higher CSF estrogen with smaller volumes of the brain somatosensory and posterior-medial networks without influence from cognition or neurodegeneration. Analysis using plasma estrogens only partially reproduced CSF estrogens’ biochemical correlates but provided inconclusive relationships with brain volume correlates. These findings highlight the association between CSF levels of the more biologically active estradiol and CSF inflammatory pathways involving AD risk genes as potential mechanisms linking hormone status to AD risks, and suggest caution in using CSF estrone or plasma estrogens when interpreting treatment or preventive studies. The online version contains supplementary material available at 10.1186/s12974-025-03657-3. Show less

Promising evidence indicates that treating hearing loss with hearing aids (HAs) could reduce dementia risk. We extend this evidence by investigating the effect of HAs on plasma biomarkers of Alzheimer's disease and related dementias (ADRD). We emulated two target trials using observational data from Australian participants of the ASPREE study. Eligible participants had self-reported hearing problems, no past HA use, and were dementia-free. HA prescriptions and frequency of HA use were measured by questionnaire. Phosphorylated-tau181 (pTau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid-β (Aβ) 42/40 were measured after approximately 6-8 years. We estimated the effect of new HA prescription (first target trial) and the frequency of HA use (second target trial) using targeted maximum likelihood estimation, with multiple imputation for missing data. Across imputed datasets, a median of 2842 eligible individuals were included (mean age 75 years, 48% female), with a median of 735 receiving a new HA prescription. Among survivors, the estimated mean differences comparing HA prescription and no HA prescription were 1.8 pg/mL (95% CI: -0.6, 4.1), 0.1 pg/mL (-7.8, 8.0), -2.2 pg/mL (-14.5, 10.1), and -0.7 (-2.6, 1.2) for the concentrations of pTau181, NfL, GFAP, and (Aβ42 × 1000)/Aβ40, respectively. Mean differences did not differ substantially across levels of potential baseline effect modifiers, including APOE-ε4 genotype and cognition. In community-dwelling older people with hearing loss and no dementia, we found minimal effects of HA prescription and frequency of HA use on plasma ADRD biomarkers after a 7-year follow-up. Show less

The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R-Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor-Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs. Show less