@article {pmid41217670,
year = {2025},
author = {Liu, ZY and Chen, GC and LaMonte, MJ and Kamensky, V and Evenson, KR and Shadyab, AH and Luo, J and Allison, M and Wild, RA and Going, SB and Eaton, CB and Stone, KL and Bea, JW and Seguin-Fowler, RA and Johnson, KC and Kaplan, RC and Rohan, TE and Wassertheil-Smoller, S and Qi, Q},
title = {Longitudinal transitions in sedentary behavior and physical activity in relation to all-cause and cause-specific mortality among postmenopausal women.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41217670},
issn = {2509-2723},
support = {K01HL129892/HL/NHLBI NIH HHS/United States ; R01HL060712/HL/NHLBI NIH HHS/United States ; R01HL140976/HL/NHLBI NIH HHS/United States ; R01-HL146132-01/HL/NHLBI NIH HHS/United States ; R01DK119268/DK/NIDDK NIH HHS/United States ; R01DK120870/DK/NIDDK NIH HHS/United States ; 5R01CA227122//Division of Cancer Epidemiology and Genetics, National Cancer Institute/ ; },
abstract = {To evaluate longitudinal transitions in sedentary behavior and physical activity for the associations with all-cause and cause-specific mortality (i.e., cardiovascular disease [CVD], cancer, respiratory, and Alzheimer's disease/dementia mortality) among postmenopausal women. This prospective cohort study included 58,168 multiethnic US postmenopausal women from the Women's Health Initiative Observational Study, who had self-reported data on various sedentary behaviors and recreational physical activity at baseline (Y0: 1993-1998; age range: 50-79 years) and after 6 years (Y6). According to sedentary time (≥ 8 h/day or not) or physical activity (≥ 8.5 MET-h/week or not) at Y0 and Y6 assessments, participants were grouped by transition in sedentary behavior (consistently non-sedentary, sedentary to non-sedentary, non-sedentary to sedentary, and consistently sedentary) or physical activity levels (consistently low, high to low, low to high, and consistently high). Over a median follow-up of 15.0 years (from Y6 to March 2019), 17,354 all-cause deaths occurred, ranging from 1336 respiratory to 5111 CVD deaths. Compared to the consistently non-sedentary group, the two groups with unfavorable transitions in sedentary behavior (i.e., from non-sedentary to sedentary or being consistently sedentary) both had a higher risk of all-cause mortality and mortality from CVD, cancer, and respiratory disease. Conversely, the two groups with favorable transitions in physical activity (i.e., transitioning to or maintaining high activity), as compared with the consistently-low activity group, both had a lower risk mortality from all causes and several specific causes. Significant interactions were observed between transitions in sedentary behavior and physical activity on the risk of all-cause and CVD mortality (P-interaction < 0.01). Specifically, unfavorable sedentary transitions were associated with an elevated risk only among women with unfavorable transitions in physical activity. Among US postmenopausal women, maintaining or transiting to a sedentary lifestyle over 6 years was associated with a higher risk of mortality, predominantly among those not achieving regular physical activity over the years.},
}

@article {pmid41217577,
year = {2025},
author = {Zheng, X and Xiang, Q and Dong, X and Shen, Y and Qu, T and Fang, W and Yang, H},
title = {Neural Stem Cell-conditioned Medium Protected Against Cognitive Dysfunction in APP/PS1 Mice.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {27},
pmid = {41217577},
issn = {1559-1182},
abstract = {More and more evidence suggested neural stem cell conditioned medium (NSC-CM) exhibited a protective effect on regenerative medicine. Our previous studies suggested that NSC-CM ameliorated Aβ2-35-induced SH-SY5Y cell apoptosis as the cell model of Alzheimer's disease (AD). Thus, we hypothesized that NSC-CM had the capacity of neuro-protecting against cognitive dysfunction in APP/PS1 mice. Male APP/PS1 mice aged 6 months as the animal model of AD were randomly assigned into two groups: the control group and NSC-CM treated group. A 100 μl NSC-CM or PBS (phosphate-buffered saline) was administered slowly by tail vein once a day for consecutive 7 days or 14 days. The new object recognition test (NORT) and open field test (OFT) were applied to test cognition and emotion. The levels of phosphorylated tau (p-Tau), NOD-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, and interleukin 1β (IL-1β) were measured by Western blot. The load of amyloid-β (Aβ) plaque was measured by thioflavin S staining while the expression of astrocytes was observed by immunofluorescence staining. NSC-CM not only significantly ameliorated cognitive and emotional dysfunctions of APP/PS1 transgenic mice but also reduced the Aβ plaque load as well as the level of p-Tau, accompanied by increased astrocyte phagocytosis and inhibiting the inflammatory activation of astrocytes as well as the levels of NLRP3, caspase-1, and IL-1β. NSC-CM might be the alternative and promising therapeutic intervention for treating AD.},
}

@article {pmid41217374,
year = {2025},
author = {Ursi, GZ and da Silva, MR and Nakakogue, LM and Fernandes, KBP and Bignardi, PR},
title = {Alzheimer Disease Patients Who Survived COVID-19 Have Rapid Disease Progression and a Higher Risk of Death at 5-year Follow-up: A Retrospective Cohort Study.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000700},
pmid = {41217374},
issn = {1546-4156},
abstract = {PURPOSE: Alzheimer disease (AD) is the most common neurodegenerative disorder, affecting millions worldwide. COVID-19 has increased the risk of acute complications and death for patients with AD, but the long-term effects on survivors have been little studied. Thus, given the potential role of SARS-CoV-2 in accelerating cognitive decline, this study aimed to assess the effect of COVID-19 on functional deterioration, AD progression, and mortality in these patients.

METHODS: This retrospective cohort study examined medical records of patients with mild to moderate AD treated at a public dementia clinic in southern Brazil between March 2020 and March 2025. Sociodemographic and clinical data were extracted, including COVID-19 status confirmed by molecular testing. AD progression was assessed using the Mini-Mental State Examination (MMSE) and the Katz Index. Multivariate statistical analyses were conducted to identify associations between COVID-19 infection and disease progression. Survival was described by Kaplan-Meier test and analyzed by Cox regression.

RESULTS: A total of 105 individuals with DA were included, of whom 28 (26.7%) were COVID-19 survivors during the follow-up period. COVID-19 patients showed rapid AD progression compared with the control group (OR 4.76; 95% CI: 1.04-21.7; P = 0.044). Likewise, SARS-CoV-2 infection decreased patients' functionality, as indicated by the Katz index (P=0.001). Functional impairment was observed in both mild and hospitalized cases of COVID-19. Hospitalized patients during COVID-19 demonstrated lower survival rates at the 5-year follow-up.

CONCLUSION: These findings suggest that SARS-CoV-2 infection may accelerate AD progression and reduce survival, particularly in cases requiring hospitalization. Future multicenter studies with large sample sizes are needed to confirm these findings.},
}

@article {pmid41217224,
year = {2025},
author = {Zhang, C and Tang, X and Wu, S},
title = {Saponin of Rhizoma Polygonati inhibits neuronal apoptosis and ameliorates cognitive deficits in Alzheimer's disease mice by modulating c-Abl/MST1 pathway.},
journal = {General physiology and biophysics},
volume = {44},
number = {6},
pages = {451-465},
doi = {10.4149/gpb_2025032},
pmid = {41217224},
issn = {0231-5882},
abstract = {Saponin of Rhizoma Polygonati (SRP) is a key bioactive component obtained from Rhizoma Polygonati, has neuroprotection, antioxidant and anticancer effects. This research aimed to explore whether SRP improves cognitive deficits in Alzheimer's disease (AD) mice. Behavioral testing was performed by the Morris water maze test. Histopathological changes and neuronal apoptosis in mouse hippocampus were observed by Hematoxylin-eosin, Nissl staining, and TUNEL staining. The impact of SRP on amyloid β-protein (Aβ) and neurofibrillary tangles (NFTs) production was determined by immunofluorescence and Glycine silver staining. Western blot detected c-Abl/Mammalian sterile 20 (STE20)-like kinase 1 (MST1) pathway, apoptosis-related protein, and Tau phosphorylation level. AD mice exhibit cognitive deficits compared to normal mice, and SRP ameliorates cognitive deficits. The hippocampal tissues of AD mice showed neuronal damage and apoptosis, with Aβ deposition, loss of Nissl bodies and formation of NFTs. SRP attenuated neuronal damage in AD mice, inhibited Aβ deposition and NFTs formation. Additionally, SRP blocked the c-Abl/MST1 pathway in AD mice. c-Abl inhibitor enhanced the neuroprotective effect of SRP in AD mice, while c-Abl agonist weakened this effect. SRP inhibits hippocampal histopathological damage and enhances cognitive ability in AD mice through blocking the c-Abl/MST1 pathway.},
}

@article {pmid41217024,
year = {2025},
author = {Godino, L and Battistuzzi, L and Varesco, L and Turchetti, D and Gentili, V and Chiari, P and Palese, A},
title = {Perspectives of Italian lay persons who would decline genetic risk information: "I think I'd be living in constant worry".},
journal = {Journal of genetic counseling},
volume = {34},
number = {6},
pages = {e70126},
doi = {10.1002/jgc4.70126},
pmid = {41217024},
issn = {1573-3599},
abstract = {This study explores lay public perspectives on intrafamilial genetic risk communication, focusing on individuals who hypothetically choose not to receive genetic information, a largely overlooked population in genetic counseling research. A nested cross-sectional online survey combining both closed- and open-ended questions was used. Quantitative data included sociodemographic characteristics, family functioning as measured with the SCORE-15, genetic literacy (score range 0-4), and preferences regarding whether participants would want to be informed of a genetic risk in their family across three hypothetical scenarios (Cystic Fibrosis, Hereditary Breast and Ovarian Cancer and early-onset Alzheimer's disease). These data were analyzed using descriptive and inferential statistics. Qualitative data, consisting of open-ended responses on the reasons for not wanting to be informed, were analyzed inductively through reflexive thematic analysis. Of the 609 lay participants, 44 (7.2%) expressed a hypothetical preference not to be informed of a genetic risk in their family. Qualitative analysis of their responses revealed four main themes: (1) worry about anxiety and emotional distress in oneself and loved ones; (2) protection against psychological harm; (3) probability, uncertainty, and skepticism about preventive medicine; and (4) worry about stigma. These findings highlight the emotional, ethical, and social complexity behind the decision to decline genetic risk information and underscore the need for strategies to encourage and facilitate intrafamilial genetic risk communication that goes beyond education alone.},
}

@article {pmid41216966,
year = {2025},
author = {Hovde, MJ and Maaser-Hecker, A and Bae, JS and Tanzi, RE},
title = {Inhibition of Acyl-CoenzymeA: Cholesterol Acyltransferase 1 promotes shedding of soluble triggering receptor on myeloid cells 2 (TREM2) and low-density lipoprotein receptor 1 (LRP1)-dependent phagocytosis of amyloid beta protein in microglia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70879},
doi = {10.1002/alz.70879},
pmid = {41216966},
issn = {1552-5279},
support = {//Freedom Together Fund/ ; T32 AG000222-31//Cure Alzheimer's Fund/ ; T32AG000222/AG/NIA NIH HHS/United States ; //NIH/ ; },
abstract = {INTRODUCTION: Lipid regulation is crucial role in Alzheimer's disease (AD) pathogenesis. In AD, microglia show elevated sterol O-acyltransferase 1/Acyl-coenzymeA: Choleseterol Acyltransferase 1 (SOAT1) expression, encoding Acyl-coenzymeA: Cholesterol Acyltransferase 1 (ACAT1), which produces cholesteryl esters (CEs) in lipid droplets. Inhibiting ACAT1 has been shown to reduce amyloid beta (Aβ) pathology, though the mechanism is unclear.

METHODS: We inhibited ACAT1 using avasimibe (AV) in wild-type, triggering receptor expressed on myeloid cells 2 (TREM2) knockout (KO), and low-density lipoprotein receptor related protein 1 (LRP1) KO mouse BV2 and human induced pluripotent stem cell-derived microglia and measured the impact on Aβ uptake to determine the mechanism through which the inhibition of ACAT1 enhances Aβ uptake.

RESULTS: ACAT1 inhibition increased LRP1 levels and soluble TREM2 (sTREM2) release via enhanced TREM2 cleavage by ADAM metallopeptidase domain 10/17 (ADAM10/17). KO of TREM2 or blockade of sTREM2 release prevented AV-enhanced Aβ uptake. This effect was rescued by recombinant sTREM2, but only when LRP1 was present.

DISCUSSION: ACAT1 inhibition promotes microglial Aβ uptake in a sTREM2- and LRP1-dependent manner, offering insights into novel therapeutic strategies for AD.

HIGHLIGHTS: Inhibition of ACAT1, the major enzyme that catalyzes cholesterol storage via esterification enhances microglia-mediated Aβ uptake. Increased Aβ uptake is dependent on the presence of both TREM2 and LRP1. Inhibition of ACAT1 increases cleavage of TREM2 via ADAM10/17 to release sTREM2. Treatment of microglial cells with sTREM2 rescues Aβ uptake in TREM2 KO BV2 cells. Inhibition of ACAT1 promotes Aβ uptake through increased shedding of TREM2, which enhances Aβ uptake through a LRP1-dependent mechanism.},
}

@article {pmid41216919,
year = {2025},
author = {Heikal, SA and Fawi, G and Khedr, EM and Othman, M and Moustafa, SA and Elsheikh, NG and Tawfik, HM and Elfarrash, S and Salama, S and Ali, EM and Hassanin, HI and Salama, M},
title = {The Egyptian Dementia Network (EDN): Baseline characteristics from the first dementia registry in an African Arab country.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70770},
doi = {10.1002/alz.70770},
pmid = {41216919},
issn = {1552-5279},
support = {//100 PhDs for Africa programme/ ; //UM6P- EPFL Excellence in Africa Initiative/ ; //American University in Cairo, Research Support/ ; },
abstract = {INTRODUCTION: Dementia is a growing public health challenge in low- and middle-income countries (LMICs) like Egypt, where data are scarce. The Egyptian Dementia Network (EDN) registry addresses this gap by capturing epidemiological, clinical, and environmental data across Egypt.

METHODS: In this multicenter study, 662 participants from six governorates were enrolled using standardized tools.

RESULTS: The cohort had advanced age (mean 68.3 years), low education (65.9% illiterate), and high comorbidities including hypertension (55%) and diabetes (23%). Alzheimer's disease (62%) and vascular dementia (23%) predominated. Only 24.4% received pharmacological treatment and 2.1% psychosocial support, highlighting care gaps. Household insecticide exposure (20.4%) was notable.

DISCUSSION: EDN demonstrates the feasibility of implementing a national dementia registry in LMICs, generating baseline insights into demographic, clinical, and environmental risks. In addition, registry-linked biosamples have enabled pilot multi‑omics and exposome analyses, underscoring its potential as a scalable scientific platform for future dementia research.

HIGHLIGHTS: Established Egypt's first national, multicenter dementia registry. Aimed to characterize dementia profiles and care gaps across diverse regions. Identified late-stage diagnosis and limited access to dementia interventions. Uncovered unique environmental risk factors relevant to the Egyptian context. Provides a foundation for policy, research, and improved dementia care in Egypt.},
}

@article {pmid41216912,
year = {2025},
author = {Sohrabpour, A and Sarovic, D and Zetterberg, H and Hämäläinen, MS and Baillet, S and Khan, S},
title = {Tracking electrophysiological signatures of Alzheimer's disease: a systematic review of multimodal studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70835},
doi = {10.1002/alz.70835},
pmid = {41216912},
issn = {1552-5279},
support = {//The David Cohen (DC) Biomagnetism Felloship/ ; 2023-00356//The Swedish Research Council/ ; 2022-01018//The Swedish Research Council/ ; 2019-02397//The Swedish Research Council/ ; 101053962//The European Union's Horizon/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//The Alzheimer's Drug Discovery Foundation/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Foundation/ ; FO2022-0270//The Erling-Persson Family Foundation/ ; UKDRI-1003//UK Dementia Research Institute/ ; R01NS104585/NH/NIH HHS/United States ; R01EB026299-05/NH/NIH HHS/United States ; CRC-2017-00311//CIHR Canada Research Chair of Neural Dynamics of Brain Systems/ ; 436355-13//Natural Sciences and Engineering Research Council of Canada/ ; 202503PJT-542788/CAPMC/CIHR/Canada ; //Canada Brain Research Fund (CBRF)/ ; /ALZ/Alzheimer's Association/United States ; //Brain Canada/ ; PS2023-0041//The Swedish Brain Foundation/ ; },
abstract = {We conducted a review of the electrophysiological manifestations of Alzheimer's disease (AD) as captured by electroencephalography (EEG) and magnetoencephalography (MEG), with a focus on tracking their evolution through disease progression. To link electrophysiological features to the underlying neurobiology of AD, we prioritized studies that integrated EEG/MEG with other data modalities, such as positron emission tomography (PET) imaging and/or fluid biomarkers (cerebrospinal fluid [CSF] or blood/plasma) of amyloid beta (Aβ) and tau. Our analysis contextualizes these findings within current mechanistic hypotheses of AD pathophysiology. A key highlight of the present review is that electrophysiological changes along the AD disease progression may follow a non-monotonic trajectory, underscoring a need for caution when developing biomarkers for early detection or staging the disease with non-invasive electrophysiology. We also discuss outstanding challenges in the interplay between AD pathology and electrophysiological dynamics. This review highlights the potential of multimodal approaches to refining our understanding of AD and improving its early diagnosis. HIGHLIGHTS: A systematic review of electrophysiological signatures of AD in multimodal studies. Existing findings are contextualized with AD pathophysiology and neurobiology. Electrophysiological signatures of AD evolve in a dynamic, non-linear fashion. α $\alpha $ oscillations show a non-monotonous behavior in different stages of AD progression. EEG/MEG biomarkers hold significant promise for the early detection/monitoring of AD.},
}

@article {pmid41216906,
year = {2025},
author = {Edwards, L and Gonzalez, AI and Thomas, KR and Smirnov, DS and Brenner, EK and Nation, DA and Chang, F and Blennow, K and Salmon, DP and Galasko, D and Bangen, KJ},
title = {Interactive effects of blood-brain barrier breakdown and Alzheimer's disease biomarker status on cognitive decline in older adults without dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70910},
doi = {10.1002/alz.70910},
pmid = {41216906},
issn = {1552-5279},
support = {//NIA/NIH/ ; AG062429//NIH P30/ ; R01 AG063782/AG/NIA NIH HHS/United States ; AG082726//NIH/NIA RF1/ ; SG-23-1038904 QC/ALZ/Alzheimer's Association/United States ; #2017-00915//the Swedish Research Council/ ; #2022-00732//the Swedish Research Council/ ; #AF-930351//Swedish Alzheimer Foundation/ ; #AF-939721//Swedish Alzheimer Foundation/ ; #AF-968270//Swedish Alzheimer Foundation/ ; #AF-994551//Swedish Alzheimer Foundation/ ; #ALZ2022-0006//Swedish Alzheimer Foundation/ ; #FO2024-0048-TK-130//Swedish Alzheimer Foundation/ ; FO2024-0048-HK-24//Swedish Alzheimer Foundation/ ; #ALFGBG-965240//Swedish government and the County Councils/ ; #ALFGBG-1006418//Swedish government and the County Councils/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//Zenith Award/ ; //La Fondation Recherche Alzheimer/ ; //Kirsten and Freddy Johansen Foundation/ ; JPND2019-466-236//European Union Agency for Cybersecurity/ ; //the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement/ ; #ALZ2022-0006//Hjärnfonden/ ; #FO2024-0048-TK-130//Hjärnfonden/ ; FO2024-0048-HK-24//Hjärnfonden/ ; RF1 AG082726/NH/NIH HHS/United States ; },
abstract = {INTRODUCTION: Some research suggests that blood-brain barrier (BBB) integrity is altered in Alzheimer's disease (AD). Few studies have examined markers of BBB integrity and their interactions with AD risk factors on multi-domain cognition.

METHODS: 83 older adults without dementia underwent lumbar puncture, apolipoprotein E (APOE) genotyping, and neuropsychological testing with up to 5 years of follow-up. Soluble platelet-derived growth factor receptor beta (sPDGFRβ) was measured in cerebrospinal fluid.

RESULTS: Higher baseline sPDGFRβ was associated with better cross-sectional attention, visuospatial, and executive functioning, but with steeper longitudinal decline in executive function. When considering AD risk status, higher sPDGFRβ was associated with faster longitudinal decline in all cognitive domains in biomarker-positive relative to biomarker-negative individuals and in language in APOE ɛ4-positive relative to ɛ4-negative individuals.

DISCUSSION: Elevated sPDGFRβ may increase risk of cognitive decline, particularly in individuals with a higher risk for AD. Future studies should explore mechanisms that contribute to these relationships.

HIGHLIGHTS: Cerebrospinal fluid (CSF) soluble platelet-derived growth factor receptor beta (sPDGFRβ) is a promising marker of blood-brain barrier (BBB) integrity. Higher sPDGFRβ was cross-sectionally associated with better cognition at baseline. Higher sPDGFRβ was longitudinally associated with steeper decline in cognition, particularly among amyloid beta (Aβ) 42/Aβ40+ individuals. CSF concentration of sPDGFRβ may predict cognitive decline in those with increased dementia risk.},
}

@article {pmid41216867,
year = {2025},
author = {McCoy, TH and Perlis, RH},
title = {Predicting hospice eligibility among dementia patients using language models.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70878},
doi = {10.1002/alz.70878},
pmid = {41216867},
issn = {1552-5279},
support = {R01MH123804//the National Institute of Mental Health/ ; U01MH136059//the National Institute of Mental Health/ ; R01MH120991//the National Institute of Mental Health/ ; },
abstract = {INTRODUCTION: Alzheimer's disease and related dementias (ADRD) are increasing in prevalence, and access to potential benefits of hospice care remains challenging. Large language models (LLMs), like GPT-4o, applied to electronic health records (EHRs) could support decisions by estimating mortality risk.

METHODS: We analyzed patients with ADRD diagnosis from two academic medical centers. GPT-4o was used to estimate 6-month mortality risk from discharge summaries without any retraining or preprocessing. We used Cox regression to assess associations between predictions and time to death.

RESULTS: Of 9872 individuals, 3563 (36%) died within 6 months. GPT-4o predictions stratified risk of death within 6 months (log-rank p < 0.001, area under the curve [AUC] = 0.79); predictions were strongly associated with mortality in Cox regression models (adjusted hazard ratio [aHR] = 31.02 95% confidence interval [CI] 27.44-35.08, p < 0.001) with similar results between sites.

DISCUSSION: GPT-4o can stratify mortality risk using routinely generated documentation, potentially facilitating hospice referral decisions, but more prospective work is needed.

HIGHLIGHTS: Large language models (LLMs) can estimate 6-month mortality in patients with dementia. GPT-4o estimates of mortality risk from discharge summaries were highly discriminative (area under the curve [AUC] = 0.79). Predictions may support hospice referral decisions.},
}

@article {pmid41216864,
year = {2025},
author = {Ray, S and Kumar, M and Chemparathy, DT and Dash, PK and Sil, S},
title = {HIF-1 Targeting Intervention Renders Protection From Alzheimer's-Like Pathology in a Humanized Mice Model of HIV Infection.},
journal = {Journal of extracellular vesicles},
volume = {14},
number = {11},
pages = {e70191},
doi = {10.1002/jev2.70191},
pmid = {41216864},
issn = {2001-3078},
support = {//UNMC Startup funds to S S/ ; R21AG069541/NH/NIH HHS/United States ; },
abstract = {HIV-associated neurocognitive disorders (HAND) affect 30%-50% of individuals living with HIV on combination antiretroviral therapy, with Alzheimer 's-like pathology as a potent comorbidity of HAND. Our previous studies have implicated hypoxia-inducible factor-1 alpha (HIF-1α) as a central regulator of HIV-1 Tat-mediated amyloid production in astrocytes, which are further released via astrocyte-derived extracellular vesicles (ADEVs), inducing synaptodendritic injury and Alzheimer's-like pathology in naive mice. Based on this premise, we hypothesized that ADEVs carrying HIF-1α-targeting small interfering RNA (siRNA) would alleviate HIV-1-induced Alzheimer's-like pathology and neurodegeneration in CD34+ NSG HIV-infected humanized mice. Intranasally administered mCherry-TSG101-tagged ADEVs in mice demonstrated efficacy of brain delivery, especially to the hippocampus and cortex. In CD34+ NSG mice infected with HIV-1, intranasal delivery of HIF-1α siRNA-loaded ADEVs suppressed HIF-1α, reduced amyloid precursor protein (APP), AβmoC64, Aβ fibrils, and hyperphosphorylated tau (pTau), dampened glial activation as indicated by reduced GFAP and IBA1 expression, and partially restored synaptic proteins, which were dysregulated due to HIV-1 infection. Trends of improvement were also observed in behavioural deficits in spatial memory, anxiety-like behaviour, and sensorimotor gating induced by HIV-1. These findings position HIF-1α as a pivotal mediator of HIV-associated Alzheimer's-like pathology and neurodegeneration in the CD34+ NSG mice and underscore the promising role of ADEV-mediated HIF-1α siRNA delivery as a non-invasive therapeutic strategy for HAND.},
}

@article {pmid41216853,
year = {2025},
author = {King, MW and Jacob, SM and Sharma, A and Lawrence, JH and Musiek, ES},
title = {Circadian rhythms and the light-dark cycle interact to regulate amyloid-beta plaque accumulation and tau phosphorylation in 5xFAD mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70885},
doi = {10.1002/alz.70885},
pmid = {41216853},
issn = {1552-5279},
support = {5R01AG054517/AG/NIA NIH HHS/United States ; 5T32GM008151//National Institutes of General Medical Science/ ; A2024031F//the BrightFocus Foundation/ ; },
abstract = {INTRODUCTION: Circadian rhythm disruption is an early symptom of Alzheimer's disease (AD), though it remains unclear how the light-dark (LD) cycle and the central circadian clock in the suprachiasmatic nucleus (SCN) influence AD pathobiology.

METHODS: We disrupted the SCN clock via deletion of Bmal1 in GABAergic neurons (VGAT-iCre; Bmal1 KO), crossed to the 5xFAD amyloid-beta (Aβ) model, and raised mice under LD or constant dark (DD) conditions. We examined circadian rhythms, sleep, Aβ plaques, and phospho-tau (p-tau) pathology, and gene expression.

RESULTS: VGAT-Bmal1 knockout (KO) mice showed weakened rhythms in LD and arrhythmicity in DD conditions. LD conditions promoted Aβ plaque accumulation in 5xFAD mice, while VGAT-Bmal1 deletion reduced amyloid precursor protein (APP) cleavage, Aβ plaque accumulation, and peri-plaque p-tau, and induced extracellular matrix (ECM) gene expression in LD, but not DD, conditions.

DISCUSSION: In 5xFAD mice, LD cycles interact with the central circadian clock to reinforce Aβ deposition, while central clock disruption or constant darkness unexpectedly mitigate plaque pathology.

HIGHLIGHTS: 5xFAD mice accumulate more Aβ plaque pathology when raised under standard LD conditions than when raised in DD conditions. VGAT-Bmal1 KO eliminates locomotor rhythms in DD conditions and weakens locomotor, sleep, and transcriptional rhythms in LD conditions. VGAT-Bmal1 KO; 5xFAD mice aged in LD conditions accumulated less total Aβ plaque and peri-plaque p-tau than their Cre- littermates. VGAT-Bmal1 KO had no effect onplaque pathology in mice aged in constant darkness. Amyloid precursor protein carboxy terminal fragments (APP-CTFs) were suppressed in VGAT-Bmal1 KO mice under LD conditions, suggesting reduced Aβ production. Transcriptomic analysis shows induction of AEBP1 in VGAT-Bmal1 KO, which regulates ECM genes and has been associated with AD pathology in humans.},
}

@article {pmid41216845,
year = {2025},
author = {Erani, F and Terao, CM and Cooper, S and Weigand, AJ and Bangen, KJ and Edmonds, EC and Coughlin, DG and Thomas, KR},
title = {Neuropsychiatric symptom phenotypes for early detection of risk in older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70869},
doi = {10.1002/alz.70869},
pmid = {41216845},
issn = {1552-5279},
support = {AARG-22-723000/ALZ/Alzheimer's Association/United States ; RF1AG082726//NIH/NIA/ ; RF1AG082726-S1//NIH/NIA/ ; P30AG062429//NIH/NIA/ ; R01AG063782//NIH/NIA/ ; K23NS120038//NIH/NIA/ ; },
abstract = {INTRODUCTION: We examined whether early neuropsychiatric symptom (NPS) patterns were associated with cognitive and neuropathologic changes.

METHODS: Latent class analysis within 20,599 cognitively unimpaired older adults in the National Alzheimer's Coordinating Center dataset identified NPS phenotypes. Progression to cognitive impairment, cognitive trajectories, and neuropathology across phenotypes were assessed.

RESULTS: Four NPS phenotypes were identified: (1) Low-All, (2) High-Depression, (3) High-Agitation/Anxiety/Irritability (hAAI), and (4) High-All. Risk of progression to mild cognitive impairment (MCI)/dementia differed across phenotypes (Low-All < High-Depression < hAAI < High-All, p < 0.001). High-All and hAAI showed the lowest baseline performance and lower practice effects on cognitive tests, while High-Depression had persistently lower attention scores. The hAAI group had greater amyloid and neuritic plaque burden and higher arteriosclerosis severity compared to other groups (p < 0.01) DISCUSSION: Higher global NPS, and those with high agitation, anxiety, and irritability, showed greater odds of cognitive decline than depressive symptoms alone, underscoring the potential prognostic utility of early NPS patterns in predicting cognitive decline.

HIGHLIGHTS: Identified four, data-driven neuropsychiatric symptoms (NPS) phenotypes in cognitively unimpaired older adults NPS phenotypes were differentially linked to progression, cognition, and pathology High-all and high-anxiety, agitation, and irritability had poorer baseline cognition NPS phenotypes may serve as early indicators of neurodegenerative disease risk.},
}

@article {pmid41216839,
year = {2025},
author = {Chen, J and Gao, L and Che, Z and Chen, S and Xue, C and Wu, H and Qi, W and Huang, Y and Fan, J and Zhong, Y and Zou, C and Li, Q and Liu, X and Zhang, B},
title = {Repetitive transcranial magnetic stimulation-driven modulation of unbiased functional connectivity in the supracallosal anterior cingulate cortex causally ameliorates information processing speed in amnestic mild cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70895},
doi = {10.1002/alz.70895},
pmid = {41216839},
issn = {1552-5279},
support = {2023-LCYJ-MS-11//Drum Tower Hospital, Medical School of Nanjing University/ ; RC2022-023//Nanjing Drum Tower Hospital/ ; BE2022679//Development Plan (Social Development) Project of Jiangsu Province/ ; 81701675//National Natural Science Foundation of China/ ; 82202812//National Natural Science Foundation of China/ ; 82330059//National Natural Science Foundation of China/ ; 82271965//National Natural Science Foundation of China/ ; WK2021Z06//Key Research Foundation of Wannan Medical College/ ; },
abstract = {INTRODUCTION: Amnestic mild cognitive impairment (aMCI) exhibits biased functional connectivity (FC) abnormalities impairing neural plasticity modulation. This study aimed to identify unbiased FC deficits using a brain-wide association study (BWAS) and investigate repetitive transcranial magnetic stimulation (rTMS)-driven plasticity restoration.

METHODS: BWAS identified unbiased FC-altered voxels (robustness-validated). Region-of-interest (ROI)-wise FC analysis localized disrupted circuits, which were modulated through precuneus-targeted rTMS. Effective connectivity (EC) tested whether the precuneus exerted a causal influence on these disrupted circuits. Correlation analyses linked FC plasticity to cognitive and clinical outcomes.

RESULTS: Eleven brain regions with 31 altered unbiased FC circuits were robustly identified, centered on the bilateral anterior cingulate cortex (ACC). rTMS causally restored FC in the right supracallosal ACC and postcentral gyrus, correlating with improved information processing speed (IPS). Remarkably, 80.77% (21/26) of aMCI responded clinically to rTMS.

DISCUSSION: This study first maps unbiased FC lesions in aMCI, confirming rTMS-mediated ACC plasticity causally enhances IPS. These findings inform network-targeted therapies to delay Alzheimer's disease (AD) progression.

HIGHLIGHTS: This is the first study to robustly map unbiased FC lesions in aMCI patients using a BWAS. rTMS causally restored FC in right supracallosal ACC in aMCI patients. FC and EC recovery demonstrated causal links to improvements in IPS and MoCA scores. Remarkably, 80.77% (21/26) of aMCI patients responded clinically to rTMS modulation.},
}

@article {pmid41216806,
year = {2025},
author = {Oveisgharan, S and Yu, L and Wang, Y and Yang, J and Vialle, R and Lopes, KP and Tasaki, S and Young-Pearse, TL and De Jager, PL and Petyuk, VA and Schneider, JA and Seyfried, NT and Bennett, DA},
title = {Amyloid beta binding partners in the brain tissue of older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70882},
doi = {10.1002/alz.70882},
pmid = {41216806},
issn = {1552-5279},
support = {P30AG10161/NH/NIH HHS/United States ; P30AG72975/NH/NIH HHS/United States ; R01AG17917. R01AG015819/NH/NIH HHS/United States ; U01AG072572/NH/NIH HHS/United States ; U01AG046152/NH/NIH HHS/United States ; R01AG088643/NH/NIH HHS/United States ; R01AG088643/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: The mechanism linking extracellular amyloid beta (Aβ) with intraneuronal tau tangles, pathological hallmarks of Alzheimer's disease (AD), is not understood; it was tested in the current study through Aβ binding partners.

METHODS: Data were from decedents of community-based clinical-pathological studies. Of 52 Aβ binding partners, suggested by non-human studies, levels of 34 together with total Aβ protein were quantified in the dorsolateral prefrontal cortex. Post mortem pathological assessment immunohistochemically quantified Aβ load and tau tangle density.

RESULTS: The strongest mediations between Aβ and tau tangles were observed for Ras-related C3 botulinum toxin substrate 1 (RAC1) and sodium/potassium-transporting ATPase subunit alpha-3 (ATP1A3), which collectively mediated 10.1% of the association between Aβ and tau tangles. In contrast, Aβ mediated >70% of the associations of matrix proteins with tau tangles.

DISCUSSION: Identification of Aβ binding partners that mediate the association between Aβ and tau tangles may provide new targets for AD treatment.

HIGHLIGHTS: RAC1 linked Aβ with tau tangles. ATP1A3 linked Aβ with tau. RAC1 and ATP1A3 collectively mediated 10.1% of the association between Aβ and tau. Aβ mediated >70% of the associations of matrix proteins, such as APOE, with tau.},
}

@article {pmid41216805,
year = {2025},
author = {Lopergolo, D and Gasparini, D and Bianchi, S and Pucci, B and Tripodi, D and Leoni, V and Chincarini, A and Sestini, S and Zetterberg, H and De Stefano, N and Mignarri, A},
title = {Miglustat in Alzheimer's Disease Associated With Heterozygous NPC1 Mutation: Exploratory Case Series and Preliminary Findings.},
journal = {European journal of neurology},
volume = {32},
number = {11},
pages = {e70419},
doi = {10.1111/ene.70419},
pmid = {41216805},
issn = {1468-1331},
support = {2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//Alzheimer Drug Discovery Foundation (ADDF), USA/ ; ADSF-21-831376-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831381-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831377-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-24-1284328-C//AD Strategic Fund and the Alzheimer's Association/ ; 22HLT07//European Partnership on Metrology/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; },
abstract = {INTRODUCTION: Several studies have previously demonstrated an increased risk of dementia and brain amyloid deposition in individuals with heterozygous NPC1 mutations. Moreover, in a recent study, we identified the first family with autosomal dominant late-onset Alzheimer's disease (AD) caused by a heterozygous NPC1 mutation. Unfortunately, there are currently no effective treatments available for this condition. Miglustat, which impacts the metabolism of oxysterols, has been shown to exert an anti-amyloidogenic effect in a human cellular model of AD.

METHODS: In our exploratory uncontrolled study, three patients from the previously published family were orally treated with miglustat for 12 months. They underwent monthly clinical evaluations and routine blood tests. Additionally, neuropsychological evaluations, brain amyloid-PET imaging, and biochemical analyses on plasma and CSF were performed.

RESULTS: All three patients achieved clinical stability, showed a sustained reduction in serum oxysterol levels, and experienced a marked decrease in brain amyloid burden.

DISCUSSION: Based on our preliminary observations and hypothesis-generating findings, along with the growing evidence suggesting AD as a lipid disorder, miglustat should be further tested in a larger cohort of heterozygous NPC1 mutated patients and probably evaluated as a potential disease-modifying treatment for AD.},
}

@article {pmid41216795,
year = {2025},
author = {Kim, BH and Seo, SW and Kim, J and Nho, K and , },
title = {Cerebrospinal fluid proteins in relation to longitudinal cognitive trajectories.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70894},
doi = {10.1002/alz.70894},
pmid = {41216795},
issn = {1552-5279},
support = {P30 AG010133/NH/NIH HHS/United States ; P30 AG072976/NH/NIH HHS/United States ; R01 AG081951/NH/NIH HHS/United States ; R01 LM012535/NH/NIH HHS/United States ; U01 AG072177/NH/NIH HHS/United States ; U19 AG074879/NH/NIH HHS/United States ; },
abstract = {INTRODUCTION: We investigated longitudinal cognitive trajectories in relation to cerebrospinal fluid (CSF) proteomics in Alzheimer's disease (AD).

METHODS: Differential protein abundance analysis of proteomics (SomaScan 7K) data was performed for composite scores for domain-specific cognitive functions (memory [MEM], executive function [EF], and language [LAN]) and their longitudinal changes in AD. This was followed by co-abundance network analysis, functional enrichment analysis, and machine learning to identify co-abundant protein modules, associated biological pathways, and prediction models of cognitive trajectories.

RESULTS: We identified proteins and pathways associated with composite scores for domain-specific cognitive functions and their longitudinal changes. Proteins related to MEM and EF were primarily enriched in microglia and oligodendrocytes, respectively. The prediction model for the trajectories of cognitive decline achieved an area under the curve of up to 0.79.

DISCUSSION: Our findings suggest protein signatures and their functional pathways associated with longitudinal changes for cognitive decline, providing molecular insights into longitudinal cognitive trajectories in AD.

HIGHLIGHTS: Altered cerebrospinal fluid (CSF) protein levels were associated with cognitive functions at baseline. Altered CSF protein levels were associated with changes of cognitive decline. Proteins associated with memory were primarily enriched in microglia. Proteins associated with executive function were enriched in oligodendrocytes. The prediction performance for cognitive trajectories was improved up to 30.9%.},
}

@article {pmid41216790,
year = {2025},
author = {Strell, P and Waldron, MA and Johnson, ST and Shetty, A and Crane, AT and You, Y and Steer, CJ and Low, WC},
title = {Characterization of the intraspecies chimeric mouse brain at embryonic day 12.5.},
journal = {Cell transplantation},
volume = {34},
number = {},
pages = {9636897251384571},
doi = {10.1177/09636897251384571},
pmid = {41216790},
issn = {1555-3892},
abstract = {Incidence of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis have increased dramatically as life expectancy has risen year-over-year, and can lead to neurologic changes. Neurological changes within the central nervous system, specifically the brain, include cell loss and deterioration that impact motor function, memory, executive function, and mood. Available treatments are limited and often only address symptomatic manifestations of the disease rather than disease progression. Cell transplantation therapy has shown promise for treating neurodegenerative diseases, but a source of autologous cells is required. Blastocyst complementation provides an innovative method for generating autologous neural cells. By injecting mouse induced pluripotent stem cells into a wild type mouse blastocyst, we generated a chimeric mouse brain derived of both donor and host neuronal and non-neuronal cells. At embryonic day 12.5 (E12.5), automated image analysis of mouse-mouse chimeric brains showed the presence of GFP-labeled donor-derived dopaminergic and serotonergic neuronal precursors. GFP-labeled donor-derived cholinergic precursor neurons and non-neuronal microglia-like and macrophage-like cells were also observed using more conventional imaging analysis software. This work demonstrates that the generation of mouse-mouse chimeric neural cells is possible; and that characterization of early neuronal and non-neuronal precursors provides a first step toward utilizing these cells for cell transplantation therapies for neurodegenerative diseases.},
}

@article {pmid41216660,
year = {2025},
author = {Foster-Powell, A and Meno-Tetang, G and Rostami-Hodjegan, A and Ogungbenro, K and Mager, DE},
title = {Translatability of Animal Models for Alzheimer's Disease Using a Machine Learning Based Workflow.},
journal = {Clinical and translational science},
volume = {18},
number = {11},
pages = {e70387},
doi = {10.1111/cts.70387},
pmid = {41216660},
issn = {1752-8062},
support = {/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
abstract = {Despite significant investment, no effective disease-modifying therapies for Alzheimer's disease (AD) have been developed to date. As understanding of the underlying causes of AD evolves, numerous animal models have been generated to study the disease. However, persistent therapeutic failures raise questions about the reasons for these shortcomings, including whether they stem from poor target selection and/or limitations in replicating key aspects of AD pathophysiology in animal models. In this study, a machine learning-based workflow previously reported in the literature was modified and used to identify shared dysregulation in phenotype-defining pathways across both animal models and human datasets-termed translatable pathways. This approach provided a framework for assessing the translational relevance of three widely used AD models: APP/PS1, 3×Tg, and 5×FAD, from hippocampal microarray data. The analysis suggested no translatable pathways in the APP/PS1 and 3×Tg preclinical models, whereas key pathways were identified in the 5×FAD (SREBP control of lipid synthesis and cytotoxic T-lymphocyte pathways) model. Additionally, applying the workflow to publicly available microarray data from ibuprofen-treated mice accurately predicted the clinical failure of ibuprofen for treating AD in human trials. This study highlights the importance of evaluating the translatability of animal models to human disease and provides a suitable framework for improving the selection of preclinical models in Alzheimer's research.},
}

@article {pmid41216328,
year = {2025},
author = {Mohammadi, S and Zarei, S},
title = {Predicting Alzheimer's disease from environmental risk factors: An fMRI-based functional connectivity and advanced machine learning approach.},
journal = {Journal of environmental health science & engineering},
volume = {23},
number = {2},
pages = {39},
pmid = {41216328},
issn = {2052-336X},
abstract = {Alzheimer's disease (AD) is a prevalent and severe neurodegenerative disorder influenced by both genetic and environmental factors-such as air pollution, toxic elements, pesticides, and infectious agents. In recent years, machine learning techniques have become essential in biomedical research, advancing fields like drug delivery and medical imaging through predictive modeling and pattern recognition. Functional connectivity derived from functional magnetic resonance imaging (fMRI) serves as a promising noninvasive biomarker for AD by mapping the brain's connectome and revealing neural network disruptions. In this study, we employed the Robust Multitask Feature Extraction Method to evaluate six supervised machine learning algorithms logistic regression, naïve Bayes, support vector machine, random forest, XGBoost, and CatBoostmfor AD diagnosis. A dataset of 140 fMRI images from an equal number of AD patients and healthy individuals (mean age 67.3 ± 6.7 years) was analyzed. The XGBoost algorithm demonstrated exceptional performance, achieving an accuracy of 98.2%, a recall of 96.6%, perfect precision (100%), an F1-Score of 98.2%, and a Matthews correlation coefficient of 0.96 effectively minimizing false positives and negatives. Although CatBoost and Random Forest also yielded robust results, logistic regression and naïve Bayes showed lower reliability. Overall, XGBoost emerges as a robust solution for the early and precise prediction of Alzheimer's disease, carrying significant implications for proactive patient care and treatment strategies. Beyond these findings, emerging research is exploring multimodal imaging techniques-such as PET and EEG and deeper neural network architectures to further enhance early diagnostic accuracy and treatment personalization in AD.},
}

@article {pmid41215901,
year = {2025},
author = {Sawmiller, D and Li, S and Mori, T and Habib, A and Rongo, D and Delic, V and Bradshaw, PC and Shytle, RD and Sanberg, C and Bickford, P and Tan, J},
title = {Corrigendum to "Beneficial effects of a pyrroloquinolinequinone-containing dietary formulation on motor deficiency, cognitive decline and mitochondrial dysfunction in a mouse model of Alzheimer's disease" [Heliyon Volume 3, Issue 4, April 2017, Article e00279].},
journal = {Heliyon},
volume = {11},
number = {14},
pages = {e43829},
doi = {10.1016/j.heliyon.2025.e43829},
pmid = {41215901},
issn = {2405-8440},
abstract = {[This corrects the article DOI: 10.1016/j.heliyon.2017.e00279.].},
}

@article {pmid41215663,
year = {2025},
author = {Guo, Z and Ni, H and Lu, Y and Cui, Z and Wang, Y and Zhu, Z and Wei, X and Xia, C and Xu, M and Du, L and Yang, Y and Shu, S and Wang, K and Wang, Z and Shan, C and Wang, D},
title = {TNEA Regulates Hippocampal Oscillation by Improving Inhibitory Synaptic Plasticity to Ameliorates Cognitive Impairment in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e10885},
doi = {10.1002/advs.202510885},
pmid = {41215663},
issn = {2198-3844},
support = {62127810//National Natural Science Foundation of China/ ; 82272612//National Natural Science Foundation of China/ ; 82374581//National Natural Science Foundation of China/ ; 21DZ2271000//Shanghai Key Laboratory of Health Identification and Assessment/ ; YC-2023-0604//Pudong New Area of Highland Discipline development program/ ; PWRq2023-36//Pudong New Area Outstanding Young Medical Professionals Training Program/ ; YC-2024-0104//Pudong Traditional Chinese Medicine Standardization & Capacity Building Project/ ; },
abstract = {Three-needle electroacupuncture (TNEA) has demonstrated efficacy in improving cognitive function in both Alzheimer's disease (AD) model animals and patients, although its underlying mechanism remains unclear. Here this work investigates the potential connection between cognitive-enhancing effect and TNEA in 5×familial Alzheimer disease（5xFAD) mice model, a model characterized by Amyloid-beta (Aβ) pathology. This work finds alterations in gamma/theta oscillations and deficits in inhibitory monosynaptic transmission in the hippocampal CA1 region of AD. Parvalbumin-positive (PV[+]) interneurons are crucial for generating gamma oscillations and modulating theta oscillation, thereby maintaining the excitation-inhibition (E/I) balance in local neural circuits. In 5xFAD mice, TNEA modulated PV[+] interneuron function, enhancing gamma oscillations during quiescent states. Furthermore, during the novel object recognition test (NORT), TNEA increased theta oscillation power by strengthening presynaptic inhibitory interneurons involved in monosynaptic connections. Collectively, these findings suggest TNEA is a viable minimally invasive treatment approach for AD.},
}

@article {pmid41215623,
year = {2025},
author = {Li, LL and Wang, RZ and Wang, Z and Hu, H and Xu, W and Zhu, L and Sun, Y and Chen, KL and Chen, SF and He, XY and Yuan, MY and Huang, YY and Liu, X and Liu, P and Ye, QY and Wang, J and Ju, ZZ and Zhang, W and Hu, B and Guo, Y and Cao, XY and Li, YX and Zuo, CT and Cheng, W and Jiang, T and Tan, L and Chen, XC and Zhao, QH and Cui, M and Peng, GP and Xin, JW and Yu, JT},
title = {Safety and short-term outcomes of lecanemab for Alzheimer's disease in China: a multicentre study.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf427},
pmid = {41215623},
issn = {1460-2156},
abstract = {Lecanemab is a newly approved monoclonal antibody targeting amyloid plaques for the treatment of early Alzheimer's disease. This study aimed to evaluate the safety and short-term biomarkers and cognition changes of lecanemab in Chinese clinical practice. This multicenter real-world study involved patients receiving lecanemab treatment across seven hospitals in China. Patients underwent comprehensive assessments before treatment. Lecanemab was administered via intravenous infusion every 2 weeks. Treatment-related symptoms were monitored through self-report, and amyloid-related imaging abnormalities were assessed via magnetic resonance imaging. Amyloid and tau biomarker changes were measured using positron emission tomography imaging or plasma testing. Follow-up cognitive assessments were evaluated after 6 months of treatment. Short-term outcomes were analyzed using linear mixed-effect models, without an untreated control group. A total of 407 patients who received at least one lecanemab infusion were involved in this study, with a mean follow-up time of 5.6±3.39 months. The mean age was 68.08 years, with 67.57% of patients being female. Of the participants, 56.51% were APOE ε4 carriers, and 83.19% were at biological stage C. During the study period, 22.22% of the patients experienced treatment-related symptoms, and 12.15% developed at least one amyloid-related imaging abnormality. Only four symptomatic and seven severe amyloid-related imaging abnormality cases were reported. APOE ε4 status was not related to adverse events in the Chinese population. Patients with a higher number of microhemorrhages at baseline were more likely to develop adverse events. No significant differences in adverse events were observed between the moderate Alzheimer's disease dementia group and the mild cognitive impairment group. By the end of the research period, 9.38% of the patients withdrew from lecanemab. After 6 months of treatment, favourable short-term outcomes in biomarkers and stable cognitive function were observed. This study demonstrates that lecanemab treatment is feasible and well-tolerated among the Chinese population, with lower rates of adverse events and favourable short-term outcomes observed. Administration of lecanemab in moderate AD dementia population was relatively safe and further studies are warranted.},
}

@article {pmid41215534,
year = {2025},
author = {Marshall, AG and Stephens, D and Neikirk, K and Masenga, SK and Shao, B and Crabtree, A and Vue, Z and Beasley, HK and Garza-Lopez, E and Scudese, E and Rodriguez, BI and Le, H and Damo, S and Taffet, GE and Ochayi, OM and McMillan, R and Afolabi, JM and Exil, V and Oliver, A and Sharma, V and Martin, P and Gaye, A and Harris, C and Tomeau, B and Bell, L and Hamilton, M and Gillyard, T and Webster, R and Jackson, M and Prakash, P and Frierson, S and Dash, C and Mungai, M and Kirabo, A and Gaddy, JA and Wandira, N and Hinton, A and Reddy, AK},
title = {Alterations in Cardiovascular Parameters in 5xFAD Murine Model.},
journal = {Cell biochemistry and function},
volume = {43},
number = {11},
pages = {e70138},
doi = {10.1002/cbf.70138},
pmid = {41215534},
issn = {1099-0844},
support = {//This study is supported by National Institute of Health (NIH) NIDDK T-32, number DK007563 entitled Multidisciplinary Training in Molecular Endocrinology to Z.V.; The Fogarty International Center and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health grants 2D43TW009744 and R21TW012635. The American Heart Association Award Number 24IVPHA1297559 (https://doi.org/10.58275/AHA.24IVPHA1297559.pc.gr.193866). The United Negro College Fund/Bristol-Myers Squibb E.E. Just Faculty Fund, Burroughs Wellcome Fund Career Awards at the Scientific Interface Award, Burroughs Wellcome Fund Ad-hoc Award, National Institutes of Health Small Research Pilot Subaward to 5R25HL106365-12 from the National Institutes of Health PRIDE Program, DK020593, Vanderbilt Diabetes and Research Training Center for DRTC Alzheimer's Disease Pilot & Feasibility Program to A.H.J. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript./ ; },
abstract = {Alzheimer's Disease (AD) is a global health issue, affecting over 6 million people in the United States, with that number expected to increase as the population ages. As a neurodegenerative disorder that affects memory and cognitive functions, it is well established that AD is associated with cardiovascular risk factors beyond only cerebral decline. In this study, we measured hemodynamic parameters related to cardiovascular and cerebrovascular function in 5xFAD mice with AD and their littermates. Specifically, we measured cardiovascular pulse wave velocity parameters, a marker of arterial stiffness and cardiovascular risk, and cerebrovascular pulse wave velocity, a novel technique to measure cerebral arterial stiffness. Our results showed that while 5xFAD mice exhibited significant differences in ejection time, pulse pressure, and Tei index, many other cardiovascular and cerebral parameters were not different. Despite reports that amyloid plaque deposition begins at an early age of 1.5 months in 5xFAD mice, our results did not indicate significant cardiovascular changes. Studies to elucidate cardiovascular and cerebrovascular parametric changes should be done at later ages where the underlying changes are more profound.},
}

@article {pmid41214981,
year = {2025},
author = {Mosele, JI and Manzano, JI and Sampayo-Rodríguez, SP and Iñiguez, M and Recio-Fernández, E and Yuste, S and Matute, PP and Motilva, MJ},
title = {Red wine (poly)phenols supplementation reduces amyloid-beta (aβ) pathology in APP/PS1 mice model: Possible implications of gut-brain axis explored by untargeted fecal metabolomics.},
journal = {Food research international (Ottawa, Ont.)},
volume = {221},
number = {Pt 3},
pages = {117484},
doi = {10.1016/j.foodres.2025.117484},
pmid = {41214981},
issn = {1873-7145},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder influenced by genetics and lifestyle. The Mediterranean diet, especially moderate red wine (RW) intake, may offer neuroprotection through (poly)phenols acting on amyloid pathology, neuroinflammation, and the gut-brain axis. This study evaluated RW and dealcoholized red wine (DRW) effects on hippocampal Aβ in APP/PS1 mice. DRW reduced Aβ40 and Aβ42, levels, with males showing greater sensitivity. Untargeted fecal metabolomics revealed DRW modulates sex-specific metabolic pathways. In males, enriched lipid and mitochondrial pathways were observed, while in females, DRW impacted broader networks, including nucleotide, TCA cycle, and hormone metabolism. Guanosine and estradiol phenylpropionate correlated with Aβ42 in females, indicating sex-specific mechanisms. Findings suggest RW components may attenuates AD pathology via amyloid reduction and metabolic modulation, being dose and sex dependent. This highlights the potential of gut-derived metabolites in mediating (poly)phenol-driven neuroprotection and the importance of personalized dietary approaches to AD.},
}

@article {pmid41214803,
year = {2025},
author = {Tranfa, M and Pieperhoff, L and Pontillo, G and Luckett, ES and Collij, LE and Oliveira, TG and Tesi, N and Vilor-Tejedor, N and Altmann, A and Roccatagliata, L and Pardini, M and Holstege, H and Reinders, M and Payoux, P and Martinez-Lage, P and Ritchie, CW and Waldman, A and Wardlaw, JM and Gispert, JD and Salvadó, G and Brunetti, A and Mutsaerts, HJMM and Wink, AM and Barkhof, F and Lorenzini, L},
title = {Polygenic pathways shape white matter vulnerability to Alzheimer's disease-related pathophysiological changes.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {240},
pmid = {41214803},
issn = {1758-9193},
support = {23AARF-1029663//Alzheimer Association Research Fellowship/ ; RYC2022-038136-I//State Research Agency grant/ ; 03-004-2020-T049//Dutch Heart Foundation/ ; 115736//EU/EFPIA Innovative Medicines Initiative (IMI)/ ; 101204296//MSCA postdoctoral fellowship/ ; },
abstract = {BACKGROUND: The accumulation of amyloid-β1-42 (Aβ1-42) peptides and phosphorylated-Tau181 (p-Tau181) tangles from the preclinical stages of Alzheimer's disease (AD) has led to a biological definition of the disease. However, among Aβ1-42-positive individuals, cognitive decline onset varies, and some never develop symptoms. Genetic influences on molecular pathways and their interactions with proteinopathy may underlie this heterogeneity. Leveraging data from a large sample of cognitively intact older adults in the European Prevention of Alzheimer Dementia (EPAD) cohort, we examined how AD-related pathophysiological changes (i.e., Aβ1-42 and p-Tau181), polygenic pathways and their interaction are associated with WM micro- and macrostructural properties.

METHODS: We selected 803 individuals (mean age = 64.7 ± 7.3 years, 458 [57.0%] females, 275 [34.2%] APOE-ε4 carriers) with CSF-Aβ1-42 and p-Tau181 measurements available, full genotyping, and structural and diffusion MRI. Polygenic risk scores (PRSs) were computed using 85 AD-related genetic variants. These were mapped to their corresponding genes and, after excluding those belonging to the APOE locus, clustered by function into six pathway-specific PRSs (i.e., immune activation, signal transduction, inflammation, lipid, amyloid, and clearance pathways). Diffusion MRIs were processed through the fixel-based analysis framework to derive fiber density (FD) and fiber cross-section (FC) metrics, which were averaged within WM tracts. Linear models assessed the effects of AD-related pathophysiological changes, global and pathway-specific PRSs, and their interactions on FD and FC at both the tract and fixel levels. Models were corrected for multiple comparisons.

RESULTS: P-Tau181 was primarily associated with greater FD. The lipid pathway was associated with greater FD and FC, with these effects predominantly occurring in the left hemisphere, consistent with evidence of hemispheric dominance. The clearance pathway moderated the effect of Aβ1-42 on FD, with a positive slope in A + compared to A- individuals. The immune activation pathway moderated the effect of p-Tau181 on FD, with a negative slope in T + compared to T- individuals.

CONCLUSIONS: Pathway-specific genetic vulnerability to AD is associated with alterations in WM tracts both directly and by moderating the effects of AD-related pathophysiological changes. AD-associated genetic risk should be integrated into the AD diagnostic framework to enable targeted screening and intervention for future preclinical trials aimed at specific biological pathways.},
}

@article {pmid41214767,
year = {2025},
author = {Cho, M and Ban, HJ and Nam, HR and Chu, CH and Jeon, JP and Kim, SC},
title = {A machine learning framework for classifying dementia risk in mild cognitive impairment: evidence from a Korean genome-wide association study cohort.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {241},
pmid = {41214767},
issn = {1758-9193},
support = {National Institute of Health (NIH) research project (project No. 2024-NI-010-00)//National Institute of Health, Korea Disease Control and Prevention Agency/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that presents challenges for early detection and intervention. Mild cognitive impairment (MCI), a critical precursor of AD, progresses to dementia in a substantial proportion of individuals annually. Genetic factors, particularly single nucleotide polymorphisms (SNPs), play a key role in the pathogenesis of AD, as identified by genome-wide association studies (GWAS). Therefore, we aimed to develop and evaluate predictive models for classifying patients with MCI into high- and low-risk groups for dementia using SNP chip data and machine learning (ML) algorithms.

METHODS: Using data from the Biobank Innovations for Chronic Cerebrovascular Disease with Alzheimer's Disease Study, we conducted a GWAS to identify dementia-associated SNPs in a Korean population cohort. The SNPs identified were used to train six ML algorithms-random forest (RF), k-nearest neighbor (KNN), artificial neural network (ANN), support vector machine (SVM), XGBoost, and LightGBM to predict dementia risk. Three predictive models were developed using different SNP subsets: Model 1 (54 SNPs, subjective cognitive decline [SCD] vs. AD + Vascular dementia [VD]), Model 2 (60 SNPs, SCD vs. AD), and Model 3 (76 SNPs, union set of SNPs from the AD vs. SCD and AD + VD vs. SCD). Performance was evaluated primarily using AUC and PR-AUC, which summarize discrimination independent of threshold choice. Thresholds were pre-specified within training folds using Youden's J (balanced sensitivity/specificity) and F1-max (converter-sensitive) criteria, and then applied unchanged to the temporally separated follow-up cohort.

RESULTS: In repeated cross-validation, boosting models achieved the strongest performance (e.g., Model 3, XGBoost AUC = 0.881 ± 0.074, PR-AUC = 0.924 ± 0.055). Probabilistic outputs were well-calibrated (Brier scores 0.116-0.183), and calibration plots confirmed good agreement between predicted and observed risks. In a temporally separated follow-up cohort (n = 61, 14 converters), discrimination was modest (AUROC approximately 0.45-0.55), reflecting limited power but showing consistent enrichment of events in predicted high-risk groups. Under F1-max thresholds, sensitivity was high (approximately 0.86-0.93) with NPV approximately 0.80-0.92, whereas specificity was modest (approximately 0.19-0.30) and PPV approximately 0.20-0.27, highlighting the trade-off between capturing converters and limiting false positives.

CONCLUSIONS: Our study highlights the potential of integrating genetic data with ML-based approaches for personalized dementia risk assessment. Although performance was modest in temporal validation, these findings support the feasibility of SNP-based ML stratification in Korean MCI populations.},
}

@article {pmid41214730,
year = {2025},
author = {Bergo, NJ and Lee, S and Siebrand, CJ and Mayeri, Z and Andersen, JK and Walton, CC},
title = {Detection of extracellular amyloid beta aggregates by an Aducanumab-based synNotch receptor: an in vitro proof-of-concept study.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1255},
pmid = {41214730},
issn = {1479-5876},
support = {RF1 AG068296/AG/NIA NIH HHS/United States ; R01 AG081989/AG/NIA NIH HHS/United States ; Diana Jacobs Kalman/AFAR Scholarships for Research in the Biology of Aging//Diana Jacobs Kalman/AFAR Scholarships for Research in the Biology of Aging/ ; },
abstract = {BACKGROUND: Synthetic Notch (synNotch) receptors are a powerful gene regulation platform that activate transcription in response to membrane-bound ligands and extracellular matrix components, with emerging applications in cancer, autoimmunity, and regenerative medicine. Whether synNotch can be adapted to detect and respond to extracellular neurotoxic protein aggregates-such as amyloid beta (Aβ), a hallmark of Alzheimer's disease (AD)-remains unknown.

METHODS: To address this, we engineered an Aβ-responsive synNotch receptor (Adu-synNotch) by fusing the single-chain variable fragment (scFv) derived from Aducanumab (Aduhelm®), an FDA-approved anti-Aβ antibody, to the extracellular domain of synNotch. This construct was expressed in NIH 3T3 cells and paired with downstream reporters CLIP-tag, secreted Metridia luciferase (MetLuc), and synthetic expression cassettes encoding chimeric human-mouse versions of the therapeutic antibodies Lecanemab (Leqembi®) and Aducanumab. Cells were exposed to Aβ(1-42) aggregates, and synNotch activation was assessed via CLIP-tag imaging, MetLuc secretion assays, and immunocytochemistry for Lecanemab and Aducanumab.

RESULTS: NIH 3T3 cells expressing Adu-synNotch responded to extracellular Aβ aggregates with robust induction of CLIP-tag and MetLuc reporters, along with secretion of chimeric Lecanemab and Aducanumab antibodies. Activation was dose-dependent and the secreted antibodies bound to Aβ aggregates, confirming that extracellular Aβ can serve as a functional synNotch ligand.

CONCLUSIONS: These findings establish that synNotch receptors can be engineered to detect and respond to pathological extracellular protein aggregates such as Aβ. This expands the scope of synNotch-based systems and supports their potential for developing precision cell-based therapies for neurodegenerative diseases like AD.},
}

@article {pmid41214536,
year = {2025},
author = {Li, P and He, Y and He, M},
title = {The comprehensive impact of exercise interventions on cognitive function and quality of life in alzheimer's disease patients: a systematic review and meta-analysis.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {871},
pmid = {41214536},
issn = {1471-2318},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and reduced quality of life. Exercise interventions are considered a promising non-pharmacological strategy to enhance cognition and well-being in AD patients. However, effects across different cognitive domains and quality of life remain unclear due to variations in study designs, intervention types, and outcome measures.

OBJECTIVE: This systematic review and meta-analysis evaluated the effects of exercise interventions on cognitive function, executive function, memory, and quality of life in AD patients by synthesizing evidence from randomized controlled trials (RCTs).

METHODS: We conducted a comprehensive search in PubMed, Embase, and Web of Science. Forty-five studies met inclusion criteria and were included in the quantitative synthesis. Primary outcomes included global cognition, executive function, memory, and quality of life. Meta-analyses were performed using standardized mean differences (SMD) and 95% confidence intervals (CI). Risk of bias was assessed via the Cochrane tool, and heterogeneity was quantified using the I² statistic.

RESULTS: Exercise interventions Significantly improved global cognition, with SMDs of 0.30 (95% CI: 0.17-0.43, p < 0.00001) for MMSE and 0.39 (95% CI: 0.08-0.70, p = 0.01) for MoCA, with low heterogeneity (I² = 36% and 0%). ADAS-Cog showed a small, non-significant effect (SMD = - 0.09, 95% CI: - 0.35 to 0.17, p = 0.49). Executive function (SMD = 0.13, p = 0.09) and memory (SMD = 0.09, p = 0.34) did not improve significantly. Quality of life improved significantly (SMD = 0.17, 95% CI: 0.03-0.31, p = 0.02; I² = 5%), measured using tools such as QOL-AD and Qualidem.

CONCLUSION: Evidence suggests that structured, multimodal exercise programs-combining aerobic (≥ 150 min/week), resistance (2-3 times/week), and balance training (2-3 times/week) for at least 12 weeks with individualized intensity-may improve global cognition and quality of life in Alzheimer's disease patients.},
}

@article {pmid41214481,
year = {2025},
author = {Wu, YE and Chen, WT and Wan, FJ and Tzeng, NS},
title = {Galantamine-Induced Akathisia in a Patient With Alzheimer Dementia.},
journal = {American journal of therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1097/MJT.0000000000002056},
pmid = {41214481},
issn = {1536-3686},
}

@article {pmid41214447,
year = {2025},
author = {Fu, JF and Robinson, T and Rodriguez Alonso, M and Francis Malave, A and Jutten, RJ and Properzi, MJ and Healy, BC and Thompson, JC and Del Carmen Montenegro, G and Thibault, E and Penney, D and Davis, R and Sperling, RA and Papp, KV and Johnson, KA and Price, JC and Rentz, DM},
title = {Higher Amyloid and Tau Burden Is Associated With Faster Decline on a Digital Cognitive Test.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70233},
pmid = {41214447},
issn = {2328-9503},
support = {P41EB01589/EB/NIBIB NIH HHS/United States ; P41EB030006/EB/NIBIB NIH HHS/United States ; R00AG081457/AG/NIA NIH HHS/United States ; P01AG036694/AG/NIA NIH HHS/United States ; R01AG046396/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: A 2-min digital clock-drawing test (DCTclock) captures more granular features of the clock-drawing process than the pencil-and-paper clock-drawing test, revealing more subtle deficits at the preclinical stage of Alzheimer's disease (AD). A previous cross-sectional study demonstrated that worse DCTclock performance was associated with higher Aβ and tau burden in older cognitively normal (CN) participants. This study investigates whether longitudinal changes in DCTclock performance are associated with amyloid-β (Aβ) and tau burden in preclinical AD.

METHODS: A total of 219 CN participants completed baseline and follow-up DCTclock assessments, baseline Aβ ([[11]C]PiB) and tau ([[18]F]Flortaucipir) PET imaging. Global Aβ and regional tau burden were estimated. Linear mixed models examined associations between longitudinal DCTclock and (1) Aβ, (2) tau, and (3) Aβ and tau burden, adjusted for age, sex, and education. Cognitive domain-specific performance and fine-grained features of DCTclock were analyzed.

RESULTS: Elevated baseline Aβ or tau was most strongly associated with accelerated decline in DCTclock performance, particularly in the Information Processing cognitive domain, with stronger associations noted for tau burden. The associations were driven by pen-stroke latency-related features. Participants without elevated Aβ or tau burden demonstrated improved performance in these latency features, suggesting practice effects.

INTERPRETATION: Longitudinal declines in DCTclock performance, especially in Information Processing involving speed and executive function, were linked to early Aβ and tau burden in preclinical AD. These findings highlight the potential of digital cognitive assessment tools for tracking disease progression and assessing therapeutic efficacy in clinical trials.},
}

@article {pmid41214238,
year = {2025},
author = {Mushtaq, U and Ahmad, B and Khanday, FA and Ahmad, M},
title = {CHI3L1: An Emerging Player in Neuroinflammation and Neurodegeneration.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {23},
pmid = {41214238},
issn = {1559-1182},
abstract = {Neuroinflammation is now being identified as the major factor in the development of various neurological disorders. It is a vital process in neurons and the brain that maintains homeostasis under normal and healthy conditions. However, in hyperactivated states, neuroinflammation can also go awry when microglia and astrocytes enter a toxic, reactive state that can release chemicals that damage neurons. When innate immune cells encounter pathogens, infection, cell debris, or misfolded proteins, they release certain chemokines and cytokines to eliminate the intruding particles and protect the brain. However, persistent inflammatory reactions are harmful and can lead to neurodegeneration by continuously releasing toxic chemicals and proteins. Chitinase-3-like protein 1 (CHI3L1), a secretory protein, is emerging as a key inflammatory molecule that is strongly upregulated during neuroinflammation and has been implicated in the pathogenesis of many diseases. The brain's activated astrocytes are the main source of CHI3L1 and are a dependable biomarker for inflammatory pathologies affecting the central nervous system (CNS), including neurodegeneration and autoimmune diseases. The protein has been implicated in many neurological disorders, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and others, mediating neuroinflammation and neurodegeneration. CHI3L1 has contrasting functions in the CNS and other tissues. While the protein promotes cell proliferation and migration in various non-neuronal cancers, at the same time, it simultaneously promotes neurodegeneration and apoptosis in the CNS. This paper reviews the current developments in our knowledge of the pathogenic role of the CHI3L1 protein in various neurological disorders.},
}

@article {pmid41214088,
year = {2025},
author = {Ryu, HU and Yeom, SW and Shin, BS and Kim, JS and Kang, HG},
title = {Long-term outcomes of successful cardiac resuscitation.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39323},
pmid = {41214088},
issn = {2045-2322},
abstract = {Studies examining long-term prognosis after successful cardiac resuscitation (SCR) are limited owing to the high mortality and challenges of long-term follow-up. Consequently, data regarding brain disorders are lacking. In this retrospective study, we examined the incidence of brain disorders following SCR and explored the association between various confounding factors using data from the South Korean National Health Insurance Service. Patients who underwent SCR between 2010 and 2017 were recruited, with washout/follow-up periods of 2/3 years, yielding 572 and 1,144 patients in the successful cardiac resuscitation and control groups, respectively, following propensity score matching. Hazard ratios and 95% confidence intervals for brain disorders (stroke, epilepsy, Alzheimer's disease, and Parkinson's disease) were estimated using multivariate Cox proportional hazards models. Patients who underwent SCR had a 1.82-fold higher risk of developing brain disorders (95% CI: 1.40-2.37) than controls. Hazard ratios were 1.68 (95% CI: 1.09-2.61), 2.37 (95% CI: 1.58-3.53), and 1.56 (95% CI: 1.02-2.40) for stroke, epilepsy, and Alzheimer's disease, respectively. However, for Parkinson's disease, the hazard ratio (1.35 [95% CI: 0.48-3.78]) was not statistically significant, likely due to the small sample (15 patients). This study confirmed the increased risk of brain disorders in patients who undergo SCR.},
}

@article {pmid41213966,
year = {2025},
author = {Massey, Q and Nihoyannopoulos, L and Zeidman, P and Warner, T and Bhatia, K and Gandhi, S and Lambert, C},
title = {Refining the diagnostic accuracy of Parkinsonian disorders using metaphenomic annotation of the clinicopathological literature.},
journal = {NPJ Parkinson's disease},
volume = {11},
number = {1},
pages = {314},
pmid = {41213966},
issn = {2373-8057},
support = {MR/R006504/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {The diagnostic precision of Parkinsonian disorders is not accurate enough. Even in expert clinics, up to one in five diagnoses are incorrect. Gold standard diagnosis is post-mortem confirmation of the underlying proteinopathy; however, many clinicopathological studies focus on either a single disease or frame analyses in one temporal direction that may underestimate the true extent of mis- and missed diagnoses. We identified 125 published clinicopathological studies since 1992, extracted phenotype information for ~9200 post-mortem cases, curated the data in a standardised machine-readable format and used this to develop a probabilistic model to quantify diagnostic likelihood based on clinical observations. We found diagnostic accuracy was highest for multiple system atrophy (MSA, 92.8%) and lowest for dementia with Lewy bodies (DLB, 82.1%). MSA and progressive supranuclear palsy were most frequently mis-labelled as Parkinson's disease (PD) in life (7.2% and 8.3% of cases), whereas the most common PD misdiagnosis was Alzheimer's (~7% cases). We calculated likelihood ratios for a large range of clinical phenotypes and demonstrated how these can be used to help refine and improve diagnostic accuracy. This work delivers a harmonised, open-source dataset representing over 30 years of published results and represents a key foundation for flexible predictive models that leverage different sources of information to better discriminate Parkinsonian disorders during the early and prodromal phases of the illness.},
}

@article {pmid41213934,
year = {2025},
author = {Huber, H and Arranz, J and Arslan, B and Leuzy, A and Kittel, O and di Molfetta, G and Benejam, B and Videla, L and Barroeta, I and Soriano, LDH and Maure-Blesa, L and Rodríguez-Baz, Í and Arriola Infante, JE and Illán-Gala, I and Bejanin, A and Montoliu-Gaya, L and Lleó, A and Carmona-Iragui, M and Alcolea, D and Blennow, K and Zetterberg, H and Fortea, J and Ashton, NJ},
title = {Plasma p-tau217 as a biomarker of Alzheimer's disease pathology in individuals with Down syndrome.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {9900},
pmid = {41213934},
issn = {2041-1723},
support = {H2020-SC1-BHC-2018-2020//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; 2326 - GRT-2024A//Fondation Jérôme Lejeune (Jérôme Lejeune Foundation)/ ; 23S06157-001//"la Caixa" Foundation (Caixa Foundation)/ ; 2017-00915, 2022-00732; 2023-00356, 2022-01018, 2019-02397//Vetenskapsrådet (Swedish Research Council)/ ; },
abstract = {Diagnosing Alzheimer's disease (AD) in adults with Down syndrome (DS), a population with a high genetically determined risk of AD, remains challenging. In this large observational study including n = 2329 samples from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) and euploid controls from the Sant Pau Initiative on Neurodegeneration (SPIN) with and without symptomatic AD, we investigate if the strong diagnostic performance of plasma p-tau217 observed in sporadic AD extends to the DS population. Plasma p-tau217 discriminated cognitively stable individuals with DS from those with AD dementia with an AUC of 0.96 (95% CI, 0.95-0.97), and from those with prodromal AD with an AUC of 0.90 (95% CI, 0.87-0.92). Amyloid β (Aβ) positive and Aβ negative individuals with DS were distinguished with an AUC of 0.95 (95% CI, 0.92-0.99). In this study, we demonstrate that plasma p-tau217 is highly accurate in detecting amyloid β positivity and predicting clinical progression in individuals with DS, outperforming other plasma biomarkers. These findings support its use as a reliable, noninvasive tool for early AD detection and management in individuals with DS.},
}

@article {pmid41213811,
year = {2025},
author = {Zheng, G and Yu, FF and Huang, Y and Mazumder, S and Vargas, SL and Unschuld, PG and Kagerer, SM and Li, X and Liu, J},
title = {Hippocampal Subfield Susceptibility Alterations in Mild Cognitive Impairment Revealed by 7T MRI.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9094},
pmid = {41213811},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Hippocampal magnetic susceptibility alterations may serve as early neurodegenerative biomarkers of Alzheimer's disease (AD), but subfield-level evidence in mild cognitive impairment (MCI) remains limited. This study utilizes submillimeter high-resolution quantitative susceptibility mapping (QSM) to investigate hippocampal subfield susceptibility changes in MCI.

MATERIALS AND METHODS: Thirteen individuals with MCI and thirteen cognitively normal controls (NC) underwent 7T MRI scans including Magnetization-Prepared Two Rapid Acquisition Gradient Echoes (MP2RAGE) and multi-echo Gradient Echo (GRE) imaging (for QSM). Visibility of hippocampal strata radiatum, lacunosum, and moleculare (SRLM) was assessed using a visual rating scale. Hippocampal subfields (CA1, CA2, CA3, dentate gyrus (DG), and subiculum (Sub)) were segmented, and magnetic susceptibility values (ꭓ) were extracted for each subfield. The susceptibility difference (Δꭓ) between DG and other subfields were also calculated. Associations between subfield susceptibility measures and cognitive performance were then assessed.

RESULTS: Qualitative analysis revealed a distinct hyperintense curved pattern in the hippocampus on the 7T QSM image, corresponding to the SRLM. In NC subjects, this pattern was clearly visible exhibiting consistently delineated boundaries, while it appeared blurred or absent in most MCI subjects. The visual rating results showed that NC subjects had significantly higher scores than MCI subjects (Hedges' g = 1.43, 95% confidence interval [CI; 0.60, 2.35], p = 0.003), with most NC subjects rated 3-4 and most MCI subjects rated 1-2. Quantitative analysis of hippocampal subfield susceptibility revealed significantly elevated susceptibility (ꭓ) in the left DG in MCI compared to NC (Hedge' g = 0.88, 95% CI [0.10, 1.72], p = 0.03), leading to reduced susceptibility contrast between SRLM and adjacent CA1-CA3 or DG. Furthermore, regional differences of susceptibility (Δꭓ) between key subfields (left CA1 vs. DG and Sub vs. DG) were significantly reduced in MCI, reflecting a loss of subfield contrast. These quantitative changes were significantly associated with lower cognitive performance, even when controlling for age.

CONCLUSIONS: 7T QSM reveals susceptibility changes in hippocampal substructures in MCI individuals, providing a potential early biomarker for AD.

ABBREVIATIONS: AD = Alzheimer's disease; Aβ = amyloid-beta; DG = dentate gyrus; HSF = Hippocampal Segmentation Factory; MCI = mild cognitive impairment; NC = normal controls; QSM = quantitative susceptibility mapping; SRLM = hippocampal strata radiatum, lacunosum, and moleculare; Sub = Subiculum.},
}

@article {pmid41213697,
year = {2025},
author = {Chen, J and Zhang, X and Chen, X and Yu, W and Jia, M and Zhu, L and Liu, Z and Hu, J},
title = {Effect of time-restricted feeding on cognitive dysfunction in Alzheimer's disease and the role of ApoE polymorphism: protocol for a randomised controlled trial.},
journal = {BMJ open},
volume = {15},
number = {11},
pages = {e099591},
pmid = {41213697},
issn = {2044-6055},
abstract = {INTRODUCTION: With the global ageing population accelerating, the prevalence of Alzheimer's disease (AD) continues to rise annually. However, the underlying mechanisms of AD remain unclear, and effective treatments are still lacking. Apolipoprotein E (ApoE) gene polymorphism and dietary habits are critical risk factors for AD. Time-restricted feeding (TRF), an intermittent fasting strategy that limits the daily window of food intake while maintaining nutritional balance, has garnered significant attention in recent years for its potential to improve cognitive dysfunction. This study aims to investigate the effect of TRF on cognitive improvement in AD patients within the context of genetic background and to explore the role of ApoE polymorphism in these mechanisms.

METHODS AND ANALYSIS: This single-centre, prospective, randomised, open-label, blinded-endpoint trial will recruit 160 patients with mild to moderate cognitive impairment due to AD from Peking University Shenzhen Hospital. Participants will be stratified based on ApoE genotype into ApoE4 non-carriers and ApoE4 carriers, then randomly assigned to either a TRF intervention group or a normal control group for a 24-month intervention period. The primary outcomes are changes in the Minimum Mental State Examination scale score, Montreal Cognitive Assessment scale score and Clinical Dementia Rating-Sum of Boxes scale score. Key secondary outcomes include the Activities of Daily Living scale score, blood AD biomarkers, lipid levels, ketone body levels and cerebral glutamate levels. Follow-up assessments will be conducted at baseline, 6, 12, 18 and 24 months.

ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the Research Ethics Committee of Peking University Shenzhen Hospital (Ethics No. 2024-151). Written informed consent will be obtained from all participants before the commencement of the trial. The findings will be disseminated through peer-reviewed publications.

TRIAL REGISTRATION NUMBER: ChiCTR2400092653.},
}

@article {pmid41213497,
year = {2025},
author = {Hu, K and Li, C and Liu, Y and Pan, C and Xie, P and Wen, L and Xu, H and Tang, Y and Zheng, P and Huang, Y},
title = {Arabinoxylan ameliorates memory deficits and amyloid pathology in male 5 × FAD mice via modulation of gut microbiota structure.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.11.010},
pmid = {41213497},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD), a prevalent neurodegenerative disorder, is primarily characterized by β-amyloid (Aβ) deposition. Current therapies alleviate symptoms but lack agents capable of modifying disease progression. Meanwhile, cross-regional studies indicate that AD patients exhibit disrupted gut microbiota composition, which is closely associated with cerebral molecular dysregulation. Building on this gut-brain connection, this study aimed to attenuate AD progression by targeting gut microbiota through microbially metabolized carbohydrates. Specifically, using 5 × FAD mice modeling AD pathology, we conducted 16S rRNA sequencing, targeted metabolomics of microbiota-derived metabolites, and bulk RNA sequencing experiments to investigate gut-brain axis alterations. Our results show that AD mice exhibited gut dysbiosis, depletion of short chain fatty acids (SCFAs), and transcriptomic dysregulation in the hippocampus, particularly affecting aging and synaptic plasticity-related genes. Dietary intervention with arabinoxylan significantly increased SCFAs-producing bacteria (Oscillospiraceae and Eubacterium_coprostanoligenes_group), elevated butyric acid, and thereby reversed expression levels of these aging and synaptic plasticity-related genes. Mechanistically, arabinoxylan alleviated AD-like symptoms by modulating the microbiota-gut-brain (MGB) axis; this beneficial effect occurred through enrichment of probiotic bacteria that produce SCFAs to regulate hippocampal synaptic plasticity genes. Collectively, this work proposes arabinoxylan as a novel prebiotic strategy and identifies candidate therapeutic targets for AD treatment.},
}

@article {pmid41213496,
year = {2025},
author = {Abdulkhaliq, AA and Alasiri, G and Almoghrabi, YM and Kim, B and Khan, J and Ajoolabady, A and Ren, J and Tuomilehto, J and Borai, A and Pratico, D},
title = {Role of TREM2 in neuroinflammation.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115547},
doi = {10.1016/j.expneurol.2025.115547},
pmid = {41213496},
issn = {1090-2430},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is cell surface transmembrane receptor of the TREM family, predominantly expressed on microglia within the central nervous system (CNS). Accumulating evidence has highlighted a critical role for microglial TREM2 in modulating inflammatory signaling pathways, thereby influencing the course of neuroinflammation - a central pathological hallmark of various neurodegenerative and CNS disorders. In this review, we aim to elucidate the molecular mechanisms by which TREM2 regulates neuroinflammatory processes, with a particular focus on the most recent advances in the field. A deeper understanding of TREM2-mediated signaling may uncover novel therapeutic targets and pathways with significant translational potential for treatment of CNS diseases.},
}

@article {pmid41213450,
year = {2025},
author = {Huang, Y and Han, M and Fu, Y and Wang, G and Kong, L and Mo, J and Cao, D and Chu, Z and Li, W},
title = {HY-021068 improves neuronal ferroptosis by activating Nrf2 signaling in APP/PS1 Mice and Aβ1-42-induced HT22 cells.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178349},
doi = {10.1016/j.ejphar.2025.178349},
pmid = {41213450},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unclear pathogenesis and no effective treatment methods. HY-021068 (HY), a novel class I drug, exhibits significant neuroprotective properties in ischemic brain injury. Recent studies suggest that neuronal ferroptosis may be a critical contributor to the onset and progression of AD. However, it is still unclear whether HY treatment has protective effects on AD by inhibiting ferroptosis. In this study, APP/PS1 double transgenic mice were used to investigate the effect and mechanism of HY in AD. In vitro, HT22 cells were stimulated with Amyloid β1-42 (Aβ1-42) (5 μM) to elucidate the therapeutic effect of HY and its potential mechanism. The present study indicated that HY treatment significantly improved cognitive dysfunction, enhanced synaptic integrity by upregulating PSD95 and Synapsin I, and reduced Aβ plaque load, APP, beta-secretase 1 (BACE1) expression, and Tau hyperphosphorylation. Furthermore, HY increased glutathione peroxidase 4 (Gpx4) and Cystine/glutamate transporter (xCT) levels, while reduced DMT1 and transferrin receptor expression, eventually inhibiting neuronal ferroptosis. Mechanistically, HY decreased reactive oxygen species (ROS) accumulation and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by elevating Nrf2, haem oxygenase 1 (HO1), and NAD(P)H quinone oxidoreductase 1 (NQO1) expression. The in vitro study also suggested that the Nrf2 inhibitor ML385 markedly diminished the protective effects of HY, while the Nrf2 activator dimethyl fumarate (DMF) resulted in a significant enhancement of HY's therapeutic effects in Aβ1-42-induced HT22 cells. Molecular docking and cellular thermal shift assay showed that HY had an interaction with Nrf2. These results suggested that HY could ameliorate AD-related cognitive decline and neuronal ferroptosis through activating Nrf2 pathway, positioning it as a promising therapeutic strategy for AD.},
}

@article {pmid41213445,
year = {2025},
author = {Arulchelvan, E and Vanneste, S},
title = {Accelerated long-term forgetting across neuropsychiatric disorders: A review of mechanisms and a neurobiological perspective of forgetting.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106461},
doi = {10.1016/j.neubiorev.2025.106461},
pmid = {41213445},
issn = {1873-7528},
abstract = {Accelerated long-term forgetting (ALF) is the rapid loss of newly-learnt information, typically noticeable after ~30minutes, and observed across diverse neuropsychiatric disorders including epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury, stroke, and genetic conditions such as 22q11.2 deletion syndrome. Traditionally, ALF has been attributed to impaired memory consolidation or acquisition, with emphasis on hippocampal dysfunction or epileptic activity. However, these explanations are insufficient, as ALF also occurs in individuals without hippocampal damage or seizure activity. This review critiques these historical perspectives and proposes a unifying framework: that ALF may, to some degree, stem from hyperactive intrinsic forgetting mechanisms, rather than solely impaired consolidation. Drawing from recent research on memory engrams, synaptic plasticity, and forgetting, the review highlights the role of synaptic remodelling, neurotransmission, glial cell activity, actin cytoskeleton dynamics, hippocampal neurogenesis, and dopaminergic signalling in modulating engram accessibility, and thus memory persistence. Disruption in these pathways - evident across multiple neuropsychiatric conditions - may converge to produce ALF as a shared cognitive symptom. This reframing suggests that ALF may in part represent a maladaptive form of active forgetting, driven by disease-specific disruptions to otherwise adaptive neurobiological processes. Furthermore, ALF is framed as one end of a broader "forgetting continuum," with downregulated forgetting contributing to memory persistence (in conditions such as PTSD, autism savant syndrome, or highly superior autobiographical memory) on the other. Understanding ALF through this lens may unify its presence across diverse conditions and open avenues for targeted therapeutic interventions that aim to modulate memory persistence by addressing the brain's intrinsic forgetting machinery.},
}

@article {pmid41213330,
year = {2025},
author = {Joho, D and Sato, K and Kumita, W and Saido, TC and Sasaki, E and Sasaguri, H},
title = {Advances in non-human primate models for Alzheimer's disease research.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {104984},
doi = {10.1016/j.neures.2025.104984},
pmid = {41213330},
issn = {1872-8111},
abstract = {Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. It is characterized by cognitive decline and brain pathology, including amyloid-β (Aβ) plaques, neurofibrillary tangles, and neuroinflammation. While rodent models have contributed to our understanding of a multiplicity of disease mechanisms, their limitations in replicating human age-related neurodegenerative diseases pose challenges for translating research findings to the clinical setting. The common marmoset (Callithrix jacchus), a small non-human primate, has emerged as a promising model for neuroscience and aging research. Age-related Aβ and tau pathologies develop naturally in the marmoset, which also possess a brain network organization, including a default mode network, that closely resembles that of humans. AD-related pathologies have also been experimentally induced in marmosets through injection of materials extracted from post-mortem brain tissue of AD patients. Recent advances in genome-editing technologies have enabled the development of marmoset models carrying familial AD mutations. These models offer new opportunities to investigate early pathological changes in the disease and to evaluate potential therapeutic agents. Taken together, these findings highlight the value of the marmoset as a translational model bridging the gap between rodent studies and human AD research.},
}

@article {pmid41213329,
year = {2025},
author = {Adachi, M and Banno, H and Inoue, H},
title = {Drug discovery research with the iPSC models of neurodegenerative diseases.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {104985},
doi = {10.1016/j.neures.2025.104985},
pmid = {41213329},
issn = {1872-8111},
abstract = {Induced pluripotent stem cells (iPSCs) are widely used in research because they can be used to create models of diseases with the same genomic background as in patients. Recently, it has become recognized that the use of iPSCs for screening can promote drug discovery research. Additionally, research is being conducted to develop high-quality models for drug discovery and to link translational research with clinical studies. The present work focuses on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), and broadly introduces the latest research using iPSCs, from disease mechanism studies to drug discovery research. In addition, clinical trials based on research with iPSCs have been conducted: bosutinib, ropinirole and ezogabine for ALS, WVE-004 and BIIB078 for ALS with frontotemporal dementia (ALS/FTD), and bromocriptine for familial AD. Finally, we also wish to mention screening studies utilizing artificial intelligence (AI).},
}

@article {pmid41213276,
year = {2025},
author = {Gurkan, G and Akdag, B and Erdogan, MA and Erbas, O},
title = {Comparative Evaluation of Imatinib and Nilotinib in a Streptozotocin-Induced Rat Model of Alzheimer's Disease : Neuroprotective, Anti-inflammatory, and Cognitive Outcomes.},
journal = {Journal of Korean Neurosurgical Society},
volume = {},
number = {},
pages = {},
doi = {10.3340/jkns.2025.0110},
pmid = {41213276},
issn = {2005-3711},
abstract = {OBJECTIVE: Alzheimer's disease is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) peptide aggregation, representing a major therapeutic target. Emerging evidence suggests certain chemotherapeutic agents may attenuate Aβ pathology.

METHODS: This study investigated the effects of Imatinib, a tyrosine kinase inhibitor with limited blood-brain barrier (BBB) penetration, and Nilotinib, with enhanced BBB permeability, in an intracerebroventricular streptozotocin (ICV-STZ) rat model of Alzheimer's disease. Outcomes included behavioral assessments (learning latency), hippocampal CA1 and CA3 neuronal counts, and brain concentrations of TNF-α, NF-κB, BDNF, and NRG-1.

RESULTS: ICV-STZ administration significantly elevated TNF-α and NF-κB levels and reduced BDNF and NRG-1 expression. Both Imatinib and Nilotinib mitigated these alterations, with Imatinib demonstrating greater efficacy despite its limited BBB permeability. Imatinib and Nilotinib reduced TNF-α and NF-κB levels, increased BDNF and NRG-1 expression, and significantly improved cognitive performance, with latency periods extending from 69.8 seconds in the disease model to 193.5 and 183.1 seconds, respectively.

CONCLUSION: Imatinib and Nilotinib ameliorated neuroinflammation, restored neurotrophic support, and improved cognitive deficits in a preclinical Alzheimer's disease model. These findings highlight the therapeutic potential of tyrosine kinase inhibitors, warranting further translational research in human studies.},
}

@article {pmid41213170,
year = {2025},
author = {Jin, W and Xu, Y and Wang, Z},
title = {Modeling Alzheimer's Disease Biomarkers' Trajectory in the Absence of a Gold Standard Using a Bayesian Approach.},
journal = {Statistics in medicine},
volume = {44},
number = {25-27},
pages = {e70283},
doi = {10.1002/sim.70283},
pmid = {41213170},
issn = {1097-0258},
support = {R01AG068002/AG/NIA NIH HHS/United States ; R01MH128085/MH/NIMH NIH HHS/United States ; },
abstract = {To advance our understanding of Alzheimer's Disease (AD), especially during the preclinical stage when patients' brain functions are mostly intact, recent research has shifted towards studying AD biomarkers across the disease continuum. A widely adopted framework in AD research, proposed by Jack and colleagues, maps the progression of these biomarkers from the preclinical stage to symptomatic stages, linking their changes to the underlying pathophysiological processes of the disease. However, most existing studies rely on clinical diagnoses as a proxy for underlying AD status, potentially overlooking early stages of disease progression where biomarker changes occur before clinical symptoms appear. In this work, we develop a novel Bayesian approach to directly model the underlying AD status as a latent disease process and biomarker trajectories as nonlinear functions of disease progression. This allows for more data-driven exploration of AD progression, reducing potential biases due to inaccurate clinical diagnoses. We address the considerable heterogeneity among individuals' biomarker measurements by introducing a subject-specific latent disease trajectory as well as incorporating random intercepts to further capture additional inter-subject differences in biomarker measurements. We evaluate our model's performance through simulation studies. Applications to the Alzheimer's Disease Neuroimaging Initiative (ADNI) study yield interpretable clinical insights, illustrating the potential of our approach in facilitating the understanding of AD biomarker evolution.},
}

@article {pmid41213085,
year = {2025},
author = {Studzian, M and Bobula, B and MacIver, MB and Bocian, R and Kobrzycka, A and Caban, B and Kowalczyk, T and Grebowski, J and Michlewska, S and Jankowski, MM and Tokarski, K and Kazmierska-Grebowska, P},
title = {Lamotrigine Restores Impairments in Theta Rhythms and LTP as Early Biomarkers of Aβ1-42-Induced Hippocampal Network Dysfunction.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0796},
pmid = {41213085},
issn = {2152-5250},
abstract = {Neuronal excitation/inhibition (E/I) imbalance, epileptiform activity, and synaptic dysfunction are present in individuals diagnosed with dementia, including sporadic Alzheimer's disease (sAD), even at early stages. These abnormalities are associated with altered neuronal oscillatory activity, as seen in EEG recordings of sAD patients and transgenic rodents. Hippocampal theta oscillations are crucial for sensorimotor integration, memory consolidation, and network coordination, and depend on synaptic and ionic mechanisms, including the Ih current, mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Lamotrigine (LTG), an HCN channel modulator, influences neuronal excitability and oscillations. Amyloid beta (Aβ) peptide, specifically Aβ1-42 form plays a key role in AD pathology, promoting hyperexcitability, synaptic dysfunction, and neurodegeneration, particularly in the hippocampus (HPC) and associative cortices. However, only a few electrophysiological studies have examined HPC theta in relation to early cognitive deficits in sAD animal models. Our first goal was to study the temporal progression of theta oscillations impairment following repeated unilateral intracerebroventricular (ICV) Aβ1-42 infusions in rats at 7, 14, and 21 days, in vivo and in vitro. Second, we assessed whether local LTG administration could restore theta oscillations and long-term potentiation (LTP) in this model. We found that: i) Aβ1-42 ICV infusions led to significant reductions in theta amplitude and power on days 7 and 14, with a complete loss by day 21; ii) LTG restored LTP and theta rhythms in terms of power and amplitude in HPC obtained from Aβ1-42-treated animals 14 days post-ICV infusion; iii) histological analysis confirmed neurodegeneration, Tau hyperphosphorylation, astrogliosis, increased number of parvalbimun positive (PV+) interneurons, and GluN2B receptor upregulation in HPC of Aβ1-42-treated animals 14 days post-ICV infusion. These findings suggest that hippocampal theta disruption may serve as an early biomarker of network dysfunction in sAD, and that LTG-mediated partial restoration of theta and LTP offers a potential early therapeutic strategy.},
}

@article {pmid41213082,
year = {2025},
author = {Jerez-Garrido, N and Jiménez-García, AM and Sánchez-Borda, D and Arias, N},
title = {Neuropsychological Diagnostic Tools in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0618},
pmid = {41213082},
issn = {2152-5250},
abstract = {Due to baseline differences in cognitive test performance and their variable capacity to predict progression from Mild Cognitive Impairment (MCI) to Alzheimer's disease (AD), this systematic review and meta-analysis aimed to identify the most frequently used neuropsychological tests and their predictive value. Given the high prevalence of MCI, identifying accurate diagnostic tools is crucial. This study examined cognitive test differences between MCI patients and healthy individuals in clinical studies. A random-effects meta-analysis was conducted to account for variability. To this end, a comprehensive search was conducted across PubMed, Scopus, ScienceDirect, and Cochrane databases. Of the 103 studies that met the inclusion criteria and were reviewed, 34 were excluded from the meta-analysis due to the absence of control groups, and 7 articles were excluded because there were not enough comparable studies to perform a meaningful analysis. The meta-analysis revealed significant cognitive impairment in global cognition, language, and emotional well-being. Some studies reported hippocampal atrophy and amyloid-β/tau deposition in MCI patients progressing to AD, while others found benefits from physical and cognitive training. These findings highlight the need for standardized cognitive assessments to identify MCI patients at risk of AD conversion and implement effective treatments. Nevertheless, this meta-analysis faced limitations due to missing patient data, including the MCI subtype and disease duration.},
}

@article {pmid41213069,
year = {2025},
author = {Lin, Y and Zhao, H and Meng, D and Wang, M},
title = {The Role of T Cells in Alzheimer's Disease.},
journal = {Critical reviews in immunology},
volume = {45},
number = {6},
pages = {53-67},
doi = {10.1615/CritRevImmunol.2025061107},
pmid = {41213069},
issn = {1040-8401},
abstract = {Alzheimer's disease (AD) is a global neurodegenerative disorder characterized by progressive cognitive decline. Its core pathology involves neurofibrillary tangles mediated by hyperphosphorylated tau protein and senile plaques formed by extracellular deposits of β-amyloid. As the global incidence of AD continues to rise, human health faces a serious threat. However, the complexity of its pathogenesis poses significant challenges to current prevention and treatment strategies. Recent studies reveal that T cells, as key components of the adaptive immune system, exhibit abnormalities in both quantity and function within the brains of AD patients. They infiltrate brain parenchyma through multiple pathways-including the blood-brain barrier, choroid plexus, and meningeal lymphatics-and are deeply involved in AD pathology. In this review, we first introduce recent discoveries in the pathogenesis of AD, including tau protein, β-amyloid plaques, and neuroinflammation. We then describe the immune mechanisms and infiltration pathways of T cells in AD. Finally, we focus on the mechanisms by which different T cell subtypes contribute to brain damage in AD, aiming to provide a theoretical foundation for developing AD therapies guided by neuroimmune homeostasis.},
}

@article {pmid41212845,
year = {2025},
author = {Campanelli, L and Sendoya, JM and Brody, S and Galeano, P and Do Carmo, S and Cuello, AC and Castaño, EM and Gonzalés-Jimenez, A and Verheul-Campos, J and Medina-Vera, D and de Fonseca, FR and Wernersson, R and Morelli, L},
title = {Correction: New insights into the molecular biology of Alzheimer's-like cerebral amyloidosis achieved through multi-omics approaches.},
journal = {PloS one},
volume = {20},
number = {11},
pages = {e0336509},
pmid = {41212845},
issn = {1932-6203},
abstract = {[This corrects the article DOI: 10.1371/journal.pone.0330859.].},
}

@article {pmid41212661,
year = {2025},
author = {Lin, L and Huang, H and Zhang, Y and Li, F and Yang, H and Su, F and Lei, J and Bergeron, MF and Li, F and Zheng, D and Zhao, H and Zhou, X and Wesson Ashford, J and Chen, D and Xiao, Y and Pei, Z},
title = {Utility of a contemporary digital cognitive-motor biomarker in Huntington's and Parkinson's diseases.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393639},
doi = {10.1177/13872877251393639},
pmid = {41212661},
issn = {1875-8908},
abstract = {BackgroundCognitive impairment significantly impacts the quality of life in patients with neurodegenerative disorders, including Huntington's disease (HD), Parkinson's disease (PD), and Alzheimer's disease (AD).ObjectiveThis study aims to assess the utility of MemTrax, a contemporary digital continuous recognition task platform originally developed for AD, as an effective tool for revealing cognitive and clinical motor impairments in HD and PD populations as aligned with respective disease staging.MethodsA total of 135 healthy controls, 131 HD, and 212 PD participants were included in the study. MemTrax metrics, recognition accuracy (MTx-%C), response time (MTx-RT), and a composite score (MTx-Cp) were correlated with clinical motor and cognition scales and disease staging.ResultsMemTrax metrics showed stage-dependent declines in both HD and PD. In HD, both MTx-%C and MTx-Cp decreased significantly from pre-HD stage to stage 2 (p < 0.001), showing negative correlations with motor impairment and cognitive scales. In PD, MTx-Cp declined across Hoehn and Yahr stages (1-4, p < 0.001), with strong negative correlations to Unified Parkinson's Disease Rating Scale Part III (UPDRS III) and positive links to Montreal Cognitive Assessment/Mini-Mental State Examination. Additionally, MTx-RT increased with disease progression and correlated positively with UPDRS III, indicating it could assess psychomotor slowing in PD (p < 0.01).ConclusionsMemTrax effectively captures cognitive-motor decline in HD and PD. The responsivity of MemTrax to the severity of these disorders extends its utility beyond AD, positioning MemTrax performance as a cross-disease digital biomarker for early detection in neurodegenerative diseases.},
}

@article {pmid41212655,
year = {2025},
author = {Cohen-Mansfield, J and Cohen, R},
title = {Evaluating the feasibility and perceived benefits of enhanced group activity kits for engaging persons living with dementia at home: A pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393479},
doi = {10.1177/13872877251393479},
pmid = {41212655},
issn = {1875-8908},
abstract = {BackgroundProviding meaningful activities to persons living with Alzheimer's disease or other dementias in home settings is challenging because it typically involves the expense of professionals instructing the caregivers. Enhanced group activity kits (EGAKs) have been shown to enhance the wellbeing of persons living with dementia (PLwD) in group settings.ObjectiveTo investigate the feasibility and potential benefits of EGAKs in one-on-one settings without the expense of visiting professionals.MethodsRecruitment started with 75 referrals, from nursing agencies, family caregivers' support groups, a health services organization for older persons and their families, and an occupational therapists WhatsApp group, resulting in 34 family caregivers from greater Tel Aviv and Jerusalem metropolitans, Israel, completing a baseline interview. From those who completed the baseline interview, 16 PLwD experienced EGAKs with facilitators (family members, formal caregivers, or friends). Facilitators completed EGAKs-related questionnaires and a post-EGAKs-use interview. This mixed methods study includes a quantitative analysis of the EGAKs' facilitators' perceptions of the extent of success and an inductive content analysis to identify EGAKs' benefits and potential outcomes.ResultsFor most PLwD, one-on-one EGAKs were perceived as successful, making PLwDs' and facilitators' shared time more interesting and enjoyable. Four EGAKs' use benefits emerged: Affecting mood, feelings, and emotions; Affecting cognition and behavior; Shifts in perceptions; and improving communication and relationship between the PLwD and facilitators.ConclusionsWhen used in a home setting, EGAKs are often feasible and are often perceived to increase PLwDs' engagement in activities and improve their wellbeing.},
}

@article {pmid41212653,
year = {2025},
author = {Vranceanu, AM and Szapary, CL and Cornelius, T and Monin, JK and Syme, M and Okereke, OI and Lyons, KS and Plys, E},
title = {Behavioral dyadic interventions in the context of Alzheimer's disease and related dementia: A call to action.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392184},
doi = {10.1177/13872877251392184},
pmid = {41212653},
issn = {1875-8908},
abstract = {Alzheimer's disease and related dementias (ADRD) affect persons living with dementia (PLWD) and care partners, often disrupting emotional well-being and relationship dynamics. Despite growing evidence of dyadic interdependence in dementia care, most psychosocial interventions remain individually focused, missing an opportunity to improve relational and health outcomes. Dyadic dementia interventions (DDIs) aim to support both members of the dyad through shared communication, coping, and mutual support. The primary objective of this review is to introduce the guiding principles of the CONFIDE-ADRD Roybal Center at Massachusetts General Hospital, as these provide a useful roadmap for advancing scalable, theory driven, and person-centered DDIs. We explore the promise and challenges of DDIs, including inconsistent application of theory, measurement difficulties, and barriers to recruiting dyads from a broad range of populations with disparities. Drawing from chronic illness models and dementia-specific programs, we propose a roadmap for building scalable, theory-driven DDIs grounded in mechanistic science. We introduce CONFIDE-ADRD as a national initiative providing funding, training, and expert consultation to accelerate DDI development. The Center's 14 guiding principles support person-centered, context-sensitive intervention design that targets both individual and relational mechanisms of change. As dementia care becomes increasingly relational and dynamic, robust dyadic approaches are critical to reducing care burden, strengthening relationships, and improving outcomes for both PLWD and care partners. Readers are encouraged to engage with CONFIDE-ADRD's resources and contribute to the advancement of dyadic dementia care research.},
}

@article {pmid41212652,
year = {2025},
author = {DuBois, KN and Pal, S and Reader, JM and Jackman, B and Perkins, MD and Khobeir, N and Bakulski, KM and Heidebrink, J and Hampstead, BM and Morgan, DG and Kanaan, NM},
title = {Evaluation of a panel of plasma biomarkers for Alzheimer's disease in a diverse research cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393405},
doi = {10.1177/13872877251393405},
pmid = {41212652},
issn = {1875-8908},
abstract = {BackgroundPlasma biomarkers show significant promise for Alzheimer's disease (AD) diagnostics and risk prediction, however, much less is known about how these assays perform in a diverse research cohort of older adults.ObjectiveTo compare plasma biomarkers with clinical diagnoses and assess variability by demographic factors in a diverse research cohort.MethodsAmong 331 University of Michigan Memory and Aging Project (UM-MAP) participants, plasma biomarkers (pTau-217, pTau-181, GFAP, NfL, Aβ42, Aβ40, t-Tau) were measured. Demographic information (age, sex, education, race) was self-reported. Clinical consensus phenotypes (dementia of the Alzheimer Type (DAT), mild cognitive impairment (MCI), cognitively unimpaired (CU) were based on neuropsychological assessments. Logistic regression with machine learning for model variable selection was used to compare participants by clinical phenotypes.ResultsComparing CU and DAT participants, areas under the curve (AUCs) from receiver operator characteristic curves of single biomarker models ranged from 0.74-0.89. Optimal performance (AUC 99.7) was observed from stepwise regression with backward selection, which identified pTau-217, GFAP, sex, education, APOE ε4 allele, and race as model variables. When comparing MCI and DAT participants, only pTau-217 differed significantly (AUC 0.80). pTau-181 and pTau-217 levels were higher in white participants than Black/African American participants across all clinical phenotypes.ConclusionsPlasma biomarkers demonstrate promise for improving diagnostic accuracy in diverse research cohorts. Incorporating demographic variables facilitates enhanced interpretability of biomarker levels and the development of reference ranges.},
}

@article {pmid41212651,
year = {2025},
author = {Alphin, KH and Suerken, CK and Rudolph, MD and Gaussoin, S and Lockhart, SN and Craft, S and Brinkley, TE},
title = {Obesity, cardiometabolic health status, and brain health in community-dwelling older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393500},
doi = {10.1177/13872877251393500},
pmid = {41212651},
issn = {1875-8908},
abstract = {BackgroundThough mid-life obesity is a known risk factor for dementia, how obesity in late life impacts brain health is not well understood, especially in the presence of comorbid risk factors like hypertension (HTN) and impaired glucose tolerance (IGT).ObjectiveWe investigated associations between obesity, neuroimaging measures, and cognition in middle aged and older adults, specifically testing whether higher body mass index (BMI), waist circumference (WC), and waist-to-hip ratio are associated with brain health independent of HTN and IGT.MethodsA total of 599 participants with brain MRI, cognitive testing, and anthropometric measurements were examined. Chi square and one-way ANOVA tests were performed to compare participant characteristics across BMI categories. Linear regression models assessed relationships between anthropometric, neuroimaging, and cognitive outcomes with and without adjustment for relevant covariates. We also explored interactions between anthropometric measures and APOE ε4 status and cognitive status.ResultsHigher BMI was associated with higher cerebral blood flow (CBF) in both white matter (β = 0.2294 ± 0.0431, p < 0.001) and gray matter (β = 0.0872 ± 0.0405, p = 0.032), higher free water (β = 0.0906 ± 0.0425, p = 0.034), lower fractional anisotropy (β = -0.0891 ± 0.0433, p = 0.040), and better global cognition (β = 0.022 ± 0.007, p = 0.002) and cognitive composite scores (ps < 0.01), independent of IGT and HTN. Similar associations were observed for waist circumference. Evidence of effect modification by APOE ε4 carrier status and cognitive status were found for white matter CBF, white matter hyperintensities, fractional anisotropy, and cognition.ConclusionsObesity measures are positively associated with better brain structure, function, and cognition in aging adults, highlighting the importance of managing body weight in older age to maintain optimal brain health.},
}

@article {pmid41212649,
year = {2025},
author = {Rokach, MS and Gershfeld-Litvin, A},
title = {Against nature: The experiences of parents caring for an adult child with young-onset dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393589},
doi = {10.1177/13872877251393589},
pmid = {41212649},
issn = {1875-8908},
abstract = {BackgroundYoung-onset dementia (YOD), diagnosed before age 65, most often appears as Alzheimer's disease (AD) or frontotemporal dementia (FTD). Compared to late-onset dementia (LOD), YOD poses distinct caregiving, emotional, and social challenges. While research has expanded, it has largely centered on spouses and children, leaving the experiences of parents caring for an adult child with YOD underexplored and in need of greater scholarly attention.ObjectiveThis study aims to investigate the unique experiences of parents caring for an adult child diagnosed with YOD.MethodsQualitative semi-structured interviews were conducted with 12 Hebrew-speaking Jewish Israeli parents who provided informal care to an adult child diagnosed with YOD. The sample included cases of FTD and dementia with Lewy bodies (DLB). Participants were recruited through purposive sampling, and the data were analyzed using thematic analysis.ResultsThematic analysis revealed three themes. The first, "The Diagnosis," captured parents' descriptions of the long and complex diagnostic process, from initial recognition of symptoms to the formal diagnosis. The second, "Parent-Child Relationship," reflected experiences of loss and shifting dynamics within the relationship. The third, "Assimilation Into the Caregiver Role," highlighted significant changes in personal identity alongside emotional, and practical caregiving challenges.ConclusionsCaring for an adult child with YOD involves a profound sense of loss and presents substantial challenges to parental identity, particularly as parents themselves age. These findings highlight the critical need for tailored interventions, improved communication, and strengthened support within healthcare and mental health systems to effectively address the unique needs of parent caregivers.},
}

@article {pmid41212647,
year = {2025},
author = {Hamdi, A and Stathopoulou, P and Gharbi, A and Saadouli, I and Najjari, A and Kacem, I and Ouzari, HI and Bel Mokhtar, N and Tsiamis, G and Gouider, R and Klibi, N},
title = {Salivary microbiome dysbiosis in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393229},
doi = {10.1177/13872877251393229},
pmid = {41212647},
issn = {1875-8908},
abstract = {BackgroundInvestigating human oral microbiota is now of great interest, being clinically significant for general and oral health. Many research studies have started to focus on the link between oral microbial dysbiosis and Alzheimer's disease. However, little is known about North African populations.ObjectiveWe aimed to distinguish the dissimilarity in the structure of microbial oral flora between the Alzheimer's disease patients and healthy controls in a Tunisian population.MethodsWe investigated the salivary microbiota using next-generation shotgun sequencing.ResultsThe overall structure of the oral microbial community of the Alzheimer's disease patient group was obviously different from the healthy control group. Significantly higher levels of Haemophilus (25.26%) were noticed in the AD group. However, Neisseria (10.17%) showed lower levels compared to the HC group. Considering the disease severity, Selenomonas and Aggregatibacter showed gradually higher levels as the disease progressed. Porphyromonas showed the highest levels in the mild stage of the disease, while Treponema, Selenomonas, and Peptostreptococcus were associated with severe stage. The presence of key taxa, Aggregatibacter and Selenomonas may constitute a dysbiosis signature in individuals with AD.ConclusionsThese findings may be of high relevance for orienting further studies on evaluating the physio-pathological process, confirming the implication of oral microbiota in AD and opening diagnostic and therapeutic avenues.},
}

@article {pmid41212646,
year = {2025},
author = {Song, W and Fang, M and Geng, Z and Pang, X and Yang, C and Chen, M and Song, B and Hu, C and Hu, Y and Hu, W and Zhou, S and Yan, Y and Wu, X and Wang, K},
title = {Mechanistic study of Alzheimer's disease with behavioral and psychological symptoms based on electroencephalography microstates.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393715},
doi = {10.1177/13872877251393715},
pmid = {41212646},
issn = {1875-8908},
abstract = {BackgroundBehavioral and psychological symptoms of dementia (BPSD) are common in Alzheimer's disease (AD), yet their mechanisms remain unclear.ObjectiveWe aim to explore the possible neurophysiological mechanisms of BPSD using high temporal resolution electroencephalography (EEG) microstate technology, laying the foundation for clinical evaluation and subsequent treatment.MethodsWe enrolled 52 AD patients (25 with BPSD, 27 without) and 29 age- and gender-matched healthy controls (HC). All participants underwent various neuropsychological assessments and resting-state EEG recordings. Resting-state EEG data were analyzed employing microstate analysis techniques, with a focus on four key microstate parameters: duration, occurrence, coverage, and transition probability. Inter-group comparisons were performed using post-hoc tests, with statistical significance determined through False Discovery Rate (FDR) correction. Furthermore, the correlations between the indicators and neuropsychological assessment scores were analyzed.ResultsCompared to the HC and non-BPSD groups, the BPSD group showed an increase in the transition rate from microstate A to microstate C. Compared to the HC group, the BPSD group showed an extension in the duration of microstate A and a decrease in the frequency of microstate D. Compared to the HC group, the non-BPSD group showed prolonged durations (A, B, mean) and reduced occurrences (C, D, mean).The partial correlation analysis with years of education as a covariate showed that in the BPSD group, the duration of microstate A was correlated with the severity of the Neuropsychiatric Inventory (NPI) and the Hamilton Anxiety Scale (HAMA).ConclusionsAD with and without BPSD exhibits different altered brain dynamics.},
}

@article {pmid41212591,
year = {2025},
author = {Jo, T and Lee, EH and , },
title = {Uncertainty-aware genomic classification of Alzheimer's disease: a transformer-based ensemble approach with Monte Carlo dropout.},
journal = {Briefings in bioinformatics},
volume = {26},
number = {6},
pages = {},
doi = {10.1093/bib/bbaf587},
pmid = {41212591},
issn = {1477-4054},
support = {P30 AG072976, U19 AG024904, U01 AG068057, U19 AG074879, U01 AG072177, U24 AG074855/NH/NIH HHS/United States ; AARG 22-974053/ALZ/Alzheimer's Association/United States ; },
abstract = {Alzheimer's disease (AD) has complex genetic factors that make accurate prediction from genomic data challenging. Current methods lack confidence estimates for their predictions. Our objective is to develop and evaluate an uncertainty-aware deep learning framework for AD prediction that can identify which predictions are reliable. We developed Transformer-based, Uncertainty-aware, Ensemble Network (TrUE-Net), a deep learning framework that combines transformer and random forest models to predict AD from whole-genome sequencing data. The key innovation is using Monte Carlo Dropout to estimate prediction confidence, allowing the model to identify cases where it is uncertain. We analyzed 1050 individuals (607 AD, 443 controls) from Alzheimer's Disease Neuroimaging Initiative cohort. On 525 test samples, accuracy of TrUE-Net without uncertainty threshold was 65.1% with area under the receiver operating characteristic curve 0.664. Using uncertainty thresholds, the model classified 75.4% of samples (n = 396) as 'uncertain' and 24.6% (n = 129) as 'certain'. The uncertain group showed accuracy of 62.6% and F1 of 0.584, while the certain group showed accuracy of 72.9% and F1 of 0.821. Uncertainty quantification through Monte Carlo Dropout provides a framework for assessing prediction reliability in genomic AD classification, potentially allowing more informed interpretation of model outputs.},
}

@article {pmid41212562,
year = {2025},
author = {Boustani, MA and Ben Miled, Z and Owora, AH and Fowler, NR and Dexter, P and Puster, E and Grout, RW and Summanwar, D and Erazo, SF and Disla, S and Coppedge, K and Galvin, JE},
title = {Digital Detection of Dementia in Primary Care: A Randomized Clinical Trial.},
journal = {JAMA network open},
volume = {8},
number = {11},
pages = {e2542222},
doi = {10.1001/jamanetworkopen.2025.42222},
pmid = {41212562},
issn = {2574-3805},
abstract = {IMPORTANCE: Detection of Alzheimer disease and related dementias (ADRD) is a challenge in primary care settings. The Quick Dementia Rating System (QDRS) and the Passive Digital Marker (PDM) were developed as 2 scalable tools for early detection of ADRD. The QDRS is a patient-reported outcome measure, while the PDM is a machine learning algorithm that uses electronic health record (EHR) data. Both can be embedded in the EHR for ease of use.

OBJECTIVE: To evaluate the effect of the combined approach of QDRS plus PDM in improving the annual rate of new documented ADRD diagnoses in primary care practices.

This randomized clinical trial was performed between July 2, 2022, and July 1, 2024. Nine federally qualified primary health care clinics in Indianapolis, Indiana, were randomized to usual care (no routine screening for ADRD), PDM only, or QDRS plus PDM. Participants were treated as per the randomization arm. Participants included adults 65 years and older, without a diagnosis of mild cognitive impairment, dementia, or severe mental illness. Data analysis was based on intention to treat and was performed between November 1, 2024, and August 20, 2025.

INTERVENTION: Randomization of clinic to usual care, PDM only, or QDRS plus PDM.

MAIN OUTCOMES AND MEASURES: The primary outcome was 12-month cumulative incidence of ADRD diagnoses; the secondary outcome was any ADRD diagnostic workup, such as laboratory tests, neuropsychological testing, or brain imaging.

RESULTS: The study included 5325 patients (mean [SD] age, 71.1 [5.9] years), 3312 (62.2%) of whom were female. Compared with the usual care clinics (12-month incidence, 213 of 1724 [12.4%]), the odds of an incident ADRD diagnosis were higher in the clinics randomized to QDRS plus PDM (12-month incidence, 355 of 2301 [15.4%]; adjusted odds ratio [AOR], 1.31; 95% CI, 1.05-1.64) but not the clinics randomized to PDM only (12-month incidence, 134 of 1300 [10.3%]; AOR, 0.84; 95% CI, 0.63-1.11]). Compared with the usual care clinics (12-month incidence, 500 of 1724 [29.0%]), the odds of ADRD diagnostic assessments were higher in the QDRS plus PDM clinics (12-month incidence, 844 of 2301 [36.7%]; AOR, 1.41; 95% CI, 1.12-1.77) but not the PDM clinics (12-month incidence, 362 of 1300 [27.8%]; AOR, 0.94; 95% CI, 0.72-1.22).

CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that the combined approach was effective at scale for the early detection of ADRD in primary care settings. This is an important feature in busy primary care settings that can benefit both the health care system and patients.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05231954.},
}

@article {pmid41212470,
year = {2025},
author = {Soni, U and Pujari, R},
title = {Therapeutic Potential of Phytocompounds Gentisic Acid and Alpha Resorcylic Acid against Alzheimer's Disease: A Network Pharmacology, In Silico, and In Vitro Approach.},
journal = {Cell biochemistry and biophysics},
volume = {},
number = {},
pages = {},
pmid = {41212470},
issn = {1559-0283},
}

@article {pmid41212436,
year = {2025},
author = {Vizuete, AFK and Moreira, AP and Zin, LEF and de Oliveira Marques, C and Pacheco, RF and Leal, MB and Menezes, L and Gonçalves, CA},
title = {Neuroprotective Roles of Metformin in a Streptozotocin-Induced Dementia Model in Rats.},
journal = {Neurotoxicity research},
volume = {43},
number = {6},
pages = {48},
pmid = {41212436},
issn = {1476-3524},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in humans, with high social and economic costs. AD is predominantly a sporadic disorder, and its risk increases with age and in individuals with type 2 diabetes mellitus (T2DM). Metformin is considered the first line drug for treatment of T2DM and has a plethora of effects in the peripheral and nervous system. However, the neuroprotective mechanism of action of this drug is still under debate. In order to assess the effects of metformin in dementia, we investigated the optimal time to start metformin treatment in animals that were submitted to intracerebroventricular (ICV) administration of streptozotocin (STZ) (3 mg/kg) to induce a sporadic AD-like rodent model of dementia. We used two protocols of metformin administration: early metformin (50 mg/Kg/daily) treatment (2 days after STZ model induction, lasting 28 days) and late metformin (50 mg/Kg/daily) treatment (20 weeks after STZ model induction, lasting 28 days). Both time points improved cognitive behavior in STZ rats, as evaluated by the novel object recognition and Morris's water maze tasks. Moreover, both treatments reduced neuroinflammatory parameters, such as TLR4, RAGE, TNF-α and NF-κB protein expression, induced in STZ animals. Metformin downregulated the methylglyoxal/RAGE/NOX‑2 signaling pathway by restoring glyoxalase 1 activity and GSH levels, which are impaired in the STZ-induced dementia model. Our data contribute to understanding the neuroprotective role of metformin, particularly in conditions involving insulin resistance, such as diabetic encephalopathy and AD.},
}

@article {pmid41212353,
year = {2025},
author = {Shademan, B and Yousefi, H and Sharafkhani, R and Nourazarian, A},
title = {LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {102},
pmid = {41212353},
issn = {1573-6830},
support = {(IR.KHOY.REC.1402.030//Khoy University of Medical Sciences/ ; },
abstract = {Alzheimer's disease (AD) leads to a progressive loss of cognitive abilities and memory. A critical factor now recognized as driving AD pathology is neuroinflammation-inflammation occurring in the nervous system, which contributes to neuronal harm and communication breakdowns. our research investigated the specific effects of neuroinflammation on neuronal signaling pathways. In this study, we primarily employed the SH-SY5Y neuroblastoma cell line as an in vitro neuronal model to investigate inflammatory responses relevant to AD etiology, alongside supplementary observations in primary neurons and 3D spheroids for comparative analysis. Our analysis focused on modifications of key molecules, including the neuroprotective protein Brain-Derived Neurotrophic Factor (BDNF), pro-inflammatory cytokines such as IL-6 and TNF-α, and crucial regulatory kinases. Our results demonstrated that LPS treatment dramatically lowered the vitality and decreased BDNF levels in the SH-SY5Y cells. Furthermore, we observed a considerable elevation in the pro-inflammatory cytokines IL-6 and TNF-α, coupled with elevated levels of COX-2 and iNOS. Gene expression data validated that LPS treatment altered the expression of essential signaling kinases (Protein Kinase A (PKA), Protein Kinase B (AKT), and Mitogen-Activated Protein Kinase (MAPK)). Our first comparative analysis revealed that 3D spheroid cultures may elicit more pronounced inflammatory responses than standard 2D cultures; nevertheless, our detailed investigation primarily focused on the SH-SY5Y model. This study revealed that LPS-induced neuroinflammation affects neuronal signaling in vitro, thereby revealing a relationship between inflammation and neuronal dysfunction in cellular models of neuroinflammation. These findings highlight pathways that may be relevant to AD pathophysiology; however, further in vivo studies are necessary to demonstrate their translational relevance to humans.},
}

@article {pmid41212342,
year = {2025},
author = {Zhong, R and Yang, H and Li, X and Wang, F and Zhai, L and Gao, J},
title = {Mitochondria-Mediated Mechanisms of Ferroptosis in Neurological Diseases.},
journal = {Neurochemical research},
volume = {50},
number = {6},
pages = {354},
pmid = {41212342},
issn = {1573-6903},
support = {202403070986//Health Science and Technology Project of Shandong Province/ ; RZ1900011598//post-doctoral foundation of Qingdao University/ ; },
abstract = {Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, is increasingly recognized as a critical contributor to the pathogenesis of various neurological disorders. Mitochondria, the powerhouses of cells, play dual roles as both initiators and mediators of ferroptosis by integrating lipid peroxidation cascades, oxidative stress responses, and iron homeostasis dysregulation. This review first comprehensively explores the multifaceted mechanisms by which mitochondria mediate ferroptosis in neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Friedreich's ataxia (FRDA), amyotrophic lateral sclerosis (ALS), epilepsy, stroke, and brain injury, with a focus on mitochondrial lipid peroxidation and iron metabolism dysregulation. Building on these mechanistic insights, we further discuss emerging evidence suggesting that targeting mitochondrial pathways may represent a promising therapeutic strategy for mitigating ferroptosis-associated neuronal damage. By synthesizing these findings, our review establishes a conceptual foundation for developing innovative neuroprotective interventions through precise modulation of mitochondrial function within ferroptotic pathways.},
}

@article {pmid41212264,
year = {2025},
author = {Zhang, L and Ge, Y and Wu, J and Wang, M and Huang, N and Luo, Y},
title = {Research on the Application of Mesenchymal Stem Cells for Addressing Mitochondrial Damage in Neurodegenerative Diseases.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {101},
pmid = {41212264},
issn = {1573-6830},
support = {ZYK254//Graduate Research Fund of Zunyi Medical University/ ; 82160858//National Natural Science Foundation of China/ ; ZK (2024)-680//Science and Technology Department of Guizhou Province/ ; (2024) No. 6, HZ-2022-45//Zunyi Science and Technology Bureau/ ; R&D 2020-06//The First People's Hospital of Zunyi for Research and Experimental Development/ ; },
abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose serious threats to human health, and their pathogenesis is closely related to mitochondrial damage. Mitochondrial dysfunction includes abnormal energy metabolism, oxidative stress imbalance, disturbed calcium homeostasis and altered mitochondrial dynamics, which in turn trigger neuronal apoptosis and neuroinflammation. Mitochondrial dysfunction is a hallmark of many NDs. In addition to their multi-lineage differentiation potential, ability to promote neuronal repair, and capacity to modulate the neuroimmune microenvironment, Mesenchymal stem cells (MSCs) also hold potential for restoring mitochondrial dysfunction. MSCs have important therapeutic potential and mechanistic research value in the context of neurodegenerative disorders through the modulation of mitochondrial homeostasis and its transcellular transfer process. In this paper, we systematically summarize the mechanisms, technological advances, and translational challenges associated with mitochondrial damage in NDs and the role of MSCs in NDs through the modulation of mitochondrial damage and discuss their potential and limitations as a general therapeutic strategy.},
}

@article {pmid41211864,
year = {2025},
author = {Fallot, LB and Natarajan, C and Anderson, CA and Nagelli, EA and Burpo, FJ and Limbocker, R},
title = {From Pathology to Materials Science and Engineering: Harnessing the Amyloid State for Biotechnological Applications.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.5c11847},
pmid = {41211864},
issn = {1944-8252},
abstract = {The aberrant misfolding and aggregation process of specific peptides and proteins plays a seminal role in the onset and development of over 60 protein misfolding diseases, including Alzheimer's and Parkinson's diseases. These proteins can convert from the endogenous, monomeric, and often largely intrinsically disordered state to the pathological, highly ordered amyloid state, which results in the formation of long, thread-like fibrillar species with extensive β-sheet structure and hallmark tinctorial and biophysical properties. Beyond pathology, the amyloid state has been well-studied for its role in physiological processes in numerous organisms through functional amyloids. In this review, we consider principles governing amyloid formation, with a focus on leveraging the unique biophysical properties and templating abilities of amyloids to produce diverse amyloid-containing materials with wide-ranging biotechnological applications, including, but not limited to, aerogels and hydrogels of varied function, drug delivery, tissue engineering, antimicrobials, purification and detection, protein-based packaging and food science, chemical catalysis, and bioelectronics. We conclude with a brief discussion on the opportunities and challenges ahead for implementing amyloid-based biotechnologies in society.},
}

@article {pmid41211647,
year = {2025},
author = {Buhlin, K and Eriksdotter, M and Jansson, L and Pussinen, PJ and Schultzberg, M and Lira-Junior, R},
title = {The association of periodontal inflammation and inflammatory markers with cognitive dysfunction: A case-control study.},
journal = {Journal of periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1002/jper.70020},
pmid = {41211647},
issn = {1943-3670},
abstract = {BACKGROUND: This study investigated the association of inflammatory markers in saliva, plasma, and cerebrospinal fluid (CSF) with cognitive decline and periodontitis.

METHODS: Patients with Alzheimer disease (AD, n = 52), mild cognitive impairment (MCI, n = 51), subjective cognitive decline (SCD, n = 51), and controls (n = 76) between 50 and 80 years were included. Participants underwent an oral examination, and blood and stimulated saliva were collected. In addition, CSF samples were collected from patients but not controls. Levels of interleukin (IL)-1β, IL-8, IL-10, IL-17A, and tumor necrosis factor-alpha (TNF-α) were analyzed by multiplex immunoassays.

RESULTS: Increased salivary levels of IL-1β, IL-10, and IL-17A were found in MCI compared to controls, while in plasma increased IL-8 levels were seen in all 3 patient groups compared to controls (p < 0.001). TNF-α plasma levels were higher in SCD and AD (p < 0.05). IL-17A levels in CSF were higher in participants with no/mild periodontitis compared to generalized periodontitis (p = 0.023). Participants with severe periodontitis showed higher levels of IL-8 both in saliva (p = 0.027) and plasma (p < 0.001), as well as higher TNF-α levels in plasma (p = 0.041).

CONCLUSIONS: Inflammation markers could indicate an increased risk for cognitive decline, especially in cases of more severe periodontitis.

PLAIN LANGUAGE SUMMARY: Evidence has indicated an association between periodontitis and cognitive impairment. Hence, this study investigated whether inflammatory markers in saliva, plasma, and cerebrospinal fluid are associated with cognitive decline. Cases with mild or more severe signs of cognitive impairment had more signs of periodontal disease. Levels of some, but not all, inflammation markers were elevated among patients compared to cognitively healthy controls. Oral inflammation could indicate an increased risk for cognitive decline, and chronic inflammation may act as a common pathway. Early periodontal intervention and maintaining oral health may contribute to cognitive well-being.},
}

@article {pmid41211332,
year = {2025},
author = {Guo, L and Gaunt, JR and Cheah, CCH and Chen, AI and Claudine, S and Dawe, GS and Goh, ELK and Kho, SH and Kumar, P and Lim, GGY and Lim, KL and Lim, YA and Saido, TC and Saito, T and Sasaguri, H and Sng, JCG and Yeap, YJ and Yip, AKK and Zainolabidin, N and Ch'ng, TH and Augustine, GJ},
title = {APOE4-APP interactions exert early influences on cerebrovascular structure and function: implications for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1629830},
pmid = {41211332},
issn = {1662-4548},
abstract = {BACKGROUND: APOE4 and APP are two of the main genetic risk factors for Alzheimer's disease (AD). Although there have been suggestions that these two factors interact, most of the in vivo evidence for such interactions comes from transgenic mouse models that suffer from complications associated with protein overexpression. Our goal was to examine the consequences of interactions between APOE4 and APP on brain function while avoiding the use of transgenic mice.

METHODS: We generated and characterized double-mutant knock-in mice incorporating familial APP mutations and humanized APOE4.

RESULTS: In the brains of 3-month-old double-mutant mice there were significant alterations in vascular remodeling genes, vascular structure and blood-brain barrier permeability. These changes were not observed in either APOE4 or APP single-mutant mice and, thus, were caused by interactions between the two genes. These interaction effects were transient, because they were absent in 8-month-old double-mutant mice.

CONCLUSION: These findings indicate that early vascular changes, driven by the interaction of APP and APOE4, may influence the progression of AD. Our work highlights the need to focus on the synergistic vascular actions of APOE4 and APP, particularly at younger ages.},
}

@article {pmid41211302,
year = {2025},
author = {Butterbrod, E and Rabin, L and Tommet, D and Jones, RN and Dubbelman, MA and Crane, PK and Jessen, F and van der Flier, WM and Gifford, KA and Sikkes, SAM and , },
title = {Perspectives on the measurement of self-perceived cognitive function in older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70158},
pmid = {41211302},
issn = {2352-8729},
abstract = {INTRODUCTION: This survey investigated perspectives of research and clinical professionals on optimal content and features of measurement of self-perceived cognitive functioning.

METHODS: Respondents were professionals working with older adults with self-reported cognitive concerns. The survey addressed views on harmonization and preferences for items, response formatting, practical features, and instrument validation. We evaluated item preferences in consideration of a previous statistical harmonization.

RESULTS: Ninety professionals from 20 different countries completed the survey. Most professionals (87%) indicated a need for a harmonized instrument. Respondents agreed that an instrument should measure current ability alongside change therein, focus on memory, and adopt Likert scale responses. Recommendations for assessment timeframe, practical features, and validation priorities varied. Respondents differentially endorsed items previously found to be statistically informative.

DISCUSSION: Respondents agreed on overarching measurement topics, with varying recommendations for specific content and features. Together with statistical information, these results provide a starting point for a harmonized instrument.

HIGHLIGHTS: Professionals see a need for a harmonized tool to measure cognitive concerns.Professionals have diverse preferences for measurement content and its validation.Item relevance as seen by professionals aligned considerably with statistical value.Integration of statistical information with expert and patient opinion is crucial.},
}

@article {pmid41211301,
year = {2025},
author = {McWilliam, OH and Bsoul, R and Lund, EL and Waldemar, G and Hasselbalch, SG and Simonsen, AH and Bruun, M and von Buchwald, C and Aanæs, K and Pedersen, CK and Andersen, ISB and Bech, M and Areškevičiūtė, A and Frederiksen, KS},
title = {α-Synuclein seed amplification assay in Lewy body dementia versus Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70203},
pmid = {41211301},
issn = {2352-8729},
abstract = {INTRODUCTION: Differentiating dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) is challenging. Seed amplification assay (SAA) is sensitive for the detection of misfolded α-synuclein.

METHODS: Patients with DLB (N = 31) and AD (N = 25) were recruited and evaluated. Misfolded α-synuclein was assessed in cerebrospinal fluid (CSF), skin, urine, and olfactory mucosa using SAA.

RESULTS: The accuracy of α-synuclein-SAA for DLB was 87% (95% confidence interval [CI]: 77% to 98%) in CSF, 85% (95% CI: 75% to 98%) in skin, 58% (95% CI: 47% to 69%) in olfactory mucosa, and 59% (95% CI: 51% to 66%) in urine. The core symptoms - fluctuations, REM sleep behavior disorder, and parkinsonism - had accuracies for SAA positivity of ≥79%. Notably, 95% of SAA-positive patients also had hyposmia.

DISCUSSION: These findings support the use of CSF and skin α-synuclein-SAAs as diagnostic tools for DLB, with strong associations between SAA and clinical phenotype. In particular, intact olfactory function is associated with a lower risk of SAA positivity.

HIGHLIGHTS: CSF and skin biopsies show high diagnostic accuracy for α-synuclein, demonstrating good concordance.Strong correlations exist between core symptoms of DLB and pathological α-synuclein.A very high sensitivity of hyposmia for pathological α-synuclein is observed.A novel proof-of-concept is offered for the potential detection of pathological α-synuclein in urine, marking the first such comparative analysis between patients with DLB and AD.},
}

@article {pmid41211300,
year = {2025},
author = {Teipel, S and Lutz, M},
title = {Bayesian analyses for research on Alzheimer's disease and related disorders-updating one's knowledge.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70109},
pmid = {41211300},
issn = {2352-8729},
}

@article {pmid41211299,
year = {2025},
author = {Marshall, GA and Ravona-Springer, R},
title = {Objective measures of instrumental activities of daily living and neuropsychiatric symptoms in aging and early-stage Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70097},
pmid = {41211299},
issn = {2352-8729},
}

@article {pmid41211293,
year = {2025},
author = {Nimworaphan, J and Markowitz, DM and Sergott, RC},
title = {Fluorescence lifetime imaging ophthalmoscopy adds the retina to cortical pathology for visual dysfunction in neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1659264},
pmid = {41211293},
issn = {1664-2295},
abstract = {Because neurodegenerative diseases such as Parkinson's and Alzheimer's Diseases [AD and PD] as well as the progressive forms of multiple sclerosis [MS] are invariably associated with clinically significant cortical symptoms such as language difficulties, motor skill deficits and cognitive impairments, especially memory, a tacit assumption evolved that visual disorders related to cortical dysfunction must localize only to the temporal, parietal and occipital lobes. Based upon our current understanding, retinal changes in MS are most likely secondary to optic neuropathy, whereas in AD and PD, they appear to represent primary retinal changes. The paradigm was reinforced by the lack of retinal findings using ophthalmoscopy. Spectral domain optical coherence tomography [OCT], optical coherence angiography [OCT-A], and fundus autofluorescence [FAF] have challenged this creed by uncovering structural changes within the retina over and above what can occur as a consequence of optic neuropathy in the case of MS. Still, definitive diagnostic and prognostic data have yet to emerge. Fluorescence lifetime imaging ophthalmoscopy [FLIO], a non-invasive, non-contact, painless imaging technology, measures nanosecond lifetimes of endogenous retinal fluorophores, some of which are linked to mitochondrial activity. Therefore, FLIO is a metabolic, not a structural imaging modality. Because mitochondrial dysfunction occurs in many neurodegenerative diseases, FLIO offers a unique strategy for investigating retinal metabolism in AD, PD, and MS. This article reviews the basic biomedical engineering of FLIO and reports preliminary data from these diseases, correlated with disease duration. These functional in vivo data are consistent with retinal metabolic changes in AD, PD, and progressive MS that were "hiding in plain sight" from structural examinations.},
}

@article {pmid41211282,
year = {2025},
author = {Olaolorun, F and Howes, MR and Elufioye, T and Odeku, OA and Olopade, J and Chazot, P},
title = {Iron chelation as a therapeutic target in vanadium neurotoxicity and Parkinson's disease: role of medicinal plants.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1667943},
pmid = {41211282},
issn = {1664-2295},
abstract = {Bioprospecting plant natural products has yielded significant success in the development of symptomatic treatment of neurodegenerative diseases, including the two most common, Alzheimer's and Parkinson's diseases (PD). Dysregulation of iron has been strongly implicated in the pathophysiology of these serious intractable diseases. A series of Nigerian endemic plants' methanolic extracts were explored using a Ferrozine binding iron chelation assay. This identified Spondias purpurea L. (SP) leaves as a potential therapeutic candidate and this was determined by evaluation of oxidative stress in 6-hydroxydopamine (6-OHDA)-exposed monoamine cell culture and Drosophila models of PD and vanadium neurotoxicity. SP treatment protected CAD cells against 6-OHDA toxicity and improved survival in PINK-1 mutant flies, though it had little effect on motor deficits. Furthermore, SP treatment reduced the vanadium-induced reactive oxygen species, and notably, staggered SP treatment significantly extended lifespan in vanadium-treated flies. Overall, Spondias purpurea L. leaf methanolic extract exhibited iron-chelating, antioxidant, neuroprotective, and life-extending properties, relevant to Parkinson's disease and vanadium-induced toxicity.},
}

@article {pmid41211099,
year = {2025},
author = {Viani, A and Custo, A and d'Angremont, E and Garibotto, V and Frisoni, GB and Gutman, BA and Lorenzi, M},
title = {Disease Progression Modeling and Stratification for detecting sub-trajectories in the natural history of pathologies: Application to Alzheimer's disease trajectory modeling.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {3},
number = {},
pages = {},
pmid = {41211099},
issn = {2837-6056},
abstract = {Quantifying the progression of degenerative diseases remains crucial for early diagnosis, prevention, and treatment. However, accurately modeling disease biomarker evolution is hindered by substantial variability in disease trajectories among individuals, driven by demographic, genetic, and lifestyle factors. This variability gives rise to heterogeneous phenotypic manifestations, underscoring the need for stratification based on underlying disease subtypes. Recent advances have shown promise in unsupervised stratification of disease trajectories. Yet, current approaches face significant challenges related to robustness, biomarker specificity, interpretability, and temporal resolution of clustering results. To address these challenges, we introduce Disease Progression Modeling and Stratification (DPMoSt), a new probabilistic model designed to optimize clusters of continuous trajectories along a long-term disease time axis. This approach allows for the determination of subtype-specific biomarkers, improving the accuracy of patient stratification and generalization on external cohorts. We demonstrate DPMoSt on both synthetic and real-world data for the modeling of Alzheimer's disease (AD) evolution. In the synthetic experiments, DPMoSt shows high accuracy in reconstructing trajectory subtypes and identifying the biomarkers' specificity for the clustering problem. Our experiments in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate the ability of DPMoSt to identify AD subtypes associated with accelerated cognitive decline and higher prevalence of the APOE4 variants. This result was validated on the external memory clinic cohort of the Geneva University Hospitals, confirming the association between cognitive decline and APOE4 in the pathological subtype. These results highlight the robustness of DPMoSt as well as its potential for broader applicability, offering a powerful tool for studying disease progression and subtype differentiation across diverse populations.},
}

@article {pmid41211047,
year = {2025},
author = {Zhang, N and Hu, BW and Li, XM and Huang, H},
title = {Rethinking parvalbumin: From passive marker to active modulator of hippocampal circuits.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {760-773},
pmid = {41211047},
issn = {2667-2421},
abstract = {Parvalbumin (PV)-expressing interneurons are critical regulators of neural circuit dynamics, and for decades, the PV protein has served as their definitive molecular marker. This review confronts a central, yet underappreciated, paradox: the incongruity of a kinetically slow Ca[2+] buffer (PV) being the defining feature of the brain's fastest-spiking neurons. We synthesize evidence from molecular biophysics, genetics, in vivo circuit analysis, and disease modeling to dissect the dual role of PV as both a cellular marker and an active functional regulator. We argue that PV's slow kinetics are not a coincidence but a crucial adaptation that shapes short-term synaptic plasticity, protects against metabolic stress during high-frequency firing, and allows the circuit to shift between states of plasticity and stability. This reframing resolves the paradox by demonstrating how a "slow" molecule is essential for "fast" neuronal function. Furthermore, we highlight that dysfunction of the PV system is a convergent hub of pathology in numerous neurological and psychiatric disorders, including schizophrenia, epilepsy, and Alzheimer's disease. By moving beyond its identity as a passive marker, we establish PV as an active modulator of neural computation and a potential therapeutic target for restoring network function in disease.},
}

@article {pmid41210976,
year = {2025},
author = {Thapa, R and Adhikari, N and Gautam, S and Sun, M and McOmie, S and Davydzenka, V and Smith, D and Syring, J and Kaligis, H and Kosmicki, JM and Chen, R and Li, Y},
title = {Single-nucleus RNA sequencing reveals GABAergic vulnerability and reactive gliosis driven by loss of TDP-43.},
journal = {iScience},
volume = {28},
number = {11},
pages = {113745},
pmid = {41210976},
issn = {2589-0042},
abstract = {TDP-43 is an RNA-binding protein important for RNA processing, whose loss of function is involved in multiple neurodegenerative disorders, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease (AD). We performed single-nucleus RNA-sequencing to study the convergent and divergent molecular signatures of short-term and long-term TDP-43 depletion in the medial prefrontal cortex (mPFC) using Tdp-43 [F/F] mice, compared with that of 5xFAD mice, a well-established AD mouse model with β-amyloid plaque pathology. Our results demonstrated a significant loss of GABAergic neurons in the mPFC after short-term TDP-43 depletion. This was accompanied by a remarkable reactive gliosis in the mPFC. Our results revealed a strong GABAergic and glial involvement during early stages of TDP-43 loss of function, suggesting that the GABAergic system is vulnerable to TDP-43 pathology and could be considered a potential target for developing therapeutic strategies and biomarkers for early detection in TDP-43 linked AD-related dementia.},
}

@article {pmid41210921,
year = {2025},
author = {Newlin, NR and Kim, ME and Kanakaraj, P and McMaster, E and Cho, C and Gao, C and Hohman, TJ and Beason-Held, L and Resnick, SM and O'Bryant, SE and Phillips, N and Barber, RC and Bennett, DA and Barnes, LL and Biber, S and Johnson, S and Archer, D and Li, Z and Zuo, L and Moyer, D and Landman, BA},
title = {Harmonizing 10,000 connectomes: site-invariant representation learning for multi-site analysis of network connectivity and cognitive impairment.},
journal = {Journal of medical imaging (Bellingham, Wash.)},
volume = {12},
number = {6},
pages = {064001},
pmid = {41210921},
issn = {2329-4302},
abstract = {PURPOSE: Data-driven harmonization can mitigate systematic confounding signals across imaging cohorts caused by variance in scanners and acquisition protocols. As diffusion magnetic resonance imaging data are often acquired with different hardware and software, harmonization is essential for integrating these scattered datasets into a cohesive analysis for improved statistical power. Large-scale, multi-site studies for Alzheimer's disease (AD), a neurodegenerative condition characterized by high data variability and complex pathology, pose the challenge of both site-based and biological variation.

APPROACH: We learn lower-dimensional representations of structural connectivity invariant to imaging cohort, geographical location, scanner, and acquisition factors. We design a conditional variational autoencoder that creates latent representations with minimal information about imaging factors and maximal information related to patient cognitive status. With this model, we consolidate 9 cohorts and 35 unique imaging acquisitions (for a total of 38 imaging "sites") into a cohesive dataset of 6956 persons (16.4% with mild cognitive impairment and 10.7% with AD) imaged for 1 to 16 sessions for a total of 11,927 diffusion-weighted imaging sessions.

RESULTS: These site-invariant representations successfully remove significant (p < 0.05) site effects in 12 network connectivity measures of interest and enhance the prediction of cognitive diagnosis (from 68% accuracy to 73% accuracy).

CONCLUSIONS: The proposed model yields reproducible precision across 15 data configurations. This approach demonstrates the effectiveness of representation learning in enhancing biological signals by mitigating acquisition-specific confounding factors in neuroimaging studies.},
}

@article {pmid41210797,
year = {2025},
author = {El-Sayed, AIM and Mokhtar, FA and Alfaifi, MY and Anazi, HK and Makhlof, MEM},
title = {Characterization and Phenolic Profiling of Anticandidal Polycladia myrica and Its Mediated Iron Nanoparticles with the Evaluation of Their Antioxidant, Anti-Alzheimer, Catalytic Degradation, and Anticancer Activity via the P53 Pathway.},
journal = {ACS omega},
volume = {10},
number = {43},
pages = {52032-52045},
pmid = {41210797},
issn = {2470-1343},
abstract = {As a potent reducing and capping agent, Polycladia myrica extract was used to create iron nanoparticles (FeNPs). UV-visible, Fourier transform infrared (FTIR), X-ray diffractive analysis (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), zeta potential, hydrodynamic analysis with the determination of polydispersity index (PDI), and transmission electron microscopy (TEM) were used to characterize the produced iron nanoparticles. By examining the peak at 320 nm, UV-visible spectroscopy confirmed the production of PFeNPs. Additionally, various in vitro biological assays were conducted, demonstrating significant therapeutic potential. The cytotoxic assay was performed using lung carcinoma cells (A-549) and normal human lung fibroblast (MRC-5) cell lines, which demonstrated promising safe results with IC50 = 225.91 ± 8.93 μg/mL and CC50 = 488.80 ± 17.23 μg/mL, respectively, due to the forced apoptosis caused by the accumulation of both ROS and p53 levels inside cancer cells. PFeNPs demonstrated weak α-amylase inhibition with a percent of 33.96 ± 3.12 and potent acetylcholinesterase inhibition with a percent of 71.42 ± 3.64. The anticandidal activity of FeNPs biofabricated from P. myrica against C. albicans was estimated. The inhibition zone diameters of PFeNPs and Nystatin reference drug (mean ± SD) were about 18.82 ± 0.87 and 19.74 ± 0.98, respectively. MIC was determined to be about 500 and 312.5 μg/mL for both our algal FeNPs and the standard used drug, respectively. These results were confirmed by scanning electron microscopy, which revealed lysis and bursting of the exterior cell surface, along with deformation and death of Candida albicans cells in treated Candida isolate. These results strongly suggested the possibility of introducing PFeNPs as a cotherapy for Candida infections in diabetic cancer patients.},
}

@article {pmid41210610,
year = {2025},
author = {Thomas, ST and Palanikumar, L and Darby, DG and Brodtmann, AG},
title = {FDG-PET anterior cingulate cortex hypometabolism as a marker of cerebral small vessel disease in Alzheimer's and vascular cognitive impairment and dementia.},
journal = {Cerebral circulation - cognition and behavior},
volume = {9},
number = {},
pages = {100404},
pmid = {41210610},
issn = {2666-2450},
abstract = {BACKGROUND: The anterior cingulate cortex (ACC) is an important hub in the executive and salience networks. While fluorodeoxyglucose-positron emission tomography (FDG-PET) is valuable in dementia diagnosis, there is no FDG-PET imaging 'signature' in vascular cognitive impairment and dementia (VCID). We investigated whether ACC hypometabolism on FDG-PET brain imaging in people with VCID correlated with cerebral small vessel disease (CSVD), estimated via white matter hyperintensity (WMH) severity, and clinical features, comparing these results with an Alzheimer dementia (AD) cohort.

METHODS: We performed a retrospective clinical database review of patients seen at a specialist cognitive neurology service between 2009 and 2024 to identify patients with VCID and AD diagnoses. Demographic details, cognitive (Addenbrooke's Cognitive Examination-Revised, ACE-R) and behavioural (Cambridge Behavioural Inventory, CBI) screens were collated where available. Two clinicians independently performed unblinded, visual assessments of clinical FDG-PET maps, rating for the presence or absence of ACC hypometabolism. WMH severity was estimated via Fazekas scale on clinical MRI as a measure of CSVD.

RESULTS: 379 people were identified: 98 VCID (median (IQR) age: 71 (63-77)), and 281 CE (median (IQR) age 72 (66-79)). ACC hypometabolism was observed more frequently in people with VCID (74 %) than AD (34 %). ACC hypometabolism correlated with greater vascular risk factor burden and higher Fazekas scores.

CONCLUSION: ACC hypometabolism correlated with WMH severity but was not specific to VCID. ACC hypometabolism on FDG-PET may represent a functional marker of vascular damage to frontal-subcortical circuits.},
}

@article {pmid41210484,
year = {2025},
author = {Zhang, Q and Mao, JD and Chen, H and Wang, M and Wu, YM and Wang, C},
title = {Ferroptosis as a potential therapeutic target for post-traumatic stress disorder.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1648047},
pmid = {41210484},
issn = {1662-5099},
abstract = {The underlying mechanisms of post-traumatic stress disorder (PTSD) are still not fully understood, creating significant obstacles for developing effective therapeutic strategies. Recently, ferroptosis, an iron-dependent form of regulated cell death, has been shown to play a role in several psychiatric disorders, such as major depressive disorder (MDD), stress-induced anxiety, Alzheimer's disease (AD), and Parkinson's disease (PD). While direct evidence for the role of ferroptosis in PTSD is still limited, an increasing number of studies suggest that the pathological features of PTSD may trigger the ferroptosis cascade. Additionally, the typical hallmarks of ferroptosis, such as iron dysregulation, lipid peroxidation, and failure of antioxidant defense systems, may intersect with the pathogenesis of PTSD. Importantly, some treatments for PTSD, such as antioxidants and free radical scavengers, have been proven to inhibit ferroptosis, which further supports the case for ferroptosis as a potential pathogenic mechanism in PTSD. To thoroughly investigate the mechanistic links between ferroptosis and PTSD, we analyze the relevant literature on ferroptosis and PTSD in this review. Our aim is to elucidate the potential relationships between ferroptosis and PTSD, thereby providing novel insights for future research directions. Furthermore, we call for more experimental and clinical studies to explore this relationship further, with the ultimate goal of developing more effective therapeutic strategies for PTSD.},
}

@article {pmid41210483,
year = {2025},
author = {Pereira Sena, P and Friedrich, L and Villarreal, A and Fath, F and Sopco, L and Hernández-Guillamon, M and Saraiva-Pereira, ML and Britton, G and Weber, JJ and Schmidt, T},
title = {Proteostasis disruption and lipid dyshomeostasis in neurodegeneration: exploring common druggable targets across sporadic and monogenic disorders.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1681079},
pmid = {41210483},
issn = {1662-5099},
abstract = {Neurodegenerative disorders pose an increasing burden in the aging society. These conditions share several molecular pathomechanisms, some of which may offer opportunities for therapeutic intervention. In this review, we explore a representative selection of sporadic and hereditary neurodegenerative diseases-namely Alzheimer's disease, cerebral amyloid angiopathy, and the polyQ disorders spinocerebellar ataxia types 2 and 3, as well as Huntington's disease-which all feature the accumulation of intra- or extracellular protein deposits as a hallmark. We place particular emphasis on dysregulations in proteostasis-underlying the formation of these aggregates-and the less commonly addressed disturbances in lipid metabolism. By highlighting potential mechanistic links across different classes of neurodegenerative diseases, we aim to provide new insights that may guide the identification of shared druggable targets and the development of broad-spectrum therapeutic strategies.},
}

@article {pmid41209748,
year = {2025},
author = {Li, Y and Zhao, S and Chen, X and Wang, Z and Liang, X and Liu, Y and Dong, Y},
title = {Causal Association of Alzheimer's Disease with Low Back Pain: A Mendelian Randomization Study.},
journal = {Journal of pain research},
volume = {18},
number = {},
pages = {5857-5865},
pmid = {41209748},
issn = {1178-7090},
abstract = {PURPOSE: Previous observational studies have demonstrated that Low back pain (LBP) often coexists with Alzheimer's Disease (AD), however, the causal relationship remains unclear. The purpose of this study is to explore the causal relationship between AD and LBP through Mendelian randomized analysis.

METHODS: Instrumental variables (IVs) were derived from the genome-wide association study (GWAS) of AD. Information regarding Instrumental variables (IVs) in LBP was extracted from a GWAS database. MR-Egger, weighted median, inverse variance weighted (IVW)and Weighted mode were used to evaluate the causal effects. Cochran's Q test and MR-Egger intercept were applied to detect the heterogeneity and horizontal pleiotropy, respectively. Outliers were found and remove based on MR-PRESSO analysis to mitigate the effect of horizontal pleiotropy on the results. Deleting each genetic variant applying the leave-one-out analysis can help evaluate the robustness of results. Finally, MR-PRESSO Raw and Outlier-corrected were used to enhance the credibility of the results.

RESULTS: IVW assessment provided strong evidence that AD is positively associated with LBP (Odds Ratio (OR)= 1.046, 95% confidence interval(CI) = 1.023-1.070, P=5.8×10[-5]). There was no heterogeneity in our study (p > 0.05). The results of the pleiotropy test indicated that there was no pleiotropy in our IVW analysis (p > 0.05). MR-Egger, Weighted median, Weighted mode analysis results are consistent with our IVW analysis results. There is a genetic relationship between Alzheimer's disease and low back pain.

CONCLUSION: This study provides evidence for a causal relationship between AD and LBP. It emphasizes the necessity of improving pain management for patients with Alzheimer's disease in clinical practice. However, the data were derived from a European population, which may limit the generalizability of the results to other populations.},
}

@article {pmid41209583,
year = {2025},
author = {Bagheri, S and Saso, L},
title = {Biophysical insights into the molecular mechanisms of beta amyloid aggregation and its toxic effects in Alzheimer's disease.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1704653},
pmid = {41209583},
issn = {2296-889X},
abstract = {Alzheimer's disease is recognized as the most common neurodegenerative disorder, characterized by the presence of amyloid plaques, which have consistently garnered significant attention. Since the disease was first identified, extensive research has been devoted to investigating these plaques. As our understanding of the disease has progressed, the detrimental role of plaques has been questioned, leading to the hypothesis that amyloid oligomeric aggregates are the main culprits. Nevertheless, subsequent research indicated that the concentrations of amyloids employed in the experiments were considerably elevated compared to physiological conditions, and that at physiological concentrations, amyloids do not exhibit significant accumulation or toxicity. This article aims to offer a detailed biophysical perspective on the formation of amyloid aggregates under physiological conditions and their impact on membranes, providing valuable insights for researchers in this field.},
}

@article {pmid41209367,
year = {2025},
author = {Xie, Z and Hu, J and Stallings-Smith, S and Kulshreshtha, A and Hong, YR},
title = {Rural-urban differences in modifiable dementia risk factors among U.S. populations aged 45 years or older.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395318},
pmid = {41209367},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) have become a significant public health concern, and the burden is disproportionately concentrated in rural areas.

OBJECTIVE: To examine rural-urban differences in the prevalence of modifiable dementia risk factors and their treatment among U.S. adults aged 45 years and older, and to investigate how these disparities vary by age group and geographic region.

METHODS: This cross-sectional study analyzed nationally representative data from the 2023 National Health Interview Survey in 2025. Prevalence of 11 modifiable dementia risk factors (hypertension, high cholesterol, diabetes, obesity, hearing loss, visual impairment, traumatic brain injury, low education, depression, social isolation, smoking) and 7 corresponding treatments were assessed via self-report. Adjusted rate ratios (aRR) were estimated using robust Poisson regression models.

RESULTS: The study population consisted of 16,981 individuals (mean age: 62.4, 51.6% female, 68.7% non-Hispanic White, 15.5% in rural areas). Rural residents had significantly higher prevalence of hypertension (aRR, 1.11; 95% CI, 1.06-1.17), obesity (aRR, 1.22; 95% CI, 1.15-1.30), diabetes (aRR, 1.29; 95% CI, 1.15-1.45), and hearing loss (aRR, 1.22; 95% CI, 1.12-1.34) compared to urban residents. Disparities were most significant among adults aged 45-64 years and in South/Midwest regions. Treatment rates for cardiometabolic conditions were high (>85%) and similar across regions, but treatment for sensory/behavioral risk factors remained low.

CONCLUSIONS: Rural U.S. adults face higher burden of modifiable dementia risk factors, particularly cardiometabolic and sensory impairments. Targeted public health strategies are needed to address structural inequities and improve dementia prevention in rural communities.},
}

@article {pmid41209366,
year = {2025},
author = {Khan, H and Dayamba, L and Rafiq, A},
title = {Risk factors and gender disparity of cognitive impairment among cancer and neurological diseases regarding rural West Texas.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395304},
pmid = {41209366},
issn = {2542-4823},
abstract = {BACKGROUND: The prevalence of Alzheimer's disease or dementia is rising among the elderly population in the United States and globally. Sociodemographic, cancer, and neurological disorders are associated with cognitive impairment of people living in rural communities.

OBJECTIVE: This study identified the association of cognitive impairment with cancer and neurological disorders of the elderly in Cochran and Parmer Counties of rural West Texas.

METHODS: Pearson's chi-squared, two-sample independent proportions, binary logistic regression, and multivariable logistic regression methods were utilized to analyze data.

RESULTS: Individuals aged 70 and above experiencing memory loss in Cochran and Parmer Counties had a statistically significant association with cognitive impairment (p < 0.001). In Parmer County, females diagnosed with breast cancer demonstrated a significant relationship with cognitive impairment (p < 0.05). Neurological factors, including muscle strength, cerebellar function, ability to rise from a chair, and Romberg test results, were significantly associated with an increased risk of cognitive impairments among females in both counties. After adjusting for covariates, males aged 60-69 in Parmer County, as well as memory loss among both genders, were significantly associated with cognitive impairment (p < 0.001). Additionally, females with cognitive impairment in Cochran County exhibited higher dependence on mental health services compared to males (p < 0.05).

CONCLUSIONS: Examining the association between cognitive impairment or Alzheimer's disease and cancer and neurological disorders is important for developing interventions aimed at reducing their prevalence in underserved rural West Texas Counties.},
}

@article {pmid41209083,
year = {2025},
author = {Wang 王子怡, Z and Li 李卉, H and Shi 史博文, B and Qin 秦琪凯, Q and Ye 叶琼, Q and Thompson, GJ},
title = {Female 3xTg-AD mice demonstrate hyperexcitability phenotype of Alzheimer's disease in structure-function and function-behavior relationships.},
journal = {Network neuroscience (Cambridge, Mass.)},
volume = {9},
number = {4},
pages = {1199-1220},
pmid = {41209083},
issn = {2472-1751},
abstract = {Alzheimer's disease (AD) causes cognitive decline with aging, hypothetically due to the accumulation of beta-amyloid (Aβ) plaques. The 3xTg-AD mouse model is increasingly used due to its initial absence of significant physical or behavioral impairments in youth and progressive Aβ plaque development with age. This mouse model thus provides an opportunity for comparison with human AD through two stages of study. Using wild-type (WT) and 3xTg-AD mice, aged 22 and 40 weeks (before and after the large increase in Aβ plaques), we measured functional connectivity (FC) and structural connectivity (SC) between brain regions. At 22 weeks, 3xTg-AD mice unexpectedly had higher SC and FC, and there was positive correlation between behavioral performance and FC density. By 40 weeks, SC and FC was lower in AD mice (similar to human AD patients), but the behavior-functional correlation was negative. Thus, our methods identified a shift in 3xTg-AD mice between two abnormal states relative to WT, moving from a hyperconnected to a hypoconnected state. Such a shift matches the hyperexcitability phenotype of AD observed in human patients, and thus suggests that 3xTg-AD mice can model the multistage etiology of AD of that phenotype.},
}

@article {pmid41208739,
year = {2025},
author = {Oomens, JE and Biber, SA and Albert, M and Alosco, ML and Arfanakis, K and Benzinger, TLS and Brewer, JB and Burns, JM and Chin, E and Chin, NA and Clark, LR and Cohen, AD and Dage, JL and Detre, JA and Dickerson, BC and DiFilippo, FP and Donohue, MC and van Dyck, CH and Fan, AP and Grabowski, TJ and Habes, M and Harrison, TM and Hedden, T and Hohman, TJ and Jagust, WJ and Jefferson, AL and Jicha, GA and Kecskemeti, SR and Kantarci, K and Keene, DC and Knoefel, JE and Kukull, WA and Lin, W and Lao, P and Lepping, RJ and Levendovszky, SR and Masurkar, AV and McConathy, JE and Rivera-Mindt, M and Morhardt, DJ and Noll, DC and Okonkwo, OC and Parrish, TB and Rabinovici, GD and Rahman-Filipiak, A and Reiman, EM and Risacher, SL and Rosen, H and Rudolph, MD and Schneider, LS and Silbert, LC and Song, AW and Stark, CEL and Swerdlow, RH and Thompson, PM and Vaillancourt, D and Villemagne, VL and Wolk, DA and Qiu, D and Foroud, TM and Johnson, SC and Mormino, EC},
title = {The Consortium for Clarity in ADRD Research Through Imaging (CLARiTI): Overview of consortium sites and anticipated enrollment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70880},
doi = {10.1002/alz.70880},
pmid = {41208739},
issn = {1552-5279},
support = {U01-AG082350/NH/NIH HHS/United States ; },
abstract = {INTRODUCTION: The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI.

METHODS: We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts.

RESULTS: Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site-level strategies in enrollment into CLARiTI versus other imaging efforts.

DISCUSSION: We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network.

HIGHLIGHTS: The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi-etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).},
}

@article {pmid41208730,
year = {2025},
author = {Ke, J and Ding, J and Xu, Y and Yu, C and Hong, Y and Li, S and Meng, T and Ping, Y and Yuan, H and Hu, F},
title = {Engineering microglial exosome-mediated microRNA-124-3p delivery for Alzheimer's disease combinational therapy.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5bm01080b},
pmid = {41208730},
issn = {2047-4849},
abstract = {Currently, single-target therapy and difficulty in brain drug delivery gravely impede the treatment of Alzheimer's disease (AD). The promising development of microRNA-124-3p (miR-124-3p) serves as a possibility for multiple therapeutic approaches for AD. However, the effective delivery of miR-124-3p to AD-affected brain regions remains a major challenge, primarily due to the blood-brain barrier (BBB) and the inherent instability of therapeutic miR-124-3p. Herein, we engineered miR-124-3p-enriched microglial exosomes (Exo-124-3p) as a biomimetic nanomedicine for the multifunctional treatment of AD. Exo-124-3p can traverse the BBB and facilitate activated-microglia targeting. Subsequently, the on-demand release of miR-124-3p from Exo-124-3p decreased the aggregation of β-amyloid (Aβ) plaques, attenuated the activation of microglia/astrocytes, and exhibited a valuable neuroprotective effect, thereby remolding the AD focal microenvironment. Notably, the in vivo results demonstrated that Exo-124-3p significantly improved the cognitive function in an AD mouse model. Mechanistically, it was elucidated that Exo-124-3p can bind to the 3'UTR region of MEKK3, ultimately inhibiting the MEKK3/NF-κB signaling pathway, thereby ameliorating AD neuroinflammation. Consequently, this study not only provides a promising therapeutic approach for AD combinational therapy, but also advances the development of miRNA delivery in other brain diseases.},
}

@article {pmid41208717,
year = {2025},
author = {Pavlik, VN and Weber, CJ and Masdeu, JC and Baker, LD and Yu, MM and York, M and Whitmer, RA and Landau, SM and Harrison, TM and Holland, TM and Lovato, L},
title = {Cognitive reserve predicts baseline tau burden in the U.S. POINTER trial imaging cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70892},
doi = {10.1002/alz.70892},
pmid = {41208717},
issn = {1552-5279},
support = {/ALZ/Alzheimer's Association/United States ; R01AG062689 to SML/AG/NIA NIH HHS/United States ; K01AG078443 to TMH/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Higher cognitive reserve (CR) is associated with reduced dementia risk. We hypothesized that higher CR is associated with less baseline Alzheimer's disease (AD) pathology in the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort.

METHODS: A subsample of participants underwent amyloid beta and tau positron emission tomography imaging. Regression analysis was used to model the association between educational attainment (EA) as a CR proxy measure, amyloid positivity, and entorhinal cortex (ERC) and meta-temporal region of interest (meta-ROI) tau standardized uptake value ratio (SUVR).

RESULTS: In 911 participants with complete imaging data, higher CR was significantly associated with lower ERC tau SUVR. CR was not associated with amyloid status or meta-ROI tau.

DISCUSSION: In the U.S. POINTER cohort, higher EA predicted lower tau burden in the ERC. Meta-ROI tau levels may be too low in this cognitively unimpaired sample to reveal associations. CR may have a role in promoting biological resistance to AD pathology.

HIGHLIGHTS: Higher cognitive reserve is associated with a lower dementia risk and better cognitive performance after a diagnosis of Alzheimer's disease. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk trial imaging cohort was cognitively unimpaired at baseline and a subsample received amyloid and tau positron emission tomography scans. Higher educational attainment, a proxy measure of cognitive reserve, was significantly related to tau levels in the entorhinal cortex region of interest.},
}

@article {pmid41208712,
year = {2025},
author = {Godrich, D and Pasteris, J and Martin, ER and Kunkle, B and Naj, AC and Hamilton, K and Wang, H and Lee, WP and Dumitrescu, L and Hohman, TJ and Mayeux, R and Larson, EB and Crane, PK and Keene, CD and Latimer, C and Mukherjee, S and Kofler, J and Kamboh, MI and Bennett, DA and Molina-Porcel, L and Schellenberg, G and Pericak-Vance, MA and Cuccaro, M and Scott, WK and Rundek, T and Kukull, W and Montine, T and Beecham, GW and , },
title = {Genome-wide association studies of TDP-43 proteinopathy and hippocampal sclerosis reveal shared genetic associations with APOE and TMEM106B.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70760},
doi = {10.1002/alz.70760},
pmid = {41208712},
issn = {1552-5279},
support = {R01-AG062695//Primary Funding includes (additional funding in Acknowledgements)/ ; AG074855//Primary Funding includes (additional funding in Acknowledgements)/ ; U01-AG016976//National Alzheimer's Coordinating Center (NACC)/ ; U24-AG21886//National Cell Repository for Alzheimer's Disease (NCRAD)/ ; U24-AG041689//National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS)/ ; U01-AG032984//Alzheimer's Disease Genetics Consortium (ADGC)/ ; RC2-AG036528//Alzheimer's Disease Genetics Consortium (ADGC)/ ; U24-AG074855//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; U01-AG068057//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; R01-AG059716//ADSP Phenotype Harmonization Consortium (ADSP-PHC)/ ; AG006781//Adult Changes in Thought (ACT)/ ; AG066567//Adult Changes in Thought (ACT)/ ; AG030653//University of Pittsburg/ ; AG041718//University of Pittsburg/ ; AG064877//University of Pittsburg/ ; P30-AG066468//University of Pittsburg/ ; P30-AG010161//Rush University (ROSMAP)/ ; R01-AG019085//Rush University (ROSMAP)/ ; R01-AG15819//Rush University (ROSMAP)/ ; R01-AG17917//Rush University (ROSMAP)/ ; R01-AG3014//Rush University (ROSMAP)/ ; },
abstract = {INTRODUCTION: Transactive response DNA binding protein 43 kDa (TDP-43) proteinopathy has been linked to cognitive decline and often co-occurs with hippocampal sclerosis (HS). To identify genetic markers of TDP-43 proteinopathy and HS, we performed genome-wide association studies (GWASs) of HS and TDP-43 inclusions.

METHODS: Genetic data were obtained through the Alzheimer Disease Genetics Consortium and collaborating sites (HS: N = 9509; TDP-43: N = 4669). Statistical analyses included association analysis with HS and TDP-43 inclusions and meta-analysis, a mediation analysis, and fine mapping of the transmembrane protein 106B (TMEM106B) region.

RESULTS: Two regions achieved genome-wide significance with TDP-43: apolipoprotein E (APOE) and TMEM106B. Three loci reached genome-wide significance with HS: APOE, TMEM106B, and granulin precursor (GRN). Fine mapping of TMEM106B identified 93 variants in the credible set. Mediation analyses showed that genetic effects on HS were partially mediated through TDP-43 proteinopathy.

DISCUSSION: We identified associations with TDP-43 inclusion and HS, showing shared genetic risk across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, Alzheimer's disease, and limbic-predominant age-related TDP-43 encephalopathy.

HIGHLIGHTS: HS and TDP-43 contribute to dementia and often co-occur. The etiology and relationship of HS and TDP-43 remains unclear. HS and TDP-43 share genetic risk factors in the genes APOE and TMEM106B. Genes have direct effects on HS, with additional effects mediated through TDP-43.},
}

@article {pmid41208711,
year = {2025},
author = {Dong, X and Bai, M and Qian, J and Xiao, J and Zhang, S and Hou, X and Zhou, C},
title = {Harmful impact of blood lead on the prevalence of Alzheimer's disease among middle-aged and older adults and the modifying role of physical activity: Evidence from the National Health and Nutrition Examination Survey (NHANES) study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70785},
doi = {10.1002/alz.70785},
pmid = {41208711},
issn = {1552-5279},
support = {ZR2024QG047//Natural Science Foundation of Shandong Province/ ; 2023M742059//China Postdoctoral Science Foundation/ ; SDCX-RS-202400011//Postdoctoral Innovation Project of Shandong Province/ ; 72274109//National Science Foundation of China/ ; 72574128//National Science Foundation of China/ ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a major public health challenge. This study aims to explore the combined effects of blood lead levels (BLL) and physical activity (PA) on AD prevalence among middle-aged and older adults.

METHODS: A total of 13,426 middle-aged and older adults (57.8% over 60 years old; 49.7% males) were included. Firth's penalized logistic regression models were used for statistical analysis.

RESULTS: High blood lead level (High-BLL) was associated with an 86.7% increase in AD prevalence. For PA levels, engaging in sufficiently active PA was associated with a 72% reduction in AD prevalence. In addition, the combination of sufficiently active PA with high-BLL, moderate blood lead level (Moderate-BLL), or low blood lead level (Low-BLL) was associated with an 83.9%, 65.9%, or 76.5% reduction in AD prevalence, respectively.

DISCUSSION: Although higher BLL is associated with increased AD prevalence, engaging in PA can reduce the AD prevalence caused by BLL, with greater benefits observed from sufficiently active PA.

HIGHLIGHTS: Higher blood lead levels (BLL) are associated with an increased prevalence of Alzheimer's disease (AD), whereas engaging in physical activity (PA) is associated with a reduced prevalence. Furthermore, engaging in sufficient occupational PA and sufficient leisure-time PA are both associated with a lower prevalence of AD. Engaging in PA can reduce the AD prevalence caused by BLL, with greater benefits observed from engaging in sufficiently active PA. The combined effects of BLL and PA levels on AD prevalence may vary among populations with different gender, marital status, socioeconomic status, or smoking status.},
}

@article {pmid41208701,
year = {2025},
author = {Semenkova, A and Piguet, O and Johnen, A and Schroeter, ML and Godulla, J and Linnemann, C and Baumgartner, M and Otto, M and Felbecker, A and Wezel, S and Kressig, RW and Berres, M and Sollberger, M},
title = {Reference-Group Adjusted Behavioural Dysfunction Questionnaire Score Discriminates Highly Behavioural-Variant Frontotemporal Dementia From Major Depressive Disorder and Alzheimer's Disease Dementia.},
journal = {European journal of neurology},
volume = {32},
number = {11},
pages = {e70424},
doi = {10.1111/ene.70424},
pmid = {41208701},
issn = {1468-1331},
support = {//Alzheimer Schweiz/ ; //Stiftung EMPIRIS/ ; //Béatrice Ederer-Weber Stiftung/ ; //Freiwillige Akademische Gesellschaft/ ; GNT2008020//National Health and Medical Research Council/ ; 774/5-1//Deutsche Forschungsgemeinschaft/ ; 01GI1007A//German Federal Ministry of Education and Research/ ; //eHealthSax Initiative of the Sächsische Aufbaubank/ ; },
abstract = {BACKGROUND: Given the fact that behavioural variant frontotemporal dementia (bvFTD) is characterised by behavioural disorders, the assessment of these disorders is essential for early diagnosis of bvFTD. In this regard, the recently developed Behavioural Dysfunction Questionnaire (BDQ) that captures the bvFTD-specific behavioural disorders is promising in discriminating mild-stage bvFTD from other neurodegenerative and psychiatric disorders. In this study, we aimed to increase the discriminatory power of the BDQ by adaptation of its scoring depending on the reference group to bvFTD.

METHODS: In this combined prospective and retrospective cross-sectional study, data of 241 patients [i.e., 50 patients with mild-stage bvFTD, 71 patients with major depressive disorder (MDD) and 120 patients with mild-stage Alzheimer's disease dementia (ADD)] were analysed. We calculated the BDQ score in two ways: (1) as the average score of the domains' mean scores and (2) by adjusting the scoring depending on the reference group by using machine learning techniques, validated by fivefold cross-validation.

RESULTS: The adjusted BDQ score showed a higher (bvFTD vs. MDD) or similar (bvFTD vs. ADD) discriminatory power than the unadjusted BDQ score, with a considerably smaller difference between cut-offs with at least 90% sensitivity and at least 90% specificity.

CONCLUSIONS: We recommend using adjusted BDQ scores when MDD or ADD are the reference groups to bvFTD. Similar approaches should be taken for other reference groups to bvFTD to best reflect the thinking of clinicians who have specific reference groups in mind as differential diagnoses to bvFTD.},
}

@article {pmid41208653,
year = {2025},
author = {Kim, S and Shin, JJ and Kang, M and Yi, Y and Kim, E},
title = {Synaptic and Non-Synaptic Functions of PTPRD: A Receptor Tyrosine Phosphatase at the Crossroads of Neural Circuitry and Metabolism.},
journal = {Journal of neurochemistry},
volume = {169},
number = {11},
pages = {e70292},
doi = {10.1111/jnc.70292},
pmid = {41208653},
issn = {1471-4159},
support = {IBS-R002-D1//Institute for Basic Science/ ; },
abstract = {Protein-tyrosine phosphatase receptor-type D (PTPRD) is an adhesion-coupled phosphatase that translates extracellular binding codes into intracellular phosphotyrosine signaling from embryogenesis through adulthood. Alternative inclusion of the Ig-domain mini-exons meA and meB tailors the ectodomain surface, thereby dictating high-affinity engagement with IL1RAPL1, IL1RAP, Slitrks, LRFN4/5 (SALM3/5), neuroligin-3, and other postsynaptic partners. Intracellularly, the catalytically active D1 domain and scaffold-like D2 module, anchored to liprin-α, coordinate presynaptic vesicle release, postsynaptic receptor composition, and synaptic plasticity. Beyond synapses, PTPRD restrains embryonic neurogenesis, promotes STAT3-dependent gliogenesis, accelerates oligodendrocyte myelination, and guides Sema3a/Fyn-mediated axon and dendrite patterning. In the adult brain it serves as the high-affinity hypothalamic and cerebellar receptor for asprosin, thereby coupling systemic energy and hydration states to feeding and drinking behavior. Human genetic studies and mouse models link these molecular activities to a spectrum of conditions-including restless legs syndrome, addiction, Alzheimer's disease, ADHD, OCD, autism spectrum disorder, and metabolic syndrome. Because PTPRD functions are pathway-specific and shaped by mini-exon usage or redundancy with other family members (PTPRS/PTPRF), domain- or ligand-selective interventions represent plausible therapeutic strategies. Elucidating its full ligand repertoire, substrate landscape, and structural basis for allosteric regulation will be critical for converting this versatile receptor from a mechanistic curiosity into a tractable target for neurodevelopmental, neuropsychiatric, and metabolic disorders.},
}

@article {pmid41208522,
year = {2025},
author = {Wrigley, S and Huynh, ALH and Amadoru, S and Zeimer, H and Tan, I and Woodward, M and Braitberg, G and Yates, PA},
title = {Monoclonal Antibody Therapies in Alzheimer's Disease: A Guide for Emergency Physicians.},
journal = {Emergency medicine Australasia : EMA},
volume = {37},
number = {6},
pages = {e70167},
doi = {10.1111/1742-6723.70167},
pmid = {41208522},
issn = {1742-6723},
abstract = {Whilst the advent of novel disease-modifying medications for Alzheimer's disease represents potential benefit for patients and caregivers, they may be associated with adverse events that present important considerations for emergency and primary care. This article seeks to highlight some of the challenges Emergency Departments may encounter in relation to clinical presentations of people being treated with novel anti-amyloid monoclonal antibodies in the Australian context. Given the potential for harm if not recognised and managed appropriately, it is imperative that emergency clinicians are aware of possible treatment-related adverse events and have access to appropriate decision-making support and resources.},
}

@article {pmid41208407,
year = {2025},
author = {Ahn, SJ and Goya, B and Bertomo, C and Sciortino, R and Racchumi, G and Garcia Bonilla, L and Anrather, J and Iadecola, C and Faraco, G},
title = {Neutrophil stalling does not mediate the increase in tau phosphorylation and the cognitive impairment associated with high salt diet.},
journal = {Cardiovascular research},
volume = {},
number = {},
pages = {},
doi = {10.1093/cvr/cvaf217},
pmid = {41208407},
issn = {1755-3245},
abstract = {AIMS: High dietary salt intake has powerful effects on cerebral blood vessels and has emerged as a risk factor for stroke and cognitive impairment. In mice, high salt diet (HSD) leads to reduced cerebral blood flow (CBF), tau hyperphosphorylation and cognitive dysfunction. However, it is still unclear whether the reduced CBF is responsible for the effects of HSD on tau and cognition. Capillary stalling has been linked to cognitive impairment in models of Alzheimer's disease and diabetes. Therefore, we tested the hypothesis that capillary stalling also contributes to CBF reduction, tau accumulation, and cognitive impairment in HSD.

METHODS AND RESULTS: We used in vivo two-photon imaging to assess capillary stalling in C57BL6/J male mice fed a normal diet or HSD. We found that HSD increased stalling of neutrophils in brain capillaries and decreased CBF. Neutrophil depletion using anti-Ly6G antibodies reduced the number of stalled capillaries and restored CBF, measured by red blood cell speed. Despite the improved CBF, chronic neutrophil depletion did not rescue HSD-induced cognitive impairment, assessed by Barnes maze and nest building behavior. Furthermore, levels of phosphorylated tau in cortex and hippocampus remained elevated in HSD mice after neutrophil depletion.

CONCLUSIONS: These novel findings show that, capillary stalling contribute to CBF reduction in HSD, but not to tau phosphorylation and cognitive deficits. Therefore, the hypoperfusion caused by capillary stalling is not the main driver of the tau phosphorylation and cognitive impairment.},
}

@article {pmid41208143,
year = {2025},
author = {Zhang, ZY and Ding, T and Kong, J and Wang, QC and Zhang, XT and Shi, CM and Yang, JT and Liu, JF},
title = {Global Profiling of Lysine Ubiquitylation in the Human Hypothalamus.},
journal = {Proteomics. Clinical applications},
volume = {},
number = {},
pages = {e70029},
doi = {10.1002/prca.70029},
pmid = {41208143},
issn = {1862-8354},
support = {2023YFC2507102//National Key R&D Program of China/ ; CIFMS2022-I2M-1-011//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2022-I2M-2-001//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2021-I2M-1-057//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2021-I2M-1-049//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2021-I2M-1-044//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2021-I2M-1-016//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; CIFMS2021-I2M-1-001andCIFMS2022-I2M-1-020//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, China/ ; 82341064//National Natural Science Foundation of China/ ; 82090010//National Natural Science Foundation of China/ ; 82090011//National Natural Science Foundation of China/ ; 22HHXBSS00008//Haihe Laboratory of Cell Ecosystem Innovation Fund/ ; 22HHKYZX0034//Haihe Laboratory of Cell Ecosystem Innovation Fund/ ; 2060204//State Key Laboratory Special Fund/ ; },
abstract = {PURPOSE: Ubiquitylation is a vital post-translational modification involved in various biological processes, yet its role in the human hypothalamus remains largely unexplored. This study aims to profile the ubiquitinome of the human hypothalamus, uncovering the ubiquitylation landscape and its potential implications in hypothalamic function.

EXPERIMENTAL DESIGN: We employed LC‒MS/MS to analyze hypothalamic tissues from six healthy elderly individuals, focusing on identifying and characterizing ubiquitinated sites and proteins. Motif analysis, functional enrichment, and protein-protein interaction (PPI) network were conducted to profile the landscape.

RESULTS: Our analysis identified 21,815 ubiquitinated sites across 5314 proteins and five types of modification motifs in the normal human hypothalamus. Ubiquitinated proteins were predominantly localized to the cell membrane. Functional enrichment related to neuronal and endocrine pathways, especially with MAPK signaling. PPI network analysis focused on five ubiquitinated proteins, including PRKACA, PRKACB, PRKCA, PRKCB, and PRKCG. Additionally, we analyzed their relationship with E3 ligases using UbiBrowser.

This study offers the first comprehensive analysis of the human hypothalamic ubiquitinome. Our work provides a reliable foundation for future research into the implications of ubiquitylation in neuroendocrine-related disorders.

SUMMARY: The human hypothalamus is crucial in regulating metabolism, stress response, and circadian rhythms. Dysfunctions in these processes are linked to various disorders, including Alzheimer's disease, obesity, and sleep disorders. Although ubiquitylation is a key protein modification that affects cellular function, its specific role within the hypothalamus remains poorly understood. This study provides the first detailed profile of lysine ubiquitylation in the human hypothalamus, identifying over 21,000 ubiquitinated sites on more than 5000 proteins. The findings provide valuable insights into the ubiquitylation landscape, highlighting key ubiquitinated proteins and pathways that may be involved in neuroendocrine diseases. This research provides a foundation for future research and highlights the potential of ubiquitylation as a therapeutic target for neurological and endocrine disorders.},
}

@article {pmid41208074,
year = {2025},
author = {Gupta, RA and Rajni, and Shah, K and Dewangan, HK},
title = {Review on Molecular Targeting, Pharmacological Action, and Advanced Biopharmaceutical Aspects for the Management of Alzheimer's Disease.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128387875250805042824},
pmid = {41208074},
issn = {1873-4286},
abstract = {Alzheimer's disease (AD) is an ongoing progressive neurodegenerative disorder that predominantly affects elderly individuals. A systematic literature search was conducted using electronic databases such as PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trial reports, and experimental studies published in English within the last 15 years were considered. The keywords used for the search included "Alzheimer's disease," "amyloid-beta," "tau protein," "neuroinflammation," "immunotherapy," "drug repurposing," and "experimental treatment strategies." It is the most common form of dementia, ultimately leading to death in advanced stages. Recent advances in AD have featured the expected role of antiamyloid, anti-tau, and anti-inflammatory therapies. Nonetheless, these treatments are still in various stages of preclinical and clinical trials. Moreover, drug repurposing is another promising avenue to identify effective therapeutic alternatives for Alzheimer's disease. This review highlights the underlying pathophysiological mechanisms of AD along with the limits of existing treatments. It also includes two methodologies, specifically; active immunotherapy and passive immunotherapy. Active immunotherapy tactics include the administration of antigens to stimulate antibody production. Additionally, this study discusses several experimental drugs and novel pharmaceutical approaches for AD.},
}

@article {pmid41208050,
year = {2025},
author = {Mueller, KD and Soldan, A and Langhough, R and Bruno, D and Jauregi-Zinkunegi, A and Basche, K and Hale, MR and He, D and Moghekar, A and Hermann, B and Albert, M and Pettigrew, C},
title = {Proper Name Recall as an Early Indicator of Preclinical Alzheimer Disease Pathology.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000695},
pmid = {41208050},
issn = {1546-4156},
abstract = {BACKGROUND: Early detection of Alzheimer disease (AD) is crucial; however, standard neuropsychological tests often lack sensitivity. Process scores, such as proper name (PN) recall from Logical Memory, may improve the detection of AD-related biomarker positivity. We examined whether baseline PN recall predicted future cerebrospinal fluid (CSF) amyloid (Aβ42/Aβ40) and tau (pTau181) status, and whether biomarker status predicted PN recall trajectories.

METHODS: We analyzed 271 cognitively unimpaired BIOCARD participants (mean age=57.3, 60.3% female, mean follow-up=15.5) using logistic regression and mixed-effects models to examine the associations between PN recall and CSF biomarkers.

RESULTS: Higher baseline PN recall predicted lower amyloid positivity [odds ratio (OR)=0.72, P=0.015]. Amyloid and tau positivity have been linked to a faster decline in PN. Biomarker-positive participants in the biomarker-negative group lacked practice effects.

CONCLUSIONS: PN recall predicts future AD biomarker positivity and may enhance early detection of AD-related cognitive decline.},
}

@article {pmid41207874,
year = {2025},
author = {Luna-Viramontes, NI and Morlett-Paredes, A and Ordoñez-Lozano, I and de la Cruz-López, F and Gonzalez-Chavez, VE and Vargas-Hernández, G and Pérez-Pérez, EG and Méndez-Llaca, RE and Villanueva-Fierro, I and Ortiz-Butron, R and Hernandes-Alejandro, M and Garcés-Ramírez, L and Luna-Muñoz, J},
title = {Brain banks in Latin America: Infrastructure for diagnosis, research, and scientific equity in Mexico and the Caribbean.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70819},
doi = {10.1002/alz.70819},
pmid = {41207874},
issn = {1552-5279},
abstract = {The establishment of brain banks is a strategic initiative to advance research on neurodegenerative diseases in Latin America. This article highlights the development, operations, and multidisciplinary framework of the National Dementia BioBank in Mexico and the National Brain Bank in the Dominican Republic. Both centers focus on the molecular characterization of pathological proteins central to Alzheimer's disease, such as tau and amyloid beta. Standardized protocols have been implemented for tissue donation, preservation, and post mortem analysis. Beyond supporting diagnostics and research, these centers promote scientific literacy and public engagement through traveling exhibitions and outreach initiatives. Together, these brain banking efforts enhance regional scientific capacity, strengthen international collaboration, and advance the representation of historically underserved populations. Their work contributes to a more equitable and globally relevant neuroscience landscape, positioning Latin America as a growing contributor to translational research in aging and dementia. HIGHLIGHTS: Creation of two national brain banks in Mexico (National Dementia BioBank) and the Dominican Republic (National Brain Bank-UNPHU) with standardized protocols for donation, preservation, and post mortem analysis of tau and amyloid beta under international parameters. Integration of advanced histopathological and molecular diagnostic platforms combining classical stains (H&E, Bielschowsky) with immunoperoxidase, multiplex immunofluorescence staining, confocal microscopy, and AI-powered automated analysis for quantification and recognition of topographic patterns. Design of an inclusive tissue collection model that prioritizes the genomic and sociocultural representation of mestizo, Afro-Caribbean, and Indigenous populations, reducing Eurocentric bias and enhancing the global validity of studies on Alzheimer's and other dementias. Development of a culturally sensitive, ethical, and neuroethical framework, with an informed consent process accessible in multiple languages and literacy levels, and safeguarding confidentiality through rigorous data coding. Implementation of innovative outreach strategies (traveling exhibitions, augmented/virtual reality, public lectures) to promote a culture of brain donation and democratize knowledge about neurodegeneration in diverse communities.},
}

@article {pmid41207870,
year = {2025},
author = {Magana-Ramirez, CM and Gillen, DL and Hom, CL and Jaimes, L and Chilukuri, SS and McMahon, N and Lin, C and Kuhlman, R and Hu, T and Head, E and Lott, IT and Sultzer, DL},
title = {Neuropsychiatric symptoms and emerging dementia in people with Down syndrome and older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70871},
doi = {10.1002/alz.70871},
pmid = {41207870},
issn = {1552-5279},
support = {P30AG066519//NIH/NIA/ ; R25AI170491//NIH/NIAID/ ; DGE-1839285//NSF/ ; UO1 AG051406//NIA/NICHD/ ; UO1 AG051412//NIA/NICHD/ ; U24 AG072122/AG/NIA NIH HHS/United States ; P30AG062429//NIA/NIH/ ; P30AG066468//NIA/NIH/ ; P30AG062421//NIA/NIH/ ; P30AG066509//NIA/NIH/ ; P30AG066514//NIA/NIH/ ; P30AG066530//NIA/NIH/ ; P30AG066507//NIA/NIH/ ; P30AG066444//NIA/NIH/ ; P30AG066518//NIA/NIH/ ; P30AG066512//NIA/NIH/ ; P30AG066462//NIA/NIH/ ; P30AG072979//NIA/NIH/ ; P30AG072972//NIA/NIH/ ; P30AG072976//NIA/NIH/ ; P30AG072975//NIA/NIH/ ; P30AG072978//NIA/NIH/ ; P30AG072977//NIA/NIH/ ; P30AG066519//NIA/NIH/ ; P30AG062677//NIA/NIH/ ; P30AG079280//NIA/NIH/ ; P30AG062422//NIA/NIH/ ; P30AG066511//NIA/NIH/ ; P30AG072946//NIA/NIH/ ; P30AG062715//NIA/NIH/ ; P30AG072973//NIA/NIH/ ; P30AG066506//NIA/NIH/ ; P30AG066508//NIA/NIH/ ; P30AG066515//NIA/NIH/ ; P30AG072947//NIA/NIH/ ; P30AG072931//NIA/NIH/ ; P30AG066546//NIA/NIH/ ; P30AG086401//NIA/NIH/ ; P30AG086404//NIA/NIH/ ; P20AG068082//NIA/NIH/ ; P30AG072958//NIA/NIH/ ; P30AG072959//NIA/NIH/ ; },
abstract = {INTRODUCTION: Neuropsychiatric symptoms (NPS) are common as Alzheimer's disease (AD) dementia emerges, both in older adults (OA) and in individuals with Down syndrome (DS).

METHODS: We compared neuropsychiatric inventory (NPI) scores and NPI score trajectories in large cohorts of individuals with DS and OA. Participants were stratified as cognitively normal/stable, mild cognitive impairment, or dementia.

RESULTS: The pattern of NPI domain scores in cohorts with DS (n = 396) or OA (n = 35,217) were qualitatively similar across the cognitive groups. The relationships between cognitive group and both the NPI total score and the rate of NPI score change over time were similar in the two cohorts (multivariate Wald test, p = 0.28 and p = 0.52, respectively).

DISCUSSION: These findings support a conjecture that the shared pathophysiology among individuals with DS and OA may be reflected in the similar clinical profiles and clinical trajectories. NPS are important considerations in the early diagnosis and clinical management.

HIGHLIGHTS: Neuropsychiatric symptoms (NPS) often precede cognitive decline in late-onset AD. People with Down syndrome (DS) are a vulnerable population for AD. Psychiatric symptoms in people with DS and emergent dementia are poorly understood. Symptoms in people with DS and older adults (OA) were similar across cognitive groups. Similar symptoms in the two groups may reflect shared amyloid or related pathology.},
}