Journals
2025 EN
Capuano Ana W. · Sarsani Vishal · Tasaki Shinya
+8 more
Abstract INTRODUCTION Type 2 diabetes increases the risk of Alzheimer's disease (AD) dementia. Insulin signaling dysfunction exacerbates tau protein phosphorylation, a hallmark of AD pathology. However, the comprehensive impact of diabetes on patterns of AD‐related phosphoprotein in the human brain remains underexplored. METHODS We performed tandem mass tag–based phosphoproteome profiling in post mortem human brain prefrontal cortex samples from 191 deceased older adults with and without diabetes and pathologic AD. RESULTS Among 7874 quantified phosphosites, microtubule‐associated protein tau (MAPT) phosphorylated at T529 and T534 (isoform 8 T212 and T217) were more abundant in AD and showed differential associations with diabetes. Network analysis of co‐abundance patterns uncovered synergistic interactions between AD and diabetes, with one module exhibiting higher MAPT phosphorylation (15 MAPT phosphosites) and another displaying lower MAP1B phosphorylation (22 MAP1B phosphosites). DISCUSSION This study offers phosphoproteomics insights into AD in diabetes, shedding light on mechanisms that can inform the development of therapeutics for dementia. Highlights The risk of Alzheimer's disease (AD) dementia is increased among older adults living with diabetes. The patterns of AD‐related phosphoprotein in the human brain in older adults are differential among older adults living with diabetes. Microtubule‐associated protein tau phosphorylated at T529 and T534 (isoform 8 T212 and T217) showed differential associations with diabetes. Phosphosite co‐abundance networks of synergistic interactions between AD and diabetes were identified.
Journals
2025 EN
Acharya Vibha · Fan KangHsien · Snitz Beth E.
+5 more
Abstract INTRODUCTION Many complex traits and diseases show sex‐specific biases in clinical presentation and prevalence. METHODS To understand sex‐specific genetic architecture of cognitive decline across five cognitive domains (attention, memory, executive function, language, and visuospatial function) and global cognitive function, we performed sex‐stratified genome‐wide meta‐analysis in 3021 older adults aged ≥ 65 years (female = 1545, male = 1476) from three prospective cohorts. Gene‐based and gene‐set enrichment analyses were conducted for each cognitive trait. RESULTS We identified a novel genome‐wide significant (GWS) intergenic locus for decline of memory in males near RPS23P3 on chromosome 4 (rs6851574: minor allele frequency [MAF] = 0.39, P male = 4.10E‐08, β male = 0.19; P interaction = 3.76E‐04). We also identified a subthreshold GWS locus for decline of executive function on chromosome 12 in females near the NDUFA12 gene, involved in oxidative phosphorylation (rs11107823: MAF = 0.12, P female = 9.35E‐08, β female = 0.28; P interaction = 7.42E‐06). DISCUSSION Sex‐aware genetic studies can help in the identification of novel genetic loci and enhance sex‐specific understanding of cognitive decline. Highlights Our genome‐wide meta‐analysis of single variants identified two new genetic associations, one in males and one in females. The novel male association was observed with the decline of memory in the intergenic region near the RPS23P3 gene on chromosome 4. This intergenic region has previously been implicated in several brain and cognition related traits, including anatomical brain aging, brain shape, and educational attainment. The novel female‐specific association was observed with decline in executive function on chromosome 12 near the NDUFA12 gene, which is involved in oxidative phosphorylation. Sex‐stratified analyses offer sex‐specific understanding of biological pathways involved in cognitive aging.
Journals
2025 EN
Zhang Wei · Young Juan I. · Gomez Lissette
+6 more
Abstract INTRODUCTION Distinguishing between molecular changes that precede dementia onset and those resulting from the disease is challenging with cross‐sectional studies. METHODS We studied blood DNA methylation (DNAm) differences and incident dementia in two large longitudinal cohorts: the Offspring cohort of the Framingham Heart Study (FHS) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. We analyzed blood DNAm samples from > 1000 cognitively unimpaired subjects. RESULTS Meta‐analysis identified 44 CpGs and 44 differentially methylated regions consistently associated with time to dementia in both cohorts. Our integrative analysis identified early processes in dementia, such as immune responses and metabolic dysfunction. Furthermore, we developed a methylation‐based risk score, which successfully predicted future cognitive decline in an independent validation set, even after accounting for age, sex, apolipoprotein E ε4, years of education, baseline diagnosis, and baseline Mini‐Mental State Examination score. DISCUSSION DNAm offers a promising source as a biomarker for dementia risk assessment. Highlights Blood DNA methylation (DNAm) differences at individual CpGs and differentially methylated regions are significantly associated with incident dementia. Pathway analysis revealed DNAm differences associated with incident dementia are significantly enriched in biological pathways involved in immune responses and metabolic processes. Out‐of‐sample validation analysis demonstrated that a methylation‐based risk score successfully predicted future cognitive decline in an independent dataset, even after accounting for age, sex, apolipoprotein E ε4, years of education, baseline diagnosis, and baseline Mini‐Mental State Examination score.
Journals
2025 EN
Wei YuJung Jenny · Winterstein Almut G. · Schmidt Siegfried
+4 more
Abstract INTRODUCTION Whether prescription opioid exposure, duration, and dose are associated with cognitive function remains inconclusive. METHODS A longitudinal cohort among 3097 older adults with chronic pain and without dementia was conducted using Health and Retirement Study (HRS) linked to Medicare data from 2006 to 2020. Prescription opioid exposure, cumulative use for ≥ 90 days, and high‐dose use (≥ 90 morphine milligram equivalents [MME] daily) were assessed biennially. Memory score and dementia probability were derived from HRS cognitive measures and analyzed using linear mixed‐effects models. RESULTS Adjusted memory decline and dementia probability were not statistically different between patients with (vs. without) opioid exposure and between patients with cumulative use for ≥ 90 days (vs. < 90 days) but were higher between participants with high‐dose opioid use (vs. low‐dose) at the end of the follow‐up. DISCUSSION Prescription opioid exposure and duration were not associated, but high‐dose opioid use was associated with greater memory decline and dementia probability. Highlights Opioid use versus no use was not related to memory decline and dementia probability. Long‐term opioid use was not related to memory decline and dementia probability. High‐dose opioid use was related to greater memory decline and dementia probability.
Journals
2025 EN
Chen XuQiao · Zuo Xinxin · Becker Ann
+10 more
Abstract INTRODUCTION Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS‐AD). Our findings identified widespread dysregulation of the endolysosomal network (ELN) in DS and DS‐AD brains, driven by increased APP gene dose, hyperactivation of RAB5, and elevated levels of guanine nucleotide exchange factors (GEFs) for RABs 7 and 11. METHODS We investigated whether increasing APP gene dose and RAB5 hyperactivation contributed to neuropathogenesis and whether a clinically feasible intervention could reverse ELN changes. The Dp16 DS‐AD mouse model was treated with a mouse App ‐specific antisense oligonucleotide ( App ‐ASO) and Rab5 ‐specific ASOs targeting Rab5a and Rab5b . RESULTS App ‐ASO treatment normalized full‐length APP (fl‐APP) and its products, RAB5 activity, and downstream RABs 7 and 11 pathways. Rab5 ‐ASOs reduced RAB5 levels and restored endosomal Rab activity. Both ASO treatments mitigated DS‐AD‐linked pathologies. DISCUSSION These findings highlight ELN dysregulation in DS and the therapeutic potential of ASO‐based strategies targeting APP or Rab5 to counteract DS‐AD features. HighlightsApp ‐ASO treatment reduced the levels of APP and its products and normalized endosomal Rab activity and GEF levels in Dp16 mice. Administration of Rab5 ‐ASOs reduced RAB5 levels and normalized endosomal Rab activity and GEF levels in Dp16 mice. Both ASO treatments were well tolerated and mitigated APP‐linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, and synaptic protein loss. App ‐ASO or Rab5 ‐ASOs reversed established pathological phenotypes in Dp16 mice.
Journals
2025 EN
Wang Hong · Serap Monkul Nery Emel · Ardayfio Paul
+14 more
Abstract INTRODUCTION TRAILBLAZER‐ALZ 6 (NCT05738486) is a multicenter, double‐blind, ongoing phase 3b study in early symptomatic Alzheimer's disease. METHODS Participants ( n = 843) were randomized 1:1:1:1 (standard + three alternative donanemab dosing arms). Primary outcome was relative risk reduction (RRR) of amyloid‐related imaging abnormalities with edema/effusions (ARIA‐E) at 24 weeks assessed with Bayesian logistic regression. Amyloid plaque levels by positron emission tomography and serum donanemab pharmacokinetics were measured. RESULTS ARIA‐E frequencies for standard, modified titration, dose skipping, and C max arms were 23.7%, 13.7%, 18.6%, and 18.3%, respectively, at 24 weeks and similar at 52 weeks: 24.2%, 15.6%, 18.6%, and 18.8%, respectively. Modified titration met the 24‐week primary outcome with 94% probability of achieving ≥ 20% RRR versus the standard arm. Modified titration also had significantly lower ARIA‐E severity, but similar cumulative exposure and mean amyloid reduction compared to the standard arm. DISCUSSION Gradual up‐titration of dose significantly reduced ARIA‐E risk while demonstrating comparable pharmacokinetics/pharmacodynamics compared to standard dosing. Highlights In TRAILBLAZER‐ALZ 6, the amyloid‐related imaging abnormalities‐edema/effusions (ARIA‐E) frequency was 13.7% in the modified titration arm compared to 23.7% in the standard arm at week 24. The modified titration arm met the primary endpoint of ARIA‐E relative risk reduction at 24 weeks versus the standard arm. The modified titration versus standard arm at week 24 had comparable non‐ARIA‐E related safety profile, amyloid reduction, plasma phosphorylated tau217 reduction, cumulative exposure, and pharmacokinetics. Data at week 52 were consistent with week 24 results.
Journals
2025 EN
Miner Annalise E. · Groh Jenna R. · Farris Chad
+23 more
Abstract The goal of this paper is to introduce the hypothesis that white matter (WM) and vascular injury are long‐term consequences of repetitive head impacts (RHI) that result in a novel T2 fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging pattern. A non‐systematic literature review of autopsy and FLAIR studies of RHI‐exposed adults was first conducted as a foundation for our hypothesis. A case series of RHI‐exposed participants is presented to illustrate the unique FLAIR WM hyperintensities (WMH) pattern. Current literature shows a direct link between RHI and later‐life WM/vascular neuropathologies, and that FLAIR WMH are associated with RHI, independent of modifiable vascular risk factors. Initial observations suggest a distinctive pattern of WMH in RHI‐exposed participants, termed RHI‐associated WMH (RHI‐WMH). RHI‐WMH defining features are as follows: (1) small, punctate, non‐confluent, (2) spherical, and (3) proximal to the gray matter. Our hypothesis serves as a call for research to empirically validate RHI‐WMH and clarify their biological and clinical correlates. Highlights Repetitive head impacts (RHI) have been associated with later‐life white matter (WM) and vascular neuropathologies. T2 FLAIR MRI of RHI‐exposed participants reveals a potentially unique WM hyperintensity (WMH) pattern that is termed RHI‐associated WMH (RHI‐WMH). RHI‐WMH are characterized as (1) small, punctate, and non‐confluent, (2) spherical, and (3) proximal to the gray matter at an area anatomically susceptible to impact injury, such as the depths of the cortical sulci.
Journals
2025 EN
Maust Donovan T. · Davis Rachel C. · Muench Ulrike
+2 more
Abstract INTRODUCTION Coordinating care for people living with dementia (PLWD) requires understanding which clinicians deliver care and the settings of that care. METHODS We used the Medicare Carrier file to characterize the settings in which clinicians deliver care to PLWD, clinician types providing care, and whether clinicians record a dementia diagnosis. RESULTS A total of 1,934,318 PLWD received care from 783,225 unique clinicians in 2019; PLWD saw a median of eight clinicians (interquartile range 5, 14). The most common settings were office (74.8% of PLWD), emergency room (63.9%), inpatient hospital (52.1%), and skilled nursing facility (37.1%). In addition, 87.0% of PLWD received care from a primary care physician, 62.9% from a nurse practitioner, and 33.1% from a physician assistant. Of the clinicians providing care, 2.4% are psychiatrists, 1.7% are neurologists, and 0.5% are geriatric subspecialists. DISCUSSION Care for PLWD must be coordinated across multiple clinicians and settings, recognizing that few PLWD receive psychiatry, neurology, or geriatric subspecialty care. Highlights In 2019 the median Medicare beneficiary living with dementia saw eight different clinicians. Care of beneficiaries living with dementia is distributed across settings, with large percentages seen in each of the office, emergency room, inpatient hospital, and skilled nursing settings. Primary care physicians and nurse practitioners are the clinician types seen by the largest percentage of beneficiaries living with dementia. Geriatric subspecialist physicians account for less than 1% of the clinicians that provide care to beneficiaries living with dementia.
Journals
2025 EN
Tang Huilin · Donahoo William T · DeKosky Steven T.
+4 more
Abstract INTRODUCTION Whether reductions in glycated hemoglobin (HbA1c) levels and body mass index (BMI) mediate the association between glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and Alzheimer's disease and related dementias (ADRD) risk is unknown. METHODS This cohort study included 22,908 patients aged ≥ 50 years with type 2 diabetes (T2D) newly prescribed GLP‐1RA or other second‐line glucose‐lowering drugs (GLDs). Causal mediation analysis was used to estimate to what extent the effect of GLP‐1RAs on ADRD risk was attributable to lowering HbA1c or BMI. RESULTS Compared to other GLD users, GLP‐1RA users had significant reductions in HbA1c levels by 0.16% and BMI by 0.23 kg/m 2 , along with a 26% lower ADRD risk. The direct protective effect of GLP‐1RAs on ADRD risk persisted even after accounting for HbA1c and BMI reductions, with minimal mediation effects observed through these factors. DISCUSSION GLP‐1RAs reduce ADRD risk, largely independent of their effects on HbA1c and BMI. Highlights Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) were associated with reductions in glycated hemoglobin (HbA1c) and body mass index (BMI) compared to other second‐line glucose‐lowering drugs(GLDs). GLP‐1RA users were associated with a 26% lower risk of Alzheimer's disease and related dementias (ADRD) than other GLD users. The protective effect of GLP‐1RAs against ADRD in adults with type 2 diabetes (T2D) is largely independent of their effects on HbA1c and BMI.
Journals
2025 EN
Li Oceanna Yueran · Shin Steven · Zhou Sa
+2 more
Abstract INTRODUCTION Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative diseases (NDs). This study examined astrocytic contributions to neuropsychiatric symptoms (NPS), focusing on astrocytic protein activity and its relationship with NPS severity, accounting for clinical and pathological features of NDs. METHODS Cerebrospinal astrocytic proteins (glial fibrillary acidic protein [GFAP], chitinase‐3‐like protein 1 [YKL‐40], and aquaporin‐4 [AQP4]) from Alzheimer's Disease Neuroimaging Initiative (ADNI) (AD) and Parkinson's Progression Markers Initiative (PPMI) (PD) were analyzed using K‐means clustering. Six NPS domains, ND‐specific pathologies (amyloid‐beta/Aβ for AD, alpha‐synuclein/αSyn for PD), and nonspecific pathology (phosphorylated tau/ptau) were assessed. RESULTS In both samples, three astrocytic clusters were identified, and the “highYKL|lowOthers” cluster (high YKL‐40, low GFAP/AQP4) consistently showed lower ptau and NPS severity compared to the “highAll” cluster (high GFAP, YKL‐40, AQP4). In PPMI, the “highYKL|lowOthers” cluster also attenuated the relationship between αSyn and NPS compared to the “highAll” cluster. DISCUSSION Astrocytic activity relates to NPS, highlighting astrocytic proteins as potential therapeutic targets for NPS in NDs. Highlights Astrocytic protein clusters were linked to NPS severity in AD and PD cohorts. The “highYKL|lowOthers” cluster showed lower ptau and NPS severity than “allhigh” cluster in AD and PD cohorts. Astrocytic proteins may serve as therapeutic targets for managing NPS in NDs.