@article {pmid41735834,
year = {2026},
author = {Xiong, C and Agboola, F and Luo, J},
title = {Estimating the baseline age when longitudinal changes in biomarkers accelerate: application to an imaging study of preclinical Alzheimer disease.},
journal = {BMC medical research methodology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12874-026-02806-3},
pmid = {41735834},
issn = {1471-2288},
support = {P30 AG066444, P01 AG03991, P01 AG026276, R01 AG067505, U19AG071754, U19AG069701/NH/NIH HHS/United States ; },
}

@article {pmid41735635,
year = {2026},
author = {Fieldhouse, R},
title = {China is waging war on Alzheimer's. What can its approach teach the rest of the world?.},
journal = {Nature},
volume = {650},
number = {8103},
pages = {816-818},
pmid = {41735635},
issn = {1476-4687},
}

@article {pmid41735609,
year = {2026},
author = {Gad, SR and George, MY and El-Gogary, RI and Hathout, RM},
title = {Breaking Barriers: Intranasal Microemulsions for the Efficient Nose-to-brain Delivery of Glycyrrhetinic Acid.},
journal = {AAPS PharmSciTech},
volume = {27},
number = {3},
pages = {},
pmid = {41735609},
issn = {1530-9932},
mesh = {Animals ; *Glycyrrhetinic Acid/administration & dosage/chemistry/pharmacokinetics ; Administration, Intranasal/methods ; Emulsions/chemistry/administration & dosage ; Rats ; *Brain/metabolism/drug effects ; Nasal Mucosa/metabolism/drug effects ; Male ; Sheep ; Drug Delivery Systems/methods ; Particle Size ; Rats, Sprague-Dawley ; Drug Carriers/chemistry ; Alzheimer Disease/drug therapy ; },
abstract = {Herbal drugs have been investigated for multiple neurodegenerative diseases because of their multi-targeted mechanisms of action and relatively low toxicity profile. However, due to their unfavorable physicochemical properties that limit their action, nanocarriers are warranted to enhance their delivery and hence their therapeutic effect. In this study, an intranasal microemulsion (ME) of the lipophilic molecule glycyrrhetinic acid (GA), a triterpenoid derived from licorice root that is widely known for its antioxidant and anti-inflammatory properties, was developed for the treatment of Alzheimer's disease (AD). Pseudo-ternary phase diagrams were constructed and the prepared ME systems were optimized using Simplex lattice mixture experimental design. The selected loaded lauroglycol MEs (GA-ME LG) were of droplet size 5.61 ± 0.01 nm and PDI of 0.521 ± 0.032. They showed a significantly high physical stability up to 3 months at room temperature and in the refrigerator. The ex vivo permeation study across sheep nasal mucosa revealed that GA-loaded ME LG exhibited a significant increase in steady-state flux after 8 h compared to GA suspension by 5.67-fold (p < 0.05). SCOP-induced memory impairment in rats was ameliorated by intranasal injection of GA ME LG at a concentration of 1 mg/kg, in a comparable way to the oral route (at a dosage 50 times higher than MEs) (p < 0.05). Additionally, GA ME LG counteracted SCOP-induced oxidative damage (p < 0.05). Collectively, GA-loaded MEs can deliver GA to the brain efficiently and might offer potential treatment for AD patients.},
}

Animals
*Glycyrrhetinic Acid/administration & dosage/chemistry/pharmacokinetics
Administration, Intranasal/methods
Emulsions/chemistry/administration & dosage
Rats
*Brain/metabolism/drug effects
Nasal Mucosa/metabolism/drug effects
Male
Sheep
Drug Delivery Systems/methods
Particle Size
Rats, Sprague-Dawley
Drug Carriers/chemistry
Alzheimer Disease/drug therapy

@article {pmid41735428,
year = {2026},
author = {Li, F and Chen, K and Zhang, T and Xu, L and Gu, X and Lin, J and Jiang, J},
title = {Menstrual and reproductive factors and risk of Alzheimer's disease in elderly women: a cohort study in Eastern China.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-40329-5},
pmid = {41735428},
issn = {2045-2322},
support = {LTGY24H260004//Zhejiang Provincial Natural Science Foundation of China/ ; LGF21H260002//Zhejiang Provincial Public Welfare Technology Application Research Project of China/ ; 2024KY891//Medical Health Science and Technology Project of Zhejiang Provincial Health Commission/ ; },
abstract = {Epidemiological studies suggest that proxies of lifetime estrogen exposure are associated with the risk of Alzheimer's disease (AD). However, results remain limited and inconsistent. This study aimed to examine whether menstrual and reproductive factors, proxies of estrogen exposure, are associated with the risk of AD in Chinese postmenopausal women. Information on menstrual and reproductive factors was obtained through the baseline survey of the Zhejiang Ageing and Health Cohort Study. During the three follow-up waves, AD diagnoses were conducted. We excluded participants with prevalent cognitive impairment or incomplete data of cognitive assessment at baseline, and incident cases of cognitive impairment without AD diagnosis across follow-up. Log-binomial model and the generalized additive model (GAM), controlled for a wide range of potential confounders, were generated to examine the association. Finally, 5606 women were included, and 597 developed AD during follow-up. The age of participants ranged from 60 to 95 years (mean = 65.7 years, SD = 6.5) at baseline. Women with a longer reproductive lifespan (> 34 years, compared with 32-34 years) had a lower risk of AD (RR = 0.81, 95% CI 0.67-0.98). Menopause due to ovariectomy was associated with a higher risk of AD (RR = 2.17, 95% CI 1.16-4.08), compared to those with natural menopause. The shorter length of menstrual cycles (≤ 27 days, compared with 28-30 days) was associated with an increased risk of AD (RR = 1.47, 95% 1.15-1.87), and shorter length of menstrual period (≤ 3 days, compared with 4-6 days) was associated with a decreased risk of AD (RR = 0.73, 95% 0.59-0.90). Women with 2 or more parity showed a higher risk of AD, while women with 2 or more miscarriages and abortions had a lower risk of AD. Older age at first childbirth (> 22 years, compared with 21-22 years) was associated with a decreased risk of AD (RR = 0.47, 95% CI 0.38-0.58). A U-shaped association was identified between mean breastfeeding duration and AD. Oral contraceptive use was also associated with an increased risk of AD. Our results show that menstrual and reproductive factors are statistically significantly associated with the risk of AD in Chinese postmenopausal women.},
}

@article {pmid41735210,
year = {2026},
author = {Ashesh, AM and Gupta, S and Jawaid, T and Wal, P and Bhise, MR and Kumar, A and Gasmi, A},
title = {Antibody Therapies Targeting Amyloid-β and Tau in Alzheimer's Disease with Insights on Mechanisms, Clinical Trials, and Challenges.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266418206251122102530},
pmid = {41735210},
issn = {1873-4294},
abstract = {Alzheimer's Disease (AD) is characterized by amyloid-β (Aβ) deposits and neurofibrillary tangles containing phosphorylated tau protein. Around 57 million people worldwide were estimated by the World Health Organization to have dementia in 2021, with AD being the most prevalent type. The burden of AD is still rising. By 2036, there will likely be close to 20 million AD cases worldwide, according to projections that show a sharp increase brought on by population aging. Normal neural transmission is disrupted with Aβ plaques and hyperphosphorylated tau tangles, eventually resulting in the death of neurons and cognitive impairment. Currently, no therapies provide a cure; available treatments are symptomatic. The main focus of scientists has been on targeting Aβ and tau proteins. A number of anti-Aβ and anti-tau monoclonal antibody therapies targeting the buildup of Aβ and tau in the brain have been discovered recently. An announcement was made in September 2022 regarding the phase 3 research, suggesting Lecanemab had achieved its main objective of slowing the progression of clinical dementia. The CLARITY AD Phase 3 trial, which was published in the New England Journal of Medicine on January 5, 2023, assessed lecanemab, a monoclonal antibody, in patients with early-stage Alzheimer's disease or Mild Cognitive Impairment (MCI) brought on by Alzheimer's disease who had biomarker evidence of amyloid pathology. Lecanemab showed a statistically significant, although clinically modest, slowing of decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) in the 18-month double-blind, placebocontrolled trial. Clinical worsening was reduced by 27% when compared to placebo (mean difference of -0.45; 95% CI: -0.67 to -0.23). Similar modest benefits were observed across quality of life and daily functioning measures, and all primary and secondary cognitive and functional endpoints were met. The change in CDR-SB fell short of the minimal clinically significant difference that is frequently mentioned for this patient population, and the observed clinical benefit is typically characterized as small to moderate. Crucially, lecanemab-treated participants had a higher incidence of amyloidrelated imaging abnormalities (ARIA) such as edema and microhemorrhages (about 21.5%) than the placebo group (about 9%). Although the majority of ARIA events were controllable, there were a few documented instances of severe consequences, especially when anticoagulation was used. On 9th June 2023, an FDA advisory group unanimously decided that Lecanemab demonstrates clinical benefits for therapy of early Alzheimer's disease, marking the opening door for full approval. The results demonstrate lower Aβ and tau, a real therapeutic advantage, going beyond simple alterations in biomarkers, representing a major breakthrough in the treatment of AD. This review provides a summary of mechanisms, results of the clinical trials of anti-tau and anti-Aβ antibody treatments up to February 2024, as well as recommendations for their future developments.},
}

@article {pmid41735175,
year = {2026},
author = {Piccialli, I and Roviello, G and Magliocca, G and Esposito, E and Pannaccione, A},
title = {Exploring Linalool-Based Phytotherapy for Excitatory/Inhibitory Imbalance in Alzheimer's Disease: A Review of Lavender and Cannabis Therapeutic Effects on Sleep, Seizures, and Cognition.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70191},
pmid = {41735175},
issn = {1099-1573},
support = {2022ZTKFXS//Italian Ministry of University and Research (MUR), under the PRIN 2022 Program/ ; PE0000006//MUR under the PNRR Program/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral disturbances. While its pathogenesis is complex, increasing evidence supports the role of an imbalance between excitatory and inhibitory (E/I) neuronal activity in disease progression. E/I imbalance contributes to synaptic impairment, network hypersynchrony, and ultimately cognitive deterioration. Despite advances in understanding AD pathophysiology, no highly effective or disease-modifying treatments are currently available. This review explores the pharmacological properties of linalool, a monoterpene found in high concentrations in Lavandula angustifolia and in Cannabis sativa L. as minor component, which has demonstrated several neuromodulatory effects. Unlike current AD therapies that typically target cholinergic or NMDA-mediated mechanisms in isolation, linalool exerts a multi-target action that may help restore E/I balance. These effects also underlie its well-established anxiolytic and sedative properties, though their therapeutic relevance extends beyond behavioral symptoms to include the modulation of neuronal network function in neurodegeneration. We also examine studies on lavender extracts, rich in linalool, with the potential to influence sleep regulation, neuronal excitability, and cognitive function. Finally, we discuss the emerging role of cannabis extracts and the potential entourage effect of linalool and phytocannabinoids in targeting neuronal excitability. Overall, the findings discussed in the present review highlight linalool-containing phytocomplexes as promising candidates for supportive or complementary strategies in managing E/I imbalance and cognitive decline in AD.},
}

@article {pmid41735150,
year = {2026},
author = {Burry, E and Plumacker, F and Villain, N and Amaral, S and Damier, P and Delrieu, J and Mackowiak, MA and Michalon, R and Mohr, S and Planche, V and Rollin-Sillaire, A and Tannou, T and Wallon, D and Desmoulin Canselier, S and Lebouvier, T and François, G},
title = {Simulated shared and supported decision making for amyloid immunotherapy in Alzheimer's disease: A bicentric study.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2026.01.267},
pmid = {41735150},
issn = {0035-3787},
abstract = {Lecanemab, the first anti-amyloid therapy approved by the European Medicines Agency, has demonstrated a statistically and clinically significant but moderate slowing of decline in early Alzheimer's disease (AD). In contrast, its long-term impact on the disease course is not formally established. Any benefit, therefore, needs to be carefully weighed against its adverse effects and practical constraints, which must be discussed with patients and caregivers within a shared decision-making process (SMD). However, applying SDM in this context is challenging due to treatment complexity, cognitive impairment and the involvement of care partners. Supported decision-making, which aims to assist individuals with decisional limitations in participating in important choices, has been promoted as a relevant approach. In this bicentric study conducted in France, we evaluated a simulated supported decision-making process in 25 patients with early AD who were eligible for lecanemab and faced the decision to choose anti-amyloid immunotherapy. We created a written decision aid using a consensus-based method to provide clear, accurate, and scientifically validated information to patients and care partners. After a one-week reflection period, both patients and care partners demonstrated a good overall understanding of the information provided, though care partners showed higher levels of comprehension and retention. The treatment was considered acceptable by most patients and their care partners. While patients ultimately remain the decision-makers, these findings highlight the central role of care partners in strengthening supported decision-making, notably through frameworks such as the French "trusted person" model.},
}

@article {pmid41735073,
year = {2026},
author = {Li, L and Zhang, RZ and Ma, C and Wei, YT and Dou, TT and Yan, XK},
title = {[Research progress on the mechanism of acupuncture improving Alzheimer's disease by regulating mitochondrial function].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {2},
pages = {240-248},
doi = {10.13702/j.1000-0607.20241297},
pmid = {41735073},
issn = {1000-0607},
mesh = {*Alzheimer Disease/therapy/metabolism/genetics/physiopathology ; Humans ; *Acupuncture Therapy ; *Mitochondria/metabolism/genetics ; Animals ; },
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disease, and mitochondrial dysfunction is closely related to the pathogenesis of AD. Acupuncture is one of the effective methods for treating AD, which can significantly improve AD symptoms and delay disease progression, and research on its mechanism of action has been continuously deepened. This article combs and summarizes the relevant studies on acupuncture regulating mitochondrial function to improve AD. The results show that acupuncture restores and maintains mitochondrial function mainly by protecting mitochondrial morphology and structure, improving mitochondrial dynamics, regulating mitochondrial energy metabolism, modulating mitophagy, maintaining mitochondrial calcium homeostasis, reducing oxidative stress damage, and inhibiting cell apoptosis, thereby exerting a therapeutic effect on AD. Existing studies have limitations, such as focusing more on single factor of mitochondrial dysfunction, rarely considering the involvement mechanism of other cells besides neurons, incomplete experimental design schemes, and failing to consider the connection between disease stages and mitochondrial dysfunction. Future studies need to explore the functional status of mitochondria at different stages of AD pathogenesis and the specific regulatory effect of acupuncture.},
}

*Alzheimer Disease/therapy/metabolism/genetics/physiopathology
Humans
*Acupuncture Therapy
*Mitochondria/metabolism/genetics
Animals

@article {pmid41734984,
year = {2026},
author = {Lee, JH and Heo, SJ and Ryu, HE and Park, B and Kwon, YJ},
title = {Differential Associations of Lipid Profiles with Dementia and Cardiovascular Disease: Findings from the UK Biobank Cohort.},
journal = {Yonsei medical journal},
volume = {67},
number = {3},
pages = {223-237},
doi = {10.3349/ymj.2025.0046},
pmid = {41734984},
issn = {1976-2437},
support = {321030051HD030/iPET/Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries/Korea ; },
mesh = {Humans ; *Cardiovascular Diseases/blood ; Male ; Female ; United Kingdom/epidemiology ; *Dementia/blood ; Aged ; Prospective Studies ; Biological Specimen Banks ; Cholesterol, HDL/blood ; Middle Aged ; Cholesterol, LDL/blood ; *Lipids/blood ; Triglycerides/blood ; Alzheimer Disease/blood ; Cholesterol/blood ; Risk Factors ; Cohort Studies ; UK Biobank ; },
abstract = {PURPOSE: Lowering low-density lipoprotein cholesterol (LDL-C) is crucial for cardiovascular disease (CVD) prevention, but its impact on cognitive function-and the potential differences by dementia subtype and cholesterol-lowering medication use-remain unclear. This study aimed to examine the associations between lipid levels and dementia and CVD risks, considering dementia subtypes and cholesterol-lowering medication use.

MATERIALS AND METHODS: A prospective cohort study was conducted using UK Biobank data. Serum lipid levels, including LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol, and remnant cholesterol, were categorized into clinically relevant ranges. Accounting for cholesterol-lowering medication use, the primary outcomes were incident all-cause dementia, Alzheimer's dementia (AD), vascular dementia (VD), and CVD.

RESULTS: High LDL-C (≥160 mg/dL) increased AD risk across all groups {hazard ratio (HR): 1.23 [95% confidence interval (CI): 1.10-1.38], p<0.001; HR: 1.45 (95% CI: 1.08-1.93), p=0.013; HR: 1.25 (95% CI: 1.10-1.42), p<0.001, respectively},
whereas low LDL-C (<70 mg/dL) showed higher VD risk in those not taking cholesterol-lowering medication [HR: 3.02 (95% CI: 1.73-5.27), p<0.001]. Low HDL-C (≤40 mg/dL) was associated with increased AD and VD risk in non-users. High LDL-C (≥160 mg/dL) was associated with increased CVD risk in those taking cholesterol-lowering medication.

CONCLUSION: This study underscores the differential associations of lipid levels with dementia and CVD risk, depending on dementia subtype and cholesterol-lowering medication use. High LDL-C was linked to increased AD risk, whereas low LDL-C was linked to increased VD risk in those not taking cholesterol-lowering medication.},
}

Humans
*Cardiovascular Diseases/blood
Male
Female
United Kingdom/epidemiology
*Dementia/blood
Aged
Prospective Studies
Biological Specimen Banks
Cholesterol, HDL/blood
Middle Aged
Cholesterol, LDL/blood
*Lipids/blood
Triglycerides/blood
Alzheimer Disease/blood
Cholesterol/blood
Risk Factors
Cohort Studies
UK Biobank

@article {pmid41734883,
year = {2026},
author = {Bloschichak, A and Yang, MT and Makineni, R and Qin, Q and Temkin-Greener, H and Conwell, Y and Cai, S},
title = {Disparities in the Setting of Initial Dementia Diagnosis: Influence of Race, Ethnicity, and Primary Care Use.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106142},
doi = {10.1016/j.jamda.2026.106142},
pmid = {41734883},
issn = {1538-9375},
abstract = {OBJECTIVE: Prior studies noted differences in care setting for initial diagnosis of Alzheimer disease and related dementias (ADRD), but racial and ethnic differences in first diagnosis setting remains unclear. This study investigates the differences in ADRD diagnosis by race and ethnicity and examines the association of these differences with primary care use.

DESIGN: We conducted a retrospective cohort study using 2022 Medicare Fee-for-Service (FFS) claims and enrollment files.

SETTING AND PARTICIPANTS: We analyzed individuals aged 65 years or older newly diagnosed with ADRD between July 1 and December 31, 2022. Our sample included 246,471 individuals.

METHODS: The main exposures of interest were race and ethnicity and recent primary care use (≥1 visit to a primary care provider in the 6 months prior to diagnosis). The primary outcome was setting of first ADRD diagnosis, categorized as community (eg, outpatient clinic, primary care office, specialist office), acute (inpatient or emergency department), or skilled nursing facilities or nursing homes (SNFs/NHs). We applied adjusted multinomial logistic regression models and quantified differences in probabilities with marginal effects.

RESULTS: Among the 246,471 beneficiaries with newly diagnosed ADRD, 50.4% were diagnosed in the community, 40.4% in acute settings, and 9.2% in SNFs/NHs. In the absence of primary care use, Black individuals were 2.7 percentage points (pp) less likely than White individuals to be diagnosed in the community. The opposite trends were seen for Hispanic (+4.6 pp) and Asian (+15.8 pp) individuals. With recent primary care use, these differences narrowed (+14.3 pp) for Asian, widened (+8.0 pp) for Hispanic, and were no longer observed (+1.2, P > .05) for Black individuals.

CONCLUSIONS AND IMPLICATIONS: Significant racial and ethnic differences existed in the settings in which ADRD diagnoses are made. Primary care engagement increased community-based diagnoses and reduced Black-White disparities, underscoring its role in promoting earlier ADRD detection.},
}

@article {pmid41734754,
year = {2026},
author = {Yoon, SH and Yuk, JS},
title = {Association between hysterectomy and dementia risk in Korean women aged 40-59: a nationwide retrospective cohort study.},
journal = {Obstetrics & gynecology science},
volume = {},
number = {},
pages = {},
doi = {10.5468/ogs.25364},
pmid = {41734754},
issn = {2287-8572},
abstract = {OBJECTIVE: To determine whether hysterectomy for benign diseases is associated with the risk of dementia in middle-aged women.

METHODS: We conducted a retrospective cohort study using data from the Korean National Health Insurance Service database (2002-2020). Women aged 40-59 years who underwent hysterectomy for benign indications (n=16,818) were propensity score-matched (1:1) to controls who had not received hysterectomy. Subjects were followed up until the diagnosis of dementia, death, or the end of the study period (2020). Dementia (all types), Alzheimer's disease (AD), and vascular dementia (VaD) were identified by International Classification of Diseases, 10th revision codes. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for dementia associated with hysterectomy.

RESULTS: Median follow-up was 11.4 years. Dementia occurred in 302 (1.8%) women who did not undergo hysterectomy and 257 (1.5%) women who underwent hysterectomy (P=0.061). Cox analysis revealed that hysterectomy was not significantly associated with all-cause dementia (HR, 0.865; 95% CI, 0.724-1.033), with a non-significant trend towards reduced risk. Subgroup analysis also failed to identify any significant association; AD (HR, 0.696; 95% CI, 0.463-1.048) and VaD (HR, 0.625; 95% CI, 0.284-1.377) were not elevated. These findings held across age subgroups and sensitivity analyses (e.g., laparoscopic hysterectomy: HR, 0.959; 95% CI, 0.691-1.331).

CONCLUSION: In this large Korean cohort, hysterectomy for benign diseases in women aged 40-59 years was not associated with a significant change in the subsequent risk of dementia. Collectively, our results indicate that hysterectomy (with or without adnexal surgery) did not increase the incidence of dementia.},
}

@article {pmid41734662,
year = {2026},
author = {Alam, P and Hasan, GM and Mohammad, T and Hassan, MI},
title = {Next-generation computational strategies for neurodegenerative biomarkers: Multi-omics integration, AI, and molecular modeling.},
journal = {Computational biology and chemistry},
volume = {123},
number = {},
pages = {108973},
doi = {10.1016/j.compbiolchem.2026.108973},
pmid = {41734662},
issn = {1476-928X},
abstract = {Neurodegenerative diseases (NDs) are progressively debilitating conditions driven by complex molecular perturbations and selective neuronal loss. Conventional approaches to discovering biomarkers, using single-omics or empirical screening, often fail to capture the multi-factorial nature of these disorders. It is now possible to integrate large-scale omics data with structural and molecular modeling methods to reveal mechanistically relevant biomarkers using integrative computational biology. Here, we review recent advances in integrative computational strategies that combine multi-omics, encompassing genomics, transcriptomics, proteomics, and metabolomics, with structural bioinformatics and molecular modeling to identify mechanistically informative biomarkers. We cover systems-level and network-based integration methods, machine learning (ML) and artificial intelligence (AI) frameworks, and structure-guided validation approaches, including homology/AI-based modeling, molecular docking, and molecular dynamics. We also discuss case studies illustrating how omics-based predictions are validated through protein structure modeling to identify key biomarkers and therapeutic targets. Finally, we discuss major challenges, such as data heterogeneity, reproducibility, and limitations of structural modeling, and emerging trends, such as AI-powered multi-omics, single-cell spatial profiling, and digital twin simulations. Together, the integrative computational strategies are likely to accelerate the discovery of reliable, mechanistically informative, and clinically translatable biomarkers for precision medicine in NDs.},
}

@article {pmid41734660,
year = {2026},
author = {Elyse Moore, M and Karakaya, E and Altinbas, O and Bartlett, MJ and Adilbay, D and Ergul, A and Yagmurlu, K and Albayram, M and Albayram, O},
title = {Disrupted drainage in the aging brain: Meningeal lymphatic decline as a convergent axis of vulnerability.},
journal = {Neurobiology of aging},
volume = {162},
number = {},
pages = {30-48},
doi = {10.1016/j.neurobiolaging.2026.02.002},
pmid = {41734660},
issn = {1558-1497},
abstract = {The aging brain depends on coordinated fluid transport, immune surveillance, and clearance of metabolic byproducts to preserve cognitive and physiological homeostasis. While peripheral lymphatic decline is well established, growing evidence implicates brain-draining lymphatic pathways, particularly meningeal lymphatic vessels and their downstream drainage to deep cervical lymph nodes, as an aging-sensitive axis that intersects with neuroinflammation and neurodegenerative vulnerability. Here, we systematically analyzed peer-reviewed studies published between 2003 and 2025 that examined age-related changes in intracranial and cervical lymphatic circuits across human imaging, histopathology, and experimental models. Ninety-six studies met the inclusion criteria. Four themes emerged. First, aging is associated with coordinated lymphatic remodeling across peripheral and central compartments, including reduced vessel integrity, stromal remodeling, and involution of draining lymph nodes. Second, meningeal lymphatic vessels exhibit age-related, region-specific structural and molecular alterations that may coincide with impaired cerebrospinal and interstitial fluid handling and altered immune regulation. Third, advanced magnetic resonance imaging, including contrast-enhanced and non-contrast approaches, reveals reproducible age-associated changes in dural and cervical lymphatic-related signals across the lifespan, while remaining an indirect proxy for flow and transport. Fourth, early therapeutic efforts suggest that brain-draining lymphatic function may be modifiable. These approaches include augmenting meningeal lymphangiogenic signaling with VEGF-C or its cofactor; and, in selected translational settings. Collectively, the evidence supports meningeal and cervical lymphatic decline as a plausible, potentially modifiable contributor to aging-related brain vulnerability across disorders such as Alzheimer's disease and Parkinson's disease, while underscoring the need for more direct functional measurements and longitudinal human studies.},
}

@article {pmid41734659,
year = {2026},
author = {Chuwa, F and Rainey-Smith, SR and Al Shamsi, HSS and Sohrabi, HR and Taddei, K and Masters, CL and Martins, RN and Gardener, SL and , },
title = {Higher sodium intake is associated with episodic memory decline in cognitively unimpaired older males: A 6-year longitudinal study.},
journal = {Neurobiology of aging},
volume = {162},
number = {},
pages = {22-29},
doi = {10.1016/j.neurobiolaging.2026.02.003},
pmid = {41734659},
issn = {1558-1497},
abstract = {Recent evidence has suggested an association between high sodium intake and development of cognitive impairment. However, while animal studies demonstrate consistent relationships between sodium intake and cognitive impairment, this relationship remains less clear in humans. Our aim was to investigate the relationship between self-reported baseline sodium intake and cognitive decline over 72 months. Cognitively unimpaired participants (n = 1208) from the Australian Imaging, Biomarkers and Lifestyle study were included (70.87 years of age; 41 % male). Participants completed a food frequency questionnaire to quantify sodium intake and underwent comprehensive neuropsychological assessment at baseline and four additional timepoints, 18 months apart. Scores for six cognitive composite domains were generated. Linear mixed models examined associations between baseline sodium intake and cognitive decline including potential confounders in the cohort as a whole and when stratified by sex and Apolipoprotein E status. Following false discovery rate adjustment, there was a negative association between sodium intake and change in the episodic recall composite in males (β=-0.00002; SE=0.00001; FDR adjusted p = 0.044), such that males with higher sodium intake showed faster decline in episodic recall. No associations were observed in the cohort as a whole or in females. No associations were observed when the cohort was stratified by Apolipoprotein E status. Further investigation, including sex-specific approaches, is required to evaluate how sodium intake could be incorporated as one modifiable lifestyle factor aimed at delaying Alzheimer's disease onset.},
}

@article {pmid41734592,
year = {2026},
author = {Zhang, D and Zheng, H and Cui, K and Li, Y and Liu, C and Mao, J and Zheng, J and Wan, Y},
title = {Nicotinic acetylcholine receptors-targeting drug discovery.},
journal = {European journal of medicinal chemistry},
volume = {308},
number = {},
pages = {118679},
doi = {10.1016/j.ejmech.2026.118679},
pmid = {41734592},
issn = {1768-3254},
abstract = {Nicotinic acetylcholine receptors (nAChRs) are a family of pentameric ligand-gated ion channels with diverse subunit compositions and subtype-specific functional profiles, such as in neurotransmission and inflammatory modulation. The central involvement of nAChRs in neurological and psychiatric disorders has these receptors as compelling therapeutic targets, especially for nicotine addiction, Alzheimer's disease, schizophrenia, attention-deficit/hyperactivity disorder, and pain disorders. Recent advances in nAChRs structural biology have revealed detailed mechanisms of ligand binding at orthosteric and allosteric sites, and rational drug design leveraging natural toxin-derived peptides and small molecules have yielded many nAChR subtype-selective agonists, antagonists, and allosteric modulators. Despite clinical success with some candidate drugs like nicotine patch and varenicline for smoking cessation, broader therapeutic application has been limited by challenges in receptor selectivity, desensitization, and off-target effects. Here, we provide a concise overview of nAChR structural biology, outline the physiological and pathological significance of distinct receptor subtypes, and offer a comprehensive review of the progress in the discovery of nAChR-targeting ligands, either of natural toxins or small molecules, in preclinical conditions and their advances in clinical trials. We also discuss the prevailing challenges while underscoring emerging opportunities for future therapeutic innovation.},
}

@article {pmid41734527,
year = {2026},
author = {Sun, W and Wei, Y and Liu, X and Chen, J and Zhu, H and Mao, C and Jin, B},
title = {Cathodic electrochemiluminescence biosensing based on In2Se3/Ag3PO4 composite for sensitive detection of p-Tau181 protein.},
journal = {Talanta},
volume = {305},
number = {},
pages = {129550},
doi = {10.1016/j.talanta.2026.129550},
pmid = {41734527},
issn = {1873-3573},
abstract = {This study presents a highly sensitive cathodic electrochemiluminescence (ECL) biosensor for the detection of p-Tau181 protein, a critical biomarker for Alzheimer's disease. The biosensor utilizes a novel In2Se3/Ag3PO4 composite as the ECL emitter. By doping Ag3PO4 with In2Se3, the band structure is precisely modulated, which significantly enhances the ECL intensity and stability by improving charge separation efficiency and electron transfer rates. CeO2@polydopamine (PDA) core-shell nanoparticles serve as an efficient energy acceptor, quenching the ECL signal via an ECL resonance energy transfer (ECL-RET) mechanism. The biosensor was constructed in a sandwich immunoassay format, where the specific binding of the target p-Tau181 protein brings the CeO2@PDA-Ab2 conjugate into close proximity with the In2Se3/Ag3PO4-modified electrode, resulting in a concentration-dependent signal quenching. Under optimal conditions, the biosensor demonstrated a wide linear detection range from 10 pg/mL to 150 ng/mL (R[2] = 0.997) and an ultralow detection limit of 3.2 pg/mL (S/N = 3). It exhibited excellent specificity against potential interferents, outstanding stability, and was successfully applied to the detection of p-Tau181 in spiked human serum samples with satisfactory recovery rates. This work provides a promising and reliable platform for the early diagnosis and monitoring of Alzheimer's disease.},
}

@article {pmid41734411,
year = {2026},
author = {Hildesheim, FE and Jamison, KW and Leppert, IR and Zumbansen, A and Ophey, A and Funck, T and Kuceyeski, A and Thiel, A and , },
title = {Evaluating structural connectivity disruption after stroke: individual tractography or the use of a model-based approach?.},
journal = {NeuroImage. Clinical},
volume = {49},
number = {},
pages = {103967},
doi = {10.1016/j.nicl.2026.103967},
pmid = {41734411},
issn = {2213-1582},
abstract = {BACKGROUND: Ischemic stroke disrupts structural connectivity between grey matter regions, influencing functional outcomes. Diffusion MRI-based tractography allows assessment of white matter damage and may guide rehabilitation. It remains unclear how structural connectivity disruption (SCD) estimated from individual tractography compares with model-based estimates using normative tractograms.

METHODS: Diffusion MRI data were analyzed from 23 individuals with subacute ischemic stroke and 60 healthy adults from two age-specific cohorts (Human Connectome Project/HCP, Alzheimer's Disease Neuroimaging Initiative/ADNI3). In Experiment 1, SCD estimates from individual tractography were compared to scores from the model-based Network Modification (NeMo) tool in the stroke cohort. In Experiment 2, synthetic middle cerebral artery lesions were applied to healthy adults' diffusion data to compare SCD estimates from tractography on synthetically lesioned versus complete data, to SCD estimates from the model-based NeMo tool. Rank-based linear mixed-effects models compared differences across approaches, cohorts, and 13 regions of interest (ROIs).

RESULTS: In stroke, SCD scores from individual tractography and NeMo were strongly correlated (R[2] ≥ 0.81), with largest differences in the inferior parietal gyrus (median [IQR]: -4.2% [-9.2-1.4]). In healthy controls, NeMo underestimated SCD relative to individual tractography, with larger median SCD differences across ROIs in older (11.8% [7.7-13.3]) than younger adults (-6.7% [-9.3--1.9]). Cohort and ROI explained 47-69% of variance in SCD difference across approaches.

CONCLUSION: Both individual tractography and the model-based framework capture regional SCD patterns, with larger differences in older adults. The model-based framework is efficient for large-scale studies, while individual tractography may better capture patient- and age-specific SCD.},
}

@article {pmid41733927,
year = {2026},
author = {Chen, J and Zhu, L and Liu, J and Chen, J and Liang, C and Liu, C and Wang, F and Zhu, Y and Yang, X},
title = {Immune cells play a mediating role in the relationship between the gut microbiota and dementia: A Mendelian randomization study.},
journal = {Innate immunity},
volume = {32},
number = {},
pages = {17534259261426829},
doi = {10.1177/17534259261426829},
pmid = {41733927},
issn = {1753-4267},
mesh = {Humans ; *Gastrointestinal Microbiome/immunology ; Mendelian Randomization Analysis ; *Dementia/immunology/microbiology ; Genome-Wide Association Study ; *Dysbiosis/immunology ; *B-Lymphocytes/immunology ; },
abstract = {IntroductionThe gut microbiota modulates dementia pathogenesis through immune interactions. Using Mendelian randomization, we investigate immune mediated mechanisms linking microbial dysbiosis to four dementia subtypes (Alzheimer's disease, Frontotemporal dementia, Vascular dementia, Parkinson's disease dementia . Our study tests whether gut microbiome effects on dementia are transmitted via immunoregulatory pathways.MethodsGenome wide association studies data included gut microbiota, 731 immune traits, and dementia cohorts (Alzheimer's disease, Frontotemporal dementia, Vascular dementia, Parkinson's disease dementia). Two step Mendelian randomization with Inverse Variance Weighted analyses assessed mediation effects, controlled by F-statistics >10 and Steiger filtering. Sensitivity analyses addressed pleiotropy.ResultsA total of 37 gut microbiome species demonstrated potential causal effects relationships with four types of dementia, and 137 immune cell subsets exhibited potential causal effects associations with these four dementia subtypes. In the Two step Mendelian randomization analysis, CD45RA + CD28- CD8+ T cells, CD19 on IgD- CD38dim B cells, and BAFF-R on CD20- B cells were shown to exert mediating effects between class/order/family.Deltaproteobacteria and Alzheimer's disease. CD4+ CD8+ T cells were found to exert a mediating effect between genus.Roseburia and Parkinson's disease dementia . CD20- CD38- B cells, CD19 on CD20- B cells, and IgD on unswitched memory B cells were found to exert a mediating effect between class/order/family.Coriobacteriales,genus.Lactococcus and Vascular dementia.ConclusionThis Mendelian randomization study revealed that certain immune cells serve as mediators in the pathway by which the gut microbiome contributes to the onset of dementia.},
}

Humans
*Gastrointestinal Microbiome/immunology
Mendelian Randomization Analysis
*Dementia/immunology/microbiology
Genome-Wide Association Study
*Dysbiosis/immunology
*B-Lymphocytes/immunology

@article {pmid41733884,
year = {2026},
author = {Anzalone, N and De Rimini, ML and Gandolfo, N},
title = {The new era of Alzheimer's disease: a possible burden for radiologists?.},
journal = {La Radiologia medica},
volume = {},
number = {},
pages = {},
pmid = {41733884},
issn = {1826-6983},
}

@article {pmid41733741,
year = {2026},
author = {Laroche, VT and Cavill, R and Kouhsar, M and Müller, J and Reijnders, RA and Harvey, J and Smith, AR and Imm, J and Koetsier, J and Weymouth, L and MacBean, L and Pegoraro, G and Eijssen, L and Creese, B and Kenis, G and Tijms, BM and van den Hove, D and Lunnon, K and Pishva, E},
title = {Epigenomic subtypes of late-onset Alzheimer's disease reveal distinct microglial signatures.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {41733741},
issn = {1432-0533},
support = {R01AG067015//National Institute for Health Care Management Foundation/ ; MR/S011625/1//MRC/ ; AS-PG-16b-012/ALZS_/Alzheimer's Society/United Kingdom ; 733050516/ZONMW_/ZonMw/Netherlands ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/classification/metabolism ; *Microglia/metabolism/pathology ; Male ; Aged ; Female ; Epigenomics ; DNA Methylation ; Aged, 80 and over ; *Epigenesis, Genetic ; *Brain/pathology/metabolism ; Cohort Studies ; },
abstract = {Growing evidence suggests that clinical, pathological, and genetic heterogeneity in late-onset Alzheimer's disease (LOAD) contributes to variable therapeutic outcomes, potentially explaining many trial failures. Advances in molecular subtyping through proteomic and transcriptomic profiling reveal distinct patient subgroups, highlighting disease complexity beyond amyloid-beta plaques and tau tangles. This underscores the need to expand subtyping across new molecular layers, to identify novel drug targets for different patient subgroups. In this study, we analyzed genome-wide DNA methylation (DNAm) data from three independent postmortem brain cohorts (N = 826) to identify epigenetic subtypes of LOAD. We used unsupervised clustering to define subtype-specific DNAm patterns and validated them across cohorts. We then mapped subtype signatures to brain cell types using purified-cell DNAm profiles and integrated bulk and single-nucleus RNA-seq to assess each subtype's impact on gene expression. Finally, we examined clinical and neuropathological correlates to evaluate biological and clinical significance. We identified two distinct epigenomic subtypes of LOAD, consistently observed across three cohorts. Both subtypes exhibit significant yet distinct microglial methylation enrichment. Bulk transcriptomic analyses highlighted distinct biological mechanisms underlying these subtypes: subtype 1 was enriched for immune-related processes, while subtype 2 was characterized by neuronal and synaptic pathways. Single-nucleus transcriptional profiling of microglia indicated that both subtypes share AD-associated innate-immune remodeling, with subtype differences emerging primarily as state-dependent transcriptional shifts rather than large changes in state abundance. Overall, subtype 1 showed a relative weighting toward more inflammatory microglial programs, whereas subtype 2 showed stronger transcriptional remodeling in specific microglial states alongside relatively greater engagement of regulatory and clearance-associated features. These findings reveal distinct epigenetic and functional microglial states underlying LOAD subtypes, advancing our understanding of disease heterogeneity. This work lays the groundwork for targeted therapeutic strategies tailored to specific molecular and cellular disease profiles.},
}

Humans
*Alzheimer Disease/genetics/pathology/classification/metabolism
*Microglia/metabolism/pathology
Male
Aged
Female
Epigenomics
DNA Methylation
Aged, 80 and over
*Epigenesis, Genetic
*Brain/pathology/metabolism
Cohort Studies

@article {pmid41733574,
year = {2026},
author = {Zhao, S and Parr, T and Udale, R and Klar, V and Davis Jones, G and Scholcz, A and Toniolo, S and Manohar, SG and Husain, M},
title = {Transsaccadic working memory in healthy ageing and neurodegenerative disease.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.109581},
pmid = {41733574},
issn = {2050-084X},
support = {10.35802/206330/WT_/Wellcome Trust/United Kingdom ; 10.35802/226645/WT_/Wellcome Trust/United Kingdom ; MR/P00878/X/MRC_/Medical Research Council/United Kingdom ; ACF-2023-13-013//National Institute for Health and Care Research/ ; },
mesh = {Humans ; *Memory, Short-Term/physiology ; *Saccades/physiology ; Male ; Female ; *Healthy Aging/physiology ; Aged ; *Neurodegenerative Diseases/physiopathology ; Middle Aged ; Adult ; },
abstract = {The brain continuously integrates rapidly changing visual input across eye movements to maintain stable perception, yet the precise mechanisms underpinning dynamic working memory and how these break down in brain diseases remain unclear. We developed a novel eye-tracking paradigm and computational models to investigate how spatial and colour information are updated across saccades in the human brain. Our findings reveal that saccades selectively impair spatial but not colour memory. Computational modelling identified that spatial representations are maintained in a dual eye-centred frame of reference which is actively updated by a noisy memory of saccades but is vulnerable to interference. Using this model, we found that specific mechanistic failures in initial encoding and memory decay, rather than the saccadic updating process itself, account for spatial working memory deficits in Alzheimer's and Parkinson's disease. These results provide a mechanistic understanding of how dynamic spatial memory operates in health and its disruption in neurodegenerative disorders.},
}

Humans
*Memory, Short-Term/physiology
*Saccades/physiology
Male
Female
*Healthy Aging/physiology
Aged
*Neurodegenerative Diseases/physiopathology
Middle Aged
Adult

@article {pmid41732800,
year = {2026},
author = {Dougherty, RJ and Wang, J and Tian, Q and Simonsick, EM and Ferrucci, L and Schrack, JA},
title = {Rising energetic cost of walking predicts cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71193},
doi = {10.1002/alz.71193},
pmid = {41732800},
issn = {1552-5279},
mesh = {Humans ; Female ; Aged ; *Walking/physiology ; Male ; *Cognitive Dysfunction/physiopathology/diagnosis ; *Energy Metabolism/physiology ; Aged, 80 and over ; Disease Progression ; Neuropsychological Tests ; },
abstract = {BACKGROUND: The energetic cost of walking increases with age and is linked to physical function impairment, but its relation to cognitive impairment is unknown.

METHODS: A total of 687 initially cognitively normal older adults (mean age 74.0 ± 7.2 years, 52% women) underwent repeated walking energy expenditure assessments (V̇O2) and adjudicated cognitive diagnoses over 7.6 ± 3.8 years. We examined (1) trajectories in the energetic cost of walking prior to any clinical diagnosis of cognitive impairment, comparing adults who later developed cognitive impairment versus those who did not, and (2) the baseline energetic cost and future risk of cognitive impairment using linear mixed-effects and Cox regression models.

RESULTS: Ninety-one participants (13%) progressed to cognitive impairment. Progressors exhibited a steeper increase in energetic cost than non-progressors (B = 0.13; p = 0.003). Higher baseline cost predicted impairment among adults ≥75 years (hazard ratio [HR] = 1.1, 95% confidence interval [CI] = 1.00 to 1.20, p = 0.039), but not those aged 65 to 74 (HR = 0.91, 95% CI = 0.81 to 1.01, p = 0.089).

CONCLUSION: Walking efficiency provides a physiological link between mobility and cognitive health; preserving efficiency may reduce risk of Alzheimer's disease and related dementias.},
}

Humans
Female
Aged
*Walking/physiology
Male
*Cognitive Dysfunction/physiopathology/diagnosis
*Energy Metabolism/physiology
Aged, 80 and over
Disease Progression
Neuropsychological Tests

@article {pmid41732331,
year = {2026},
author = {Lecerf, S and Guinebretiere, O and Bentegeac, R and Gauthier, V and Aymes, E and Mekkaoui, C and Dumurgier, J and Amouyel, P and Durrleman, S and Nedelec, T and Lebouvier, T},
title = {Long-term effect of discontinuing anticholinesterase treatment on cognitive decline and mortality in Alzheimer's disease in France: a quasi-experiment and target trial emulation study.},
journal = {The Lancet regional health. Europe},
volume = {62},
number = {},
pages = {101607},
pmid = {41732331},
issn = {2666-7762},
abstract = {BACKGROUND: In 2018, France withdrew reimbursement for cholinesterase inhibitors (ChEIs) in Alzheimer's disease, citing modest efficacy, lack of long-term benefit, and safety concerns. This policy shift provided a unique opportunity to assess ChEI effectiveness in real-world settings, by evaluating, among patients treated with ChEI between 01/08/2017 and 01/08/2018, the impact of treatment discontinuation on cognitive decline (MMSE score) and survival.

METHODS: Using the French National Alzheimer's Database (BNA) and Meotis databases, we emulated a pragmatic, intention-to-treat trial comparing patients who discontinued ChEIs after delisting to those who continued treatment, under quasi-experimental conditions. To model cognitive trajectories, we used the inverse probability treatment-weighted (IPTW) cohort and applied mixed-effects models with random intercepts across all follow-up visits. Survival was estimated with a pooled logistic regression including treatment group, follow-up time, and an interaction between treatment and time.

FINDINGS: The mean difference in MMSE decline between discontinuers and continuers after one year was 0·97 points (95% CI 0·68-1·27, p < 0·001), reaching 1·81 points (0·91-2·71, p < 0·001), after four years. No significant difference in mortality (RR 1·10, 95% CI [0·95-1·29]) was observed over a five-year period.

INTERPRETATION: Our findings confirm and extend prior trials by demonstrating the sustained cognitive benefits of ChEIs in a real-world setting. While acknowledging the limitations associated with its retrospective nature, our study argues for reconsidering the 2018 delisting decision, as ChEIs remain safe and clinically relevant for mild-to-moderate Alzheimer's disease.

FUNDING: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.},
}

@article {pmid41732207,
year = {2026},
author = {Woffindale, C and Riera, NG and Wood, MJA and Varela, MA},
title = {Design, validation, and functional impact of oligonucleotides for multigene silencing in Alzheimer's disease.},
journal = {Molecular therapy. Nucleic acids},
volume = {37},
number = {1},
pages = {102848},
pmid = {41732207},
issn = {2162-2531},
abstract = {Alzheimer's disease (AD) is characterized by overlapping pathological processes, including amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, mitochondrial dysfunction, and neuroinflammation. Monogenic therapies have shown limited benefits, and only in a subset of patients, as other pathological processes continue to drive disease progression. Given the multifactorial and heterogeneous nature of AD, therapeutics targeting more than one gene simultaneously represent a promising strategy to achieve broader therapeutic outcomes. This study highlights the advantages of multigene RNA-based therapeutics, which may overcome compensatory mechanisms and patient heterogeneity. Here, we report the design and functional validation of antisense oligonucleotides (ASOs) specifically engineered for simultaneous silencing of more than one AD-related gene. Using algorithm-assisted sequence design, we generated 11 bispecific gapmer ASOs from 20 candidate genes. In human and mouse cellular models, these ASOs achieved potent and sustained knockdown with picomolar to low-nanomolar IC50 values. Functionally, treatment led to significant reductions in Aβ42 production, up to 70%, while maintaining favorable safety and specificity profiles. Collectively, our findings establish a proof of concept for multigene silencing in AD, demonstrating that rationally designed ASOs can provide robust target suppression across key pathological pathways. This strategy introduces a new paradigm in oligonucleotide design, with the potential to deliver disease-modifying benefits for patients with AD.},
}

@article {pmid41732200,
year = {2026},
author = {Filippi, M and Cecchetti, G and Spinelli, EG and Ghirelli, A and Rugarli, G and Pisano, S and Canu, E and Agosta, F},
title = {Anti-amyloid therapies and the transformation of Alzheimer's care pathways: early lessons from the frontline.},
journal = {The Lancet regional health. Europe},
volume = {64},
number = {},
pages = {101609},
pmid = {41732200},
issn = {2666-7762},
abstract = {The introduction of anti-amyloid monoclonal antibodies marks a major shift in Alzheimer's disease (AD) care, moving treatment toward biological modification and reshaping diagnostic and organizational models. At the Center for Alzheimer's and Related Diseases (CARD), IRCCS San Raffaele Hospital (Milan, Italy), among the first European tertiary centers to initiate both lecanemab and donanemab, we developed a structured fast-track pathway to support timely and safe access to therapy. Our early real-world experience highlights three critical domains. First, patient selection requires integration of cognitive, functional, and biological data, moving beyond rigid global score thresholds. Second, safety monitoring must balance ARIA risk with real-world feasibility through risk-adapted MRI surveillance. Third, effective implementation depends on transparent communication and continuous shared decision-making, particularly when benefit is uncertain or safety events occur. These elements underscore that the impact of disease-modifying therapies will depend not only on pharmacology, but on coordinated care models supported by real-world registries.},
}

@article {pmid41732182,
year = {2026},
author = {Almeida, M and Ferreira, MC and Fernandes, CS},
title = {Innovative technological resources for Alzheimer's disease care management: A scoping review.},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076251407129},
pmid = {41732182},
issn = {2055-2076},
abstract = {OBJECTIVE: The aim of this scoping review was to map and describe the technological tools reported in the literature that have been designed for care management in Alzheimer's disease, with a particular focus on supporting patients living with the condition, their families, caregivers, and healthcare professionals.

METHODS: The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework. A comprehensive literature search was performed across multiple databases, including Scopus, PubMed, Web of Science, and CINAHL, focusing on studies addressing technological resources aimed at supporting the care and management of Alzheimer's disease.

RESULTS: A total of 23 studies were included in the final analysis. The most frequently utilized technologies were mobile applications and wearable devices. The most identified functionalities included cognitive training, location tracking, task reminders, communication support, fall detection, and vital signs monitoring, often integrated into comprehensive solutions to enhance patient care and safety.

CONCLUSION: Overall, these technologies were designed to support both patients and caregivers. However, despite the clear benefits and innovative potential of these technologies, significant limitations remain, particularly the lack of empirical validation in real-world clinical settings and the need to ensure greater usability for older adults and individuals with cognitive impairments.},
}

@article {pmid41732170,
year = {2026},
author = {Noubouwo, JC and Ngoupaye, GT and Ngoufack, SBK and Kom, BTD and Foutsop, AF and Adassi, BM and Gnoupa, KG and Yassi, FB},
title = {Neuroprotective properties of Linzia gerberiformis aqueous leaves extract against aluminium chloride (AlCl3) -induced cognitive impairment: Involvement of cholinergic, GABAergic, and antioxidant mechanisms.},
journal = {IBRO neuroscience reports},
volume = {20},
number = {},
pages = {286-298},
pmid = {41732170},
issn = {2667-2421},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by oxidative imbalance, leading to memory deficits and cognitive impairments. Aluminium chloride (AlCl3), a neurotoxin found in certain foods and medications, disrupts neurotransmitter systems, thereby exacerbating cognitive decline. Current drug development strategies aim to counter these effects through cholinesterase inhibition, activation of GABAergic transmission, the use of antioxidants, and the promotion of neuroprotection. This work was conducted to assess the neuroprotective properties of the aqueous extract of Linzia gerberiformis (L. gerberiformis) leaves against AlCl3 induced cognitive impairment in mice. AlCl3 (70 mg/kg) was administered orally in mice to induced memory loss a core feature of Alzheimer Disease. Mice were pretreated with aqueous extract of L. gerberiformis leaves (75, 150 and 300 mg/kg) for six weeks, and memory integrity was assessed using the object location test (OLT) and the T-Maze test. One hour after completion of the T-Maze, the mice were sacrificed, the hippocampus and prefrontal cortex were then collected to assess the cholinergic (acetylcholinesterase (AChE) and acetylcholine (ACh)), GABAergic systems and oxidative stress (nitric oxide (NO), malondialdehyde (MDA) SOD, Catalase (CAT), reduced glutathione (GSH)). The aqueous extract of L. gerberiformis leaves demonstrated significant effects (P < 0.01 and P < 0.05) at doses of 75 and 150 mg/kg in improving short-term learning memory, as well as a significant enhancement (P < 0.05) of long-term spatial memory on day 3 at the dose of 75 mg/kg. AlCl3 (70 mg/kg) induced increase in AChE (P < 0.05; P < 0.01), NO (P < 0.05; P < 0.001), and MDA (P < 0.05; P < 0.01), while decreasing ACh (P < 0.01), GABA (P < 0.05; P < 0.01), SOD (P < 0.01; P < 0.001), CAT (P < 0.05), and GSH (P < 0.01) in the hippocampus and prefrontal cortex. Pretreatment with aqueous extract of L. gerberiformis leaves significantly restored these parameters (P < 0.01; P < 0.001) for Ach at the doses 75 and 150 mg/kg and GABA (P < 0.05) at all doses. Significant improvement was also observed for SOD (P < 0.05 and P < 0.01), GSH, and MDA (P < 0.05 and P < 0.01), as well as for NO (P < 0.05 and P < 0.01) in both the hippocampus and prefrontal cortex. The present study established that the aqueous extract of L. gerberiformis leaves ameliorated AlCl3-induced neurotoxicity by modulating the activation of the cholinergic, GABAergic and antioxidant pathways.},
}

@article {pmid41732138,
year = {2026},
author = {Zeng, X and Nicholson, N and Karikari, TK},
title = {Blood-based biomarkers of Alzheimer's disease: potential utility in clinical practice.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
doi = {10.1097/WCO.0000000000001475},
pmid = {41732138},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: Blood-based biomarkers (BBMs) for Alzheimer's disease are beginning to enter clinical practice. As this integration advances, it is essential to critically examine their strengths, limitations, and readiness for broader clinical application.

RECENT FINDINGS: Evidence increasingly supports the utility of BBMs for clinical management of Alzheimer's disease, with phosphorylated tau species, Aβ42/40 ratio, GFAP, and NfL among the most studied. Plasma p-tau forms have emerged as the most promising markers, showing strong correlations with amyloid plaque deposition and predictive value for disease progression. The WHO and the Global CEO Initiative have outlined minimum performance criteria for clinical use. While no BBM meets these benchmarks with a single cutpoint, adopting a two-cutpoint approach by introducing an intermediate category has enabled some assays to achieve the required accuracy. Several assays are now commercially available, and two have recently received FDA clearance to assist in confirming or ruling out amyloid-beta pathology.

SUMMARY: BBMs could transform Alzheimer's disease diagnostics by enabling scalable, minimally invasive approaches for early detection and monitoring. As implementation advances, assay harmonization, assessment of demographic and physiological influences, and real-world validation across diverse populations remain essential to ensure reliability and equitable access.},
}

@article {pmid41732122,
year = {2026},
author = {Tang, C and Yan, J and Chen, Y and Peng, X and Lei, X and Zhang, M and He, D},
title = {Waking up to the truth: Associations between sleep disorders and multidomain functional outcomes in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71200},
doi = {10.1002/alz.71200},
pmid = {41732122},
issn = {1552-5279},
support = {U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG079280//National Institute on Aging and National Institutes of Health/ ; P30 AG062422/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P20 AG068024/AG/NIA NIH HHS/United States ; P20 AG068053/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; 2021ZD0201801//STI2023-Major Projects/ ; //The Key and Dominant Discipline Construction Project of the Health Commission of Guizhou Province in 2023, China/ ; 2025-117//The Guizhou Provincial Science and Technology Support Program Project/ ; LCZX[2025]003//The Guizhou Provincial Clinical Medical Research Center Construction Project - Neurological Disease Research/ ; },
mesh = {Humans ; *Alzheimer Disease/complications/psychology/epidemiology ; *Sleep Wake Disorders/epidemiology/complications ; Male ; Cross-Sectional Studies ; Female ; *Activities of Daily Living ; Aged ; *Cognitive Dysfunction/epidemiology ; Aged, 80 and over ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Sleep disorders are common in older adults and have been increasingly linked to cognitive dysfunction in Alzheimer's disease (AD); however, their associations with functional outcomes and underlying pathways remain insufficiently characterized.

METHODS: We performed a cross-sectional analysis of 10,823 participants from the National Alzheimer's Coordinating Center database, examining associations between sleep disorders and instrumental activities of daily living (IADL) using regression, structural equation modeling (SEM), and mediation analyses.

RESULTS: Sleep disorders were significantly associated with greater cognitive impairment and poorer IADL performance among individuals with AD. Mediation analysis indicated that cognitive impairment accounted for ≈62% of the association between sleep disorders and IADL difficulties, suggesting a substantial indirect association through cognitive function.

DISCUSSION: Sleep disorders are strongly associated with cognitive impairment and functional limitations in AD. These findings highlight the potential clinical value of screening and managing sleep problems as part of comprehensive care strategies.},
}

Humans
*Alzheimer Disease/complications/psychology/epidemiology
*Sleep Wake Disorders/epidemiology/complications
Male
Cross-Sectional Studies
Female
*Activities of Daily Living
Aged
*Cognitive Dysfunction/epidemiology
Aged, 80 and over
Neuropsychological Tests

@article {pmid41732108,
year = {2026},
author = {Bledsoe, X and Wang, TC and Wu, Y and Archer, D and Chen, HH and Naj, AC and Bush, WS and Hohman, TJ and Dumitrescu, L and Below, JE and Gamazon, ER},
title = {Neuroimaging PheWAS and molecular phenotyping implicate PSMC3 in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71217},
doi = {10.1002/alz.71217},
pmid = {41732108},
issn = {1552-5279},
support = {/NH/NIH HHS/United States ; R01AG073439/AG/NIA NIH HHS/United States ; RF1AG061351/AG/NIA NIH HHS/United States ; R56AG068026/AG/NIA NIH HHS/United States ; R35HG010718/HG/NHGRI NIH HHS/United States ; R01HG011138/HG/NHGRI NIH HHS/United States ; R01GM140287/GM/NIGMS NIH HHS/United States ; //Scott Hamilton CARES Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/pathology ; *Neuroimaging ; Male ; Phenotype ; Female ; Aged ; *Brain/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Endophenotypes ; },
abstract = {INTRODUCTION: Neuroimaging genetics has advanced our understanding of Alzheimer's disease (AD); however, frameworks using functional genomics are needed to elucidate mechanisms connecting loci to neurological outcomes. To address this need, we explored relationships between AD-associated variants and disease via their impact on gene expression and neuroanatomical phenotypes.

METHODS: We mapped established AD genes to neuroimaging traits using the NeuroimaGene Atlas and predicted transcript-driven neurological features of AD by comparing gene-derived neuroimaging features with clinical neuroimaging data. Genetic covariance analyses were performed to characterize shared genetic architecture between AD endophenotypes and neuroimaging features, and to identify neuroimaging features associated with a family history of dementia.

RESULTS: Our analyses implicate PSMC3 as a contributor to AD pathophysiology and identify AD endophenotypes, including dementia family history, linked to frontal cortex thickness and volume, as well as changes in cerebrospinal fluid volume.

DISCUSSION: Our findings prioritize AD genes whose regulation is associated with vulnerable brain regions, offering a potential mechanistic framework for downstream functional validation.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging/pathology
*Neuroimaging
Male
Phenotype
Female
Aged
*Brain/diagnostic imaging/pathology
Magnetic Resonance Imaging
Endophenotypes

@article {pmid41731906,
year = {2026},
author = {Gao, Z and Wang, Y and Ren, Y and Lyu, J},
title = {Integrated Bioinformatics Analysis of Screen Mitochondrial Autophagy-Related Core Genes and Construct Diagnostic Model for Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {2},
pages = {e70387},
doi = {10.1111/jnc.70387},
pmid = {41731906},
issn = {1471-4159},
support = {ZR2021MH408//Project of Natural Science Foundation of Shandong Province/ ; 23YJAZH095//Humanities and Social Sciences Research Program of Ministry of Education in China/ ; },
mesh = {*Alzheimer Disease/genetics/diagnosis ; Humans ; *Autophagy/genetics ; *Computational Biology/methods ; *Mitochondria/genetics/metabolism ; Protein Interaction Maps/genetics ; Databases, Genetic ; },
abstract = {Identify mitochondrial autophagy genes associated with Alzheimer's disease (AD) and elucidate its underlying pathogenesis and explore potential therapeutic targets. Alzheimer's disease related gene expression data were obtained from the Gene Expression Omnibus database. Mitochondrial autophagy-related genes with a relevance score > 1 were screened based on the GeneCards database. We identified differentially expressed genes using R, followed by functional enrichment and immune cell infiltration analyses. A protein-protein interaction network was constructed based on the STRING database, and key genes were identified by Cytoscape software. A diagnostic model for Alzheimer's disease was subsequently developed based on these key genes. Nine key genes were identified for Alzheimer's disease. Gene Ontology enrichment analysis revealed that the differentially expressed genes (DEGs) were primarily involved in mitochondrial function and nucleotide metabolism. Immune infiltration analysis showed negative correlations between YWHAG and VPS35 expression and M1 macrophage abundance, while RTN4 expression positively correlated with follicular helper T cell abundance. Using logistic regression analysis, a diagnostic model for AD was constructed based on three of the key genes. The model was validated by independent external samples, where area under the curve (AUC) demonstrated its robust and excellent diagnostic performance. The nine key genes identified in this study provide new insights and potential therapeutic targets for elucidating how mitochondrial autophagy influences Alzheimer's disease. The established diagnostic model provides a theoretical basis for personalized diagnosis and treatment of Alzheimer's disease.},
}

*Alzheimer Disease/genetics/diagnosis
Humans
*Autophagy/genetics
*Computational Biology/methods
*Mitochondria/genetics/metabolism
Protein Interaction Maps/genetics
Databases, Genetic

@article {pmid41731796,
year = {2026},
author = {Irfan, B and Pal, S and Reader, J and Bakulski, KM and Paulson, H and Giordani, B},
title = {Linking sleep apnea and arthritis in the National Alzheimer Coordinating Center Cohort: A cross-sectional analysis.},
journal = {Medicine},
volume = {105},
number = {8},
pages = {e47717},
doi = {10.1097/MD.0000000000047717},
pmid = {41731796},
issn = {1536-5964},
mesh = {Humans ; Male ; Female ; Cross-Sectional Studies ; Aged ; *Alzheimer Disease/epidemiology/complications ; *Arthritis/epidemiology/complications ; Middle Aged ; *Sleep Apnea, Obstructive/epidemiology ; Aged, 80 and over ; United States/epidemiology ; Prevalence ; Comorbidity ; Risk Factors ; },
abstract = {Sleep apnea-related intermittent hypoxia and the chronic inflammation of arthritis share oxidative-stress pathways, yet their epidemiologic overlap remains under-described. The prevalence of both conditions increases with age and presents unique challenges for patient management. To quantify the association between clinician-suspected arthritis and self-reported sleep apnea and to explore whether demographic or cognitive factors modify that link. We analyzed 17,013 adults enrolled in the referral-based National Alzheimer Coordinating Center Uniform Data Set, version 3. Complete-case binary logistic regression modeled obstructive sleep apnea (OSA) (yes/no) on arthritis (yes/no) with adjustment for age, sex, race (White vs non-White), years of education, cognitive status (normal, mild cognitive impairment, Alzheimer disease), body mass index, and cardiometabolic comorbidities. A pre-specified interaction term tested whether cognition modified the arthritis-OSA association. Multiple imputation was used to address missing data. Arthritis was associated with 60% higher odds of OSA (adjusted odds ratio = 1.60, 95% confidence interval: 1.46-1.76, P < .001). The effect was attenuated in Alzheimer disease. Male sex, atrial fibrillation, stroke, diabetes, and higher body mass index were additional correlates (all P < .001); age was not independently significant. Imputation yielded similar estimates. Clinician-suspected arthritis was robustly associated with self-reported OSA even after extensive adjustment, although unmeasured confounding and exposure misclassification cannot be excluded. Both OSA and arthritis were ascertained by self-report or single-clinician designation without polysomnography, actigraphy, imaging, or serology, raising non-differential misclassification potential. The cross-sectional design prevents causal interpretation, and the predominantly White, highly educated volunteer cohort limits generalizability. Prospective, objectively phenotyped studies, ideally with arthritis sub-typing, are needed to verify directionality and clarify mechanisms. We used records from more than 17,000 volunteers at U.S. Alzheimer Disease Research Centers to ask whether people who say they have arthritis are also more likely to report OSA. After controlling for age, sex, education, cognitive status, weight, and common medical conditions, arthritis still raised the odds of OSA by about 60%. Joint pain and poor sleep can feed off 1 another, so recognizing both problems may help doctors treat them earlier. Neither arthritis nor OSA was confirmed with X-rays, lab tests, or sleep studies, we relied on what participants or clinicians reported. Furthermore, the study looked at 1 point in time, so we cannot tell which problem came 1st; and most volunteers were White and highly educated, so the findings may not reflect every community. Future research that tracks patients over time and uses overnight sleep tests and detailed arthritis subtypes will be crucial.},
}

Humans
Male
Female
Cross-Sectional Studies
Aged
*Alzheimer Disease/epidemiology/complications
*Arthritis/epidemiology/complications
Middle Aged
*Sleep Apnea, Obstructive/epidemiology
Aged, 80 and over
United States/epidemiology
Prevalence
Comorbidity
Risk Factors

@article {pmid41731757,
year = {2026},
author = {Liu, Y and Han, J and Wang, S},
title = {Catechins in insomnia-Alzheimer's disease comorbidity: A network pharmacology and molecular docking study.},
journal = {Medicine},
volume = {105},
number = {8},
pages = {e47812},
doi = {10.1097/MD.0000000000047812},
pmid = {41731757},
issn = {1536-5964},
mesh = {*Alzheimer Disease/epidemiology/drug therapy/genetics ; Humans ; *Sleep Initiation and Maintenance Disorders/drug therapy/epidemiology/genetics ; Network Pharmacology ; *Catechin/pharmacology/therapeutic use ; Molecular Docking Simulation ; Signal Transduction/drug effects ; Circadian Rhythm/drug effects/genetics ; Comorbidity ; },
abstract = {The comorbidity of insomnia and Alzheimer's disease (AD) is strongly driven by the interplay between circadian rhythm disruption and immune dysfunction. Catechins are multi-target polyphenols capable of modulating both processes, yet their precise mechanism of action remains elusive. Insomnia and AD related differentialy expressed target genes were specifically sourced from circadian rhythm and immune phenotypes. Two machine learning algorithms were then applied to refine and identify the pivotal targets from this phenotype-driven target pool. Functional enrichment analyses, including kyoto encyclopedia of genes and genomes and gene set enrichment analysis, were performed to elucidate the involved signaling pathways. The compound-comorbidity differentialy expressed target genes related to circadian and immunity network identified catechin (C) and epicatechin as core components. PED4D, HMOX1, and IGF1 were robustly identified as the pivotal targets. PDE4D was found to be centrally involved in the complement pathway. The complement pathway and the phosphatidylinositol 3-kinase/Akt signaling pathway were significantly enriched. This dual pathway regulation converges to govern microglia-mediated synaptic pruning, a process integral to both sleep and neurodegeneration. This study unveils a mechanistic link from core catechins to the regulation of synaptic pruning via circadian-immune crosstalk, offering a novel therapeutic perspective for the insomnia-AD comorbidity.},
}

*Alzheimer Disease/epidemiology/drug therapy/genetics
Humans
*Sleep Initiation and Maintenance Disorders/drug therapy/epidemiology/genetics
Network Pharmacology
*Catechin/pharmacology/therapeutic use
Molecular Docking Simulation
Signal Transduction/drug effects
Circadian Rhythm/drug effects/genetics
Comorbidity

@article {pmid41731732,
year = {2026},
author = {Chevy, A and Tisseaux, A and Ferdynus, C and Moutounaïck, M and Eychène, JM and Morello, E and Ufkes, R and Renaud, S and David, JM and Martins, V and Bruneau, L and Quang, BL},
title = {The role of culture and literacy in screening for major neurocognitive disorders for elderly patients on Reunion Island: A cross-sectional study on the concordance between the French Mini-Mental State Examination and an adapted version (MMS-Run).},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418292},
doi = {10.1177/13872877261418292},
pmid = {41731732},
issn = {1875-8908},
abstract = {BackgroundOn Reunion Island, literacy rates are estimated to be 62% for the elderly population. Education is a widely recognized protective factor for major neurocognitive disorders (MNCDs), including Alzheimer's disease, however during cognitive assessments by healthcare professionals, it can also act as a barrier.ObjectiveThis study aims to evaluate the concordance of the scores between the French version of the Mini-Mental State Examination (GRECO-MMSE) and an adapted version to the cultural context and literacy levels of the elderly Reunionese population (MMS-Run).MethodsA cross-sectional, single-center study was conducted at the University Hospital of Reunion Island from April 14, 2023 to April 12, 2024. The GRECO-MMSE and MMS-RUN were performed one day apart to elderly participants who were hospitalized in the Department of Physical Medicine and Rehabilitation (PM&R) and the Department of Geriatrics. Analyses of concordance, correlation and distribution of scores as well as analyses by cognitive domains and by literacy levels (illiterate or literate) were carried out.ResultsAmong the 61 participants, a discordance between the GRECO-MMSE and MSS-Run was observed (kappa=0.54), especially in the cognitive domains assessing orientation, attention and language (items that benefited most from adaptations). More than half of the participants were self-reported as illiterate (57%), and illiteracy was associated with increased discordance between the two tests.ConclusionsThe MMS-Run could be better suited for MNCD screening in the elderly Reunionese population. A validation study is necessary to determine appropriate threshold scores in the future.},
}

@article {pmid41731727,
year = {2026},
author = {Hakim, M and Ranjan, R and Ken-Dror, G and Yusuf, MA and Uddin, MN and Mamun, MT and Al Mamun, A and Kawnayn, G and Sharma, P},
title = {Next-generation sequencing study identifies the first genes associated with Alzheimer's disease in Bangladeshi population: The CARED study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261419066},
doi = {10.1177/13872877261419066},
pmid = {41731727},
issn = {1875-8908},
abstract = {BackgroundAlthough the molecular basis of Alzheimer's disease (AD) is often studied in Caucasians, its genetic basis in Bangladesh remains elusive.ObjectiveWe explored the association between single-nucleotide variants (SNVs) of Apolipoprotein E (APOE) and other genes for AD risk among Bangladeshis.MethodsWe recruited AD patients and controls aged ≥18 years and conducted next generation sequencing (NGS) to analyze ∼30 Mb of the human exome. The NGS targets ∼99% of the Consensus Coding Sequence and RefSeq annotations, along with the complete mitochondrial genome.ResultsA total of 132 (72 AD: 60 control) age- and sex-matched participants were sequenced. The average age of AD was comparable to that of controls (64.5 ± 11.3 versus 63.6 ± 9.8, p = 0.69), and the gender distribution (p = 0.49) was similar between the study groups. Following NGS analysis 23 SNVs from 16 potential genes were identified. The APOE variant rs429358 was associated with a significantly increased age- and sex- adjusted risk of AD (OR) 8.0 (95% CI: 2.3-27.9, p = 0.001) in the additive model, 10.5 (95% CI: 2.8-39.5, p < 0.001) in the dominant model, and 6.9 (95% CI: 1.8-26.9, p = 0.005) in the heterozygous genotype model, as determined using the Bonferroni adjustment method. The top SNV for predicting AD was the APOE variant rs429358 with a -logP value of 3, followed by BDNF gene variant rs6265 at 1.3, and CR1 gene variant rs1349409945 at 1.2.ConclusionsThe APOE variant rs429358 is linked to an 8-fold increased risk of AD among Bangladeshis.},
}

@article {pmid41731720,
year = {2026},
author = {Shimoda, N},
title = {From research to clinical practice: DNA methylation signatures as diagnostic tools for Alzheimer's disease.},
journal = {Epigenomics},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/17501911.2026.2635932},
pmid = {41731720},
issn = {1750-192X},
abstract = {Based on their ability to analyze methylation differences genome-wide in a large number of samples at a reasonable cost and time, microarrays were rapidly adopted by Alzheimer's disease (AD) researchers to isolate CpG sites with methylation levels that were changed in the blood of AD patients. However, concerns gradually arose about the reproducibility of these methylation markers. I attribute the cause to the lack of confirmation of methylation changes detected by DNA methylation arrays. Only by simply plotting an individual's methylation distribution can some false methylation differences be avoided. Furthermore, we may need to set a realistic, minimum threshold for methylation changes for clinical purposes. The prospect of using DNA methylation as a diagnostic marker for AD may be compromised by the increasing number of irreproducible markers. Therefore, establishing minimum guidelines for the search and presentation of AD-associated methylation markers is necessary when publishing. Some empirically useful guidelines are outlined in this Perspective, and applications for diagnosing AD using reliable methylation markers are also presented. One of the most desired applications of methylation markers will be to identify individuals whose cognitive abilities decline before memory problems appear, a task that has not yet been accomplished with protein markers or imaging.},
}

@article {pmid41731707,
year = {2026},
author = {Inagawa, Y and Kamiya, T and Miyagi, Y and Inagawa, S and Takenoshita, N and Sato, T and Yoshimura, M and Saito, K and Hanyu, H and Shimizu, S},
title = {Evaluation of the effects of lecanemab treatment on brain atrophy using voxel-based specific regional analysis system for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261422452},
doi = {10.1177/13872877261422452},
pmid = {41731707},
issn = {1875-8908},
abstract = {BackgroundLecanemab, a monoclonal antibody targeting amyloid-β (Aβ), has been shown to reduce Aβ plaques and slow cognitive decline in patients with Alzheimer's disease (AD). However, its effect on brain structure in real-world clinical settings remains unclear. The voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) enables quantitative assessment of brain atrophy, particularly in the medial temporal lobe, using MRI.ObjectiveTo evaluate the effects of lecanemab on brain structure by analyzing changes in Z-scores derived from VSRAD in AD patients treated with lecanemab in actual clinical practice.MethodsThis retrospective study included 16 patients with AD who received four biweekly administrations of lecanemab (10 mg/kg) between February 2023 and August 2024. Amyloid pathology was confirmed via [18]F-flutemetamol PET and cerebrospinal fluid Aβ42/40 ratio. VSRAD analysis was performed using three-dimensional sagittal T1-weighted MRI scans obtained before the first and after the fourth lecanemab administration. Changes in the Z-score of medial temporal lobe (MTL) and MTL/whole brain ratios were assessed.ResultsAfter four doses of lecanemab, the Z-score of MTL in AD patients significantly decreased from 1.61 ± 0.76 to 1.38 ± 0.67 (p < 0.01), and the MTL/whole brain ratio significantly decreased from 6.47 ± 6.48 to 4.59 ± 4.80 (p < 0.02).ConclusionsLecanemab treatment was associated with a significant reduction in the Z-score of MTL, indicating a decrease in brain volume. The clinical significance of this brain volumetric change remains uncertain, and hence longitudinal studies linking brain volume reduction with clinical outcomes, including cognition, are warranted.},
}

@article {pmid41731699,
year = {2026},
author = {Torres, ER and Lopez, ED and McBurrows, L and Kollmorgen, G and Carboni, M and Johnson, SC and Zetterberg, H and Blennow, K and Bendlin, BB},
title = {Physical activity across the life course and neural biomarkers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418259},
doi = {10.1177/13872877261418259},
pmid = {41731699},
issn = {1875-8908},
abstract = {BackgroundPhysical activity (PA) may decrease the risk of Alzheimer's disease and related disorders (ADRD), although most research has focused on exercise. In addition, ADRD prevention may be most effective when administered earlier in the life course, when changes in the brain may occur 20-25 years before the onset of symptoms. Finally, amyloid-β (A) and tau (T) accumulation are followed by neurodegeneration (N), key features of AD. However, there are additional biomarkers associated with ADRD. The association between different types of PA across the life course and biomarkers beyond the AT(N) framework is unknown.ObjectiveExamine the association between different types of PA across the life course and biomarkers beyond the AT(N) framework.MethodsPA (occupation/school, transportation, household) across the life course (school-age, adolescence, young adult, middle adult) was assessed. AD pathology, neurodegeneration, synaptic dysfunction, and gliosis were measured with the Roche NeuroToolKit, a panel of exploratory prototype assays for cerebrospinal fluid biomarkers. Significant bivariate correlations were followed by logistic regression.ResultsYoung adult occupation/school PA was a significant predictor of neurofilament light protein (NfL, OR = 0.969, 95% CI = 0.940-0.999); the full model was significant, χ[2](df = 2) = 15.57, p < 0.001, explaining 19.2-25.6% of the variance in NfL. Young adult occupation/school PA was a significant predictor of alpha-synuclein (OR = 0.968, 95% CI = 0.940-0.996); the full model was significant, χ[2](df = 1) = 6.70, p = 0.01, explaining 8.8-11.7% of the variance in alpha-synuclein.ConclusionsPA done as part of one's job or schooling during young adulthood, such as standing and walking, may be protective against dementia later in life.},
}

@article {pmid41731612,
year = {2026},
author = {Bice, PJ and Nho, K and Ertekin-Taner, N and Saykin, AJ},
title = {Systems biology of Alzheimer's Disease: a scoping review of key pathways and mechanisms.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00934-4},
pmid = {41731612},
issn = {1750-1326},
support = {U01 AG072177/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; P30 AG010133/NH/NIH HHS/United States ; },
}

@article {pmid41731608,
year = {2026},
author = {Li, Q and Alexopoulou, ZS and Dyrba, M and Mallick, E and Tröger, J and Spruth, E and Altenstein, S and Bartels, C and Glanz, W and Incesoy, EI and Butryn, M and Kilimann, I and Sodenkamp, S and Maier, F and Rostamzadeh, A and Osterrath, A and Priller, J and Schneider, A and Wiltfang, J and Laske, C and Falkenburger, B and Wagner, M and Duezel, E and Spottke, A and Petzold, GC and Jessen, F and König, A and Köhler, S and Teipel, S and , },
title = {Exploring neural correlates of automated speech-based cognitive markers through resting-state functional connectivity in aging and at-risk Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01993-x},
pmid = {41731608},
issn = {1758-9193},
abstract = {BACKGROUND: Digital speech-based assessments provide scalable tools for detecting subtle cognitive decline. Here, we investigated whether digitally derived speech-based composite score of cognition and individual speech features were associated with alterations in functional connectivity (FC) within task-related brain networks in the Alzheimer's disease spectrum, which are known to reflect cognitive performance and disease-related changes.

METHODS: Data were analyzed from 129 participants of the German PROSPECT-AD study, ranging from cognitively healthy individuals to those with mild cognitive impairment. Speech-based cognitive scores and speech features were derived from automated phone-administered semantic verbal fluency (SVF) and verbal learning tasks (VLT). Resting-state fMRI assessed FC, with intrinsic connectivity networks identified via independent component analysis and dual regression. Associations were examined using permutation-based voxel-wise regression, controlling for demographic and clinical covariates. Seed-to-voxel analyses were conducted to support network identification and complement findings.

RESULTS: Greater language network connectivity in the left middle temporal gyrus was associated with increased SVF temporal cluster switching (FWE < .05, cluster size = 12 voxels, mean T = 3.86). Exploratory analyses (uncorrected p < .01) demonstrated no significant associations between cognitive composite scores and FC. However, individual SVF and VLT speech features exhibited network-specific associations across executive, language, and default mode networks, indicating exploratory yet spatially distinct connectivity patterns.

CONCLUSION: Digital speech-based assessments may have limited current utility for detecting FC alterations in at-risk individuals. Further validation using complementary methodological approaches, shorter intervals between fMRI and speech assessments, and testing in independent cohorts, are essential to establish their reliability and clinical relevance for monitoring brain network changes.},
}

@article {pmid41731491,
year = {2026},
author = {Chen, B and Lu, HC and Huang, L and Wang, J and Bujold, M and Tang, L and Du, X and Wang, Y},
title = {A ligand-mimetic anti-TREM2 agonist antibody elevates soluble TREM2 and ameliorates pathology in mouse models of Alzheimer's disease and multiple sclerosis.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03733-2},
pmid = {41731491},
issn = {1742-2094},
abstract = {BACKGROUND: Triggering receptor expressed on myeloid cell-2 (TREM2) signaling promotes disease-associated microglia (DAM) and phagocytosis in neurodegenerative diseases. Traditional anti-TREM2 agonist antibodies block receptor shedding, lowering soluble TREM2 (sTREM2) and leading to mixed outcomes. We developed 03O05, a ligand-mimetic anti-TREM2 agonist antibody that activates TREM2 while preserving physiological shedding.

METHODS: Binding epitope and cross-reactivity were defined by Bio-Layer Interferometry (BLI) and epitope mapping/mutagenesis. Functional activity was assessed using nuclear factor of activated T cells luciferase reporter (NFAT-luciferase), in vivo DAP12 phosphorylation, and microglial phagocytosis. In vivo effects on sTREM2 levels were evaluated in wild-type (WT), human TREM2 knock-in, and 5xFAD mice by ELISA. Amyloid-beta (Aβ) plaque clearance, microglial state and neuronal health were evaluated in 5xFAD model. Remyelination and microglial status were assessed in the cuprizone model.

RESULTS: Anti-TREM2 antibody 03O05 binds a conformational epitope (M41-W44, L89) within the immunoglobulin-like domain, distal from the cleavage site, activates TREM2 signaling in vitro and in vivo, and enhances phagocytosis. A single dose treatment of 03O05 increased sTREM2 in serum and brain of WT and human TREM2 knock-in mice. In 5xFAD mice, chronic 03O05 treatment elevated serum and brain sTREM2, promoted clearance of filamentous Aβ plaques, reduced microgliosis while enhancing microglial phagocytosis, and ameliorated neuronal dystrophy. In the cuprizone model, 03O05 enhanced microglial phagocytosis and promoted remyelination by reducing degraded myelin basic protein (MBP) during recovery.

CONCLUSIONS: Unlike stalk-binding anti-TREM2 agonist antibodies, 03O05 preserves ectodomain shedding, leading to transient receptor activation and increased sTREM2 levels. This approach promotes a neuroprotective microglial phenotype without inducing neuroinflammation, reduces amyloid pathology and neuronal dystrophy, as well as supports remyelination in multiple sclerosis (MS). These findings suggest the therapeutic potential of shedding-permissive TREM2 agonism in neurodegenerative disease.},
}

@article {pmid41731425,
year = {2026},
author = {Faeed, M and Hosseini, H and Abdollahi, A and Aziz, M and Darabi, H and Sohrabi-Ashlaghi, A and Farhadi, S and Nobari, MN and Badakhshan, H},
title = {Plasma miRNAs associated with cognitive impairment and brain hypometabolism in individuals with mild cognitive impairment.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04758-z},
pmid = {41731425},
issn = {1471-2377},
abstract = {Detecting practical biomarkers to facilitate early diagnosis of Alzheimer's disease (AD) before the onset of overt symptoms is crucial for clinicians to develop preventive and therapeutic strategies. There is substantial experimental evidence indicating the dysregulation of several microRNA (miRNA) expression levels in AD. They are known to play a crucial role in modulating critical intracellular signaling pathways associated with the core pathophysiological mechanisms of AD. In this cross-sectional study, we investigated the association of blood-based miRNAs as non-invasive, cost-effective biomarkers for the early stages of AD, focusing on their impact on cognitive decline and metabolism. All data were extracted from the Alzheimer's Disease Assessment Scale (ADNI) database. A total of 152 subjects were categorized into mild cognitive impairment (MCI) and control groups based on their clinical dementia rating (CDR) scores, and significant differences between these cohorts were explored. Our objective was to establish correlations between miRNA levels and cognitive impairment tests, such as the Alzheimer's disease assessment scale (ADAS), as well as hypometabolism indices using fluorodeoxyglucose (FDG)-positron emission tomography (PET) neuroimaging. Our findings revealed associations between hsa-miR-19a-3p and hsa-miR-16-5p with brain hypometabolism, and between hsa-miR-125b-5p and cognitive performance. While these observations suggest that specific miRNAs may reflect early AD-related changes, they require replication in larger, independent, biomarker-confirmed cohorts to assess their potential clinical utility.},
}

@article {pmid41731279,
year = {2026},
author = {Yang, N and Jiang, J and Shi, J and Liu, X and Yu, C and Guo, S and Zhang, C and Gao, F and Yang, Z and Feng, H and Weng, Q and Qiu, T and Li, C and Ji, L},
title = {β-Asarone Mediates the Alleviation of Neuroinflammation in Alzheimer's Disease Via Modulation of the TREM2/PI3K/AKT Signaling Pathway.},
journal = {Inflammation},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10753-025-02435-w},
pmid = {41731279},
issn = {1573-2576},
support = {No. 2024R410C068//The Science and Technology Innovation Activity Plan for College Students in Zhejiang Province/ ; No. 2024YKJ05//The Zhejiang Chinese Medical University Postgraduate Scientific Research Fund Project/ ; No. Y202456030//The General Scientific Research Project of Zhejiang Province Department of Education/ ; No.2023KY044//Zhejiang Provincial Medical and Health Technology Project/ ; No.GZY-ZJ-KJ-23055//Key Project of Joint Construction of Traditional Chinese Medicine Modernization Research by Provincial Bureau/ ; No.2024K093//Quzhou Municipal Science and Technology Key Project/ ; No.B20252600//Hangzhou Medical and Health Technology Project/ ; No.B20252242//Hangzhou Medical and Health Technology Project/ ; No.2024ZF125//Zhejiang Provincial Traditional Chinese Medicine Science and Technology Plan/ ; No.2024ZF126//Zhejiang Provincial Traditional Chinese Medicine Science and Technology Plan/ ; No.LPWJ-01-06//Linping District Medical and Health Technology Project/ ; No.LPWJ2023-02-024//Linping District Medical and Health Technology Project/ ; No.2023ZHA-KEB315//Zhejiang Kangenbei Hospital Management Soft Science Research Project/ ; No.B20254587//Hangzhou Health Technology Plan/ ; No. 2022FSYYZY05//The Scientific Research Fund of Zhejiang Chinese Medical University/ ; No. 2023C03004//The "Pioneer" and "Leading Goose" R&D Program of Zhejiang/ ; No. 82204918//The National Natural Science Foundation of China/ ; No. 2023ZR015//The Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project/ ; },
abstract = {Neuroinflammation, driven by dysregulated microglial polarization, is a hallmark of Alzheimer's disease (AD). Recently, the triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial function, has emerged as a promising therapeutic target for AD. This study aimed to investigate the therapeutic potential and mechanism of action of the natural compound β-asarone in AD models. Our results demonstrate that β-asarone significantly improved cognitive function, reduced hippocampal neuronal damage, and decreased both Aβ deposition and Tau hyperphosphorylation in 3×Tg-AD mice. Mechanistically, β-asarone upregulated TREM2 expression, activated the PI3K/AKT pathway, and inhibited GSK3β activity, thereby promoting the polarization of microglia from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype and alleviating neuroinflammation. This study is the first to elucidate that β-asarone ameliorates AD pathology by modulating microglial polarization via the TREM2/PI3K/AKT/GSK3β signaling axis, providing experimental evidence supporting its potential as an immunomodulatory therapeutic agent for AD.},
}

@article {pmid41730900,
year = {2026},
author = {Botta, R and Locascio, JJ and Ye, R and Goodheart, AE and Gomperts, SN},
title = {APOE, Aβ42, and tau differentially impact cognitive decline in Sporadic, GBA1 and LRRK2 Parkinson's disease.},
journal = {NPJ Parkinson's disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41531-026-01290-2},
pmid = {41730900},
issn = {2373-8057},
abstract = {Cognitive impairment varies across sporadic Parkinson's disease (PD) and the common genetic subtypes glucocerebrosidase (GBA1) and leucine-rich repeat kinase 2 (LRRK2) PD and is influenced by Apolipoprotein E (APOE) polymorphisms and Alzheimer's disease (AD) co-pathology. However, the effects of APOE genotype, Aβ42 and tau on cognitive decline across these PD subtypes remain unclear. Using pooled longitudinal data across the PPMI and CPP cohorts, we examined the effects of APOE genotype and cerebrospinal fluid (CSF) Aβ42 and tau on cognitive decline across sporadic PD, GBA1-PD, LRRK2-PD, and healthy control (HC) subjects. Whereas in sporadic PD the APOE ε4 allele was associated with faster cognitive decline than APOE ε3 or ε2 alleles, no APOE effect was observed in GBA1-PD or LRRK2-PD. While lower baseline CSF Aβ42 was linked to faster cognitive decline in all groups, higher baseline CSF pTau was associated with faster decline in sporadic PD and LRRK2-PD but not in GBA1-PD. These findings underscore differential vulnerabilities to APOE genotype and AD-related biomarkers among PD subtypes, a critical consideration for clinical trials targeting cognitive decline in PD.},
}

@article {pmid41730850,
year = {2026},
author = {Guo, Y and Huang, W and Xiong, X and Chen, H and Lv, C and Liu, T and Chen, F and , },
title = {Abnormal signal transmission in white matter revealed by resting-state communication connectivity in Alzheimer's disease: A comprehensive cross-sectional and longitudinal study.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03883-0},
pmid = {41730850},
issn = {2158-3188},
support = {82271977//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82160327//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Conventional functional connectivity of blood oxygenation level-dependent (BOLD) signals varies with Alzheimer's disease (AD) progression. However, it is unable to describe how white matter (WM) is engaged in brain networks. In this study, we introduced a novel communication connectivity metric, which was defined as the triple-wise correlation coefficient between BOLD signals from pairs of gray matter volume and white matter bundles, to investigate the change of signal transition through WM bundles. A total of 169 participants with longitudinal resting-state fMRI data from the ADNI dataset were included, which consisted of 44 cognitively normal (CN), 58 early mild cognitive impairment (EMCI), 45 late MCI (LMCI), and 22 AD. Cross-sectional analyses at baseline and longitudinal within-group comparisons were conducted to examine changes in pattern correlation coefficients (CC) between 2D graphs across the AD continuum. In the cross-sectional study, the 2D graph of the CN group showed moderate correlation with those of the EMCI and LMCI groups, whereas these associations generally declined in the AD dementia group. Bootstrapping test showed that the pattern CC for the right retrolenticular part of internal capsule (RLIC.R) and posterior corona radiata (PCR.R) significantly declined in the EMCI, LMCI, and AD groups for both cross-sectional and longitudinal studies. These results demonstrated that signal transmission in RLIC.R and PCR.R has great potential to be markers in the early diagnosis of AD and tracking the progression of AD. Communication connectivity based on rs-fMRI is a promising tool for investigating WM signal transmission alterations in AD.},
}

@article {pmid41730560,
year = {2026},
author = {Amir-Behghadami, M and Gholipour, K and Mohammadzadeh, Z},
title = {Vocal biomarkers for geriatric health assessment: a scoping review protocol.},
journal = {BMJ open},
volume = {16},
number = {2},
pages = {e109480},
doi = {10.1136/bmjopen-2025-109480},
pmid = {41730560},
issn = {2044-6055},
mesh = {Humans ; Scoping Reviews as Topic ; Aged ; Biomarkers ; *Geriatric Assessment/methods ; *Voice ; Research Design ; Artificial Intelligence ; },
abstract = {INTRODUCTION: Global ageing populations require accessible, non-invasive tools for early detection and monitoring of neurological chronic and neurodegenerative diseases. Current diagnostic methods face limitations including invasiveness, high costs and infrequent clinical assessments. The human voice has emerged as a promising digital biomarker, with vocal characteristics reflecting physiological and cognitive changes associated with conditions like dementia and Parkinson's disease. While artificial intelligence (AI) and machine learning have enabled sophisticated vocal analysis, the literature remains fragmented without comprehensive synthesis. This scoping review protocol delineates a systematic approach to collate and synthesise existing research on the application of AI-driven audio biomarkers for the detection and management of neurological diseases (eg, cognitive decline, Parkinson's disease, Alzheimer's, dementia and depression) in older adults aged 65 years and above.

METHODS AND ANALYSIS: This scoping review will be conducted in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines and the methodological framework proposed by Arksey and O'Malley, incorporating recent methodological advancements. The eligibility criteria for study selection will be formulated using the PCC (Population, Concept, Context) framework. A comprehensive literature search will be performed across several electronic databases, including PubMed/MEDLINE, Scopus, Web of Science, IEEE Xplore, Embase, Compendex, CINAHL, Scientific Information Database (SID), Magiran, IranMedex and Barakat Knowledge Network System (BKNS). The search will encompass peer-reviewed articles published in Persian and English from 1 January 2012 to 31 March 2026. Two independent reviewers will screen titles, abstracts and full texts and extract data according to the predefined PCC-based eligibility criteria. Discrepancies will be resolved through discussion or, if necessary, by consultation with a third reviewer. The results will be synthesised and presented narratively, accompanied by summary tables, charts and figures to address each research question.

ETHICS AND DISSEMINATION: The Research Ethics Committee of Tabriz University of Medical Sciences approved the protocol for this scoping review (approval number: IR.TBZMED.VCR.REC.1404.223). They concluded that since the review involves only analysis of existing literature without direct patient involvement or clinical procedures, it meets the relevant ethical standards. Results from the review will be shared through peer-reviewed journals and conference presentations to provide valuable insights for researchers, clinicians and policymakers on the use of audio-based biomarkers in older adults.

PROSPERO REGISTRATION NUMBER: Not registered.},
}

Humans
Scoping Reviews as Topic
Aged
Biomarkers
*Geriatric Assessment/methods
*Voice
Research Design
Artificial Intelligence

@article {pmid41730502,
year = {2026},
author = {Elsworthy, RJ and Spencer, F and Allen, S and Dunleavy, C and Whitham, M and Lucas, SJE and Hill, EJ and Aldred, S},
title = {Investigating the effects of post-exercise serum treatments on APP processing in iPSC-derived neurons and astrocytes.},
journal = {The international journal of biochemistry & cell biology},
volume = {},
number = {},
pages = {106920},
doi = {10.1016/j.biocel.2026.106920},
pmid = {41730502},
issn = {1878-5875},
abstract = {The number of people living with Alzheimer's disease (AD) is increasing worldwide as populations age. A hallmark of AD is the accumulation of amyloid-β (Aβ) in the brain, and pathways regulating amyloid-β precursor protein (AβPP) processing are of major interest for disease-modifying and preventive strategies such as exercise. Regular exercise is associated with a reduced risk of AD, potentially through limiting Aβ accumulation, yet the underlying cellular mechanisms remain unclear. Acute bouts of exercise induce the release of circulating signalling molecules that may influence AβPP metabolism. To investigate the effects of exercise on AβPP processing, human induced pluripotent stem cell (iPSC)-derived neurons and astrocytes were treated with serum collected before and immediately after high-intensity exercise. Both healthy control and familial AD (PSEN1 A246E) neurons and astrocytes were independently exposed to 10% pre- or post-exercise serum for 30min, after which markers of AβPP processing were quantified. Post-exercise serum contained increased amounts of Lacate, BDNF, IL-6, sAβPPα, and Aβ1-42, and reduced neprilysin activity (p < 0.05). Treatment with post-exercise serum acutely elevated ADAM10 activity in neurons, which was replicated by spiking lactate in pre-exercise serum. sAβPPα was also increased in PSEN1 neurons following post exercise serum treatment with increased Aβ1-42 secretion in both PSEN1 neurons and astrocytes (p < 0.05). These findings demonstrate that human post-exercise serum can modulate AβPP processing in iPSC-derived neural cells. This supports the concept that circulating exercise-induced factors can influence neuronal pathways relevant to AD pathology.},
}

@article {pmid41730496,
year = {2026},
author = {Panda, SP and Saraswat, N and Singh, V},
title = {Gene therapy targeting synaptopathy linked with Alzheimer's and Parkinson's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.02.035},
pmid = {41730496},
issn = {1873-7544},
abstract = {Synaptic Plasticity pertains to the synapse's tendency to adapt fresh information and is a crucial step in the establishment of brain circuits that aid in memory formation. It has become one of the most intensively researched topics in all of neuroscience. Pieces of evidence are accumulating that synaptopathy (altered synaptic plasticity) mechanisms contribute to Alzheimer's disease (AD) and Parkinson's disease (PD). Toxins responsible for synaptopathy and aberrant neurotransmitter (NT) release at synapses are the aggregates of amyloid-β (Aβ) (amyloidopathy) and hyperphosphorylated tau (tauopathy). Amyloidopathy and tauopathy contributes to synaptopathy in AD. Defective NT release at the synaptic interface generates various negative consequences related with changed activity of synaptic gene, proteins, and Ca[2+] homeostasis necessary for synaptic plasticity. Great attention has been paid to α-synuclein (ASN)-dependent synaptopathy and the fundamental processes behind excessive dopaminergic nerve injury in PD. The familial-PD is caused by mutations in SNCA, LRRK2, Parkin, PINK1, and DJ-1 genes. APP, PSEN1, and PSEN2 gene variants are associated with familial AD. The genetic scissor techniques such as CRISPR and AAV delivery are based on the unique capacity to modify DNA at the base-pair level, which makes them a promising tool for the more advanced and tailored treatments for AD and PD. The purpose of this review was to examine gene therapies targeting synaptopathy, amyloidopathy and tauopathy which are presently undergoing clinical and pre-clinical trials with the aim of increasing synaptic function in AD and PD.},
}

@article {pmid41730458,
year = {2026},
author = {Suh, C and Shim, Y and Jeong, H and Joo, Y and Kim, Y and Lee, H and Choi, Y and Yoon, S and Kim, SJ and Lyoo, IK},
title = {Overweight-related alterations in brain structural covariance networks and their potential impact on cognitive function in subjective cognitive decline.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116128},
doi = {10.1016/j.bbr.2026.116128},
pmid = {41730458},
issn = {1872-7549},
abstract = {Overweight is increasingly recognized for its role in brain alterations that affect both normative and pathological aging. However, its impact on subjective cognitive decline (SCD) remains unclear. We investigated gray matter volume (GMV) within structural covariance networks (SCNs) and their associations with cognitive performance in individuals with SCD, stratified by weight status. Ninety-six adults with SCD and overweight (overweight group) and a matched cohort of 96 with SCD and normal weight (normal-weight group) underwent structural magnetic resonance imaging (MRI) and cognitive assessment. GMVs were extracted from SCNs identified via independent component analysis. Cognitive function was assessed across three domains: psychomotor speed, attention, and executive function. Group differences in GMV and cognitive performance, as well as their associations within the overweight group were evaluated. The overweight group exhibited significantly reduced GMV in the basal ganglia-thalamus network compared to the normal-weight group (Bonferroni-corrected P = 0.010). Psychomotor speed was also significantly lower in the overweight group (P = 0.035). Notably, reduced GMV in the basal ganglia-thalamus network was correlated with poorer performance across all three cognitive domains: psychomotor speed (r = 0.278, P = 0.006), attention (r = 0.234, P = 0.023), and executive function (r = 0.232, P = 0.023). These findings suggest that overweight in individuals with SCD may contribute to structural brain alterations that impair cognition, highlighting the potential value of active weight management in reducing the risk of neurodegenerative disorders such as Alzheimer's disease.},
}

@article {pmid41730413,
year = {2026},
author = {Xie, Z and Wei, J and Wang, J},
title = {Review of research advances in the cerebral lymphatic system and neurological disorders.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.02.032},
pmid = {41730413},
issn = {2090-1224},
abstract = {BACKGROUND: The identification of the central lymphatic system represents a significant advancement in contemporary neuroscientific research. As a vital conduit connecting the central nervous system to the peripheral lymphatic network, the primary components of the central lymphatic system, the glymphatic system and meningeal lymphatic vessels, maintain homeostasis within the central microenvironment through cerebrospinal fluid circulation, metabolic waste clearance, and immune cell trafficking. Recent studies affirm that structural and functional perturbations within the central lymphatic apparatus can lead to the accrual of neurotoxic proteins such as amyloid-β and tau, thereby contributing to the pathogenesis of neurodegenerative conditions like Alzheimer's and Parkinson's diseases. Additionally, in cerebrovascular pathology, impaired drainage mechanisms exacerbate blood-brain barrier disruption and cerebral edema, thereby impairing neurological recovery. Moreover, this system modulates immune cell infiltration and plays a pivotal role in the etiology and progression of multiple sclerosis, central nervous system infections, and intracranial neoplasms.

AIM OF REVIEW: This review aimed to systematically synthesize the core components of the cerebral lymphatic system, namely the glymphatic system and meningeal lymphatic vessels, and clearly outline the key influencing factors, including aquaporin-4 activity, aging, hemodynamics, sleep, and circadian rhythms. The study aimed to emphasize the mechanisms by which the cerebral lymphatic system influences neurological pathology and summarize emerging therapeutic avenues targeting lymphatic pathways within the central nervous system.

Evidence suggests that the targeted modulation of the cerebral lymphatic system has the potential to treat various neurological diseases. Nevertheless, our understanding of the molecular mechanisms remains in its early stages, with significant research gaps. Consequently, future investigations should focus on molecular characterization to identify specific therapeutic targets, thereby facilitating the translation of preclinical insights into clinical practice.},
}

@article {pmid41730379,
year = {2026},
author = {Manasa, M and Bethanagere Ramesha, G and Krishna, KL and Ambika, MS and Nadig, APR and Pathak, S and Jalawadi, P},
title = {Harnessing estrogen's neuroprotective potential in mitigating Alzheimer's pathologies in postmenopausal women: a review.},
journal = {Brain research},
volume = {},
number = {},
pages = {150226},
doi = {10.1016/j.brainres.2026.150226},
pmid = {41730379},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD) is a progressive disorder that affects the brain and leads to cognitive decline and memory loss, with postmenopausal women being unduly affected. Estrogen is believed to exert neuroprotective effects by influencing amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, synaptic function, neuroinflammation, and brain-derived neurotrophic factor (BDNF) signalling. This review examines the role of estrogen in AD pathogenesis among postmenopausal women. A systematic literature search was conducted using PubMed, Scopus, and Web of Science. Keywords included "estrogen", "Alzheimer's disease", "neuroprotection", "amyloid-beta," and "BDNF." Inclusion criteria were peer-reviewed studies from the past 10 years focusing on estrogen's effects on AD mechanisms, neurobiology, and therapeutic relevance. Articles were screened by title and abstract. Followed by a full-text review to ensure methodological rigour and relevance. Evidence indicates that estrogen reduces amyloid beta burden, inhibits tau phosphorylation, mitigates oxidative stress, preserves synaptic connectivity, and suppresses neuroinflammation. Estrogen also modulates ApoE-linked lipid metabolism and enhances BDNF signalling, supporting neuronal survival and cognitive resilience. Declining estrogen after menopause increases vulnerability to AD. Understanding estrogen's neuroprotective mechanisms may support targeted therapeutic strategies. Hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs) show potential, but further research is needed to optimise timing, dosage, and patient selection in postmenopausal AD prevention and management.},
}

@article {pmid41730374,
year = {2026},
author = {Liu, S and Huang, J and Zhou, Y and Li, Q and Lin, M and Shi, X and Xian, J and Chen, Q and Shen, Y and Wang, P and Yu, J and Wang, J and Tan, L and Tu, L and Huang, H and Feng, J},
title = {Overcoming the blood-brain barrier: the role of functionalized carbon dots in treating central nervous system diseases.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {126709},
doi = {10.1016/j.ijpharm.2026.126709},
pmid = {41730374},
issn = {1873-3476},
abstract = {Central nervous system diseases (CNSDs) pose a significant therapeutic challenge, largely due to the restrictive blood-brain barrier (BBB). While nanocarriers like liposomes, polymeric nanoparticles, and exosomes have been explored for brain delivery, carbon dots (CDs) have emerged as a particularly promising platform. These carbon-based nanomaterials offer advantages such as small size, excellent biocompatibility, and versatile surface chemistry, enabling precise functionalization. Compared to liposomes and polymer nanoparticles, CDs exhibit superior size uniformity, photophysical properties, and chemical stability. Unlike exosomes, they are synthetically controllable, scalable for mass production, and amenable to precise surface modification. A key advantage lies in their ability to cross the BBB via specific molecular mechanisms, such as receptor‑mediated transcytosis, when conjugated with targeting ligands (e.g., transferrin, lactoferrin, or cell‑penetrating peptides). This allows for disease-specific targeting, for instance, of amyloid-β plaques in Alzheimer's or overexpressed receptors in brain tumors. CDs can serve as intrinsic therapeutics or as drug carriers. However, their clinical translation depends on addressing critical issues of long-term safety, potential neurotoxicity (such as inducing oxidative stress and inflammation), and biodegradability. This review systematically summarizes the synthesis methods and functionalization strategies of CDs, alongside the molecular mechanisms underlying their BBB penetration. It focuses on their therapeutic potential for CNSDs, providing a comparative analysis with other common nanocarriers. Furthermore, it evaluates the current research and improvement strategies concerning CDs toxicity, biocompatibility, and long-term safety. Finally, the review outlines ongoing challenges and future directions for the field.},
}

@article {pmid41730251,
year = {2026},
author = {Cai, J and Zhang, Q and Li, J and Yang, C and Li, Y and Yao, H and Meng, L},
title = {Synergistic effect of Co-MoS2 and Au-rGO nanomaterials: Layer-by-layer electrochemical immunosensor realizes high selective trace detection of Aβ oligomers.},
journal = {Bioelectrochemistry (Amsterdam, Netherlands)},
volume = {170},
number = {},
pages = {109249},
doi = {10.1016/j.bioelechem.2026.109249},
pmid = {41730251},
issn = {1878-562X},
abstract = {Quantitative detection of amyloid-beta oligomers (AβO) is crucial for early diagnosis of Alzheimer's disease (AD). Herein, a simple, label-free electrochemical immunosensor was constructed by integrating cobalt-doped molybdenum disulfide (Co-MoS2) and gold-doped reduced graphene oxide (Au-rGO) via hydrothermal and self-assembly methods. The Co-MoS2/Au-rGO/GCE composite electrode was then immobilized with anti-Aβ42 antibodies. Differential pulse voltammetry (DPV) showed a linear detection range of 1.1 × 10[-9] M to 1.1 × 10[-14] M for AβO, with a limit of detection (LOD) of 6.87 × 10[-15] M (S/N = 3). Quality control serum tests confirmed excellent reproducibility, stability, and accuracy. This immunosensor enables sensitive AβO determination and holds potential for point-of-care testing (POCT) of other AD biomarkers.},
}

@article {pmid41730245,
year = {2026},
author = {Dharia, S and Valderrama, CE and Liu, Q and Smith, SD},
title = {Exploring the interaction of APOE-ε4 and PICALM rs3851179 with dynamic functional connectivity in healthy middle-aged adults at risk for Alzheimer's disease.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae4926},
pmid = {41730245},
issn = {1741-2552},
abstract = {This study investigates whether dynamic functional connectivity (dFC) dwell-time patterns derived from resting-state fMRI (rs-fMRI) can distinguish Alzheimer's disease (AD) genetic risk profiles, specifically the APOE-ε4 (A+) and PICALM rs3851179 (P+) variants, in cognitively healthy, middle-aged adults. Approach. We estimated recurring dFC clusters from rs-fMRI data and quantified the dwell-time (total duration spent in specific connectivity states) for three cohorts: not-at-risk, A+P-, and A+P+. To evaluate the utility of these temporal features, group differences in dwell-time profiles were assessed, and logistic regression with permutation testing was employed to classify genotypes based on dFC patterns. Main results. Individuals in at-risk groups (A+P- and A+P+) exhibited significantly reduced dwell-time in left-hemisphere hubs compared to the not-at-risk group, aligning with known left-hemisphere vulnerability in early AD progression. The logistic regression models achieved above-chance discrimination of genotypes, with permutation tests confirming a significant trend when distinguishing not-at-risk individuals from the combined at-risk cohorts. Significance. These findings suggest that the temporal dFC features are sensitive to subtle functional brain alterations linked to AD genetic risk before clinical symptoms appear. Dwell-time features represent a promising physiological marker for early risk stratification and warrant further validation in larger longitudinal datasets. Our code is available at https://github.com/Shyamal-Dharia/APOE-PICALM-dFC-dwell-time.git. .},
}

@article {pmid41729967,
year = {2026},
author = {Elleaume, C and Hebling Vieira, B and Floris, DL and Langer, N},
title = {The influence of sample size and covariate distributions on neuroanatomical normative modeling.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.108952},
pmid = {41729967},
issn = {2050-084X},
support = {10001C_197480/SNSF_/Swiss National Science Foundation/Switzerland ; grant no. FK-23-086//UZH PostDoc Grant/ ; 10001C_220048/SNSF_/Swiss National Science Foundation/Switzerland ; IC00I0-227750/SNSF_/Swiss National Science Foundation/Switzerland ; grant no. 2021-PI02//Dementia Research Synapsis Foundation/ ; },
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/pathology ; Sample Size ; Aged ; Middle Aged ; *Brain/anatomy & histology/diagnostic imaging ; *Neuroimaging/methods ; Aged, 80 and over ; Cohort Studies ; },
abstract = {Normative models are increasingly used to characterize individual-level brain deviations in neuroimaging studies, but their performance depends heavily on the reference sample used for training or adaptation. In this study, we systematically investigated how sample size and covariate composition of the reference cohort influence model fit, deviation estimates, and clinical readouts in Alzheimer's disease (AD). Using a discovery dataset (OASIS-3, n = 1032), we trained models on healthy control (HC), subsamples ranging from 5 to 600 individuals, while varying age and sex distributions to simulate biases in reference populations. We further assessed the use of adaptive transfer learning by pre-training models on the UK Biobank (n = 42,747) and adapting them to the clinical dataset applying the same subsampling strategies. We evaluated model performance on a fixed HC test set and quantified deviation score errors, outlier detection, and classification accuracy in both the HC test set and the AD cohort. The findings were replicated in an external validation sample (AIBL, n = 463). Across all settings, model performance improved with increasing sample size, but demographic alignment of the covariates, particularly in age, was essential for reliable deviation estimates. Models trained directly within the dataset achieved stable fit with approximately 200 HCs, while adapted models reached comparable performance with as few as 50 individuals when pre-trained on large-scale data. These results show that robust individual-level modeling can be achieved using moderately sized but demographically matched cohorts, supporting broader application of normative modeling in aging and neurodegeneration research.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/pathology
Sample Size
Aged
Middle Aged
*Brain/anatomy & histology/diagnostic imaging
*Neuroimaging/methods
Aged, 80 and over
Cohort Studies

@article {pmid41729767,
year = {2026},
author = {Stites, SD and Dedhia, M and Harkins, K and Karlawish, J and Langbaum, JB and Mather, M and Barber, SJ},
title = {Learning about a heightened genetic risk for dementia: Expected stigma is greater than experienced stigma.},
journal = {Psychology and aging},
volume = {},
number = {},
pages = {},
doi = {10.1037/pag0000970},
pmid = {41729767},
issn = {1939-1498},
support = {/ALZ/Alzheimer's Association/United States ; //Novartis Pharma AG/ ; //Amgen/ ; //National Institutes of Health; National Institute on Aging/ ; //Fidelity Biosciences Research Initiative/ ; //GHR Foundation/ ; //Banner Alzheimer's Foundation/ ; /AG/NIA NIH HHS/United States ; //University of Pennsylvania; University Scholars Program/ ; },
abstract = {What social repercussions do older adults expect to experience if they learn they are at heightened genetic risk for Alzheimer's disease (AD)? We compared these individuals' hypothetical expectations to the actual experiences of AD stigma reported by those who knew their apolipoprotein E (APOE) ϵ4 genotype, a key genetic risk factor for AD dementia. As part of a multisession study, participants aged 60-85 completed a 23-item modified Social Impact Scale to assess AD stigma. At Time 1, participants who knew their APOE genotype were divided into two experiential groups: APOE ϵ4 carriers (n = 65) and ϵ4 noncarriers (n = 46). Experiential group participants reported their experiences of stigma. Participants unaware of their APOE genotype (n = 180) formed the hypothetical group and reported the level of stigma they expected if they were to learn they had an elevated risk for AD. Results showed that expected stigma was significantly greater than experienced stigma. At Time 1, mean agreement with modified Social Impact Scale statements was 26.1% in the hypothetical group compared with only 2.3% in the ϵ4 carrier experiential group. The largest expectation-experience gaps concerned competence and social belonging. These findings suggest that older adults overestimate the social consequences of learning they are at genetic risk for AD. Theoretically, the results add to our understanding of the disability paradox, which refers to outsiders predicting worse life outcomes for people with chronic conditions than those individuals report themselves. Our findings show similar mispredictions occur even in the absence of symptoms. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid41729539,
year = {2026},
author = {Abu Raya, M and Suemoto, CK and Paes, VR and Leite, REP and Pasqualucci, CA and Naslavsky, MS and Rodriguez, RD and Nitrini, R and Ferriolli, E and Allen, IE and La Joie, R and Grinberg, LT},
title = {Sex Differences in Amyloid Pathology by Race, Ancestry, and Apolipoprotein E ε4 in an Admixed Autopsy Sample.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0054},
pmid = {41729539},
issn = {2168-6157},
abstract = {IMPORTANCE: Sex and racial or ancestral disparities in Alzheimer disease remain incompletely understood; autopsy studies that examine amyloid, tau, and genetic factors are scarce.

OBJECTIVE: To test whether neuritic plaque burden and cognitive outcomes differ by sex and whether sex modifies the effects of apolipoprotein E ε4 (APOEε4), informant-reported race, and African ancestry.

This was a cross-sectional study using postmortem neuropathological data from the Biobank for Aging Studies, University of São Paulo, São Paulo, Brazil. A total of 2268 autopsies from a population-based, diverse clinicopathological sample were collected between April 2004 and March 2025.

EXPOSURES: Sex, informant-reported race (Black, White), African ancestry proportion, and APOEε4 carrier status.

MAIN OUTCOMES AND MEASURES: Neuritic plaque burden (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] score), and cognitive function (Clinical Dementia Rating-Sum of Boxes [CDR-SB]). Ordinal logistic regression examined association of sex with CERAD scores and 2- and 3-way interactions among sex, race, ancestry, and APOEε4; adjusting for age, education, vascular factors, and Braak stages. Linear models related pathology to CDR-SB, adding copathologies.

RESULTS: The analysis included 2268 autopsies (median [IQR] age, 74.8 [63.8-83.3] years; 1152 [51% male] and 1116 [49%] female; 802 [35%] Black and 1466 [65%] White; other race groups not included owing to small numbers); female individuals were older than male individuals and more likely to exhibit cognitive impairment (CDR global score ≥0.5). Female individuals had higher plaque burden than male individuals (unadjusted odds ratio [OR], 1.97; 95% CI, 1.67-2.29; P < .001), and this association remained significant in adjusted models for sociodemographic and vascular factors and APOEε4 status (adjusted OR, 1.65; 95% CI, 1.33-2.20; P < .001). APOEε4 carriers of both sexes had an approximately 4-fold greater odds of plaques. Significant 2-way interactions were found between sex, APOEε4 status, race, and ancestry on CERAD scores. Black noncarriers (OR, 0.47; 95% CI, 0.34-0.67) and noncarriers of African ancestry (OR, 0.57; 95% CI, 0.43-0.76) were least likely to have high plaque burden, whereas this protection was weakened in ε4 carriers. No significant 3-way interaction was detected. Among individuals with a CERAD score of 2 or higher, female individuals were more likely than male individuals to reach Braak stage V-VI than male individuals (probability ratio, 1.25; 95% CI, 1.13-1.38; P = .002). Adding Braak stage to multivariable models attenuated the female-male difference in plaques and interaction of sex and plaque on CDR-SB was no longer significant.

CONCLUSIONS AND RELEVANCE: The findings indicate that female sex, APOEε4, and both race and African ancestry were jointly associated with amyloid in this study population. Excess amyloid among women may partly explain their greater tau burden and steeper cognitive decline. These findings highlight the importance of incorporating sex, race, and ancestry into biomarker thresholds, risk stratification, and the design of preventive or disease-modifying trials for Alzheimer disease.},
}

@article {pmid41729454,
year = {2026},
author = {Vermeulen, RJ and Rikkert, MGMO and Handels, R and Haraldsen, IRJH and Renvall, H and Rossini, PM and Marra, C and Maestú, F and Rovers, MM and Govers, TM},
title = {Evaluating dementia risk prediction in mild cognitive impairment: an early health technology assessment of the AI-Mind tool.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41729454},
issn = {2509-2723},
abstract = {This study aimed to evaluate the potential cost-effectiveness of implementing a prediction tool for estimating mild cognitive impairment (MCI) to dementia conversion risk. A decision-analytic model was developed to compare the costs and effects of current practice for subjects with MCI to a situation in which the risk of dementia is estimated using a prediction tool. Different scenarios in terms of prediction horizons, prediction characteristics (e.g. sensitivity and specificity), and treatment availability were evaluated. The model was applied to the AI-Mind tool, which is currently under development for predicting MCI to dementia risk. In a clinical situation, with no widely applicable and highly effective disease-modifying treatment available, implementing a dementia risk prediction tool leads to lower QALYs and higher costs compared to current practice without such a prediction tool (9.32 vs 9.36 QALYs and €115,837 vs €115,032 for the analyses in this paper). This loss in QALYs was caused by the impact on quality of life associated with predicted dementia conversion risk. Risk prediction followed by efficient treatment strategies based on the predicted risk could lead to a cost-effective alternative in case of specific treatment characteristics. These findings suggest that standalone (i.e. without highly effective treatment options) use of a dementia risk prediction tool may not be cost-effective, but it could result in a cost-effective alternative in combination with a treatment with favourable efficacy and cost profile.},
}

@article {pmid41729452,
year = {2026},
author = {Tahmasian, M and Elberse, JD and Ahmadi, R and Liu, W and Rosenzweig, I and Genon, S and Eickhoff, SB and Mander, BA},
title = {Sleep disturbances and Alzheimer's disease: a multiscale approach from exposome to neurobiology and precision medicine.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41729452},
issn = {2509-2723},
abstract = {Sleep disturbances and Alzheimer's disease (AD) are interconnected public health challenges. However, the underlying mechanisms of their complex relationships remain elusive. Here, we propose a hypothetical integrative, stream-like model outlining how external and internal exposome factors accelerate brain aging, thereby exacerbating circadian dysregulation, orexin-mediated hyperexcitability, metabolic imbalance, and inflammaging. These changes can lead to increased sleep fragmentation and reduced slow-wave sleep, triggering widespread neuroinflammation, glymphatic dysfunction, and the accumulation and dissemination of beta-amyloid and tau peptides. These processes collectively accelerate synaptic dysfunction, neuronal loss, and cognitive decline. We also highlight recent neuroimaging evidence that elucidates the neural substrates underlying the relationship between poor sleep and AD. Moreover, tackling their shared burden necessitates the active consideration of inter-individual variability in vulnerable populations through artificial intelligence and computational approaches, aligning with the core tenets of precision medicine. We hope this review encourages clinicians to prioritize monitoring and treating sleep disturbances to reduce the incidence, severity, and consequences of dementia in the general population.},
}

@article {pmid41729391,
year = {2026},
author = {Zhang, B and Bian, W and Zhu, K and Dai, Y and Cai, M and Cheng, J and Chen, X and Xiang, Z and Liu, Y and Lu, W},
title = {Metformin Restores Innate Fear Deficits in Young Adult Female APP/PS1 Mice via Basolateral Amygdala Activation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41729391},
issn = {1559-1182},
support = {2025C02111//Key Research and Development Program of Zhejiang Province/ ; To B.Z.//The start-up fund of Hangzhou City University/ ; No.202513021031//The National College Students' Innovative Entrepreneurial Training Plan Program of China/ ; No.202513021039//the National College Students' Innovative Entrepreneurial Training Plan Program of China/ ; LD24H280001//Natural Science Foundation of Zhejiang Province/ ; },
mesh = {Animals ; *Metformin/pharmacology/therapeutic use ; *Fear/drug effects ; Female ; *Basolateral Nuclear Complex/drug effects/metabolism ; Mice, Transgenic ; *Presenilin-1/metabolism ; *Amyloid beta-Protein Precursor/metabolism/genetics ; Mice ; Mice, Inbred C57BL ; Alzheimer Disease/drug therapy ; Proto-Oncogene Proteins c-fos/metabolism ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by cognitive decline and neuropsychiatric symptoms, among which impaired fear responses are particularly notable. While studies have established that learned fear is compromised in AD, the status of innate fear in this context remains unclear. We found that young adult female APP/PS1 mice exhibited reduced freezing and avoidance responses to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) compared to their wild-type littermates, indicating an impaired innate fear response. Additionally, c-Fos-positive cells in the basolateral amygdala (BLA), a key region for fear processing, were significantly lower in the APP/PS1 mice. Notably, metformin treatment significantly restored TMT-induced freezing behavior and increased c-Fos-positive cells in the BLA, suggesting that it can reverse the innate fear deficit in this AD model. Mechanistically, chemogenetic inactivation of the BLA abolished the therapeutic effects of metformin on the innate fear deficit. Our study suggests metformin as a promising candidate for therapeutic intervention aimed at improving innate fear-related behavioral deficits in AD.},
}

Animals
*Metformin/pharmacology/therapeutic use
*Fear/drug effects
Female
*Basolateral Nuclear Complex/drug effects/metabolism
Mice, Transgenic
*Presenilin-1/metabolism
*Amyloid beta-Protein Precursor/metabolism/genetics
Mice
Mice, Inbred C57BL
Alzheimer Disease/drug therapy
Proto-Oncogene Proteins c-fos/metabolism

@article {pmid41729360,
year = {2026},
author = {Belém-Souza, MV and Barra-Matos, G and de Araújo, GS},
title = {Regulon Reconstruction Uncovers Novel Deregulated Factors in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41729360},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism ; *Transcription Factors/metabolism/genetics ; Gene Regulatory Networks ; *Regulon/genetics ; Protein Interaction Maps/genetics ; Brain/metabolism/pathology ; Gene Expression Regulation ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative age-related disorder characterized by widespread transcriptional deregulation across multiple brain regions. Among the molecular players involved, the transcription factors (TFs) can regulate the expression of AD-related peptides (β-amyloid and tau). We aim to unveil reconstructed TF-centered networks and their dynamics across multiple brain regions. In this study, we conducted an exhaustive differential gene expression analysis, reconstructed TF-TF-centered regulatory networks, and performed master-regulation analyses across multiple regions. We used bulk RNA-seq data from 2,229 post-mortem samples from the ROSMAP, MAYO, and MSBB cohorts. To place these regulatory programs in a disease-relevant context, we integrated protein-protein interaction (PPI) data, experimental TF-target data, and AD-associated genetic risk loci as a translational layer. We assessed TF-centered regulons for 1,605 TFs and identified 354 master-regulators (MR-TFs) across multiple brain regions, including the parahippocampal gyrus, temporal cortex, and cerebellum, which exhibited the highest numbers of regulons. Overall, regulons fell within a moderate size range (median 55 targets), rather than into extensive large networks. Novel MR-TFs, including ADCYAP1, TEAD2, BCL6, MAFF, NFKBIA, were consistently identified as MR-TFs across tissues in AD. Furthermore, GUCY1B1, RBFOX2, and MEF2C were found conserved in the parahippocampal gyrus, inferior frontal gyrus, and posterior cingulate cortex. Additionally, our work identified the well-known AD-related genes BIN1, EGFR, and SPI1 as MR-TFs, reinforcing their functional roles as susceptibility risk markers in AD. This work established an MR-TF-centered integrated regulatory network map of AD, revealing MR-TFs as factors that orchestrate gene deregulation in a region- and cell-context-dependent approach, and providing a robust foundation for mechanistic and translational investigations in neurodegeneration.},
}

Humans
*Alzheimer Disease/genetics/metabolism
*Transcription Factors/metabolism/genetics
Gene Regulatory Networks
*Regulon/genetics
Protein Interaction Maps/genetics
Brain/metabolism/pathology
Gene Expression Regulation

@article {pmid41729309,
year = {2026},
author = {Miyazaki, K and Morita, H and Ishii, K},
title = {Shunt surgery and lecanemab therapy in patients with idiopathic normal pressure hydrocephalus and alzheimer's disease: a report of two cases.},
journal = {Acta neurochirurgica},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00701-026-06804-8},
pmid = {41729309},
issn = {0942-0940},
abstract = {Idiopathic normal pressure hydrocephalus (iNPH) is a condition in the elderly commonly treated with ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt surgery. iNPH frequently coexists with Alzheimer's disease (AD), for which anti-amyloid-β antibodies such as lecanemab have recently become available. Because lecanemab may cause hemorrhagic imaging abnormalities, the timing of shunt surgery in relation to antibody therapy raises concern regarding perioperative bleeding risk. Here, we report two patients with iNPH and AD treated with different sequences of shunt surgery and lecanemab. No hemorrhagic complications were observed, although conclusions regarding safety should be interpreted cautiously.},
}

@article {pmid41729059,
year = {2026},
author = {Subia, P and Jiang, X},
title = {The impact of APOE ε4 on cognitive performance in adults with HIV: a systematic review and meta-analysis.},
journal = {AIDS (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1097/QAD.0000000000004473},
pmid = {41729059},
issn = {1473-5571},
abstract = {OBJECTIVE: With a rapidly aging population living with HIV that may face a double-hit of neuroHIV and Alzheimer's disease, the objective of this meta-analysis was to evaluate the impact of ε4 on cognitive performance in adults with HIV.

DESIGN: The primary literature search was conducted with PubMed and other databases on studies published between 1997 and 2025. Searches were conducted from inception until June 2025.

METHODS: Out of 289 initial studies, 17 were identified for inclusion meeting pre-defined criteria. Data extraction was performed by two independent observers and followed established guidelines (PRISMA).

RESULTS: Pooled data included a total of 2610 adults with HIV, including 765 ε4 carriers (age 45.3 ± 8.1 years, 62.1% male) and 1845 non-carriers (age 44.7 ± 9.2, 67.5% male). There was no significant difference between ε4 carriers and non-carriers in diagnosis of neurocognitive impairment (OR = 1.10, 95% CI 0.8 to 1.5 p = .563), nor in performance of any of the examined cognitive domains (Hedges gs<0.2, ps > 0.17). Meta-regression analysis suggested that less education was associated with increased risk of neurocognitive impairment in carriers (p = .0143).

CONCLUSIONS: After controlling for the potential bias from "overrepresented" cohorts that appeared in multiple publications, this meta-analysis found no significant effects of ε4 on neurocognitive performance or impairment in adults with HIV, despite a weak and non-significant trend of low performance in memory and executive function in ε4 carriers. Factors such as a relatively young age may contribute to the null findings. Future studies with relatively older cohorts and more sensitive/interdisciplinary approaches are needed.},
}

@article {pmid41728859,
year = {2026},
author = {Valenzuela-Hormazábal, P and Valero-Rojas, J and Martínez-González, L and Ramos-Inza, S and Oviedo-Pino, V and González-Ortega, C and Hernando, G and López, JJ and Scorza, C and Echeverry, C and Gutierrez, M and Reyes-Parada, M and Martínez, A and Ramírez, D},
title = {Identification of Potential Multitarget Directed Ligands for Alzheimer's Disease by Coupling Virtual Screening and Experimental Validation.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.5c02202},
pmid = {41728859},
issn = {1549-960X},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder (NDD) associated with the accumulation of beta-amyloid plaques (βA), oxidative stress, and a decrease in cholinergic activity among other pathologies. Given the limitations of current treatments, multitarget strategies present a promising alternative. In this study we prioritized six AD-related protein targets: acetylcholinesterase (AChE), beta-secretase 1 (BACE-1), cannabinoid receptor type 2 (CB2), glycogen synthase kinase 3 beta (GSK-3β), monoamine oxidase A (MAO-A), and the neuronal acetylcholine receptor subunit alpha-7 (nAChR7). Ligand- and structure-based virtual screening methods were applied to identify potential multitarget directed ligands (MTDLs), reducing an initial database of 14 million compounds to 21 early stage candidate MTDLs, that were tested experimentally against AChE, BACE-1, GSK-3β, MAO-A, nAChR7, and the additional targets BChE and MAO-B; however, CB2 could not be experimentally assessed. Among the tested molecules, PJ17 exhibited a dual-target profile with submicromolar activity against AChE and GSK-3β, while PJ11 showed notable MAO-B inhibition. Molecular dynamics simulations revealed key common interactions between PJ17 and those targets providing insights into its potential for further hit-to-lead optimization. In addition, PJ17 showed a safe profile in cellular primary culture suggesting its use as a template to design multitarget drugs against AD.},
}

@article {pmid41728717,
year = {2025},
author = {Franco, A and Zayene, MA and Basly, H and Sayadi, FE},
title = {Non-Invasive Techniques for Early Alzheimer's Disease Detection: A Survey.},
journal = {Studies in health technology and informatics},
volume = {330},
number = {},
pages = {695-713},
doi = {10.3233/SHTI251458},
pmid = {41728717},
issn = {1879-8365},
mesh = {*Alzheimer Disease/diagnosis ; Humans ; Early Diagnosis ; *Diagnosis, Computer-Assisted/methods ; *Artificial Intelligence ; },
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder primarily affecting older adults, characterized by memory loss, cognitive decline, and behavioral changes. As one of the leading causes of dementia worldwide, the prevalence of AD has been rising due to the aging global population, presenting significant public health, social, and economic challenges. While no cure exists, early detection plays a crucial role in slowing disease progression and improving patient outcomes. Recent advancements in computer vision have shown great promise in medical contexts, particularly for early Alzheimer's diagnosis. Non-invasive techniques leveraging AI, such as speech analysis and gait monitoring, offer innovative approaches to detecting subtle cognitive and physical changes associated with the early stages of Alzheimer's. This work reviews the application of computer vision in medical imaging for AD diagnosis and explores emerging and non-invasive technologies that could enhance diagnostic accuracy, reduce reliance on invasive procedures, and support earlier interventions.},
}

*Alzheimer Disease/diagnosis
Humans
Early Diagnosis
*Diagnosis, Computer-Assisted/methods
*Artificial Intelligence

@article {pmid41728378,
year = {2026},
author = {Bae, S and Kim, Y and Park, S and Kim, H and Park, B},
title = {Predicting atrial fibrillation and flutter using BEHRT and identifying multimorbidity patterns using BERTopic.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1722338},
pmid = {41728378},
issn = {2673-253X},
abstract = {INTRODUCTION: Atrial fibrillation and flutter are heart rhythm disorders frequently associated with multiple other chronic conditions, complicating their management and requiring optimized care. Analyzing pre-atrial fibrillation and flutter comorbidity patterns could enable proactive, preventive, and personalized healthcare.

METHODS: This population-based nested case-control study analyzed data from the Korean National Health Insurance Corporation (2002-2019). Adults aged ≥19 years with at least three years of recorded claims were included. Cases were individuals newly diagnosed with atrial fibrillation and flutter between 2007 and 2019 following a washout period (2002-2006). Controls were matched 1:4 using stratified random sampling. Using 5-year disease histories, BEHRT, a transformer-based model, predicted atrial fibrillation and flutter, while BERTopic identified sex-specific multimorbidity patterns. Predictive performance was evaluated using the area under the receiver operating characteristic curve (AUC).

RESULTS: BEHRT achieved an AUC of 0.80 for predicting atrial fibrillation and flutter among 600,030 participants (8,661 cases and 591,369 controls). BERTopic analysis revealed sex-specific multimorbidity patterns: aortic aneurysm, hypertensive heart disease, and chronic obstructive pulmonary disease were common in males, while Alzheimer's disease, Parkinson's disease, and rheumatic heart disease were prominent in females.

DISCUSSION: The combination of BEHRT and BERTopic demonstrated the ability to predict atrial fibrillation and flutter based on multimorbid histories while identifying distinct sex-specific disease patterns. These findings underscore the potential for artificial intelligence to enhance personalized healthcare and optimize prevention and management strategies for chronic conditions.},
}

@article {pmid41728330,
year = {2026},
author = {Wood Alexander, M and Rabin, JS and Caunca, M and Iadipaolo, A and Cornelis, L and Miolane, N and Pham, A and Borger, J and Diaz, V and Paolillo, EW and Kramer, J and Pritschet, L and Taylor, C and Panizzon, MS and Rea Reyes, RE and Denkinger, MN and Ashton, NJ and Johnson, SC and Jacobs, EG and Saloner, R and Casaletto, KB},
title = {Blood-based proteomic signatures of spontaneous menopause: Implications for later-life brain aging and Alzheimer's disease risk.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.09.26345907},
pmid = {41728330},
abstract = {Menopause is a hallmark process in biological aging that has been associated with later life neurodegenerative risk. We leveraged proteomics data from multiple cohorts (N >3,000) to identify biological changes underlying menopause and its links to brain aging. In N =80 rigorously-phenotyped pre-, peri-, and postmenopausal women with serum NULISAseq proteomics, spontaneous menopause was characterized by dysregulation in inflammatory, synaptic, metabolic, and Alzheimer's disease (AD) biologic processes, which tracked with hormones and not age. Pro-inflammatory protein upregulation was especially pronounced in women with vasomotor symptoms. In two cohorts of older women (N =94; N =100), menopause-related proteomic elevations associated with poorer cognitive outcomes and plasma AD biomarkers. Finally, validation analyses in age-matched pre- and postmenopausal women with plasma Olink proteomics (N =2,814) replicated the observed proteomic shifts and revealed menopause-related upregulation of additional inflammatory and catabolic processes. The molecular signatures of menopause may inform biomarkers or therapeutic targets for brain health in women.},
}

@article {pmid41728325,
year = {2026},
author = {Dedebant, E and Even, M and Törnqvist, M and Hauw, F and Fauvel, T and Geoffroy, C},
title = {Treatment Effects of Cholinesterase Inhibitors in Alzheimer's Disease: a Causal Machine Learning Approach.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.11.26346078},
pmid = {41728325},
abstract = {INTRODUCTION: Treatment response in Alzheimer's disease (AD) varies substantially across patients, yet no validated frameworks exist to estimate heterogeneous treatment effects (HTE) from observational data while controlling for confounding bias.

METHODS: We developed a causal machine learning framework integrating expert-guided causal graphs, complementary HTE estimators, sensitivity analyses, and policy learning. We applied it to cholinesterase inhibitors (ChEIs) in MCI due to AD to patients from the NACC and ADNI cohorts.

RESULTS: Analysing 4,049 patients with 12-month and 2,223 with 36-month follow-up, all estimators indicated null or negative long-term ChEI effects on cognitive and functional outcomes, notably on functional measures. ChEIs showed slightly more deleterious effects among men than women.

DISCUSSION: This framework provides a methodology for estimating HTE from observational data. It revealed no beneficial responder subgroups, highlighting the challenge of detecting treatment heterogeneity in moderately sized cohorts. This approach can inform treatment selection for other AD therapies including memantine, anti-amyloid agents, and emerging treatments.},
}

@article {pmid41728324,
year = {2026},
author = {Baradarantohidi, E and Nagarajan, SS and Ranasinghe, KG and Haufe, S},
title = {Abnormal hippocampo-cortical theta-gamma phase-amplitude coupling in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.06.26345635},
pmid = {41728324},
abstract = {INTRODUCTION: Cognitive decline in Alzheimer's disease (AD) may arise not only from neuronal loss but also from disrupted temporal coordination across distributed networks. Prior works in healthy individuals has shown memory-related modulation of hippocampal-cortical phase-amplitude coupling (PAC). We hypothesized alteration of resting-state hippocampo-cortical PAC in AD which relates to cognitive impairment.

METHODS: Resting-state magnetoencephalography (MEG) data were obtained from 78 AD patients and 70 healthy controls. Source-reconstructed hippocampal and cortical signals were analysed using antisymmetrized bispectral methods to quantify non-linear across-site PAC.

RESULTS: AD patients showed significant disruptions of hippocampo-cortical PAC, particularly involving frontal, parahippocampal, and posterior-cingulate cortices. PAC measures were significantly associated with Mini-Mental State Examination scores within the AD group, with higher PAC corresponding to greater cognitive impairment in regions showing increased coupling relative to controls.

DISCUSSION: These findings demonstrate altered hippocampo-cortical temporal coordination in AD and suggest PAC as a potential electrophysiological marker of disease-related network dysfunction.},
}

@article {pmid41728312,
year = {2026},
author = {Parankusham, H and Krishna, E},
title = {GRAD: A Two-Stage Algorithm for Resolving Diagnostic Uncertainty in the Plasma p-tau217 Gray Zone.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.03.26345302},
pmid = {41728312},
abstract = {INTRODUCTION: Phosphorylated tau-217 (p-tau 217) is widely used as a plasma-based biomarker for Alzheimer's Disease (AD) detection, demonstrating superior accuracy for detecting brain amyloid pathology. However, 30-50% of patients fall within an intermediate diagnostic "gray zone" where biomarker results are indeterminate, often decreasing physician confidence and requiring subsequent diagnostic workup. To address this, we developed a two-stage machine learning algorithm 'GRAD: Gatekeeper & Reflex for Alzheimer's Disease' to increase clinical confidence and reduce the AD health economic burden.

METHODS: We initially analyzed 320 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with plasma biomarkers and amyloid PET. We then built a two-stage machine learning classifier mimicking real clinical workflow where the stage 1 'Gatekeeper' used the gold-standard marker: p-tau217 with respective 25%/75% probability thresholds. The stage 2 'Reflex' step applied Random Forest multi-marker classification (p-tau 217, AB42/40, NFL, GFAP) for difficult-to-diagnose gray zone cases. To ensure statistical robustness, leave-one-out cross-validation with bootstrap confidence intervals was used. We externally validated the GRAD architecture on 1,644 A4 Study participants, with MRI enhancement analysis in 1,044 gray zone cases. To measure cost-effectiveness we compared our GRAD-staged testing to universal PET.

RESULTS: The model's 'Gatekeeper' resolved 55.6% of ADNI cases with 88.8% accuracy (NPV 91.8%, PPV 85.0%). The complete pipeline achieved AUC 0.867 (95% CI: 0.825-0.904), with 80.6% sensitivity, 80.0% specificity, LR+ 4.03, LR-0.24. For the difficult-to-diagnose gray zone cases, the 'Reflex' machine learning model achieved AUC 0.755. In our A4 validation, the predictions correlated strongly with centiloid (r= 0.693). Expanding beyond plasma biomarkers, MRI integration improved gray zone classification from AUC 0.829 to 0.853 (p=0.014). The cost modeling analysis projected a 67% reduction in spending versus the current standard of universal PET.

DISCUSSION: Our clinically-staged diagnostic algorithm, 'GRAD', provides actionable classifications for the majority of patients while routing uncertain cases for additional workup. The GRAD framework offers a practical, cost-effective approach for implementing plasma biomarkers in clinical practice. Future iterations of this framework, with integration of novel biomarkers like MTBR-tau243 present a significant opportunity to alleviate the AD health-economic burden and eliminate expensive but unnecessary diagnostic measures.

HIGHLIGHTS: GRAD: Two-stage "Gatekeeper + Reflex for Alzheimer's Disease" algorithm resolves indeterminate plasma p-tau217 or 'gray zone' patients with AUC of 0.755.Overall AUC of 0.867 (95% CI: 0.825-0.904) validated via leave-one-out cross-validationExternal validation in A4 Study demonstrates strong correlation with amyloid burden (r=0.693)MRI volumetric integration provides significant incremental value (ΔAUC=+0.025, p=0.014)Projected 67-71% cost reduction compared to universal PET screening.

RESEARCH IN CONTEXT: Literature Review: We searched PubMed, Google Scholar, and medRxiv databases for studies up to December 2025 that examined plasma p-tau217 diagnostic accuracy as well as "gray zone" management of patients. While several studies demonstrate area-under-the-curve (AUC) of >0.90, these studies largely compare cognitively normal individuals to those with established AD dementia with maximal biomarker separation [1-6]. The gray zone problem, affecting 30-50% of tested individuals, remains unaddressed in the vast majority of clinical implementation frameworks [7,8]. More recent work has established probability-based interpretation [9], but more cohesive algorithms for gray zone resolution through multi-marker integration remain rare if present. Furthermore, the health economic impacts of such resolution have not been fully established.Interpretation: Our two-stage algorithm provides a workflow with clinical implementation potential, analogous to established laboratory medicine (i.e TSH with reflex free T4 testing). By first identifying high-confidence cases through univariate p-tau217 (55.6% resolution at 88.8% accuracy), and then applying multi-marker classification only to uncertain cases, we are able to achieve optimal resource utilization while simultaneously maintaining diagnostic accuracy. The finding that MRI usage provides statistically significant improvement (ΔAUC=+0.025) has practical implications given the fact that there is a reasonable level of MRI availability in clinical settings.Future Directions: While this work accomplishes several key priorities, future work is required to validate them in diverse clinical populations. In addition, integration of other plasma markers (ex. MTBR-tau243), development of clinical decision support tools, reimbursement mechanisms, and longitudinal validation for treatment monitoring will be necessary to ensure the appropriate infrastructure exists to support providers and patients. Preliminary evidence suggests that %p-tau217 (the ratio of phosphorylated to total tau-217) and MTBR-tau243, a mass spectrometry-based marker of tau tangle pathology, may substantially improve gray zone classification by capturing complementary aspects of tau biology not reflected in absolute p-tau217 concentrations alone, which is a direction that future technical work should examine further.},
}

@article {pmid41728301,
year = {2026},
author = {Xu, Y and Gunasekaran, TI and Gu, Y and Reyes-Dumeyer, D and Piriz, A and Sanchez, D and Mejia, DR and Medrano, M and Lantigua, RA and Honig, L and Wilson, R and Reyes, RER and Manly, JJ and Brickman, AM and Engelman, CD and Johnson, S and Asthana, S and Bennett, DA and Petersen, M and O'Bryant, S and Vardarajan, BN and Mayeux, R},
title = {Predictive Value of Plasma P-tau217 and APOE Genotype for Preclinical Cognitive Decline in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.06.26345774},
pmid = {41728301},
abstract = {BACKGROUND: APOE -ρ.4 is the strongest genetic risk factor for Alzheimer's disease (AD), and plasma phosphorylated tau217 (P-tau217) is a highly sensitive and specific biomarker for AD pathology. Their combined utility to predict cognitive decline before onset of AD has not been systematically evaluated.

METHODS: Using longitudinal data from multiple cohorts, we evaluated plasma P-tau217 as a predictor of when cognitive impairment occurs in AD. P-tau217 concentrations were analyzed as continuous and binary variables using cohort-specific biomarker positivity thresholds. Association of plasma P-tau217 with prevalent and incident cognitive impairment were assessed using logistic regression and Cox models, stratified by APOE genotype. Adjusted survival curves and restricted mean survival time characterized when the onset of cognitive impairment occurred. Cohort-specific estimates were pooled using random-effects meta-analyses, and analyzed by discrimination performance with AUC, incremental R², and Harrell's C-index.

RESULTS: Elevated P-tau217 levels were significantly associated with the onset of cognitive impairment. Among APOE -ε4 allele carriers, increased P-tau217 levels anticipated subsequent cognitive impairment. While P-tau217 levels reached clinically significant levels up to four years before onset of cognitive impairment independent of APOE , the symptom-free interval was briefest for APOE -ε4 carriers with elevated P-tau217.

CONCLUSIONS: Plasma P-tau217 levels and the presence APOE genotype can be used to estimate the interval before the onset of overt cognitive impairment and the diagnosis of AD. The findings here support the use of commercially available APOE genotyping and plasma P-tau217 to determine optimal timing for therapeutic intervention, particularly during the preclinical phase of the disease.},
}

@article {pmid41728290,
year = {2026},
author = {Cunha, C and Garcia-Ureña, M and Sanz Martĺnez, R and J Romero-Lado, M and Fernandez, MV and Andreassen, OA and Sims, R and Tsolaki, M and Sleegers, K and Hiltunen, M and Nicolas, G and Sanchez-Juan, P and Ingelsson, M and Giedraitis, V and Ghidoni, R and Holstege, H and van Duijn, C and van der Lee, S and Ramirez, A and Bellenguez, C and Lambert, JC and Frikke-Schmidt, R and , and O Kilpeläinen, T and J F Loos, R},
title = {Genomics link obesity and type 2 diabetes to Alzheimer's disease to unveil novel biological insights.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.10.26344393},
pmid = {41728290},
abstract = {Body mass index (BMI), type 2 diabetes (T2D) and associated cardiometabolic features modify Alzheimer's disease (AD) risk, yet shared mechanisms remain poorly understood. Using sex- and age-stratified genotyping data for BMI and T2D, we investigate how these traits converge on shared genetic pathways to AD risk. Employing multi-trait, machine learning and single-cell transcriptomics, we identify sex-specific cardiometabolic liability linked to higher BMI-associated risk in women and T2D-driven risk in men. Variant-level analyses reveal AD risk associates with genetically-driven hypotension and hypoglycaemia. We identify 35 putative effector genes in seven independent loci colocalizing between BMI/T2D and AD, mapping to peripheral immune and metabolic tissues and cell-types. Pathway enrichment identifies druggable targets in calcium and potassium channel signaling. Across 81 approved drugs modulating shared risk genes, levosimendan - a calcium sensitizer for heart failure - inhibits tau oligomerization and emerges as a repurposing candidate. These findings elucidate sex-specific cardiometabolic drivers of AD, identify actionable biological pathways, and reveal drug candidates for AD prevention and treatment.},
}

@article {pmid41728288,
year = {2026},
author = {Farfel, JM and Nag, S and Capuano, AW and Sampaio, MCM and Poole, VN and Wilson, RS and Bennett, DA},
title = {Age and the relation of common neuropathologies to dementia in Brazilian adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.11.26346038},
pmid = {41728288},
abstract = {BACKGROUND: Community-based clinical-pathologic studies have been instrumental to examine the association of Alzheimer's disease and related disorders (AD/ADRD) with age and dementia in very-old non-Latino Whites. Here, we show the age distribution of four AD and three additional common neuropathologies across the adult lifespan and examine their relation to dementia and cognitive impairment in old and young Brazilian adults.

METHODS: We examined 5,376 brains from decedents age 18 years or older (52.5% male, 39.8% Black), from the Pathology, Alzheimer's and Related Dementias Study (PARDoS), collected between July 2021 and September 2025. Clinical diagnoses were rendered by a clinician who reviewed the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), informant-based Clinical Dementia Rating (CDR) Scale, and other selected data. Four indices of AD including β-amyloid deposits (Thal stage), PHF-tau tangles (Braak stage), neocortical phosphorylated plaques and AD neuropathologic change (ADNC), and three other common neuropathologies, i.e., Lewy-body disease (LBD), chronic gross infarcts, and cerebral amyloid angiopathy (CAA) were assessed. Logistic regression was used for associations of pathologies with clinical diagnoses, adjusting for demographics.

RESULTS: Intermediate to high ADNC were first found as early as the fourth decade. Chronic gross infarcts were found in one-fifth of the brains of young adults. Intermediate to high ADNC, limbic and neocortical LBD, chronic gross infarct and moderate to severe CAA were associated with dementia and cognitive impairment (CI) in older adults with mixed pathologies being the most common. Intermediate to high ADNC was associated with CI but not dementia in young adults, whereas, chronic gross infarcts were associated with both CI and dementia in young adults; overall, mixed pathologies were a small minority.

CONCLUSION: In a community-based, clinical-pathologic study including 5300+ brains from diverse Brazilians, we show that AD and other common pathologies frequently begin in young adulthood. In older adults, mixed pathologies are most commonly associated with dementia, whereas in young adults a single pathology, most commonly chronic gross infarcts rather than ADNC is related to dementia.},
}

@article {pmid41728262,
year = {2026},
author = {Chinen, L and Busboom, MT and Meejang, J and Kastner, O and Heinrichs-Graham, E and Wilson, TW and Kurz, MJ},
title = {Adults with Down syndrome display altered entrainment of occipital cortical neurons.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcag038},
pmid = {41728262},
issn = {2632-1297},
abstract = {Down syndrome is commonly associated with a trisomy of chromosome 21 that often presents an accelerated aging profile and higher probability of developing Alzheimer's disease-like symptoms at a relatively early age. However, the physiological changes that may contribute to such symptoms remain poorly understood. To begin to address this knowledge gap, we used magnetoencephalographic neurophysiological imaging to assess the entrainment of occipital cortical neurons to a 15 Hz visual stimulus in a cohort of adults with DS without a dementia diagnosis (N = 26; Age = 27.65 ± 9.55 years) and a demographically matched cohort of neurotypical controls (N = 22; Age = 30.81 ± 8.02 years). Our results indicated that adults with Down syndrome exhibit substantially weaker entrainment of the occipital cortical neurons and elevated spontaneous activity during the prestimulation baseline period compared with the controls. These results suggest that there are alterations in the integrity of occipital neural populations that may be attributable to an imbalance in local GABAergic activity and/or disruption in cholinergic pathways. These changes may affect the strength of resting cortical rhythms, leading to the elevated spontaneous activity observed here, which has been linked to reductions in the dynamic range of neural populations and impairments in perceptual and cognitive processing. These novel results advance our understanding of the occipital cortical physiology seen in adults with Down syndrome and provide foundational knowledge for the development of biomarkers for the early detection of accelerated aging and cognitive decline in those with Down syndrome.},
}

@article {pmid41728091,
year = {2026},
author = {Mei, X and Liang, M and Ruan, N and Zhao, Z and Xu, T and Zheng, C},
title = {Multimodal neuroimaging discrimination of Alzheimer's disease, mild cognitive impairment, and late-life depression using electroencephalography and functional near-infrared spectroscopy: integrating electrophysiological and hemodynamic biomarkers.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1713472},
pmid = {41728091},
issn = {1663-4365},
abstract = {OBJECTIVE: To identify electrophysiological and hemodynamic characteristics of the cerebral cortex during the resting-state that could help differentiate Alzheimer's disease (AD), mild cognitive impairment (MCI), and late-life depression (LLD) and integrate these characteristics into a diagnostic model.

METHODS: We recorded oxygenated hemoglobin concentration (HbO) signals detected by functional near-infrared spectroscopy (fNIRS) from the prefrontal cortex, partial parietal cortex, and temporal lobe cortex, as well as electrophysiological signals detected by electroencephalography (EEG). The recording time was 30 min. Then, we used machine learning modeling with the support vector machine (SVM) algorithm to evaluate the diagnostic performances of EEG-based, fNIRS-based, and EEG plus fNIRS-based models for distinguishing AD, MCI, and LLD.

RESULTS: We investigated the differential neural signatures of patients with AD (n = 61), MCI (n = 28), and LLD (n = 27) using an EEG power spectral analysis across six frequency bands: delta (1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), low gamma (30-45 Hz), and high gamma (55-80 Hz). Two key frequency bands significantly differed among the groups. The alpha band power was significantly higher in the LLD group than in the AD and MCI groups (p < 0.05). The high gamma power was also significantly higher in the LLD group than in the MCI group (p < 0.05). Regarding fNIRS, HbO power significantly differed in 11 channels (channels 19, 22, 23, 24, 26, 27, 28, 32, 41, 42, and 43); the values were significantly lower in the AD group than in the MCI group and significantly higher in the MCI group than in the LLD group. The accuracies of the EEG, fNIRS, and combined SVM models were 0.5246, 0.5246, and 0.6066, respectively.

CONCLUSION: These findings highlight distinct EEG spectral patterns in patients with LLD compared to those with AD or MCI, particularly in alpha and high-gamma oscillations. These differences could be potential biomarkers for differentiating these conditions. Combining EEG and fNIRS analyses may further elucidate the neurophysiological mechanisms underlying these disorders.},
}

@article {pmid41727915,
year = {2026},
author = {Dolci, G and Saglia, S and Brusini, L and Calhoun, VD and Galazzo, IB and Menegaz, G},
title = {Algebraic Connectivity Reveals Modulated High-Order Functional Networks in Alzheimer's Disease.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41727915},
issn = {2331-8422},
abstract = {Functional MRI is a neuroimaging technique that analyzes the functional activity of the brain by measuring blood-oxygen-level-dependent signals throughout the brain. The derived functional features can be used for investigating brain alterations in neurological and psychiatric disorders. In this work, we employed a hypergraph to model high-order functional relations across brain regions, introducing algebraic connectivity (a(G)) for estimating the hyperedge weights. The hypergraph structure was derived from healthy controls to build a common topology across individuals. The considered cohort for subsequent analyses included subjects covering the Alzheimer's disease (AD) continuum, encompassing both mild cognitive impairment and AD patients. Statistical analysis and three classification tasks: HC vs AD, MCI vs AD, and HC vs MCI, were performed to assess differences across the three groups and the potential of the hyperedge weights as functional features. Furthermore, a mediation analysis was performed to evaluate the reliability of the a(G) values, representing functional information as the mediator between tau-PET levels, a key biomarker of AD, and cognitive scores. The proposed approach identified a larger number of hyperedges statistically different across groups compared to state-of-the-art methods. The a(G) hyperedge weights also demonstrated a higher discriminative power in all three binary classifications. Finally, two hyperedges belonging to salience/ventral attention and somatomotor networks showed a partial mediation effect between the tau biomarker and cognitive decline. These results suggested that a(G) can be an effective approach for extracting the hyperedge weights, including important functional information that resides in the brain areas forming the hyperedges.},
}

@article {pmid41727718,
year = {2026},
author = {Juárez-Romero, GU and Sun, X and Gerez, JA and Den Auwer, C and Landrot, G and Nachtegaal, M and Riek, R and Luo, J and Quintanar, L},
title = {Structural insights into copper and zinc binding to tau protein and the impact of metal binding on amyloid aggregation.},
journal = {Chemical science},
volume = {},
number = {},
pages = {},
pmid = {41727718},
issn = {2041-6520},
abstract = {Tau protein is a microtubule-associated protein central to the pathogenesis of Alzheimer's disease (AD) and other tauopathies. While metal ion homeostasis is disrupted in AD, the presence of copper and zinc in neurofibrillary tangles suggests a pathological role for metal-tau interactions. In this study, the metal binding properties of Tau441 were probed using a wide range of spectroscopic tools. Specifically, electron paramagnetic resonance, circular dichroism, nuclear magnetic resonance (NMR) and X-ray absorption spectroscopy (XAS) results point to a single high-affinity Cu[2+] binding site within the microtubule-binding domain (MTBD), coordinated by the bis-His motif in R3 (His329/His330), possibly His299 and an oxygen-based ligand. This complex can be reduced resulting in a trigonal Cu[+]-Tau441 complex involving Cys322, His299 and a third ligand (likely Cys291 or His329/330), as characterized by XAS and NMR. NMR and XAS results indicate the presence of three Zn[2+] binding sites: one high-affinity site in the MTBD involving His299, His330, Cys322 and Asp295, and two lower-affinity sites in the N-terminal region, coordinated predominantly by carboxylate and His residues. Moreover, the impact of Cu[2+] and Zn[2+] ions on the amyloid aggregation of full length Tau441 was evaluated using thioflavin T fluorescence, electrophoresis and transmission electron microscopy. Both metal ions significantly accelerate aggregation, promoting the formation of amyloid fibrils with distinct morphologies. Our study provides valuable structural insights into the copper and zinc binding sites in Tau441 that provide a rational basis to understand the impact of metal ions on amyloid fibril aggregation and morphology. The current study expands the bioinorganic facet of AD and other tauopathies, and it underscores the importance of metal-tau interactions as potential therapeutic targets in these neurodegenerative diseases.},
}

@article {pmid41727597,
year = {2026},
author = {Onishchenko, D and Mastrianni, JA and Chattopadhyay, I},
title = {Bloodwork-free Early Screening for Alzheimer's Disease via Comorbid Pattern Recognition in Electronic Health Records.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8789582/v1},
pmid = {41727597},
issn = {2693-5015},
abstract = {Early identification of Alzheimer's disease and related dementias (ADRD) remains limited by the need for specializedtests and late-stage diagnosis. The Zero-burden Risk Assessment (ZeBRA) is a AI-driven score that predictsincident ADRD up to a decade before diagnosis, using only routine electronic health record (EHR) data, withoutlaboratory tests, imaging, or questionnaires. Trained on 487,989 cases and 12,483,718 controls from nationwideU.S. insurance claims and validated on held-back samples , and two independent cohorts, ZeBRA achievedAUC = 0.93 and 0.83 for predicting out to 1-year and 10-year horizons respectively, maintaining positive likelihoodratios (>10) at 95% specificity and stable discrimination over time (AUC drop ≈ 1 to 1.3% per year). Performancewas consistent across age, sex, race, and ethnicity subgroups. In a limited prospective pilot, higher ZeBRA scorescorrelated with lower Montreal Cognitive Assessment (MoCA) scores, indicating a greater degree of cognitiveimpairment (R = -0.78). Compared with prior EHR-based models, ZeBRA provides superior accuracy, cross-site generalizability, and demonstrates noise-corrected interpretability via our novel Λ-OR attrubution metric. Its scalability, low cost, and independence from specialized testing position ZeBRA as a practical tool for population-level early detection and presymptomatic trial enrichment.},
}

@article {pmid41727576,
year = {2026},
author = {Lindi, HA and Shalbaf, R and Shalbaf, A and Shahabi, MS and Abharian, P},
title = {Interpretable Feature-Transformer Framework for Cross-Subject MCI Detection Using Nonlinear Dynamical and Graph-Theoretic EEG Features.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8744978/v1},
pmid = {41727576},
issn = {2693-5015},
abstract = {Early and accurate detection of Mild Cognitive Impairment (MCI) is essential for preventing progression toward Alzheimer's disease (AD). In this cross-subject study, we investigate the effectiveness of entropy- and graph-based EEG features for distinguishing MCI from healthy controls (HC), using two modeling approaches: (1) a Transformer network applied to the engineered feature set, and (2) an EEGNet model trained on the same feature representation for comparison. The dataset consists of resting-state, eyes-closed EEG recordings from 183 participants (127 HC, 56 MCI), collected using a 20-channel STAT™ X24 wireless system and segmented into 3-second epochs. EEG data underwent standard preprocessing, including band-pass filtering, downsampling, normalization, and class-balancing augmentation applied to the minority class. From each channel, nonlinear dynamical measures (e.g., sample and fuzzy entropy, Higuchi fractal dimension, Lyapunov exponent) and graph-theoretic connectivity descriptors derived from coherence matrices across five frequency bands were extracted, yielding a structured 19×77 feature representation. The feature-based Transformer achieved the best performance (97.04% ± 0.72), outperforming the feature-based EEGNet baseline and highlighting the benefits of combining rich handcrafted features with attention-based modeling. SHAP (SHapley Additive exPlanations) analysis provided global and local interpretability, revealing the most influential nonlinear and connectivity features as well as the EEG channels contributing most to classification. Overall, these results demonstrate the effectiveness of feature-Transformer integration and support the potential of interpretable feature-driven deep learning models for early MCI detection.},
}

@article {pmid41727572,
year = {2026},
author = {Casaletto, K and Alexander, MW and Rabin, J and Canuca, M and Iadipaolo, A and Cornelis, L and Miolane, N and Pham, A and Borger, J and Diaz, V and Paolillo, E and Kramer, J and Pritschet, L and Taylor, C and Panizzon, M and Reyes, RR and Denkinger, M and Ashton, N and Johnson, S and Jacobs, E and Saloner, R},
title = {Blood-based proteomic signatures of spontaneous menopause: Implications for later-life brain aging and Alzheimer's disease risk.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8752767/v1},
pmid = {41727572},
issn = {2693-5015},
abstract = {Menopause is a hallmark process in biological aging that has been associated with later life neurodegenerative risk. We leveraged proteomics data from multiple cohorts (N>3,000) to identify biological changes underlying menopause and its links to brain aging. In N=80 rigorously-phenotyped pre-, peri-, and postmenopausal women with serum NULISAseq proteomics, spontaneous menopause was characterized by dysregulation in inflammatory, synaptic, metabolic, and Alzheimer's disease (AD) biologic processes, which tracked with hormones and not age. Pro-inflammatory protein upregulation was especially pronounced in women with vasomotor symptoms. In two cohorts of older women (N=94; N=100), menopause-related proteomic elevations associated with poorer cognitive outcomes and plasma AD biomarkers. Finally, validation analyses in age-matched pre- and postmenopausal women with plasma Olink proteomics (N=2,814) replicated the observed proteomic shifts and revealed menopause-related upregulation of additional inflammatory and hormone signaling processes. The molecular signatures of menopause may inform biomarkers or therapeutic targets for brain health in women.},
}

@article {pmid41727571,
year = {2026},
author = {Song, Q and Zhou, X and Wang, A and Wang, Y and Liu, X and Wang, Q and Guo, S and Wen, J},
title = {A hierarchical Bayesian framework for inferring mitochondrial clonal selection from single-cell data.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8490828/v1},
pmid = {41727571},
issn = {2693-5015},
abstract = {Mitochondrial genetic heterogeneity arises from the accumulation of somatic mitochondrial DNA (mtDNA) mutations within individual cells, generating intracellular clonal populations whose selective dynamics in disease remain poorly characterized. Here, we present MitoBayes, a hierarchical Bayesian framework that jointly models mitochondrial clonal lineage structure, allele frequency variation, and single-cell disease-relevant phenotypic burdens to infer clone-specific selection pressures. Extensive benchmarking demonstrates that MitoBayes accurately recovers ground-truth selection coefficients across a wide range of genetic heterogeneity, data sparsity, and lineage complexity scenarios. Application of MitoBayes to single-cell atlases of Alzheimer's disease (AD) cortex, treatment-naïve non-small-cell lung cancer (NSCLC), and chemotherapy-resistant small-cell lung cancer (SCLC) revealed distinct, disease-specific patterns of mitochondrial clonal selection. These include selective expansion of high-risk mitochondrial clones associated with disruption of PVALB interneuron homeostasis in AD; disease-driven clonal remodeling in cycling T/NK cells from NSCLC tumors characterized by increased mitochondrial biogenesis and impaired immune regulatory programs; and preferential enrichment of a tumor-associated MT-ATP6 (m.8859A > G) clone linked to metabolic adaptation and platinum resistance in SCLC. Pan-cancer survival analyses further confirmed the clinical relevance of elevated MT-ATP6 activity, which was associated with inferior chemotherapy outcomes. Additionally, in hepatocellular carcinoma (HCC), a dominant m.2356C > G clone correlated with POLR2A activation and widespread transcriptional amplification, consistent with a mitochondria-nucleus signaling axis contributing to adverse prognosis in this cancer type. Collectively, these findings establish MitoBayes as a robust statistical framework linking mitochondrial genetic diversity to disease phenotypes and highlight mitochondrial clonal selection as a mechanistically and clinically actionable target for therapeutic and diagnostic development.},
}

@article {pmid41727529,
year = {2026},
author = {Jaidka, S and Kumar, A and Singh, TG and Bhatia, R and Singh, RK},
title = {Structure-activity landscape of Nurr1 (NR4A2) modulators: medicinal chemistry strategies for neurodegenerative disease intervention.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41727529},
issn = {2632-8682},
abstract = {Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor essential for dopaminergic neuron development, maintenance, and survival. Nurr1 is highly expressed in the substantia nigra and regulates transcription of key dopaminergic genes, including tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT). Dysregulation of Nurr1 is linked to Parkinson's disease (PD), where reduced expression contributes to neuronal loss, oxidative stress, and neuroinflammation. Nurr1 also suppresses microglial activation and pro-inflammatory cytokine production in Alzheimer's disease, including TNF-α and IL-1β. Despite its therapeutic promise, Nurr1 remains a challenging target due to its atypical ligand-binding domain architecture and persistent limitations in NR4A subfamily selectivity. Early ligands such as amodiaquine and prostaglandin derivatives showed activity but lacked selectivity and drug-like properties. Recent structural studies suggest conformationally dynamic binding sites that may support structure-guided design; however, many reported Nurr1 ligands also activate Nur77 (NR4A1) and NOR-1 (NR4A3), complicating mechanistic interpretation. This review systematically analyzes structure-activity relationships (SARs) across major chemotype families, including indoles, quinolines, triazoles, thiazoles, thiophenes, imidazo[1,2-a]pyridines, and fatty acid mimetics. We critically evaluate binding evidence, functional activity, and neuroprotective profiles, highlighting key SAR determinants such as heteroaromatic substitution patterns, hydrogen-bonding capacity, and lipophilicity. Several scaffolds demonstrate validated binding with submicromolar affinity (K d ≈ 0.11-0.17 μM); however, major gaps remain in achieving robust NR4A selectivity, establishing blood-brain barrier (BBB) penetration, and demonstrating consistent in vivo efficacy. Overall, this analysis highlights both the promise and the persistent challenges in developing Nurr1-targeted therapeutics for neurodegenerative disease intervention.},
}

@article {pmid41727509,
year = {2026},
author = {Yokoi, K and Tsujimoto, M and Suzuki, K and Takeda, A and Horibe, K and Yamaoka, A and Okada, E and Kawakami, O and Katsuno, M and Arahata, Y},
title = {Factors associated with epileptiform discharges in patients visiting a memory clinic: A retrospective study.},
journal = {Epilepsy & behavior reports},
volume = {33},
number = {},
pages = {100853},
pmid = {41727509},
issn = {2589-9864},
abstract = {Epilepsy is a common comorbidity in older adults, particularly those with neurodegenerative diseases such as Alzheimer's disease. However, recognizing epilepsy in patients with dementia can be challenging, as its symptoms often mimic cognitive fluctuations. Reliable clinical indicators validated by electroencephalography (EEG) are needed for timely diagnosis and management. This study investigated predictors of epileptiform discharges in patients visiting a memory clinic, focusing on the diagnostic role of EEG. We retrospectively screened 159 patients who underwent medical interviews with physicians and EEG testing between April 2022 and March 2023. Data from dementia-related questionnaires, comprehensive geriatric assessments, EEG, magnetic resonance imaging, and single-photon emission computed tomography were evaluated. Among the 156 patients with dementia (after excluding 3 with epilepsy), 77 exhibited epileptiform discharges, predominantly left temporal (87%) or bilateral (13%), and female patients were more often affected (p < 0.05). Logistic regression analysis revealed that discharges were associated with variable cognitive decline. Approximately two-thirds of patients with epileptiform discharges answered "yes" to the interview item assessing "cognitive decline with variability," highlighting the predictive value of this symptom. However, the remaining cases required EEG testing for detection. Our findings underscore the importance of recognizing epilepsy during dementia screening. While clinical interviews provide valuable insights, EEG remains indispensable for accurate diagnosis and treatment.},
}

@article {pmid41727487,
year = {2026},
author = {Wang, Y and Liu, S and Zhu, W and Hao, P and Xu, J and Mai, D and Chen, R and Han, H and Bian, X and Wang, B},
title = {Metabolic control of neuroinflammation: focus on itaconate and its derivatives in CNS disorders.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1726379},
pmid = {41727487},
issn = {1664-3224},
mesh = {Humans ; *Succinates/metabolism/pharmacology/therapeutic use ; Animals ; *Microglia/metabolism/immunology/drug effects ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Central Nervous System Diseases/metabolism/drug therapy ; Signal Transduction ; },
abstract = {The activation of microglia, which are the resident immune cells of the central nervous system (CNS), underpins the pathogenesis of neuroinflammatory and neurodegenerative diseases. Metabolic reprogramming has recently been recognized as a critical mechanism that regulates microglial activation because distinct activation phenotypes are tightly coupled to specific metabolic profiles that shape their functional and inflammatory responses. Accumulating evidence indicates that microglia produce itaconate through the tricarboxylic acid cycle, and itaconate and its derivatives play key antioxidant and anti-inflammatory roles. Mechanistically, itaconate has a major impact on the metabolic processes and functional state of microglia by blocking the NF-κB signaling route, activating the Nrf2 signaling pathway, and inhibiting succinate dehydrogenase synthesis as well as NLRP3 inflammatory vesicle activation. Collectively, these actions confer significant protection against CNS disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, and cerebral hemorrhage. Furthermore, structurally optimized itaconate derivatives exhibit enhanced pharmacokinetics and bioactivity. This review highlights the pivotal role of itaconate and its derivatives in microglial regulation, explores their therapeutic potential in neurological diseases, and outlines future research directions, with the aim of providing a theoretical foundation for novel metabolic interventions.},
}

Humans
*Succinates/metabolism/pharmacology/therapeutic use
Animals
*Microglia/metabolism/immunology/drug effects
*Neuroinflammatory Diseases/metabolism/drug therapy
*Central Nervous System Diseases/metabolism/drug therapy
Signal Transduction

@article {pmid41727439,
year = {2026},
author = {Quan, Y and Liu, H and Zhang, M and Li, M and He, B and Wang, K and Huang, X and Zhou, S and Han, Z and Fan, H},
title = {Ferroptosis and Alzheimer's disease: a new insight into neurodegeneration.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1701767},
pmid = {41727439},
issn = {1664-3224},
mesh = {*Ferroptosis/drug effects ; Humans ; *Alzheimer Disease/metabolism/pathology/etiology/drug therapy ; Animals ; Amyloid beta-Peptides/metabolism ; Brain/pathology/metabolism ; Neurofibrillary Tangles/metabolism/pathology ; Plaque, Amyloid/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD), a chronic and progressive neurodegenerative disorder, poses a significant threat to the health of the aging population. The pathological hallmarks of AD include the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) within the brain. While substantial neuronal loss has been consistently observed in AD, the precise mechanisms underlying neuronal elimination remain incompletely understood. As a distinct form of regulated cell death, the contribution of ferroptosis to AD pathogenesis and progression warrants further investigation. This review critically examines the amyloid cascade hypothesis within the context of AD, with particular emphasis on the molecular signatures of ferroptosis and their contributions to canonical AD pathogenesis and cognitive decline. We aim to provide an updated perspective on AD etiopathogenesis. Furthermore, we synthesize current therapeutic strategies targeting ferroptosis inhibition in AD, highlighting recent advances that hold significant implications for guiding present and future translational efforts.},
}

*Ferroptosis/drug effects
Humans
*Alzheimer Disease/metabolism/pathology/etiology/drug therapy
Animals
Amyloid beta-Peptides/metabolism
Brain/pathology/metabolism
Neurofibrillary Tangles/metabolism/pathology
Plaque, Amyloid/metabolism/pathology

@article {pmid41727334,
year = {2025},
author = {Ramezani, R and Behbahani, M and Mohabatkar, H and Sarraf Mamouri, K and Hejazi, F},
title = {Comparison of CRISPR Sequences in Archaea and Bacteria with Eukaryotic microRNAs.},
journal = {Avicenna journal of medical biotechnology},
volume = {17},
number = {4},
pages = {258-276},
pmid = {41727334},
issn = {2008-2835},
abstract = {BACKGROUND: This study explores repetitive Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) sequences from the archaea Acidianus sp. and Acidianus ambivalens (A. ambivalens), as well as from the bacterium Yersinia ruckeri (Y. ruckeri). These sequences are compared with human microRNA (miRNA) sequences to investigate potential genetic similarities and disease associations.

METHODS: CRISPR sequences were retrieved from the CRISPR/Cas[++] database, and human miRNA sequences were obtained from miRBase. Sequence alignments were performed using BLASTn with an E-value threshold of 1e-5 to identify significant similarities. Genes associated with matched human miRNAs were identified through the HGNC and GeneCards databases. Further analyses included comparison with disease-associated miRNAs reported in human and mouse datasets.

RESULTS: In Y. ruckeri, alignments revealed similarities to miRNAs linked with genes such as FOXO1, PTEN, PAX7, and DOCK3, which are associated with lung cancer and muscular dystrophies. In A. ambivalens, aligned miRNAs corresponded to loci including CHM13 and GRCh38, potentially linked to periembolic adenocarcinoma and mild pre-eclampsia. For Acidianus sp., matches were observed with miRNAs associated with genes like Irak2, NOS2, STAT1, and Numb, which have been implicated in Psoriatic arthritis, Alzheimer's disease, Hepatocellular carcinoma, and Coronary artery disease.

CONCLUSION: CRISPR sequences from these prokaryotes show notable similarities with human miRNAs, suggesting possible indirect links to genes involved in major diseases. These preliminary findings emphasize the need for further investigation into shared sequence motifs and their functional roles in host-pathogen interactions or evolutionary biology.},
}

@article {pmid41727166,
year = {2026},
author = {Jensen, KA and Weller, J and Funk, KE},
title = {RNA-seq variants reveal distinct patterns in the aging epitranscriptome: an in-depth analysis of age-matched Alzheimer's Disease patients and a cognitively normal cohort.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.14.705891},
pmid = {41727166},
issn = {2692-8205},
abstract = {BACKGROUND: Post-transcriptional modifications are those made to the RNA transcript, which can modulate RNA stability and function. Despite robust investigation of the genome, transcriptome, and proteome, little is known about post-transcriptional modifications during normal aging or Alzheimer's disease (AD) pathogenesis. Several studies have shown epitranscriptomic changes in AD brains for certain modification types, establishing epitranscriptomic links to the disease; however, the complete set of post-transcriptional modifications have not been assessed in the context of AD. Furthermore, it is not understood which genes or pathways are under epitranscriptomic regulation, how conserved and sporadic modifications are distributed, or which conserved sites are differentially modified in diseased brains. Therefore, there is a need for a more complete analysis to describe the full landscape of the epitranscriptome in AD, helping to bridge the knowledge gap between post-transcriptional modifications and the molecular etiology of AD.

METHODS: We designed and implemented a novel bioinformatics pipeline for complex epitranscriptome-wide analysis of potential RNA modification sites in sample-matched, whole-genome sequencing-filtered variant calls from RNA sequencing data. Using parametric and non-parametric tests, we tested differences in patterns for all detectable variant calls between postmortem brains of AD and cognitively normal, aged individuals.

RESULTS: We identified 544 genes with hyper-modified transcripts in AD samples compared with cognitively normal controls, a notable observation being high enrichment of genes in the "Kaposi's sarcoma-associated herpesvirus" pathway. We also identified patterns of recurring and sporadic modification sites that differed complementarily between disease and non-disease conditions. We found 17 genes (33 total sites) that were differentially modified between conditions including several sites found exclusively in the AD epitranscriptome.

CONCLUSIONS: These findings provide a more complete profile of the potential molecular underpinnings which differentiate AD brains from their non-diseased, aged counterparts and reveal patterns and modification sites which can be further investigated for how they contribute to the network of molecular interactions underlying AD. These elements are likely to be valuable candidates for investigations that aim to further the search for biomarkers and therapeutic targets.},
}

@article {pmid41727140,
year = {2026},
author = {Huffman, DJ and Ekstrom, AD and Jaha, N},
title = {Living off the grid: Spatial representations show systematic non-Euclidean distortions regardless of their age and how measured.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.10.705053},
pmid = {41727140},
issn = {2692-8205},
abstract = {UNLABELLED: Spatial memory is invaluable for most mobile organisms, yet nature of the underlying representations that we employ for spatial memory has been fiercely contested. On the one hand, the presence of place cells in the hippocampus and grid cells in the medial entorhinal cortex appear to support the argument spatial representations may follow Euclidean axioms, termed "the cognitive map hypothesis." On the other hand, decades of behavioral research in humans reveals that spatial memory often shows characteristic distortions, leading to the alternative, cognitive graph hypothesis, to account for this aspect of spatial memory. Importantly, the majority of laboratory studies tend to occur within novel environments in which participants often have only limited exposure and no personal relevance. We were interested in studying large-scale memory across multiple time scales: from a virtual environment (e.g., learned over several minutes) to a college campus (e.g., months to a few years) to a hometown environment (e.g., many years). Across several tasks, we found that participants exhibited systematic distortions in their memory for all of these environments. Likewise, we found significant correlations between performance on several spatial memory tasks (both between participants and within-participant analyses of patterns of errors), thus suggesting that these tasks tap into partially overlapping cognitive representations and supporting their construct validity. Altogether, our findings provide clear evidence for cognitive graph hypothesis and support the construct validity of several spatial memory tasks within large-scale, real-world environments that are learned over the course of several months to years.

PUBLIC SIGNIFICANCE STATEMENT: Spatial memory is key for our ability to live independent lives (e.g., patients with Alzheimer's disease lose independence, partially due to disorientation in familiar environments). Typical laboratory-based measures of spatial memory use novel environments that may differ in complexity vs. real-world environments (e.g., size, layout, number of landmarks, duration of exploration, personal relevance). We leveraged breakthroughs in technology to study spatial memory across several tasks and temporal scales, from a novel environment navigated over the course of several minutes to a university campus (e.g., months to years) to hometowns (e.g., years to decades). We observed consistent evidence for systematic distortions in spatial memory, which supports the hypothesis that spatial memory is supported by a cognitive graph, thus posing an important challenge to the extremely influential Euclidean, "cognitive map" hypothesis that was awarded a Nobel Prize in 2014.},
}

@article {pmid41727138,
year = {2026},
author = {He, Z and Zhou, J and Zhang, R and Meng, F and Nauen, DW and Troncoso, JC and Worley, PF and Zhang, W},
title = {TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.11.705390},
pmid = {41727138},
issn = {2692-8205},
abstract = {Aberrant protein aggregation is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which share overlapping genetic and pathological features. Similar aggregates are increasingly recognized in Alzheimer's disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, it remains unclear whether a shared molecular pathway drives this pathological aggregation. Here, we report that the E3 ubiquitin ligase TRIM32, together with the shuttle factor UBQLN2 and the autophagy adaptor p62/SQSTM1, form condensates that depend on E3 ligase activity and a network of intermolecular interactions. These condensates act as scaffolds that capture UBQLN2 client proteins, including TDP-43 and ANXA11, and modulate their mobility. A unique hydrophobic loop within TRIM32's substrate-binding domain mimics low-complexity motifs in ANXA11 and TDP-43, enabling selective retention via competitive binding mediated by UBQLN2 STI1 domain. Moreover, TRIM32 condensates promote amyloid aggregation of TDP-43, an effect that is exacerbated by pathogenic UBQLN2 mutation. In brains from individuals with diverse neurodegenerative diseases, TRIM32 co-localizes with pathological phospho-TDP-43 (pTDP-43) inclusions, supporting a model in which TRIM32-driven condensates function as selective proteostasis sorting compartments that broadly contribute to TDP-43 proteinopathy.},
}

@article {pmid41727136,
year = {2026},
author = {Dubinski, A and Ferdi, A and Choughari, M and Spence, H and Adhikary, A and Fauchon, C and Touati, M and Gagné, M and Liu, M and Peyrard, S and Gregory, J and Vande Velde, C},
title = {TDP-43 pathology is linked to motor neuron loss but is independent of stress granules in vivo.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.11.705439},
pmid = {41727136},
issn = {2692-8205},
abstract = {Nuclear depletion and cytoplasmic aggregation of TDP-43 are pathological hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease, and the recently defined limbic-predominant age-related TDP-43 encephalopathy (LATE). Chronic activation of the integrated stress response (ISR) and persistence of stress granules, phase-separated assemblies proposed to function as a protective mechanism, have been hypothesized to initiate the formation of pathological TDP-43 inclusions observed in post-mortem neurons. However, recent clinical trials targeting the ISR and stress granule dissolution failed to demonstrate clinical benefit despite robust target engagement, calling this model into question. Here, we employ a recurrent hyperthermia paradigm to directly examine the relationship between stress granules and TDP-43 pathology in vivo . We find that RNA-binding proteins classically associated with stress granules persist as phase-separated cytoplasmic structures in spinal motor neurons of both non-transgenic and mutant TDP-43 mice. Importantly, these structures are reversible and spatially distinct from TDP-43 puncta. Moreover, in a mutant TDP-43 mouse model with an impaired acute stress granule response, stress exposure induces TDP-43 nuclear export and cytoplasmic accumulation. Recurrent stress in these mice leads to a selective loss of spinal α-motor neurons. Together, our findings demonstrate that TDP-43 nuclear clearance and cytoplasmic demixing occur independently of stress granules in vivo , challenging prevailing models of TDP-43 pathogenesis and highlighting important implications for therapeutic strategies targeting the ISR.},
}

@article {pmid41727111,
year = {2026},
author = {Ding, DY and Bot, VA and Chen, KL and Groves, J and Pálovics, R and Masuda, D and Farinas, A and Oh, HS and Wagner, V and Lu, N and , and Cruchaga, C and Isakova, A and Schott, JM and Wyss-Coray, T},
title = {Cellular Aging Signatures in the Plasma Proteome Record Human Health and Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.10.704909},
pmid = {41727111},
issn = {2692-8205},
abstract = {Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types-spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins-using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer's disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience.},
}

@article {pmid41727014,
year = {2026},
author = {Pikus, P and Healey, GS and Xia, E and Shautidze, G and Siddapureddy, N and Lee, Y and Albanese, C and Rodriguez, O and Turner, RS and Rebeck, GW},
title = {Intravenous anti-Aβ immunotherapy acutely increases cerebral amyloid angiopathy and vascular damages in APOE4 mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.09.704876},
pmid = {41727014},
issn = {2692-8205},
abstract = {Anti-Aβ immunotherapies for Alzheimer's Disease (AD) have high rates of amyloid-related imaging abnormalities (ARIA), an adverse side effect with markedly higher rates in APOE4 carriers. We developed a mouse model of ARIA centered on human APOE3 and APOE4 genotypes with amyloidosis (5xFAD transgene) and microglia tagged with green fluorescent protein (from the CX3CR1 promoter). We measured acute changes following a single intravenous treatment with 3D6 anti-Aβ immunotherapy. Across 82 mice, APOE4 mice showed stepwise reductions in the number of plaques from one to ten days, with significant reductions in the subiculum (48%) and thalamus (40%) at ten days. There was no significant reduction in APOE3 mice. There was a concomitant significant increase in deposition of cerebral amyloid angiopathy (CAA) in APOE4 mice at one (76%) and three (51%) days in leptomeningeal vessels. The increased CAA correlated with a significant 189% increase in Aβ within microglia of APOE4 (but not APOE3) mice at one day. Smooth muscle actin staining showed significant 58% reduction near CAA. MRI analysis revealed a significant 32% increase in microhemorrhages ten days following treatment. These data demonstrate an APOE4 -specific redistribution of parenchymal amyloid to CAA by 3D6 within days, leading to increased vascular damages associated with ARIA.},
}

@article {pmid41726974,
year = {2026},
author = {Barney, RM and Quinones-Valdez, G and King, AJ and Amoah, K and Wang, W and Xiao, X},
title = {Allele-specific alternative polyadenylation links noncoding genetic variation to Alzheimer's disease risk.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.13.705798},
pmid = {41726974},
issn = {2692-8205},
abstract = {BACKGROUND: Alternative polyadenylation (APA) is a crucial post-transcriptional mechanism generating isoform diversity in the nervous system. While genetic variants significantly influence gene expression, the extent to which they regulate 3' UTR usage in the human brain remains underexplored. We aimed to characterize the landscape of allele-specific alternative polyadenylation (asAPA) and investigate its role in neurodevelopmental and neurodegenerative disorders.

RESULTS: Analyzing 1,047 RNA-seq data from 293 Alzheimer's disease (AD) and control donors across four brain regions, we identified 4,462 asAPA events involving 3,432 SNPs. We prioritized a core set of putative functional variants that drive consistent cis-regulatory effects across individuals. These functional SNPs are enriched for RNA-binding protein motifs, particularly those recognized by FMRP. In Fragile X Syndrome brains lacking FMRP, we observed widespread 3' UTR shortening, with FMRP motifs enriched in the 3' UTR extension regions of shortened transcripts, suggesting FMRP normally protects against proximal site usage. Integrating these data with population genetics, we found that asAPA SNPs significantly overlap GWAS risk loci for autism spectrum disorder (ASD), ADHD, and AD. Furthermore, comparing AD to control brains within our cohort revealed 77 asAPA genes exhibiting condition-specific shifts in allelic bias, affecting key synaptic genes including CAMK2G .

CONCLUSIONS: Our study uncovers a pervasive layer of cis-regulatory variation in the human brain that links noncoding genetics to transcript structure via RBP interactions. We identify FMRP as a key regulator of this process and demonstrate that asAPA provides a mechanistic bridge connecting genetic risk to neuronal pathology in both neurodevelopment and neurodegeneration.},
}

@article {pmid41726972,
year = {2026},
author = {Natarajan, C and Budhwani, SM and Sreenivasamurthy, SGS and Katamoni, L and Thomson, B and Marcatti, M and Cuong, PP and Taglialatela, G and Krishnan, B},
title = {Exploring the PLD1-tau interaction in Frontotemporal Dementia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.12.705569},
pmid = {41726972},
issn = {2692-8205},
abstract = {Frontotemporal dementia (FTD), a leading cause of young-onset dementia, is characterized by progressive behavioral and cognitive decline associated with frontotemporal cortical atrophy. Nearly 40% of cases exhibit tauopathy, yet the molecular drivers of tau aggregation leading to synaptic dysfunction remain poorly understood. Here, we investigated whether Phospholipase D1 (PLD1, a lipid signaling enzyme), implicated in Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), contributes to tau pathology dependent synaptic deficits in FTD. Postmortem temporal (BA38) and frontal (BA9) cortices from clinically diagnosed FTD and age-matched control subjects were analyzed using fluorescence-assisted single synaptosome long-term potentiation (FASS-LTP), immunofluorescence, proximity ligation assays (PLA), and PLD1-interactome proteomics. FASS-LTP revealed markedly reduced glutamatergic potentiation in BA38 and BA9 crude synaptoneurosomes from FTD brains compared to controls. Western blotting demonstrated elevated PLD1 expression in both crude synaptoneurosomal and cytosolic fractions from FTD subjects in BA38, but not BA9. Bielschowsky staining confirmed increased Pick body burden in FTD temporal cortex. Immunofluorescence and PLA showed robust PLD1 co-localization with total tau (HT7), hyperphosphorylated tau (AT8), and acetylated tau oligomers (TOMA2), indicating a strong spatial association between PLD1 and pathological tau species. PLD1 also exhibited enhanced co-localization with astrocytic GFAP and synaptic markers (PSD95, Nrx1β), suggesting compartmentalized involvement in glial and synaptic remodeling. Proteomic profiling of PLD1-associated complexes revealed compartment-specific alterations with cytosolic fractions enriched for metabolic enzymes, stress-response proteins, and GFAP, while crude synaptoneurosomal fractions showed depletion of presynaptic scaffolds, vesicle-trafficking regulators, and proteostasis components. Cross-compartment integration indicated that over one-third of proteins were redistributed from synapses to cytosol, consistent with trafficking and degradative impairments. Gene Ontology analysis highlighted lipid metabolism, astrocyte activation, and proteasome dysfunction as dominant pathways. Collectively, these findings identify PLD1 as a critical mediator of synaptic dysfunction and tau pathology in FTD, acting through astroglial activation and disrupting synaptic proteostasis. This study provides the human clinical relevance towards PLD1 attenuation as a therapeutic target for FTD and related tauopathies to mitigate tau-driven neurodegeneration and restore synaptic integrity.},
}

@article {pmid41726956,
year = {2026},
author = {Podder, A and Liew, YJ and Cary, GA and Carter, GW and Uyar, A},
title = {Single-subject Proteomic Signatures in Alzheimer's Disease Reflect Clinical Phenotypes and Distinguish Asymptomatic from Symptomatic Cases.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.06.704408},
pmid = {41726956},
issn = {2692-8205},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) exhibits considerable inter-individual variability in clinical presentation, neuropathological burden, and underlying molecular processes. Conventional cohort-based analyses of omics molecular data often mask individual-level heterogeneity, limiting insights into the precision therapeutic strategies. To address this challenge, we developed INDIGO (INdividual-level DIfferential GenOmics), a computational framework that quantifies molecular deviations for each individual relative to healthy controls, enabling subject-specific profiling of diseaseassociated alterations in proteomic data, with a framework that is readily applicable to other omics modalities.

METHODS: We applied INDIGO to dorsolateral prefrontal cortex (DLPFC) proteomic data from ROSMAP cohort (N = 610). Protein level deviations were aggregated into gene set activity scores for KEGG pathways and curated AD Biodomain annotations. Functional alterations across AD and Asymptomatic AD (AsymAD) individuals were evaluated and correlated with clinical metrics including APOE4 genotype, Braak stage, CERAD and MMSE scores. Graph-based clustering was used to identify molecularly distinct subgroups based on shared patterns of functional dysregulation.

RESULTS: Limited overlap was observed between cohort-level differential expression analysis and INDIGO single-subject analyses. Individual deviations in various processes, including metabolic, immune and epigenetic pathways, exhibited sex- and disease stage-specific patterns. Amyloid clearance and immune activation were strongly associated with APOE4 dosage, higher amyloid and tau burden and cognitive decline, whereas upregulation of mitochondrial and synaptic modules correlated positively with preserved cognitive function. By linking individuals through concordant directional proteomic changes, we identified molecularly coherent subgroups that transcend conventional diagnostic boundaries and include both AD and AsymAD subjects. Each subgroup displayed distinct functional signatures and defined by a unique set of key regulatory proteins.

DISCUSSION: These results demonstrate that single-subject omics profiling can resolve individual molecular signatures aligned with clinical and neuropathological variation in AD. By linking molecular heterogeneity with disease phenotypes, INDIGO provides a scalable framework for precision modeling and novel therapeutic target discovery.},
}

@article {pmid41726903,
year = {2026},
author = {Iglesias, JE and Johnson, IP and Williams-Ramirez, J and Zemlyanker, D and Tian, L and Gopinath, K and Olchanyi, M and Farnan, AD and Demopoulos, A and Rosen, MS and Sheth, KN and de Havenon, A and Kimberly, WT and Sorby-Adams, A and , },
title = {On the accuracy of image registration in portable low-field 3D brain MRI.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.11.705413},
pmid = {41726903},
issn = {2692-8205},
abstract = {Portable low-field MRI offers an affordable and mobile alternative to conventional high-field scanners, enabling imaging in point-of-care and resource-limited settings. However, its lower signal-to-noise ratio, reduced resolution, and acquisition artifacts raise concerns about the accuracy of standard image registration methods. Reliable registration is critical for a wide range of emerging applications, including frequent brain monitoring, assessment of neurodegenerative disease progression, and evaluation of treatment effects such as those of Alzheimer's therapeutics. In this work, we systematically evaluated state-of-the-art registration approaches on simulated low-field scans (obtained by downsampling high-field images) and on real low-field brain MRI data. We compared three representative approaches: classical optimization (NiftyReg), learning-based registration (SynthMorph), and synthesis-based registration (SynthSR+NiftyReg). Using downsampled high-field scans, all methods performed well, achieving high Dice scores and smooth deformation fields, indicating that reduced resolution alone does not hinder registration. In contrast, real low-field data exhibited lower accuracy, primarily due to geometric distortion and other acquisition-specific artifacts. Among the tested approaches, the synthesis-based pipeline achieved the most robust performance across subjects and modalities. Overall, existing algorithms can accommodate resolution limitations, however, future methods could further enhance coregistration by explicitly addressing the distortions present in low-field MRI scans.},
}

@article {pmid41726892,
year = {2026},
author = {Green, J and Liu, Z and Timis, S and Nelson, C and Schivitz, C and Pedin, A and Guo, C and Wang, XY and Sun, D},
title = {Deletion of NLRP3 gene blocks traumatic brain injury induced abnormal immune response in 3xTg AD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.11.705384},
pmid = {41726892},
issn = {2692-8205},
abstract = {Traumatic brain injury (TBI) is a significant risk factor for the development of Alzheimer's disease (AD) and related dementia. In both TBI and AD, inflammation plays a pivotal role. Recent studies have found that TBI triggers activation of NLRP3 inflammasome in the brain whereas the NLRP3 inflammasome plays an important role in pathogenesis of AD. To evaluate the influence of TBI on the immune response and the importance of the NLRP3 inflammasome in mediating this process we have examined the immune profiles in the brain using a novel transgenic AD mouse line with the NLRP3 gene deleted. Briefly, a group of 3xTg and 3xTg/NLRP3 [-/-] mice received a moderate TBI in the form of lateral fluid percusive injury FPI or sham surgery at the age of 4 months old, an age before the onset of AD. Injury-induced changes in immune profiling were assessed using flow cytometry, real-time quantitative PCR, or Western blot at the acute and subacute stages following TBI. We found that TBI altered immune profiles in 3xTg mice and NLRP3 gene knock out counteracts the injury effect with a significant sex-related difference. More specifically, at the acute stage after TBI in both male and female mice, TBI induced a significant infiltration of neutrophils, macrophages and γδ T-cells in the brains of 3xTg mice, however, NLRP3 knock down significantly blocked this injury effect in males and less so in females. We also found that NLRP3 gene knock down counteracted TBI-enhanced inflammatory cytokine IL1-β, TNF-α, and IL-17f expression. The abnormal immune profiling was not significant at 7 days post-injury, however, changes in cerebral vascular associated proteins including GFAP, AQP4, CD31, Occludin were observed in related to injury, NLRP3 and sex. In conclusion, our study has confirmed that TBI significantly alters immune profiles and vascular integrity in the context of predisposition of AD and the NLRP3 inflammasome is important in mediating these TBI-induced changes. Sex-related differences warrant further evaluation to define the role of NLRP3-related immune response and vascular pathology as a result to TBI and the predisposition to AD development.},
}

@article {pmid41726734,
year = {2026},
author = {Sardis, M and Noormägi, A and Jarvet, J and Gräslund, A and Wärmländer, SKTS and Tõugu, V and Palumaa, P},
title = {Binding of ApoE Isoforms to Aβ Peptides and Effects on Their Fibrillization.},
journal = {ACS omega},
volume = {11},
number = {6},
pages = {10626-10631},
pmid = {41726734},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is the most widespread neurodegenerative disease, strongly linked to amyloid depositions in the brain consisting of amyloid β (Aβ) peptides. The likelihood of developing late-onset Alzheimer's disease (LOAD) is influenced by the specific isoforms of apolipoprotein E (ApoE), with ApoE4 being the strongest known genetic risk factor for LOAD. Strong evidence suggests that ApoE impacts AD by modulating Aβ aggregation and clearance, although the precise molecular mechanisms remain incompletely understood. Microscale thermophoresis (MST) is a powerful technique for characterizing molecular interactions in solution, which has been used to determine various binding constants, although not the binding of ApoE to Aβ peptides. MST results show that ApoE isoforms bind Aβ1-40 and Aβ1-42 with low micromolar affinity. For Aβ1-42, ApoE3 shows the strongest binding (K d = 0.72 μM) and ApoE4 shows the weakest binding (K d = 2.80 μM). For Aβ1-40, ApoE4 shows the strongest binding (K d = 1.59 μM) and ApoE2 shows the weakest binding (K d = 5.29 μM). The MST results show that ApoE interacts with Aβ peptides at supraphysiological peptide concentrations. However, ApoE inhibited the fibrillization of Aβ1-42 peptide at substoichiometric concentrations, which might be related to blocking Aβ fibril elongation in vivo. The estimated IC50 values indicate that ApoE4 has a slightly stronger, and ApoE2 a slightly weaker, inhibitory effect on Aβ1-42 fibrillization.},
}

@article {pmid41726622,
year = {2026},
author = {Deng, Y and Xie, F and Wu, W and Wang, D and Guan, Y and Zhang, Q and Hu, F and Jiang, H and Guan, M},
title = {Immunocapture-LC-MS/MS Method for Quantification of the Anti-Alzheimer's Monoclonal Antibody Donanemab in Human and Mice Serum.},
journal = {ACS omega},
volume = {11},
number = {6},
pages = {9138-9144},
pmid = {41726622},
issn = {2470-1343},
abstract = {Monoclonal antibodies hold significant promise for the treatment of Alzheimer's disease (AD), and donanemab is the latest therapeutic human IgG1 antibody approved for clinical use. The development and pharmacokinetic evaluation of antibody drugs necessitate accurate quantification. Currently, immunoassays are mainly used by clinical trials to measure those antibody drugs for AD. However, immunoassays often face limitations such as cross-reactivity, insufficient specificity, and poor interlaboratory comparability. Therefore, we developed a robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method incorporating immunoaffinity enrichment for serum donanemab. This LC-MS/MS method can effectively distinguish donanemab from endogenous immunoglobulins in serum and have sufficient sensitivity. This developed LC-MS/MS method involved: (1) immunoaffinity capture and enrichment of serum donanemab and its internal standard using protein G-conjugated magnetic beads; (2) tryptic digestion of the purified antibodies; and (3) targeted quantification of unique signature peptides via LC-MS/MS for quantification. In conclusion, this method demonstrated acceptable performance, including a lower limit of quantification of 0.1 μg/mL, satisfactory precision (total CV < 8%), high accuracy (95-100% recovery), and a wide linear range (0.2-200 μg/mL), and is the first reported LC-MS/MS method for donanemab offering an alternative for therapeutic antibody monitoring of monoclonal antibody drugs.},
}

@article {pmid41726610,
year = {2026},
author = {Dao, QT and Do, TMD and Thai, QM and Tran, PT and Ngo, ST and Nguyen, TH},
title = {Identifying Potential BACE1 Inhibitors from the ChEMBL Database Using Machine Learning and Atomistic Simulation Approaches.},
journal = {ACS omega},
volume = {11},
number = {6},
pages = {9067-9075},
pmid = {41726610},
issn = {2470-1343},
abstract = {The inhibition of β-site amyloid precursor protein-cleaving enzyme 1 presents a promising therapeutic strategy for treating Alzheimer's disease by reducing amyloid-β (Aβ) production. This paper employed a computational approach that combined machine learning (ML) and atomistic simulations to accelerate the discovery of potential BACE1 inhibitors. Our ML models, trained on a set of ligands with experimental binding affinity, showed high accuracy when tested on a holdout test set. The best model was used to screen more than two million compounds in the CHEMBL33 chemical library to obtain a short list of top-hit compounds, which were further analyzed using molecular docking and fast pulling of ligand (FPL) simulations. The insights into structure and binding energetics obtained from FPL simulations elucidate the stability and interaction mechanisms of the BACE1-ligand bound state, providing data useful for the rational design of novel AD therapeutics.},
}