Journals
2025 EN
Torso Mario · Khosropanah Pegah · Chance Steven A.
+1 more
Abstract BACKGROUND This study evaluates the capability of cortical microstructural measures from diffusion magnetic resonance imaging (MRI) to predict progression from mild cognitive impairment (MCI) to dementia, compared to commonly used macrostructural measures. Identification of high‐risk individuals can support both clinical practice and trials. METHODS Structural and diffusion MRI scans of 826 participants from the National Alzheimer's Coordinating Center (NACC) were analyzed to extract macrostructural measures and three minicolumn‐related diffusivity metrics: AngleR, PerpPD + , and ParlPD. Kaplan–Meier survival analysis was used to investigate time to progression to dementia, with participants stratified by biomarker metrics. RESULTS Cortical diffusivity (PerpPD + in medial–temporal and connected regions) outperformed hippocampal volume, cortical volume, and cortical thickness in Kaplan–Meier survival analysis, predicting faster conversion to dementia. DISCUSSION Cortical microstructural measures from diffusion MRI provide powerful biomarkers for predicting progression from MCI to dementia, offering enhanced prognostic capabilities that could support earlier intervention strategies in clinical practice and improve the power of clinical trials. Highlights Cortical minicolumn‐related diffusivity metrics measure neurodegeneration. We compare the predictive value of magnetic resonance imaging (MRI) measures for mild cognitive impairment to dementia progression. Microstructural cortical disarray outperforms macrostructural markers. These results support using diffusion MRI biomarkers to identify and monitor at‐risk patients.
Journals
2025 EN
Tang Huilin · Donahoo William T. · DeKosky Steven T.
+5 more
Abstract INTRODUCTION This study assessed the heterogeneous treatment effects (HTEs) of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) on the risk of Alzheimer's disease and related dementias (ADRD). METHODS This target trial emulation study included adults (≥ 50 years) with type 2 diabetes (T2D) and newly prescribed a GLP‐1RA, SGLT2i, or other second‐line glucose‐lowering drugs (GLDs). A doubly robust learning approach was deployed to estimate the risk difference (RD) of ADRD and identify key subgroups. RESULTS Both GLP‐1RAs (RD, −1.5%) and SGLT2is (−1.7%) were associated with a reduced ADRD risk compared to other GLDs. Key subgroups were determined based on cardiovascular disease (CVD), cerebrovascular disease (CeVD), chronic kidney disease, and Hispanic ethnicity. Patients with CVD and CeVD had the greatest benefits from GLP‐1RAs (−4.8%) and SGLT2is (−4.6%). No overall difference was observed between GLP‐1RAs and SGLT2i. DISCUSSION These findings suggest the importance of personalized treatment in diabetes management regarding ADRD risk. Highlights Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) were associated with a decreased risk of Alzheimer's disease and related dementias (ADRD), while the protective association varied across subgroups defined by cardiovascular disease (CVD), cerebrovascular disease (CeVD), and chronic kidney disease (CKD). Similarly, sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) were associated with a decreased risk of ADRD, with the protective association varying among subgroups defined by CVD, CeVD, and Hispanic ethnicity. There was no difference between GLP‐1RAs and SGLT2is in the risk of ADRD.
Journals
2025 EN
Germann Jürgen · Amaral Robert S. C. · Tomaszczyk Jennifer
+34 more
Abstract INTRODUCTION Deep brain stimulation of the fornix (fx‐DBS) is being investigated for treatment of Alzheimer's disease (AD). The therapy aims at alleviating memory and cognitive circuit dysfunction. In preclinical models of AD, electrical stimulation of the memory circuit has demonstrated a possible disease‐modifying potential. Here we examined changes resulting from fx‐DBS in hippocampal atrophy and amyloid accumulation in AD patients with fx‐DBS. METHODS Repeated magnetic resonance imaging and positron emission tomography (PET) images acquired over the course of 12 months were used to assess changes in hippocampal volume in 36 ADvance trial patients compared to 40 matched untreated AD patients from the Alzheimer's Disease Neuroimaging Initiative, and in 10 separate patients with repeated flutemetamol PET and cerebrospinal fluid (CSF) markers. RESULTS We observed a reduction of hippocampal atrophy and amyloid beta (Aβ) PET binding, and an increase in the CSF Aβ/total‐tau ratio in DBS patients. DISCUSSION These findings highlight the potential of fornix deep brain stimulation to modify AD biomarkers and possibly progression in some patients. Highlights Fornix deep brain stimulation (fx‐DBS) is being investigated to treat Alzheimer's disease (AD). Results show that fx‐DBS modifies imaging and cerebrospinal fluid (CSF) markers. It reduces hippocampal atrophy and increases the amyloid beta/total‐tau CSF ratio. These findings highlight the potential of fx‐DBS to modify AD.
Journals
2025 EN
Wu ChaoYi · Chen Liu · Dickson John R.
+3 more
Abstract INTRODUCTION With the advent of Alzheimer's disease (AD)‐modifying and symptomatic treatments of demonstrated efficacy, enrolling participants as concurrent placebo controls in trials can become increasingly difficult. Synthetic controls have been proposed as a viable alternative to concurrent control groups, but their feasibility and reliability remain untested in AD studies. METHODS I‐CONECT trial, which evaluates conversational interactions on cognition, was used to test synthetic control methods. Data from the National Alzheimer's Coordinating Center‐Uniform Data Set was used to create synthetic‐controls for I‐CONECT participants using two methods: 1) case mapping and 2) case modeling. Efficacy estimates were compared between original versus synthetic‐controlled trials. RESULTS In parallel‐group designs, treatment effect sizes for the primary outcome were closely aligned between the original trial (β = 1.67) and synthetic control analyses (β = 1.40–1.65). For n‐of‐1 designs, the two methods showed high agreement in identifying treatment responders (Kappa = 0.75–0.82). DISCUSSION Synthetic control methods are feasible and reliable to create alternative controls in AD studies. CLINICAL TRIAL REGISTRATION NCT02871921. Highlights Synthetic control methods are feasible and suitable for evaluating treatment effects in various trial designs such as n‐of‐1, single‐arm, and parallel groups. Synthetic control methods can help replicate early‐phase Alzheimer's trials, informing go/no‐go decisions for larger‐scale studies. The choice of similarity algorithms is critical as it affects the quality of historical case mapping. The National Alzheimer's Coordinating Center‐Uniform Data Set (NACC‐UDS) provided an ideal pool for identifying historical cases with similar demographic, biological, and social characteristics to participants in trials, enabling the creation of synthetic control groups for Alzheimer's clinical research.
Journals
2025 EN
LudwigBorycz Elizabeth · Lee Heejin · Ryan Lindsay H.
+6 more
Abstract INTRODUCTION The number of cases of Alzheimer's disease and related dementias (ADRD) is expected to triple in the United States in the next three decades. Food insecurity may be a risk factor for cognitive decline. However, studies exploring the relationship between food insecurity and individual cognitive domains within the United States remain limited. METHODS Data came from 1410 participants from the nationally representative Health and Retirement Study. Food insecurity was assessed in 2013, and cognition was assessed using the Harmonized Cognitive Assessment Protocol in 2016. RESULTS The prevalence of food insecurity was 13.1%. After adjusting for all covariates, food insecurity was inversely associated with executive functioning (β = −1.47, 95% CI −2.65, −0.28) but not significantly associated with memory, language, visuospatial functioning, or orientation. DISCUSSION Further research is needed to understand how food insecurity may influence executive function over time and to explore potential underlying mechanisms for this association. Highlights After adjusting for age and sex with Bonferroni correction, food insecurity was inversely associated with scores on three of the five cognitive domains: memory (β = −2.67 95% CI −4.41, −0.94); executive functioning (β = −3.50 95% CI −4.62, −2.37); visuospatial (β = −3.18 95% CI −6.13, −0.24. After additional adjustment for other covariates, the inverse association between food insecurity and executive functioning remained statistically significant (β = −1.47 95% CI −2.65, −0.28). Other associations were attenuated and lost statistical significance.
Journals
2025 EN
Thapa Simrika · Anastassiadis Chloe · Vasilevskaya Anna
+13 more
Abstract INTRODUCTION Neuroinflammation, a key player in Alzheimer's disease (AD) pathogenesis, may be differentially involved in young‐onset (YOAD) compared to late‐onset (LOAD) AD. METHODS Using proximity extension assay technology, we examined 737 inflammatory markers in the CSF of 26 healthy controls (63.9 ± 8.7; 12♀), 57 patients with YOAD (60.8 ± 4.9 y/o; 40♀), and 33 with LOAD (76.6 ± 4.5 y/o; 18♀). We also assessed biomarkers of AD pathology (Aβ42, p‐tau181, t‐tau) and neurodegeneration (neurofilament light‐chain [NfL]). RESULTS Compared to controls, SCRN1 and MMP10 were increased in LOAD and YOAD, but 16 markers showed YOAD‐specific increases. Forty‐six markers were significantly associated with NfL. P‐tau181 and t‐tau mediated the association between inflammatory markers and NfL in YOAD. In LOAD we could not identify a direct or indirect relationship between neuroinflammation and neurodegeneration. DISCUSSION Using a proteomics approach, we observed an exacerbation of neuroinflammatory changes and a differential contribution of neuroinflammation to AD pathology and neurodegeneration in YOAD compared to LOAD. Highlights Olink's Proximity Extension Assay was used to compare the inflammatory profile of 26 healthy controls and 90 Alzheimer's disease (AD) patients. AD patients were further stratified into young‐onset (YOAD, n = 57) and late‐onset (LOAD, n = 33) AD. Cerebrospinal fluid (CSF) levels of MMP10 and SCRN1 were increased in both YOAD and LOAD, but 16 proteins were only increased in YOAD. Tau mediated the association between inflammatory markers and neurodegeneration in YOAD. Neuroinflammation may be differentially involved in the pathogenesis of YOAD compared to LOAD.
Journals
2025 EN
Nuytten Mieke · Voets Marieke · Debroux Eveline
+28 more
Abstract INTRODUCTION Pharmacological restoration of septin filament integrity has the potential to provide symptomatic benefit and disease modification in Alzheimer's disease (AD). METHODS REM127, a septin modulator, was assessed in mild‐to‐moderate AD (EudraCT: 2022‐000080‐43) in a phase 2a trial ( n = 14). Primary endpoints: safety and tolerability; exploratory endpoints: pharmacokinetics, cerebrospinal fluid (CSF) biomarkers, electroencephalography (EEG), and functional outcomes. RESULTS In participants on active therapy, dose‐dependent increases in serum aminotransferase were observed, leading to study discontinuation. CSF hyperphosphorylated tau (P‐tau181), endpoints reflecting synaptic function and cognitive outcomes, were changed significantly ( p < 0.05) to normal compared to placebo. DISCUSSION REM127 triggers off‐target liver adverse effects. Anticipated on‐target outcomes suggest septin modulation has symptomatic benefit and modifies processes underlying AD. Results are considered exploratory as statistical power is constrained due to the small sample size caused by early termination. Further investigation of the therapeutic concept using an optimized septin molecular glue with an improved safety profile is warranted. Highlights Septin 6/7 molecular glue REM127 was assessed in symptomatic participants with Alzheimer's disease (AD). REM127 triggers off‐target effects suggesting liver adverse effects. REM127 brain exposure was consistent with saturated target engagement. Biomarker and cognitive outcomes were changed consistent with therapeutic benefit. Septin modulation may restore synaptic function and mitigate pathology in AD.
Journals
2025 EN
LeMerise Lisette Gwendolyn · GuerreroGonzalez José · McVea Andrew
+8 more
Abstract INTRODUCTION Adults with Down syndrome (DS) accumulate amyloid beta (Aβ) plaques faster and earlier on average than neurotypical adults with sporadic Alzheimer's disease (AD). White matter (WM) microstructure characterized with diffusion tensor imaging (DTI) can indicate underlying architectural changes in longitudinal studies, suggestive of neurodegeneration. This study investigated relationships between DTI and Aβ in DS along the AD continuum. METHODS Using longitudinal amyloid Pittsburgh compound B positron emission tomography, Centiloid (CL) and DTI parameters were examined in 35 adults with DS ages 25 to 57. DTI measures of anisotropy and diffusivity were analyzed using tract‐based spatial statistics and permutation analysis of linear models, testing for significant correlation between the rates of change for CL and DTI. RESULTS All rates of DTI and Aβ changes were significantly related. Significant regions included the corpus callosum, corona radiata, and long‐association fibers. DISCUSSION Aβ burden is associated with widespread longitudinal WM changes in DS. This suggests WM microstructure alterations accompany amyloid accumulation. Highlights A Down syndrome–specific template was created. Longitudinal diffusion tensor imaging (DTI) and amyloid burden rates of change correlate. Longitudinal results show more significant regions than cross‐sectional results. DTI and amyloid changes were found over two timepoints, 3.7 years apart on average. DTI and amyloid‐PET offer greater sensitivity when tracking microstructural changes.
Journals
2025 EN
Lee Shan Y. · Diaz Valentina E. · Emanuel Olivia M.
+33 more
Abstract INTRODUCTION Glial fibrillary acidic protein (GFAP) may contribute to Alzheimer's pathology at early disease stages. GFAP moderation of Alzheimer's disease (AD)‐related neurodegeneration and cognition is unclear. METHODS We examined plasma GFAP moderation of AD biomarkers (amyloid beta [Aβ]‐positron emission tomography [PET][A]; plasma phosphorylated tau‐181 [p‐tau181][T 1 ]), neurodegeneration (plasma NfL[N plasma ]; structural magnetic resonance imaging [MRI][N MRI ]), and cognition (Cog memory ; Cog executive ) in two cohorts: University of California San Francisco (UCSF) ( N = 212, 91.0% non‐Hispanic/Latino White [NHLW], age = 74.7 [7.6] years, 75.9% cognitively unimpaired [CU]) and 1Florida Alzheimer's Disease Research Centers (1FLADRC; N = 582, 32.8% NHLW, age = 70.7 [8.5] years, 28.9% CU). RESULTS Plasma GFAP consistently moderated A–T 1 (UCSF: β = 0.46, p = 0.012; 1FLADRC: β = 0.12, p = 0.029). The association between elevated Aβ‐PET and increased (p‐tau) was strengthened at higher GFAP concentrations. In 1FLADRC, GFAP moderated T 1 –N plasma/MRI. In UCSF, GFAP moderated T 1 –Cog memory/executive and N MRI –Cog memory/executive . Higher GFAP consistently related to worse neurodegeneration and cognition (main effects). DISCUSSION Across demographically and clinically heterogeneous cohorts, plasma GFAP is a key moderator of AD and may help identify individuals at greatest risk of AD‐related neurodegeneration and cognitive decline. Highlights AD biomarkers were measured in two demographically and clinically distinct cohorts. Plasma GFAP moderated Aβ‐PET to p‐tau associations in both UCSF and 1FLADRC. Cohort‐dependent, GFAP moderated p‐tau to neurodegeneration and cognition associations. All moderations revealed strengthened disease associations with higher plasma GFAP. Plasma GFAP may help identify individuals at greatest risk of AD‐related decline.
Journals
2025 EN
Eratne Dhamidhu · Kang Matthew · Malpas Charles B
+11 more
Abstract INTRODUCTION Plasma biomarkers offer promise for improving the diagnosis of Alzheimer's disease (AD) and differentiating AD and other neurodegenerative disorders (NDs) like frontotemporal dementia (FTD) from primary psychiatric disorders (PPDs), particularly in younger patients. METHODS In this prospective study, we investigated plasma phosphorylated tau 217 (p‐tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in 341 unselected participants from a neuropsychiatry memory clinic, including AD ( n = 40), behavioral variant FTD (bvFTD) ( n = 15), PPD ( n = 69), other NDs, and controls. RESULTS Plasma p‐tau217 showed strong diagnostic performance for distinguishing AD from bvFTD (96% accuracy) and PPD (93% accuracy). NfL best distinguished all NDs from PPD, while GFAP did not bring additional value. Biomarker profiles using predefined cut‐offs and age‐adjusted z‐scores further clarified group differences. DISCUSSION Plasma p‐tau217 and NfL have strong diagnostic utility in real‐world, diagnostically complex cohorts. These findings support implementation of scalable blood‐based biomarkers to improve early and accurate diagnosis in memory clinical settings. Highlights Plasma p‐tau217 was significantly elevated in AD compared to other disorders. P‐tau217 distinguished AD from bvFTD with high accuracy. P‐tau217 distinguished AD from PPDs with high accuracy. NfL/p‐tau217 ratio and GFAP added limited diagnostic value compared to p‐tau217 and NfL. Findings support blood biomarkers in younger, real‐world clinical cohorts.