@article {pmid41453150,
year = {2025},
author = {Carlisle, TC and Nair, KV and Sillau, SH and Giron, LL and Kwak, J and Tanabe, J and Holden, SK and Pelak, VS},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e106083},
doi = {10.1002/alz70858_106083},
pmid = {41453150},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Dementia/psychology/drug therapy ; *Alzheimer Disease/drug therapy/psychology/diagnostic imaging ; Colorado ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Clinical trials for FDA-approved anti-amyloid therapies (AATs) do not mirror the real-world experience of patients seen by dementia specialists. The unique Advanced Therapy in Neurodegenerative Disorders (ATND) Clinic at the University of Colorado staffed primarily by one dementia specialist shares its experience.

OBJECTIVES: To share the experience of the unique Advanced Therapy in Neurodegenerative Disorders (ATND) Clinic at the University of Colorado including characteristics and utilization of anti-amyloid therapies (lecanemab) between April 2024 - January 2025.

METHODS: Baseline characteristics including demographics, diagnostic assessments, lecanemab utilization, and Amyloid Related Imaging Abnormalities (ARIA) assessments were collected from ATND Clinic electronic medical records.

RESULTS: Patients were referred from the larger Memory Disorders Clinic at the University of Colorado, previously diagnosed with probable Alzheimer's disease, seen between April 2024 to January 2025 (n = 96) and not clearly meeting exclusion criteria for lecanemab. The current cohort includes those: in active diagnostic work-up, 25.0% (n = 24); currently being infused, 19.8% (n = 19); who declined treatment, 28.1% (n = 27), were determined ineligible, 9.4% (n = 9), who deferred treatment, 13.5% (n = 13); stopped/transferred treatment (as of January 2025), 4.2% (n = 4). Mean age was 71.5 (+/-8.0) years, with 52.1% women. Over half (59.4%) received a baseline MRI (undergoing the diagnostic work-up) and the majority (88.9%) underwent a lumbar puncture compared to 9.5% who had an amyloid positron emission tomography scan to establish biomarker confirmation of Alzheimer's. About a fifth (20.9%) with Apolipoprotein E (APOE4) data tested homozygous for the APOEe4 allele. Two patients experienced ARIA while receiving lecanemab. On average, infusing patients completed 12.2 (+/-7.2) infusions during the 10-month observation period. The mean number of days between the first consultation with the dementia specialist in the ATND Clinic and the baseline MRI was 31.6 (+/-23.1) (n = 47) days, and the first lecanemab infusion was 79.9 (+/-38.3) (n = 19) days. Patients declined AAT treatment because of homozygous APOEe4 status (37.0%) followed by concerns regarding modest efficacy (25.9%) and burden of treatment including cost (14.8%).

CONCLUSION: The ATND Clinic's experience in the first year of treatment provides real world data of AAT experience. Investment in hiring more dementia specialists can increase patient capacity for AAT evaluation and management.},
}

Humans
Female
Male
Aged
*Dementia/psychology/drug therapy
*Alzheimer Disease/drug therapy/psychology/diagnostic imaging
Colorado
Middle Aged
Aged, 80 and over

@article {pmid41453149,
year = {2025},
author = {Sandoval, R and Novikov, V and Attaran, A and Tabatabaei, MH and Eed, A and Cowan, M and Yau, MC and Abduldayem, Y and Sharma, S and Luo, W and Shlaifer, I and Evangelista, C and Durcan, TM and Fon, EA and Menon, RS and Chiosis, G and Bussey, TJ and Saksida, LM and Chakravarty, MM and Prado, VF and Prado, MA},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103517},
doi = {10.1002/alz70856_103517},
pmid = {41453149},
issn = {1552-5279},
mesh = {Animals ; Mice ; *Biomarkers/metabolism ; Mice, Transgenic ; Disease Models, Animal ; alpha-Synuclein/metabolism ; Brain/pathology/drug effects ; Male ; *Alzheimer Disease ; },
abstract = {BACKGROUND: Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the accumulation of misfolded proteins, including amyloid-β, tau, and alpha-synuclein (a-Syn). Despite extensive research, no effective disease-modifying therapies exist. A major barrier to drug development is the poor translatability of animal models and the lack of biomarkers with predictive power for clinical efficacy. Higher-order cognitive deficits, such as impaired reversal learning, are observed in patients with synucleinopathies, suggesting that cognitive biomarkers could be valuable in preclinical drug testing. This study evaluates whether touchscreen-based cognitive testing enhances the predictive validity of preclinical drug testing. We assessed PU-AD, an HSP90 epichaperome disruptor targeting the abnormal chaperone network implicated in protein misfolding disorders, and a mouse version of Cinpanemab, an anti-a-Syn antibody that recently failed in clinical trials, despite initial positive results in animal models.

METHOD: Hemizygous M83 transgenic mice were intracerebrally injected with preformed fibrils (PFFs) to model synucleinopathy-related neurodegeneration. Mice underwent cognitive assessment using the Pairwise Visual Discrimination and Reversal (PVD-R) touchscreen task, a highly translational measure of cognitive flexibility sensitive to a-Syn toxicity. PU-AD and Cinpanemab were administered intraperitoneally post-PFF injection. Drug doses matched previous animal model studies. Motor performance was assessed with grip strength, rotarod, and wire hang tests. MRI was used to detect brain atrophy. Immunohistochemical and biochemical analyses evaluated a-Syn pathology and neuroinflammation.

RESULT: M83/PFF-injected mice showed significant reversal learning deficits earlier than motor deficits. Pharmacokinetic analysis confirmed PU-AD reached brain concentrations comparable to those in other models. PU-AD treatment rescued cognitive and motor impairments, suggesting broad neuroprotective effects. In contrast, Cinpanemab-treated mice showed no improvements in cognition and preliminary data suggest no improvements in motor symptoms. Ongoing experiments are evaluating pathology and brain atrophy.

CONCLUSION: The lack of Cinpanemab efficacy in our pre-clinical testing pipeline aligns with clinical trial results. The effectiveness of PU-AD in reducing both cognitive and motor impairments suggests it may have broad therapeutic potential in synucleinopathies. We suggest that touchscreen-based cognitive testing enhances the predictive validity of preclinical drug evaluation.},
}

Animals
Mice
*Biomarkers/metabolism
Mice, Transgenic
Disease Models, Animal
alpha-Synuclein/metabolism
Brain/pathology/drug effects
Male
*Alzheimer Disease

@article {pmid41453136,
year = {2025},
author = {Barnwal, M and Baksh, S and Shade, D and Moghekar, A and Rosenberg, PB and Porsteinsson, AP and Lyketsos, KG},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104004},
doi = {10.1002/alz70856_104004},
pmid = {41453136},
issn = {1552-5279},
mesh = {Humans ; Biomarkers/blood ; *Alzheimer Disease/blood/drug therapy/complications ; Amyloid beta-Peptides/blood ; Male ; Female ; tau Proteins/blood ; Aged ; Glial Fibrillary Acidic Protein/blood ; Peptide Fragments/blood ; Neurofilament Proteins/blood ; *Citalopram/therapeutic use ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Escitalopram for Agitation in Alzheimer's Disease (S-CitAD) was an NIH-funded RCT that randomized 173 participants with Alzheimer's Disease (AD) and agitation to escitalopram or placebo for 12 weeks assessing efficacy for clinically significant agitation. There was no significant advantage for escitalopram in treating agitation. This might be attributed to including participants at various stages of AD brain pathology that would be reflected in levels of blood biomarkers.

METHODS: We examined associations of baseline blood biomarkers and clinical measures at baseline and follow up regarding: (1) agitation severity (NPI-C-A+A); (2) cognitive status, (MMSE); and (3) escitalopram treatment. Abeta42, Abeta40, GFAP, NfL were measured using SIMOA N4PE assays, and pTau217 using the Alzpath-pTau217 SIMOA on Quanterix HD-X.

RESULTS: Abeta40, Abeta42, pTau217, GFAP, and NfL were available for 82 participants. pTau217>0.42 pg/ml and Abeta42/40<0.04 pg/ml indicated significant amyloid pathology. Of 82 participants with pTau217 data, 77 (94%) scored above threshold supporting the clinical diagnosis of AD. In contrast, only 47 were below threshold for Abeta42/40. There was 61% agreement between biomarker cut-offs for pTau217 and Abeta42/40. No baseline associations between biomarkers and NPI-C-A+A scores were significant (p >0.05). Baseline higher pTau217 predicted higher NPI-C-A+A scores at week 6 (beta=3.26, p <0.001) and week 12 (beta=2.86, p = 0.01) after randomization. Baseline associations between Abeta40, Abeta42, NfL and MMSE scores were not significant (p >0.05). However, baseline higher levels of GFAP (beta=-0.02, p = 0.0002) and pTau217 (beta=-2.68, p = 0.003) were associated with lower baseline MMSE scores. Baseline Abeta40, GFAP and NfL were not associated with treatment outcomes. After adjusting for treatment, higher baseline pTau217 was associated with greater odds of worsening NPI-C-A+A scores at weeks 6 (OR=2.79, p = 0.02) and 12 (OR=2.55, p = 0.02) compared to baseline.

CONCLUSION: Baseline blood levels of pTau217 confirmed the presence of significant AD brain amyloid pathology in 94% of participants. Independent of treatment assignment, higher baseline blood levels of pTau217 predicted lower baseline MMSE scores and higher agitation severity at weeks 6 and 12 after randomization.},
}

Humans
Biomarkers/blood
*Alzheimer Disease/blood/drug therapy/complications
Amyloid beta-Peptides/blood
Male
Female
tau Proteins/blood
Aged
Glial Fibrillary Acidic Protein/blood
Peptide Fragments/blood
Neurofilament Proteins/blood
*Citalopram/therapeutic use
Aged, 80 and over
Middle Aged

@article {pmid41453029,
year = {2025},
author = {Cogswell, PM and Preboske, GM and Klein, G and Benzinger, TLS and Bateman, RJ and Jack, CR and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103166},
doi = {10.1002/alz70856_103166},
pmid = {41453029},
issn = {1552-5279},
mesh = {Humans ; Magnetic Resonance Imaging ; *Alzheimer Disease/diagnostic imaging/drug therapy ; Biomarkers ; Male ; Female ; *Brain/diagnostic imaging/pathology ; Middle Aged ; Aged ; *Cerebral Hemorrhage/diagnostic imaging ; },
abstract = {BACKGROUND: Amyloid-Related Imaging Abnormalities (ARIA), an adverse event associated with Alzheimer's disease anti-amyloid immunotherapies, occur in the form of edema or sulcal effusion (ARIA-E) and microhemorrhages and superficial siderosis (ARIA-H). Conventional teaching is that ARIA-H is permanent hemosiderin staining of the brain. In clinical trials we have noticed that some ARIA-H microhemorrhages that occur with regional ARIA-E appear to later resolve. The goal of this study is to illustrate that, opposed to current understanding, some ARIA-H microhemorrhages may resolve.

METHODS: We identified participants from the Dominantly Inherited Alzheimer's Network Trial Unit (DIAN-TU) and open label extension (OLE) gantenerumab studies that had ARIA-E and at least one ARIA-H microhemorrhage. The T2* GRE sequence from all available MRI exams in a patient were co-registered and reviewed by a board-certified neuroradiologist. Individual microhemorrhages were tracked over the serial exams. We defined disappearing/resolving microhemorrhages as those appeared with or following ARIA-E, were visualized on at least 2 MRI exams, and were subsequently not visualized on at least 2 MRI exams.

RESULTS: A total of 12 patients met inclusion criteria of which 5 (41%) had microhemorrhages that resolved over 10-40 months follow-up after the incident ARIA. These microhemorrhages occurred in clusters in the region of ARIA-E, and only some of the regional microhemorrhages resolved over follow-up. Examples are shown in Figures 1-3.

CONCLUSIONS: The disappearance (resolution) of ARIA-H microhemorrhages is relevant to the management and continued dosing of patients receiving anti-amyloid immunotherapies as this is guided by the presence of ARIA (including cumulative treatment emergent microhemorrhages) as well as clinical symptoms. A microhemorrhage number alone may not be indicative of the potentially dynamic nature of ARIA-H.},
}

Humans
Magnetic Resonance Imaging
*Alzheimer Disease/diagnostic imaging/drug therapy
Biomarkers
Male
Female
*Brain/diagnostic imaging/pathology
Middle Aged
Aged
*Cerebral Hemorrhage/diagnostic imaging

@article {pmid41453024,
year = {2025},
author = {Wu, SA and Morrison, A and Oliveira, CC and Randa-Beaulieu, C and Cooke, HA},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e106050},
doi = {10.1002/alz70858_106050},
pmid = {41453024},
issn = {1552-5279},
mesh = {Humans ; *Dementia/psychology/therapy ; Focus Groups ; Female ; Male ; Ontario ; Aged ; British Columbia ; *Caregivers/psychology ; Middle Aged ; },
abstract = {BACKGROUND: Discourse on disease-modifying treatments (DMTs) for dementia has primarily focused on drug development, health system readiness and health care professional perspectives. There is a paucity of research focused on public perceptions held by Canadians towards these treatments. Focus groups were conducted in British Columbia and Ontario, Canada with people affected by dementia to gain an in-depth understanding of their experiences with and perceptions of DMTs.

METHOD: Between February and December 2024, the Alzheimer Society of B.C. (ASBC) and the Alzheimer Society of Ontario (ASO) held a series of separate focus groups. ASBC conducted four online focus groups with eight persons living with dementia and nine care partners, none of whom were enrolled in DMT clinical trials. ASO conducted three in-person and two online focus groups with people living with dementia (n = 12) and their care partners (n = 11) enrolled in DMT clinical trials. Focus groups ranged from 90-120 minutes and consisted of questions exploring treatments, risk tolerance and the role of our organizations to support patient navigation for DMTs. Data were analyzed using thematic analysis.

RESULT: Focus group participant experiences ranged depending on disease progression. Four themes were identified. The first, equitable access to DMTs, highlighted concerns around financial hardship, geographic limitations and the critical importance of care partner support. The second, risk tolerance, underscored differences in risk acceptance among people living with dementia and their care partners, and the variation across disease stage. The third, clear and accessible information, focused on the need for comprehensive, transparent and easy-to-understand material to ensure informed DMT decision-making. The final theme, DMTs as a source of hope, acknowledged the motivational role of clinical trials and DMT approvals symbolizing innovation and the potential for an eventual cure. ASBC and ASO were identified as trustworthy and important sources of support for DMT navigation.

CONCLUSION: Findings identify priority areas for people affected by dementia once DMTs become available in Canada. Collaborating with people with lived experience in the development of DMT care pathways will help to ensure that treatment options are accessible, deliver meaningful benefits to extend quality of life and improve quality of care.},
}

Humans
*Dementia/psychology/therapy
Focus Groups
Female
Male
Ontario
Aged
British Columbia
*Caregivers/psychology
Middle Aged

@article {pmid41453020,
year = {2025},
author = {Hoang, B and Pang, Y and Liang, S and Dodge, HH and Zhou, J},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103800},
doi = {10.1002/alz70856_103800},
pmid = {41453020},
issn = {1552-5279},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; *Biomarkers ; Male ; Female ; Aged ; Alzheimer Disease/diagnosis ; *Language ; },
abstract = {BACKGROUND: Mild Cognitive Impairment (MCI) is the prodromal stage of Alzheimer's disease. Early detection of MCI is essential for effective intervention and treatment. Recent studies have shown that linguistic marker is a promising and cost-effective approach to identify MCI. Existing studies aggregated multiple rounds of conversation and demonstrated their effectiveness, and yet the use of finer granularity of conversation is not widely studied. Intuitively, the time series of language markers reveal important dynamics that are easily wiped off by aggregation. Significant individual differences in speaking styles pose challenges for sequence models in capturing cognitive characteristics. We propose a novel temporal harmonization method that mitigates distributional differences in temporal language markers across subjects, enhancing the prediction.

METHOD: We utilized 6,771 conversations from 74 participants in Internet-Based Conversational Engagement Clinical Trial (I-CONECT) (NCT02871921). From each 30-minute conversation session, we extracted a 99-dimensional feature set including Linguistic Inquiry and Word Count, Syntactic Complexity, Lexical Diversity, and Response Length. For each subject, we have a sequence of feature vectors over time, up to 12 months. Our harmonization method leverages adversarial training via a min-max optimization framework with three components: Seq2Seq Harmonization, a Subject Classifier, and a Cognitive Classifier. The harmonization module learns to remove subject-specific components from temporal linguistic features, while the Subject Classifier infers subject identity. Finally, the Cognitive Classifier focuses on detecting MCI from the harmonized temporal features.

RESULT: We compared our approach with single-conversation input methods, where we trained neural networks to predict the outcome of individual conversations and used majority voting to determine the final output for each participant. Our results show that using temporal sequences improves detection performance compared to aggregated single-conversation outputs, both with and without harmonization. When applying temporal harmonization, the performance of subject classification significantly increases, achieving an AUC of 0.720 compared to 0.647 without harmonization.

CONCLUSION: Using only features extracted from semi-structured conversation, we achieved a reasonalbe AUC. Our study demonstrates the additional benefits of using temporal sequences of language markers to detect Mild Cognitive Impairment. Moreover, applying temporal harmonization helps remove subject-specific components in features and further enhances cognitive detection performance.},
}

Humans
*Cognitive Dysfunction/diagnosis
*Biomarkers
Male
Female
Aged
Alzheimer Disease/diagnosis
*Language

@article {pmid41453005,
year = {2025},
author = {Shah, S and Wadhwa, SS and Huerta, GI and Eliseo, SGO and Martinez, A and Campos, B and Vossel, K and Bholat, M and Diaz-Santos, M and Chang, TS},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e105676},
doi = {10.1002/alz70858_105676},
pmid = {41453005},
issn = {1552-5279},
mesh = {Humans ; Male ; Aged ; Female ; *Dementia/diagnosis/psychology/therapy ; Aged, 80 and over ; Surveys and Questionnaires ; Mental Status and Dementia Tests ; Middle Aged ; Electronic Health Records ; *Alzheimer Disease/diagnosis/psychology ; *Mass Screening/methods ; Los Angeles ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) affects over 10% of individuals aged 65 and older, with Black and Hispanic/Latino individuals experiencing a 1.5-2.0 times higher prevalence than white individuals. Despite these disparities, AD remains underdiagnosed, particularly in non-white populations. Current dementia screening tools, such as the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), face challenges in time efficiency, accessibility, and cultural sensitivity. This study aimed to implement a brief dementia screening tool integrated into the electronic health record (EHR) and evaluate its impact on diagnosis, workup, and treatment in a diverse family medicine clinic in Los Angeles County.

METHOD: The dementia screening tool (DST), developed collaboratively by the University of California Alzheimer's Disease Centers and the California Department of Public Health, was designed to be brief (<5 minutes) and adaptable. It includes a three-question patient questionnaire, an informant input option, and the Mini-Cog assessment. To enhance accessibility, the tool was translated and culturally adapted for Spanish-speaking patients. Patients aged 60+ completed the DST before their annual wellness visits, with results integrated into the EHR. This pre-post intervention study compared patients aged 60+ without a prior dementia diagnosis during the pre-intervention (February 2016-August 2022) and post-intervention (September 2022-June 2023) periods. Outcomes included new dementia diagnoses, medications, specialty referrals, labs, and imaging.

RESULT: The DST was implemented, screening 996 patients in 10 months. Screening led to 35 specialty care referrals and 15 new dementia diagnoses. New diagnoses increased from 4.17% pre-DST to 4.80% post-DST all (OR 2.10, p = 0.02) and 6.43% among those screening positive (OR 2.57, p = 0.04). Dementia medication prescriptions rose from 2.93% pre-DST to 4.94% in the post-DST all group, reaching 6.87% among those who screened positive. Specialty referrals were more frequent post-DST all (9.13%) and even higher among those screening positive (14.16%). Post-DST, all secondary outcomes significantly improved, including increased use of diagnostic labs and imaging studies.

CONCLUSION: Integrating a brief, culturally sensitive DST into primary care significantly improved dementia diagnosis rates, workup, referrals, and treatment. These findings highlight the potential for broader implementation of the DST to enhance dementia care and address health disparities in diverse populations.},
}

Humans
Male
Aged
Female
*Dementia/diagnosis/psychology/therapy
Aged, 80 and over
Surveys and Questionnaires
Mental Status and Dementia Tests
Middle Aged
Electronic Health Records
*Alzheimer Disease/diagnosis/psychology
*Mass Screening/methods
Los Angeles

@article {pmid41452990,
year = {2025},
author = {Sherimon, V and Varghese, A and P C, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103324},
doi = {10.1002/alz70856_103324},
pmid = {41452990},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Biomarkers ; Neuroimaging ; },
abstract = {BACKGROUND: Research on Alzheimer's disease (AD) requires comprehensive data resources to better understand the complex relationships among genetic, environmental, and clinical variables influencing disease onset and progression. This review systematically analyses significant AD datasets, emphasizing their technical attributes, analytical challenges, and methodological factors to enhance research usability in this domain.

METHOD: We performed a comprehensive review of published literature and data repositories relevant to AD research. Datasets such as ADNI, NACC, OASIS, Clinical Trial Data (A4, LEARN), and open-access repositories (AD, Knowledge Portal) were examined. The evaluated key characteristics comprised sample size, data modalities (neuroimaging, genomics, proteomics, clinical, longitudinal coverage, data access policies, and identified constraints).

RESULT: Comprehensive initiatives such as ADNI, and NACC contribute essential multimodal data, enabling research on AD biomarkers, progression, and treatment efficacy. Nonetheless, intrinsic issues include: Data Heterogeneity: Inconsistencies in diagnostic criteria, evaluation methodologies, and imaging modalities among studies impede data synchronization and comparability (e.g., MCI diagnosis inconsistencies between NACC and ADNI) Missing Data: Incomplete datasets require precise management of missing values to prevent skewed analysis. Sophisticated techniques for imputation and sensitivity analysis are essential. Class Imbalance: Unequal representation of diagnostic categories (e.g., normal, MCI, AD) might affect the efficacy of machine learning models, necessitating approaches such as data augmentation (SMOTE) or cost-sensitive learning. High Dimensionality: The integration of multiomics data requires feature selection techniques (such as genetic algorithms and modified particle swam optimization) to determine the most significant aspects and mitigate computational complexity.

CONCLUSION: Despite the above limitations, current AD datasets have contributed to significant advancements. Future research should focus on: Standardization: Supporting uniform data gathering and processing techniques across research initiatives. Data Integration: Formulating effective strategies for integrating multi-omics, neuroimaging, and clinical data to explain the complex relationships of variables driving AD. Advanced Analytics: Implementing complex machine learning methodologies to address class imbalance, missing data, and high dimensionality while ensuring model interoperability and generalizability. Open Science: Promoting open data sharing to enhance collaborative research and optimize data value. This review underlines the necessity for continuous initiatives to enhance data quality, address methodological challenges, and support for open science principles to expedite AD research.},
}

Humans
*Alzheimer Disease/diagnosis
*Biomarkers
Neuroimaging

@article {pmid41452870,
year = {2025},
author = {Kim, GH and Kang, D and Kang, SH and Kim, JS and Youn, YC and Lim, JS and Moon, SY and Moon, WJ and Park, YH and Shim, Y and Yang, DW and Cho, H and Choi, H and Pyun, JM and Park, KH and Choi, SH},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e106260},
doi = {10.1002/alz70858_106260},
pmid = {41452870},
issn = {1552-5279},
mesh = {Humans ; Republic of Korea ; *Registries ; *Dementia/psychology/therapy ; *Alzheimer Disease/therapy/psychology ; *Biomedical Research ; },
abstract = {Alzheimer's disease (AD) is undergoing a transformation with disease-modifying therapies (DMTs) and advanced biomarkers, shifting from symptomatic management to targeted interventions. However, high costs, potential side effects, and limited awareness hinder real-world integration, particularly in underrepresented East Asian populations like Koreans. Preliminary data suggest East Asians may experience lower rates of Amyloid-Related Imaging Abnormalities (ARIA), emphasizing the need for region-specific treatment guidelines. To address this, the Korean Dementia Association (KDA) launched JOY-ALZ (Korean JOint RegistrY for ALZheimer's Treatment and Diagnostics) in 2024 to establish a real-world data (RWD) platform for AD therapies in Korea. Overall objectives of JOY-ALZ are: • Develop a collaborative network across multiple sites for systemic patient data collection. • Record comprehensive patient data on cognitive, functional, and safety outcomes. • Enhance data acquisition by integrating neuroimaging, genetic, and biomarker data • Assess health outcomes using existing databases for long-term evaluation. • Maximize data sharing with researchers and stakeholders. To achieve this, JOY-ALZ employs the CURE Framework, which encompasses four specific aims: • Creating the RWD platform infrastructure • Uncovering outcomes: collecting data to evaluate long term safety and clinical outcomes • Reinforcing collaborations: co-enrollment with affiliated studies • Enabling global sharing: data sharing and linking Following Korean regulatory approval of lecanemab in May 2024, JOY-ALZ published Appropriate Use Recommendations (AUR) in October 2024 and hosted educational symposia. IRB submissions were initiated in December 2024 across 41 hospitals, with approval expected by June 2025 to enable comprehensive real-world data (RWD) collection, including clinical data, neuroimaging, and biosamples. In the long term, JOY-ALZ will complement global platforms like ALZ-NET, informing Korean-specific treatment guidelines, promoting equitable access to AD therapies, and fostering international collaboration by contributing high-quality RWD to the global research community. JOYALZ will play a key role in advancing AD research by leveraging RWD collected through Korea's dementia clinic network.},
}

Humans
Republic of Korea
*Registries
*Dementia/psychology/therapy
*Alzheimer Disease/therapy/psychology
*Biomedical Research

@article {pmid41452807,
year = {2025},
author = {Peiris, S and Yang, Q and Mudiyanselage, AME and Elyan, R and Geesey, K and Kanekar, S and Will, J and Eslinger, P and Karunanayaka, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103885},
doi = {10.1002/alz70856_103885},
pmid = {41452807},
issn = {1552-5279},
mesh = {Humans ; Positron-Emission Tomography ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aged ; *Amyloid beta-Peptides/metabolism ; Neuropsychological Tests ; Biomarkers/metabolism ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; *Brain/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Amyloid imaging with positron emission tomography (PET) is important for the diagnosis and treatment of Alzheimer's disease (AD). Probable AD is typically diagnosed with magnetic resonance imaging (MRI) by identifying anatomical changes unique to AD. Due to natural variations in brain volume, structural MR imaging is rather ambiguous. The standardized uptake value ratio (SUVr), derived from PET imaging, is a more accurate quantitative measure for accurate diagnosis of AD. Furthermore, cognitive decline and olfactory impairment are common preclinical symptoms of AD. To better understand brain-behavior relationships in AD spectrum, here we explored relationships with SUVr and behavioral (neuropsychological/olfactory) test scores. We hypothesized that there will be negative correlations between neuropsychological test scores and SUVR values.

METHOD: We analyzed Amyloid beta PET (Aβ) scans from 44 subjects (19 CN, 25 MCI). PET scans were conducted on a Siemens Biograph mCT 20 scanner with 10-minute scans taken 30 minutes post-injection. The images were pre-processed and registered to T1 MRI. Standardized Uptake Value Ratio (SUVr) was calculated with Clinica software. Correlation analyses was performed with DPABI software.

RESULT: Significant group differences in neuropsychological scores were observed between CN and MCI (Figure 1), were observed between CN and MCI figure. Similarly, SUVr differences were observed between CN and MCI (Figure 2). The impact of SUVr on various cognitive domains in terms of correlation analyses were investigated and shown in Figure 3. All correlations yielded highly significant results at p <0.005.

CONCLUSION: This study provides valuable insights into the relationship between Aβ PET imaging and cognitive function in both the (CN) and (MCI) subjects. The correlation between SUVr and olfactory function was insignificant. Olfactory measures such as Identification and Threshold may require further improvement to enhance their utility in AD pathophysiology. Overall, our findings show that higher amyloid beta deposition is linked to poorer cognitive performance in MCI. Our results may offer potential avenues to streamline the Neuropsychological test battery for AD by closely tying most salient metrics to amyloid beta deposition.},
}

Humans
Positron-Emission Tomography
Male
Female
*Alzheimer Disease/diagnostic imaging/metabolism
Aged
*Amyloid beta-Peptides/metabolism
Neuropsychological Tests
Biomarkers/metabolism
*Cognitive Dysfunction/diagnostic imaging/metabolism
*Brain/diagnostic imaging/metabolism
Magnetic Resonance Imaging
Middle Aged
Aged, 80 and over

@article {pmid41452745,
year = {2025},
author = {Konofagou, E},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103290},
doi = {10.1002/alz70856_103290},
pmid = {41452745},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/therapy/metabolism ; *Blood-Brain Barrier/diagnostic imaging ; Biomarkers/metabolism ; Microbubbles ; Male ; Female ; Glioma/diagnostic imaging/therapy ; Middle Aged ; Animals ; Adult ; Aged ; Magnetic Resonance Imaging ; },
abstract = {BACKGROUND: Treatment of neurological diseases has been at the forefront of medical research for more than a century with limited success due partly to the blood-brain barrier (BBB) that impedes both delivery and biodistribution of the drug delivered. Focused ulltrasound (FUS) methodologies in conjunction with systemically administered microbubbles have been shown capable of transcranially and transiently opening the BBB over the past two decades. More recently, those efforts have resulted into clinical translation in a variety of brain diseases such as brain tumors and neurodegenerative diseases such as Alzheimer's (AD) disease. Most FUS systems that have been reported for AD treatment are either confined in the MRI or use invasively implanted transducers. Our group has pioneered a portable system for opening the BBB at the patient's bedside safely and efficiently, i.e., within 20-30 min with real-time cavitation mapping.

METHOD: Five AD patients underwent FUS with microbubbles for transcranial BBB opening in their prefrontal cortex. Real-time cavitation mapping system was also implemented to transcranially map the cavitation occurrence and dose in real time throughout the BBB opening procedure in Alzheimer's disease (AD) adult and diffuse intrinsic pontine glioma (DIPG) pediatric patients. Passive acoustic mapping (PAM) with coherence factor (CF) correction is used to passively map the microbubble activity within the brain. Multi-element CF-PAM allows us to determine the exact location of the BBB opening. The system was first optimized in targeting in non-human primates followed by feasibility in the prefrontal cortex in AD patients, achieving feedback rates of 2 Hz during the clinical procedures.

RESULT: It was found that 60% of the patients exhibited beta amyloid reduction as evidenced by the SUVr reduction on PET imaging. We also found that cavitation dose can inform the beta amyloid reduction with 80% correlation between the cavitation dose and SUVRr reduction observed.

CONCLUSION: A portable FUS system was found to be safe and efficacious in reduction of beta amyloid in patients with mild to moderate AD. Real-time information on cavitation can provide feedback on both the safety and efficacy of treatment. Future studies will investigated effects on cognition and tau reduction.},
}

Humans
*Alzheimer Disease/diagnostic imaging/therapy/metabolism
*Blood-Brain Barrier/diagnostic imaging
Biomarkers/metabolism
Microbubbles
Male
Female
Glioma/diagnostic imaging/therapy
Middle Aged
Animals
Adult
Aged
Magnetic Resonance Imaging

@article {pmid41452730,
year = {2025},
author = {Honig, LS and Gonzalez, WP and Kim, JM and DiMuro, V and Bell, KL and Jagannathan, R and Noble, JM and Marder, K and Mayeux, R},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e107460},
doi = {10.1002/alz70858_107460},
pmid = {41452730},
issn = {1552-5279},
mesh = {Humans ; Aged ; Female ; Male ; Aged, 80 and over ; Middle Aged ; Adult ; *Alzheimer Disease/drug therapy/psychology ; *Dementia/drug therapy/psychology ; },
abstract = {BACKGROUND: Lecanemab and donanemab are anti-amyloid antibodies proven in 18-month clinical trials to slow progression of early Alzheimer's disease by biomarker, cognitive and functional measures. While both are now approved in many countries, lecanemab was first USA-approved in January2023, and Medicare-covered since July2023. Early-AD patients are receiving therapy, but drug access has been limited by barriers, many imposed by use recommendations, and by insurer-payor criteria. These partly reflect attempts to apply clinical trial exclusions to early AD patients, and concerns over adverse-effect rates that might occur with widespread use.

METHOD: We report, with IRB-approval, our practice experience, prescribing on-label, without other limitations, in >190 diverse patients, age 35-90, using various infusion and MRI facilities. Patients all had amyloid confirmation by CSF (72%), amyloid-PET (15%), or both (14%); 89% have accepted optional APOE-genotyping, with 41% non-carriers, 46% E4-heterozygotes, and 13% E4-homozygotes.

RESULT: Patients have had 1-40 biweekly infusions. Adverse event rates have been similar to those in clinical trials with 15% infusion reactions (headache, chills, warmth, fatigue, pruritus), usually only at first 1-3 infusions. Overall rate of ARIA-E has been 10.6% (mostly in first 3 months), with 2 of 20 cases recurrent, and with a lower incidence of ARIA-H. Only 2 patients (1%) have had symptomatic ARIA, both ARIA-E, an E4 heterozygote with cortical visual loss, and an E4 homozygote with aphasia, both with concurrent mild ARIA-H. The latter individual unfortunately died during ICU treatment for refractory focal status epilepticus; this was the only death. Most ARIA cases have resumed infusions after resolution; overall, there was discontinuation of therapy in 9% of treated patients (4% due to ARIA, 2% due to persistent infusion reactions, 3% due to disinterest).

CONCLUSION: Our single-site findings suggest that "real-world" experience with lecanemab may be not dissimilar to that in clinical trials, and that despite a small risk of unavoidable serious adverse events, there can be ease of administration and MRI procedures, good tolerability, and relative safety. It is appropriate to use extant clinical evidence, and biological plausibility, rather than provide barriers to access, in discussing potential risks and benefits, and providing access to patients and their families.},
}

Humans
Aged
Female
Male
Aged, 80 and over
Middle Aged
Adult
*Alzheimer Disease/drug therapy/psychology
*Dementia/drug therapy/psychology

@article {pmid41452714,
year = {2025},
author = {Zhang, J and Zhu, D and Hu, M and Pan, M and Chen, C},
title = {A Combination of Low-Dose Δ[9]-THC and Celecoxib as a Therapeutic Strategy for Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1206},
pmid = {41452714},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the elderly, and no effective therapies are currently available to prevent, treat, or halt its progression. Δ[9]-Tetrahydrocannabinol (Δ[9]-THC), the primary psychoactive compound in marijuana, has been considered a potential therapeutic agent, but clear evidence for its ability to prevent cognitive decline is lacking. Previous studies have demonstrated that Δ[9]-THC-induced cognitive impairments are associated with the induction of cyclooxygenase-2 (COX-2). In this study, we aimed to evaluate whether Δ[9]-THC alone or in combination with Celecoxib, a selective COX-2 inhibitor, could reduce neuropathology and improve cognitive function in AD model animals. We observed that Δ[9]-THC (3.0 mg/kg), either alone or with Celecoxib (1.0 mg/kg), significantly reduced Aβ and tau pathologies, enhanced synaptic marker expression, and prevented the onset of cognitive decline. Notably, the combination treatment produced greater improvements in spatial learning and effectively mitigated Δ[9]-THC-induced neuroinflammatory responses. Furthermore, Δ[9]-THC reversed or attenuated the dysregulated expression of synaptic and immune/inflammation-related genes and restored the downregulated expression of genes linked to AD observed in both AD patients and AD animal models, with greater efficacy when combined with Celecoxib in AD model mice. These findings suggest that the combination of low-dose Δ[9]-THC and Celecoxib holds promise as an early intervention strategy for preventing AD onset or treating mild cognitive impairment (MCI). Importantly, both Δ[9]-THC (in the form of Dronabinol and Nabilone) and Celecoxib are FDA-approved medications already in clinical use, supporting the strong translational potential of this combination therapy and its feasibility for rapid advancement to clinical trials to assess its efficacy in preventing or delaying AD onset in humans.},
}

@article {pmid41452674,
year = {2025},
author = {Weng, Y and Chen, K and Thanapornsangsuth, P and Zhang, Y},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e102920},
doi = {10.1002/alz70856_102920},
pmid = {41452674},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; *Biomarkers ; Disease Progression ; *Brain/diagnostic imaging/pathology ; Male ; Female ; Aged ; Imaging, Three-Dimensional ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is characterized by the presence of abnormal proteins in the brain. With its progression, the disease affects all the major brain areas, which causes the problems in memory, thinking, judgment ability, speech, logic, personality, and movement. Cognitive function typically decreases under such conditions. As a major cause of dementia, AD is a concern for millions of people in the world. This also makes it a huge economic problem for families and healthcare systems. Therefore, accurately monitoring AD progression is crucial for clinical assessment with timely drug interventions to develop personalized treatment plans and deliver effective treatment.

METHOD: In this study, we present a computer-assisted system that uses novel 4D monitoring technologies for intelligent AD progression. In this system, we combine 3D magnetic resonance imaging (MRI) spatial data with an addition of 1D temporal data into spatio-temporal 4D dynamic visualization for allowing the analysis of brain changes over time. We develop the 4D visualization system with the 3D Slicer software, which is a user-friendly platform for clinical assessment, and enables clinicians to visualize AD progression more accurately.

RESULT: We perform various experiments to assess the efficiency of the proposed 4D visualization computer-assisted system for intelligent monitoring AD progression. We utilize ADNI dataset, which contains brain imaging data, biofluidic biomarkers, cognitive assessments, genetic information, and demographic data. Hereby, the MRI image data from ADNI are deployed to show the progression of AD. The system allows interactive 4D dynamic visualizations for up to 160 months of 3D MRI brain images for AD patients in the ADNI dataset. The experimental results are promising, which indicates that our proposed technique is capable of helping clinicians identify AD progression by detecting alterations in brain structure over time.

CONCLUSION: The study presents an intelligent computer-assisted system based on 4D visualization for AD progression. The system is helpful to advise clinical assessment with critical information which is beneficial for diagnosis and drug treatment plan based on monitoring of AD progression.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
*Magnetic Resonance Imaging/methods
*Biomarkers
Disease Progression
*Brain/diagnostic imaging/pathology
Male
Female
Aged
Imaging, Three-Dimensional

@article {pmid41452665,
year = {2025},
author = {Patterson, CJ and Dhinagar, NJ and Gleave, EJ and Thomopoulos, SI and Chattopadhyay, T and Thompson, PM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103816},
doi = {10.1002/alz70856_103816},
pmid = {41452665},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnostic imaging ; Aged ; *Alzheimer Disease/diagnostic imaging/diagnosis ; *Biomarkers ; Magnetic Resonance Imaging ; Disease Progression ; Neuroimaging ; *Neural Networks, Computer ; *Brain/diagnostic imaging ; Aged, 80 and over ; Cohort Studies ; },
abstract = {BACKGROUND: Each year, approximately 15% of elderly individuals with mild cognitive impairment (MCI) progress to Alzheimer's disease (AD) or related dementias. Predicting this progression is crucial for informing treatment decisions, identifying protective factors, and modeling treatment effects in clinical trials. Here we trained and tested a 3D convolutional neural network (CNN) to forecast future decline (over two years) in the Clinical Dementia Rating scale sum of boxes score (sobCDR).

METHODS: We analyzed data from three independent, publicly-available cohorts: the (1) Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 1,136), (2) Open Access Series of Imaging Studies (OASIS-3; n = 241), and (3) National Alzheimer's Coordinating Center (NACC; n = 942). Participants with a 3D T1-weighted brain MRI, baseline age, sex, & BMI measures, baseline sobCDR (within 90 days of imaging), and a follow-up sobCDR score (1.75-2.25 years after baseline) were included. For evaluation, datasets were partitioned into five independent, cross-validation folds with balanced sex, age at imaging, and change in sobCDR score (scale 0: no impairment - 18: severe impairment) between baseline and 2 years. A 3D DenseNet-121 CNN was used to predict the sobCDR score 2 years after baseline, first by using only the T1-weighted MRI. This predicted value (predCDR_2Y) was then included in four linear mixed-effects models (LMEs) to predict the observed sobCDR at two years from baseline (obsCDR_2Y) that included additional demographic covariates, scanner manufacturer and participant cohort random effects (Table 1). For each linear model, we ran a corresponding null model with all the same covariates, but without the predCDR_2Y variable, to determine the added predictive value of the imaging. From the five cross-validation folds, we calculated the Pooled, out-of-sample, R2 and its standard error (SE), adjusting for the number of explanatory variables in each model.

RESULTS: All predictive models predicted follow-up sobCDR with mean absolute error of around 1 point; adding the image-derived prediction improved accuracy (Table 1).

CONCLUSION: Deep learning shows promise for enhancing prognostic models; future work will include additional deep learning methods, more diverse neuroimaging data (amyloid and tau PET and diffusion MRI), and alternative data fusion methods to integrate tabular and neuroimaging data.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnostic imaging
Aged
*Alzheimer Disease/diagnostic imaging/diagnosis
*Biomarkers
Magnetic Resonance Imaging
Disease Progression
Neuroimaging
*Neural Networks, Computer
*Brain/diagnostic imaging
Aged, 80 and over
Cohort Studies

@article {pmid41452659,
year = {2025},
author = {Kuhn, T and McAiney, CA and Lim, A and Middleton, LE},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e105549},
doi = {10.1002/alz70858_105549},
pmid = {41452659},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/psychology/complications ; Aged ; Male ; Female ; *Sleep Initiation and Maintenance Disorders/therapy/etiology/psychology ; Canada ; *Caregivers/psychology ; *Dementia/psychology ; },
abstract = {BACKGROUND: Sleep disturbance is a common experience in persons with Alzheimer's disease (PWAD) and can be stressful for care partners to manage. However, few programs have been designed to support sleep among PWAD. The few existing programs may not be appropriate for all contexts (e.g., geography, weather). Using co-design to develop or adapt interventions can help create programs that identify and overcome local barriers to programming.

METHOD: The Nighttime Insomnia and Treatment Education for Alzheimer's Disease (NITE-AD) by McCurry et al. (2005) is a program for care partners, designed to improve sleep of PWAD. Previous offerings of the NITE-AD program have effectively reduced total awake time at night among PWAD. However, adaptation of program materials and physical activity recommendations was needed for winter use in the Canadian context. The co-adaptation of the NITE-AD program (to the Nighttime Insomnia and Treatment Education for Canadians Alzheimer's Disease, NITE-CAD program) took place in 5 stages: 1) understanding the barriers, facilitators, and supports needed for winter physical activity among PWAD, 2) engaging a co-advisory team, 3) co-adapting the program; and 4) assessing the feasibility of NITE-CAD.

RESULT: Winter conditions were a barrier to physical activity, with driving in snow or ice and the extra time needed to prepare for outdoor activities as notable challenges. Some overcame these challenges through specialized equipment and/or accessible facilities. Three persons with lived experience (a care partner, a dementia exercise provider, an Alzheimer Society staff) were recruited to the co-adaptation team. Program adaptations included: having multiple physical activity options, increasing accessibility of the manual and using Canadian specific resources, and encouraging PWAD to participate in the program. Unfortunately, we were unable to assess the feasibility of NITE-CAD due to recruitment challenges. Among those who expressed interest, people were not eligible due to high risk of sleep apnea or having dementias other than Alzheimer's disease.

CONCLUSION: The co-adaptation of NITE-CAD identified and implemented changes important to the Canadian, and especially winter, context. However, more work is needed to co-design recruitment processes and eligibility criteria to ensure that the program is relevant and accessible.},
}

Humans
*Alzheimer Disease/psychology/complications
Aged
Male
Female
*Sleep Initiation and Maintenance Disorders/therapy/etiology/psychology
Canada
*Caregivers/psychology
*Dementia/psychology

@article {pmid41452613,
year = {2025},
author = {Kwon, YG and Bae, CR and Kim, Y and Kim, D},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e100124},
doi = {10.1002/alz70855_100124},
pmid = {41452613},
issn = {1552-5279},
mesh = {Animals ; *Blood-Brain Barrier/drug effects/metabolism ; Mice ; *Alzheimer Disease/drug therapy/pathology ; Disease Models, Animal ; Mice, Transgenic ; Endothelial Cells/drug effects ; Humans ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: Blood-brain barrier (BBB) dysfunction and neuroinflammation play a crucial role in the pathogenesis of Alzheiemr's disease (AD). Recent studies have reported that preserving or restoring blood-brain barrier (BBB) function could be a promising strategy for mitigating AD progression and severity. Our endothelial dysfunction blocker, CU71, enhanced tight junction and vascular integrity while decreased inflammation in human brain microvascular endothelial cell (HBMECs). We investigated the effects of CU71 on cognitive impairment BBB dysfunction, and neuroinflammatory activity in the 5XFAD mouse model of Alzheimer's disease.

METHOD: 5XFAD mice received daily oral administration of CU71 for 6 months. Cognitive functions were assessed using Y-maze, novel object recognition (NOR) and Morris water maze (MWM) tests. The study included 5 groups: (1) wild type (WT)+vehicle, (2) 5XFAD (TG)+vehicle, (3) TG +Donepezil (1 mg/kg), (4) TG+5 mg/kg CU71, (5) TG+10 mg/kg CU71. To examine the molecular mechanisms related to BBB dysfunction and neuroinflammation, immunohistochemistry, western blot and digital ELISA assay (SIMOA) were performed.

RESULT: After 6 months of CU71 treatment, significant improvements in memory and cognition were observed, as indicated by enhanced such as NOR and MWM tests, compared to the TG + vehicle treatment control group. Additionally, CU71 treatment improved vessel maintenance and rescued tight junction-related proteins. We also observed a decrease in the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1). Therefore, CU71 may be useful for treating cognitive dysfunctions observed in AD.

CONCLUSION: Our findings demonstrate that CU71 treatment ameliorates cognitive impairment by inhibiting BBB dysfunction and neuroinflammation in the 5XFAD mouse model of Alzheimer's disease.},
}

Animals
*Blood-Brain Barrier/drug effects/metabolism
Mice
*Alzheimer Disease/drug therapy/pathology
Disease Models, Animal
Mice, Transgenic
Endothelial Cells/drug effects
Humans
Cognitive Dysfunction/drug therapy

@article {pmid41452576,
year = {2025},
author = {Spilka, MJ and Xu, M and Toth, B and Hashemifar, S and Amora, R and Robin, J and Teng, E and Monteiro, C and Simpson, W},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103297},
doi = {10.1002/alz70856_103297},
pmid = {41452576},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers ; *Alzheimer Disease/complications/diagnosis/drug therapy ; Male ; Female ; Aged ; *Natural Language Processing ; Disease Progression ; *Speech ; Aged, 80 and over ; *Cognitive Dysfunction/diagnosis ; },
abstract = {BACKGROUND: Progressive language changes are evident in Alzheimer's disease (AD). Natural Language Processing (NLP) tools can provide more objective measurement of language impairment and facilitate the use of speech biomarkers for tracking clinical progression. We evaluated and compared several digital speech-based markers developed from recordings from two phase 2 clinical trials.

METHOD: Recordings of the Clinical Dementia Rating (CDR) interview were analyzed for 227 English-speaking participants enrolled in two phase 2 trials of semorinemab: Tauriel (MCI-to-mild AD; NCT03289143) and Lauriet (mild-to-moderate AD; NCT03828747). Only placebo arm data was used for the Lauriet trial due to a treatment effect on the ADAS-Cog11. Acoustic and linguistic speech features were calculated from patients' responses to the "recent experience" CDR prompt. Data were split ∼60/40% into training and test sets for development and validation of speech composite scores. We evaluated three feature selection approaches: 1) features from our previously published speech biomarker (Robin et al., 2023; 9 features), 2) features showing a stringent significant (p <0.001) effect of change over time (12 features), and 3) features with a significant (p <0.05) effect of time in addition to greater clinical interpretability (e.g., linguistic vs. signal processing features; 18 features). Speech composites were evaluated on longitudinal change, test-retest reliability, and correlations with clinical endpoints (ADAS-Cog11, CDR-SB, ADCS-ADL, MMSE).

RESULT: Within the test set, all three composites showed significant change over time, with baseline to endpoint effect sizes (Cohen's d) ranging from 0.47-0.59. Screening vs. baseline test-retest reliability was adequate (intraclass correlations ranging from 0.67-0.80). All three composites were significantly and similarly correlated with clinical endpoints at baseline (Spearman rho ranging from |0.21-0.49|).

CONCLUSION: Speech characteristics can be combined into meaningful indices of disease progression across the spectrum of MCI to moderate AD. All three composites performed well overall. The best performing composite was our previously published Tauriel derived biomarker, which had the largest effect size of change, highest test-retest reliability, and was also the most parsimonious measure with the fewest features. These results highlight the potential utility of a speech-based biomarker as an objective and low-burden measure of clinical progression to complement traditional endpoints in AD clinical trials.},
}

Humans
*Biomarkers
*Alzheimer Disease/complications/diagnosis/drug therapy
Male
Female
Aged
*Natural Language Processing
Disease Progression
*Speech
Aged, 80 and over
*Cognitive Dysfunction/diagnosis

@article {pmid41452521,
year = {2025},
author = {Zhang, Y and Fan, Y},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103682},
doi = {10.1002/alz70856_103682},
pmid = {41452521},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/classification ; Male ; Magnetic Resonance Imaging ; Female ; *Biomarkers ; Aged ; *Brain/diagnostic imaging/pathology ; Neuroimaging ; Aged, 80 and over ; Cluster Analysis ; Gray Matter/diagnostic imaging/pathology ; },
abstract = {BACKGROUND: Neurodegeneration diseases are heterogeneous, with individuals presenting varying patterns of disease progression. This inherent heterogeneity poses a major challenge for accurate diagnosis and treatment. Identifying biological meaningful subtypes among affected individuals is critical for advancing the understanding of disease mechanisms and improving diagnostic precision. This study introduces a simultaneous clustering and classification method to 1) classify subjects as either cognitively unimpaired (CU) or Alzheimer's disease (AD) and 2) group AD individuals into distinct subtypes.

METHOD: This study includes 2,374 participants with baseline T1-weighted images obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Images are processed using the t1-volume pipeline of the Clinica toolbox, yielding 120 Region-of-Interest (ROI) values, representing the average gray matter density values of anatomical regions defined by AAL2 template. These ROI values are analyzed within a mixture-of-experts (MOE) framework guided by a clustering module. Each expert is a linear classifier and a non-linear decision boundary is obtained through a weighted combination of these classifiers with the weights learned jointly by the classifiers in a discriminative manner and the clustering module to group individuals based on their feature similarity. This framework is implemented in an end-to-end training paradigm.

RESULT: The classification performance was assessed using 10-fold Stratified-KFold validation, with mean accuracy and standard deviation reported. The MOE model demonstrated the best performance when the number of clusters was set to two, outperforming a single SVM classifier and achieving performance comparable to a non-linear classifier. The MOE model also identified two subtypes among AD subjects, as illustrated in Figure 2. Both subtypes exhibited significant hippocampal atrophy, while subtype 2 showing more severe atrophy than the another, which is consistent with late-stage AD pathology.

CONCLUSION: This study demonstrated the effectiveness of MOE model in both classification and characterization of the AD heterogeneity. By approximating non-linear decision boundaries, the MOE model enhances the classification performance while simultaneously providing interpretable subtype information. This method offers valuable insights into the automatic and interpretable diagnosis of Alzheimer's disease and potentially other neurodegenerative diseases.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/classification
Male
Magnetic Resonance Imaging
Female
*Biomarkers
Aged
*Brain/diagnostic imaging/pathology
Neuroimaging
Aged, 80 and over
Cluster Analysis
Gray Matter/diagnostic imaging/pathology

@article {pmid41452500,
year = {2025},
author = {Paez, A and Gillman, SO and Dogaheh, SB and Carnes, A and Dakterzada, F and Barbe, F and Dang-Vu, TT and Piñol-Ripoll, G},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104172},
doi = {10.1002/alz70856_104172},
pmid = {41452500},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/physiopathology ; tau Proteins/cerebrospinal fluid/blood ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Prospective Studies ; Neuropsychological Tests ; Polysomnography ; Aged, 80 and over ; Spain ; *Sleep/physiology ; },
abstract = {BACKGROUND: Sleep plays vital roles in brain-health and cognition, including regulating clearance of β-amyloid (Aβ) and tau proteins that hallmark Alzheimer's disease (AD). Changes in sleep physiology can predate cognitive symptoms by decades in AD, but it remains unclear which sleep characteristics predict cognitive and neurodegenerative changes after AD onset.

METHODS: Using data from a prospective cohort study of mild-to-moderate AD (n = 60, 30 female, mean age 74.7) in Lleida, Spain, we analysed non-rapid eye-movement sleep spindles and slow oscillations (SO) at baseline and their associations with baseline amyloid-beta and tau, and with cognition from baseline to three-years follow-up. Participants underwent polysomnography (PSG), blood and cerebrospinal fluid draws for amyloid and tau at baseline, and neuropsychological assessment at baseline, 12, 24 and 36 months with the Mini-Mental Status Examination (MMSE), California verbal learning test (CVLT), Rey-Osterrieth Complex Figure Test (ROCF), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Spindle and SO detection were performed using in-house, open-source software packages developed at Concordia University. Associations between SO and spindle and SO duration, density, power, amplitude, AD biomarkers, and cognition from baseline to 36 months were investigated with false discovery rate-adjusted generalised linear models controlling for age, sex, apnoea-hypopnea index.

RESULTS: We found previously unreported associations between spindle and SO activity, biomarkers, and cognition in persons with AD. Higher spindle and SO density, duration, amplitude and power predicted significant changes in amyloid-beta 42 (β= 69.3 p =  0.001), phosphorylated (pTau-181) (β= 7.92, p = 0.001) and total-tau, and tau/Aβ42 (β= -0.52, p = 0.001), clinically and statistically significantly lower Alzheimer's Disease Assessment Scale Cognitive Subscale (better cognitive performance) (β= -9.0, p = 0.001) and higher Mini-Mental State Examination scores (better cognitive performance) (β= 15.2, p = 0.01) from baseline to 36-months, and significant changes in verbal and visual memory on the ROCF and CVLT. Spindles and SO activity also mediated the effect of pTau181/aβ42 on cognition (41-81%), while pTau181/aβ42 moderated the effect of spindles and SO on cognition.

CONCLUSIONS: Our findings demonstrate that spindle and SO activity during sleep constitute predictive and non-invasive biomarkers of neurodegeneration and cognition in AD patients and novel treatment targets for delaying cognitive decline and AD progression.},
}

Humans
Female
Male
Aged
Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/cerebrospinal fluid/physiopathology
tau Proteins/cerebrospinal fluid/blood
Amyloid beta-Peptides/cerebrospinal fluid/blood
Prospective Studies
Neuropsychological Tests
Polysomnography
Aged, 80 and over
Spain
*Sleep/physiology

@article {pmid41452429,
year = {2025},
author = {Heidari, Z and Zakaee, A and Vafadar, A and Alavimanesh, S and Charami, H and Jamali, Z and Jahromi, AH and Rakhsha, A and Savardashtaki, A},
title = {An overview of gene and cell therapy approaches for Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {10},
pmid = {41452429},
issn = {1573-7365},
mesh = {*Alzheimer Disease/therapy/genetics ; Humans ; *Genetic Therapy/methods ; *Cell- and Tissue-Based Therapy/methods ; Animals ; },
abstract = {Alzheimer's disease (AD), acknowledged as the leading cause of dementia, is defined by the accumulation of amyloid plaques and neurofibrillary tangles (NFTs) in the brain. This condition presents a significant challenge to global health due to its complex and multifaceted characteristics. Pharmacological treatments for AD mainly focus on relieving symptoms instead of addressing the fundamental progression of the condition. Currently, there are three cholinesterase inhibitors (ChEIs) that can be used for the treatment of AD: donepezil, rivastigmine, and galantamine, along with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. Although these medications can improve cognitive function and assist patients in their daily activities, it is crucial to understand that they do not halt the progression of the disease itself. Recently, innovative therapeutic strategies have been introduced for the treatment of this disease. Cell and gene therapies hold remarkable potential for the treatment of AD. Gene therapy, in particular, enables the precise modulation of AD-related genes, enhances neuroprotective factors, and mitigates the accumulation of amyloid plaques. Additionally, cell-based therapies utilizing mesenchymal stromal cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) are designed to replace lost neurons, modulate immune responses, and restore functional neural networks. Together, these innovative techniques represent significant advancement in the treatment of AD, instilling hope for enhanced patient outcomes and a higher quality of life. In this review, we emphasize the innovative cell and gene strategies, along with in vitro and preclinical studies, that explore the potential of gene and cell-based therapies as treatments for AD.},
}

*Alzheimer Disease/therapy/genetics
Humans
*Genetic Therapy/methods
*Cell- and Tissue-Based Therapy/methods
Animals

@article {pmid41452328,
year = {2025},
author = {Mroczko, B and Kulczynska-Przybik, A and Krawczuk, D and Borawska, R and Winkel, I},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103738},
doi = {10.1002/alz70856_103738},
pmid = {41452328},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; Male ; Female ; tau Proteins/cerebrospinal fluid ; *Kallikreins/cerebrospinal fluid ; Aged ; Peptide Fragments/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) constitutes an important global health challenge. Understanding the various molecular mechanisms underlying the pathogenesis of the disease is crucial for the efficient treatment of the disease. Kallikrein-related peptidases (KLKs), a family of serine proteases, have gained interest as potential biomarkers and therapeutic targets for AD. It is reported that the kalikrein family proteins may have amyloidogenic potential in the brain and KLKs may contribute to the pathogenesis of AD. In the available literature, some KLKs such as KLK6 and KLK8 were more extensively tested and are discussed as potential therapeutical targets, whereas there is a lack of information about KLK5 in AD. Given that, we investigated the KLK5 in cerebrospinal fluid (CSF) of patients with AD and explored associations with established AD biomarkers.

METHOD: The concentrations of KLK5 as well as classical CSF biomarkers, such as amyloid beta 1-42 (Aß-42), amyloid beta 1-40, Tau, as well as pTau181, were determined in cerebrospinal fluid patients with AD and subjects without cognitive decline by multiplexing, and enzyme-linked immunosorbent methods.

RESULT: Significantly higher CSF concentrations of KLK5 were found in AD patients compared to the subjects without cognitive decline. Furthermore, in the group of patients with AD, the levels of KLK5 significantly correlated with the CSF amyloid beta ratio.

CONCLUSION: Our findings indicate that kallikrein 5 may play a role in the pathogenesis of AD, particularly in the amyloid pathology. KLKs may serve as additional indicator in combination with classical well-known biomarkers such as Aβ and tau proteins.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid
*Amyloid beta-Peptides/cerebrospinal fluid
Male
Female
tau Proteins/cerebrospinal fluid
*Kallikreins/cerebrospinal fluid
Aged
Peptide Fragments/cerebrospinal fluid
Middle Aged
Aged, 80 and over

@article {pmid41452267,
year = {2025},
author = {Cai, X and Huang, Y and Wang, T and Gao, J and Tang, Y and Zhu, C and Rong, S},
title = {Mesoporous PdPt Nanozymes with Target Peptides and Cascade Reactive Oxygen Species Scavenging for Boosting Alzheimer's Disease Treatment.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.5c17413},
pmid = {41452267},
issn = {1936-086X},
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disease that has become a major health problem nowadays. Inhibiting the aggregation of amyloid-β (Aβ) peptides has made progress in AD treatments. Here, we synthesized mesoporous PdPt nanozymes to immobilize target peptide KLVFFAED for high-efficiency AD treatment. Thanks to the high surface area of the mesoporous nanospherical structure of PdPt nanozymes, lots of KLVFFAED were grafted with a concentration as high as 439.2 μg mL[-1], amplifying inhibition activity against Aβ aggregations. Importantly, the system has a pre-eminent photothermal property in the near-infrared region and exhibits the ability to photothermally disintegrate Aβ aggregates. Moreover, the integrated superoxide dismutase/catalase mimetic activity of PdPt nanozymes also achieves cascade reactive oxygen species (ROS) scavenging to alleviate oxidative stress and neuroglial damage, thus delaying the progression of AD. Therefore, the designed system can simultaneously block Aβ aggregation, destabilize Aβ fibrils, and clear ROS, which together enhance the therapeutic effects, providing important insights into the applications of nanozymes for AD therapy.},
}

@article {pmid41452201,
year = {2025},
author = {Azam, MA and Vipin, A and Leow, YJ and Sandhu, GK and Tanoto, P and Kandiah, N},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e107780},
doi = {10.1002/alz70857_107780},
pmid = {41452201},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis/pathology ; Aged ; Neuropsychological Tests/statistics & numerical data ; Amyloid beta-Peptides/blood ; Magnetic Resonance Imaging ; Alzheimer Disease/diagnosis ; White Matter/pathology/diagnostic imaging ; *Dementia, Vascular/diagnosis ; Biomarkers/blood ; Machine Learning ; Aged, 80 and over ; },
abstract = {BACKGROUND: Vascular Cognitive Impairment (VCI) is the second most common cause of dementia after Alzheimer's Disease (AD) (Gorelick et al.,2011). The coexistence of cerebrovascular pathology with AD pathology adds complexity to the diagnosis and treatment of VCI, underscoring the importance of early identification of MCI and its types - Vascular, Alzheimer's and Mixed.

METHOD: The data of 389 subjects from the Biomarker and Cognition Study (BIOCIS) at the Dementia Research Centre (Singapore), classified into Cognitively Normal (CN) and MCI, with detailed neuropsychological information and cognitive and behavioural domain impairment information was analysed. T2-weighted FLAIR imaging was used to quantify subjects' White Matter Hyperintensities (WMH) load. Plasma amyloid beta 42/40 ratio was used to quantify amyloid levels. Subjects with MCI and high WMH load had significantly more executive dysfunction and lower processing speed along with higher impulse dyscontrol and increased apathy. These domains were used to create 4 simplified multi-domain digital games to assess different neuropsychological domains. Machine learning models were created and trained on data to differentiate the different pathologies based on neuropsychological features derived from the cognitive games. 230 new subjects (112 with MCI) were recruited for the validation of the developed digital games. Out of the 112 subjects with MCI, 56 had a high WMH load and they were in the Vascular MCI group. The Vascular MCI group was then split into Mixed (n = 26, high Amyloid) and Vascular (n = 26, low Amyloid).

RESULT: A combined game score derived from the game features, was able to detect MCI from CN with an Area Under the Curve (AUC) of 0.89 as well as detect Vascular from non-Vascular with an AUC of 0.88. Within the Vascular group, it was able to detect Mixed MCI with an AUC of 0.9 and within the non-Vascular group it was able to detect Alzheimer's MCI (high Amyloid) with an AUC of 0.9.

CONCLUSION: The ReCOGnAIze app has shown promising results in detecting MCI and differentiating Vascular, Alzheimer's and Mixed which can guide decision making for further evaluations for clinical diagnoses and interventions.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis/pathology
Aged
Neuropsychological Tests/statistics & numerical data
Amyloid beta-Peptides/blood
Magnetic Resonance Imaging
Alzheimer Disease/diagnosis
White Matter/pathology/diagnostic imaging
*Dementia, Vascular/diagnosis
Biomarkers/blood
Machine Learning
Aged, 80 and over

@article {pmid41452143,
year = {2025},
author = {Ghildiyal, S and Vipin, A and Sandhu, GK and Tanoto, P and Kandiah, N},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e102435},
doi = {10.1002/alz70856_102435},
pmid = {41452143},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Biomarkers ; Neuropsychological Tests ; *Cognitive Dysfunction/genetics ; Apolipoprotein E4/genetics ; Risk Factors ; Cohort Studies ; Aged, 80 and over ; },
abstract = {BACKGROUND: Factors contributing to the progression of cognitive decline include age, lower education, vascular risk factors: hypertension(HTN), hyperlipidemia(HLD), diabetes mellitus(DM), and Apolipoprotein E4(ApoE4). The interaction between aging and vascular processes increases the risk of cognitive impairment and neurological disorders. Similarly, ApoE4 is a major genetic risk for late-onset Alzheimer's Disease. The interaction between vascular risk factors and ApoE4 status on cognitive impairment requires further exploration.

METHOD: 838 non-demented participants(Age=60.36±10.55) were recruited in the community-based BIOCIS cohort. The cohort was stratified based on vascular risk: no vascular risk(n = 110), one vascular risk(n = 343), multiple vascular risks(n = 385). Subsequent analysis was stratified into midlife(45-65, n = 448) and later life(>65, n = 310). Participants were administered global cognitive tests (MoCA, VCAT), and comprehensive neuropsychological assessments including episodic memory(EM), executive function(EF), processing speed(PS), visuospatial function(VS) and semantic fluency(SF)(transformed into z-scores). Participants were classified as cognitively normal(CN), subjective cognitive decline(SCD) and mild cognitive impairment(MCI) according to Petersen's-(2004) and NIA-AA criteria. Vascular risk factors included clinical history(HTN, HLD, DM), medication consumption, systolic blood pressure, total cholesterol and fasting HBA1C. ApoE allelic variation was determined via Taqman SNP genotyping qRT-PCR methodology.

RESULT: Participants with increasing vascular risk burden were older(p <0.001) and less educated(p = 0.024) and displayed poorer cognitive performance across cognitive domains: MoCA, VCAT, EM, EF, PS, SF(all p <0.001) and VS(p <0.01). Individually, risk factors such as HLD and DM have a significant impact on cognitive impairment(CI). In later life, the odds of MCI classification are nearly doubled in individuals with HLD(OR=1.94, 95%CI=1.09-3.48, p = 0.024) and DM(OR=1.93, 95% CI=1.07-3.54, p = 0.029). In ApoE4 carriers, HTN significantly increases the odds of CI. In midlife, the interaction between HTN and ApoE4 quadruples and triples the risk of SCD(OR=4.17, 95% CI=1.07-19.01, p = 0.048) and MCI(OR=3.13, 95% CI=1.11-9.10, p = 0.033) respectively. All results remain significant despite controlling for age, education and gender.

CONCLUSION: In a non-demented Southeast Asian cohort, higher vascular risk factor count heightens the risk of cognitive impairment. While individually HTN, unlike HLD and DM, does not directly impact cognitive syndrome classification, in conjunction with ApoE4, it substantially increases the likelihood of cognitive impairment in midlife. For ApoE4 carriers, aggressive treatment of HTN is imperative to prevent progression of cognitive impairment.},
}

Humans
Male
Female
Aged
Middle Aged
*Biomarkers
Neuropsychological Tests
*Cognitive Dysfunction/genetics
Apolipoprotein E4/genetics
Risk Factors
Cohort Studies
Aged, 80 and over

@article {pmid41452134,
year = {2025},
author = {Holzhauser, S and Goldhardt, O and Sommer, P and Wegehaupt, T and Böhle, R and Henrichs, L and Grimmer, T},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e107757},
doi = {10.1002/alz70857_107757},
pmid = {41452134},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis ; Aged ; *Activities of Daily Living ; *Dementia/diagnosis/psychology ; Neuropsychological Tests ; Aged, 80 and over ; ROC Curve ; Middle Aged ; },
abstract = {BACKGROUND: The increasing global prevalence of dementia, where early intervention can significantly impact treatment outcomes and costs, necessitates effective early diagnostic tools, particularly in primary care settings. This study evaluates the Bayer Activities of Daily Living (Bayer-ADL) scale as a potential screening tool to distinguish between Mild Cognitive Impairment (MCI) and dementia.

METHOD: Conducted at the Center for Cognitive Disorders, Technical University of Munich, the study analyzed data from 503 patients who also had a comprehensive diagnostic work-up including a standardized assessment of the presence and severity of dementia, using the Clinical Dementia Rating scale (CDR) and a thorough neuropsychological examination using the Consortium-to-Establish-a-Registry-in-Alzheimer' Disease neuropsychological assessment battery (CERAD-NAB) using bivariate correlations, linear regression, and ROC curves. To select key questions of the ADL scale a stepwise variable selection process was applied.

RESULT: The findings demonstrate that three key questions of the Bayer-ADL scale effectively differentiate MCI from dementia with high predictive accuracy (AUC = 0.836). The 3-tem short version offers comparable predictive power to the full scale (37% each), suggesting its utility in primary care for streamlined dementia assessment.

CONCLUSION: Consideration should be given to offering the 3-item short version of the questionnaire to improve the efficiency and accuracy of dementia screening in primary care settings.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis
Aged
*Activities of Daily Living
*Dementia/diagnosis/psychology
Neuropsychological Tests
Aged, 80 and over
ROC Curve
Middle Aged

@article {pmid41452081,
year = {2025},
author = {Kenowsky, S and Shao, Y and Heller, S and Golomb, JB and Zhang, Q and Vedvyas, G and Dafflisio, G and Marsh, K and Sadowski, M and Wisniewski, T and Masurkar, AV and Reisberg, B},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e107125},
doi = {10.1002/alz70858_107125},
pmid = {41452081},
issn = {1552-5279},
mesh = {Humans ; *Dementia/psychology/drug therapy ; Aged ; Female ; Male ; Memantine/therapeutic use ; *Alzheimer Disease/drug therapy/psychology ; Aged, 80 and over ; Cholinesterase Inhibitors/therapeutic use ; },
abstract = {BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) occur frequently and cause suffering, burden, and institutionalization in Alzheimer's disease affected persons. Medications prescribed to treat BPSD are expensive and often are not highly effective. Brexpiprazole recently approved to treat Alzheimer's agitation carries a retail drug price of $79.50/pill. Acetylcholinesterase inhibitors (ACHI) have been found to ameliorate BPSD in Alzheimer's persons in some studies. However, they are not commonly prescribed for BPSD by community physicians. We published results of a 28-week, clinician-blind, randomized, controlled trial of our comprehensive, individualized person-centered management (CI-PCM) program in moderate-to-severe, community-residing Alzheimer's persons receiving memantine (doi:10.1159/000455397). We examined BPSD using the Behavioral Pathology in Alzheimer's Disease Frequency Weighted Severity Scale, which showed significantly decreased BPSD in the CI-PCM group at 28-weeks (p <0.05). Additionally, the total amount of psychotropic medication prescribed to treat BPSD was lower in CI-PCM subjects at 28-weeks in comparison to baseline (p <0.0001, https://doi.org/10.1002/alz.056048). Herein, we examine if CI-PCM subjects in our 2017 trial benefited from psychotropic medication cost savings and whether differential ACHI usage accounted for improvements in BPSD in the CI-PCM group.

METHODS: Medication usage was captured at each study visit. Blinded investigators reviewed subject charts (N = 20), for total psychotropic drug usage and total psychotropic medication prescribed to treat BPSD. Retail drug pricing of each prescription was obtained from the NYU outpatient pharmacy to standardize costs. Total cost of psychotropic medication prescribed to treat BPSD was calculated for each individual and study group at baseline and weeks 4,12, and 28. Differences between groups were compared using the Wilcoxon Sum Rank test.

RESULTS: There were no statistically significant differences between groups in ACHI used or not (p = 0.401), number of days on and days off ACHI (p = 0.58) or in costs of psychotropic medication taken. CI-PCM subjects paid $8,804.69 and Comparator subjects paid $24,901 from baseline to week 28 to treat BPSD.

CONCLUSIONS: CI-PCM subjects saved an average of $1,609.63 and experienced improvements in BPSD whereas comparators spent 2.8 times more and had worsening BPSD. ACHI treatment did not differ significantly between the two groups or account for the improvement in CI-PCM group BPSD.},
}

Humans
*Dementia/psychology/drug therapy
Aged
Female
Male
Memantine/therapeutic use
*Alzheimer Disease/drug therapy/psychology
Aged, 80 and over
Cholinesterase Inhibitors/therapeutic use

@article {pmid41452020,
year = {2025},
author = {Lawrence, J},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e110767},
doi = {10.1002/alz70859_110767},
pmid = {41452020},
issn = {1552-5279},
mesh = {Humans ; *Drug Development/methods ; *Alzheimer Disease/drug therapy ; *Clinical Trials as Topic ; Machine Learning ; },
abstract = {BACKGROUND: Innovative statistical methodologies have been proposed to improve Alzheimer's clinical trial efficiency: (i) Models leveraging data across multiple post-baseline visits might provide greater power compared to traditional MMRM approaches which focus on mean changes at the last visit. (ii) Machine learning techniques, such as those incorporating prognostic covariates or regression trees with fused leaves, may improve precision in treatment effect estimation. (iii) Alternative analyses such as time-to-event or ranking-based approaches are becoming relevant as AD clinical trials increasingly focus on prevention and asymptomatic participants. This session seeks to stimulate a collaborative dialogue among regulatory agencies, Alzheimer's associations, industry, and academia to evaluate the feasibility, benefits, and limitations of these methodologies in the context of AD clinical trials.

METHODS: This presentation will review the methodologies introduced by five speakers, formulating discussion questions around their statistical validity, challenges, and limitations in application and interpretability.

RESULTS: The session discussions are expected to deepen understanding of how innovative statistical approaches address the unique challenges of AD clinical trials. Insights gained may inform pathways for integrating novel methods into trial designs and analyses.

CONCLUSIONS: Advances in our understanding of AD disease progression and treatment effects provide a opportunity to explore some innovative statistical methodologies. Rigorous evaluation and open dialogue are essential to utilize these methods effectively, ensuring they enhance trial efficiency and maintain the rigor required for regulatory decision-making.},
}

Humans
*Drug Development/methods
*Alzheimer Disease/drug therapy
*Clinical Trials as Topic
Machine Learning

@article {pmid41451974,
year = {2025},
author = {Chaubey, K and Dou, L and Vázquez-Rosa, E and Cintrón-Pérez, C and Franke, K and Voorhees, J and Cheng, F and Pieper, AA},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103515},
doi = {10.1002/alz70856_103515},
pmid = {41451974},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/metabolism ; *Biomarkers/metabolism ; Proteomics ; Disease Models, Animal ; Humans ; Rats, Inbred F344 ; Rats ; Metabolomics ; *Brain/metabolism/drug effects ; Male ; Depression/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive brain disorder that severely impairs behavior and cognitive functions. This includes depression, which often appears earlier than cognitive impairment. This study reports early-stage proteomic and metabolomic signatures associated with AD in the TgF344AD rat model of AD, at a time when rats display depression but not cognitive impairment. The results are compared to human AD proteomic and metabolomic databases to determine clinical relevance of the findings.

METHOD: Nine-month-old TgF344AD rats, at an early stage of AD when they display depression-like behavior but are not yet cognitively impaired, were treated daily for six months with either vehicle or the neuroprotective compound P7C3-S243. This compound has been shown to stabilize NAD[+] homeostasis in models of AD, and this course of treatment was previously reported to prevent the development of neuropsychiatric symptoms in this rat model. We analyzed brain proteomics using label-free proteomics via UPLC-MS/MS on a Q-Exactive Orbitrap HF-X system and conducted metabolomics analysis through Metabolon. The obtained signatures were then compared to human AD proteomic and metabolomic databases to identify similar directional changes, and major molecular mechanisms were elucidated.

RESULTS: We identified a total of 904 proteins that significantly changed at the proteomic level and 95 metabolites that were significantly altered at the metabolomic level, when comparing TgF344AD rats to their wild type littermates. Many of these proteins and metabolites exhibited changes in the same direction in human AD brain proteomic and metabolomic databases. Furthermore, many of the AD-associated signatures that changed in both humans and rats were normalized towards wild-type levels after six months of daily treatment with P7C3-S243 administered to TgF344AD rats.

CONCLUSION: We have identified common and unique molecular signatures of AD at the proteomic and metabolomic levels that are held in common across the TgF344 AD rat model and the human AD brain. We additionally determined which of the aberrant expression patterns held in common across rat and human AD brain are normalized by a neuroprotective treatment that prevents the onset of disease in these rats. This points us towards new insight into mechanisms underlying effective prevention of AD.},
}

Animals
*Alzheimer Disease/metabolism
*Biomarkers/metabolism
Proteomics
Disease Models, Animal
Humans
Rats, Inbred F344
Rats
Metabolomics
*Brain/metabolism/drug effects
Male
Depression/metabolism

@article {pmid41451969,
year = {2025},
author = {Kay, DG and Grady, KP and Wahlert, AJ},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e107147},
doi = {10.1002/alz70859_107147},
pmid = {41451969},
issn = {1552-5279},
mesh = {Humans ; *Galantamine/pharmacokinetics/analogs & derivatives/administration & dosage/therapeutic use ; Male ; *Cholinesterase Inhibitors/pharmacokinetics/administration & dosage ; *Drug Development ; Female ; Middle Aged ; Biological Availability ; Aged ; Delayed-Action Preparations ; Adult ; *Alzheimer Disease/drug therapy ; },
abstract = {BACKGROUND: ZUNVEYL (benzgalantamine, galantamine benzoate gluconate), is a pharmacologically inactive prodrug of galantamine. ZUNVEYL was FDA approved in 2024 for BID dosing for the treatment of mild to moderate Alzheimer's dementia, via the 505(b)(2) regulatory pathway, relying on FDA's previous finding of safety and efficacy for the listed drugs (LDs) Razadyne® (galantamine hydrobromide tablets), and Razadyne® ER (galantamine hydrobromide extended-release capsules). When dosed as a delayed-release (DR) tablet, ZUNVEZYL bypasses the stomach and, is absorbed in the small intestine potentially reducing the gastrointestinal side effects common for acetylcholinesterase inhibitors. Consequently, ZUNVEYL may offer advantages over the other acetylcholinesterase inhibitors by reducing gastrointestinal adverse effects which limit patient compliance. Here we report the outcome of a study designed to assess the relative bioavailability of ZUNVEYL DR tablets to galantamine hydrobromide extended-release (ER) capsules, under steady state conditions.

METHODS: This was an open-label, balanced, randomized, multiple dose, two-treatment, two-arm, two-period, comparative steady state study of ZUNVEYL DR tablets, 5 mg (BID, for 7 days) compared to galantamine hydrobromide ER, 8 mg (QD, for 7 days), in healthy adult subjects (N=40). The study protocol underwent ethics review and was conducted under GCP conditions.

RESULTS: Table 1 and Figure 1 describe the pharmacokinetic parameters calculated from the plasma analysis of galantamine derived from ZUNVEYL and galantamine hydrobromide ER. ZUNVEYL represented less than 1% of total circulating drug, which provided further evidence of safety.

CONCLUSIONS: ZUNVEYL was well-tolerated with no serious adverse event noted. The steady state study established a scientific bridge to the LD, galantamine hydrobromide ER capsules. Although the extent of absorption measured by the AUC[0-24]ss was comparable between ZUNVEYL and the LD, the Cmaxss was slightly higher than the LD. The safety of the higher Cmax of galantamine derived from ZUNVEYL compared to galantamine hydrobromide ER capsules is supported by the lower Cmax of galantamine derived from ZUNVEYL compared to the galantamine hydrobromide immediate release tablets [see abstract # 107030].},
}

Humans
*Galantamine/pharmacokinetics/analogs & derivatives/administration & dosage/therapeutic use
Male
*Cholinesterase Inhibitors/pharmacokinetics/administration & dosage
*Drug Development
Female
Middle Aged
Biological Availability
Aged
Delayed-Action Preparations
Adult
*Alzheimer Disease/drug therapy

@article {pmid41451958,
year = {2025},
author = {Smith, AM and Lorkiewicz, SA and Montoliu-Gaya, L and Wilson, TN and Ashton, N and Arslan, B and Plastini, MJ and Young, CB and Winer, JR and Shahid, M and Vossler, H and Ramirez, V and Pan, T and Kerchner, GA and Andreasson, KI and Henderson, VW and Montine, TJ and Tian, L and Mormino, EC and Zetterberg, H and Poston, KL and Abdelnour, C},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104596},
doi = {10.1002/alz70856_104596},
pmid = {41451958},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; Male ; Female ; Aged ; *Amyloid beta-Peptides/blood/cerebrospinal fluid ; tau Proteins/blood/cerebrospinal fluid ; *alpha-Synuclein/cerebrospinal fluid/blood ; *Alzheimer Disease/blood/diagnosis/cerebrospinal fluid ; Middle Aged ; Peptide Fragments/blood/cerebrospinal fluid ; Glial Fibrillary Acidic Protein/blood/cerebrospinal fluid ; Neurofilament Proteins/blood ; Cohort Studies ; Aged, 80 and over ; },
abstract = {BACKGROUND: Coexistence of amyloidosis (Aβ), tauopathy, and alpha-synucleinopathy (αSyn) is common in neurodegenerative disease and drives heterogeneity in clinical presentation, disease progression, and treatment response. Understanding how in vivo biomarkers perform within the context of multiple underlying neuropathologies is therefore critical. While novel plasma biomarkers accurately detect Aβ, their application in the presence of αSyn remains underexplored. This study investigated the diagnostic accuracy of plasma biomarkers for detecting Aβ in individuals with and without αSyn pathology.

METHOD: Five plasma biomarkers were analyzed (pTau181, pTau217, Aβ42/40, GFAP, and NfL) in a cohort of 180 Stanford research participants (mean age = 69); 48% were asymptomatic (healthy controls) and 52% were symptomatic (clinically diagnosed along the Alzheimer's or Lewy body disease spectra). The CSF SAAmplify-αSYN test and Aβ42/40 ratio (Lumipulse G platform) were used to determine αSyn status (αSyn+ and αSyn-) and Aβ status (Aβ+ and Aβ-). Descriptive comparisons were conducted for plasma biomarkers across Aβ/aSyn groups (αSyn-/Aβ-, n = 60; αSyn-/Aβ+, n = 53; αSyn+/Aβ-, n = 35; and αSyn+/Aβ+, n = 32). Diagnostic accuracies of plasma biomarkers in predicting Aβ status were evaluated in αSyn+ and αSyn- individuals with receiver-operating characteristic (ROC) curve analyses and compared with the DeLong test.

RESULT: Plasma pTau181, pTau217, Aβ42/40, and GFAP levels were abnormal in Aβ+ groups, regardless of αSyn status (Figure 1). Plasma NfL levels were higher in the αSyn+/Aβ+ group compared to other groups. Plasma pTau217 showed the largest median fold change between Aβ+ and Aβ- participants. In αSyn+ participants, plasma pTau217 and Aβ42/40 individually showed the highest accuracies (AUC values up to 0.92) in detecting Aβ (Figure 2). In αSyn- participants, individual and combined biomarker models performed similarly, with no biomarker significantly outperforming another. Including age, sex, and APOE4 status did not improve model accuracy for detecting Aβ in αSyn+ participants, but improved plasma NfL's accuracy for detecting Aβ in aSyn- participants.

CONCLUSION: Plasma pTau217 (individually and combined with other biomarkers) accurately detects Aβ in αSyn+ participants. These findings highlight potential for using plasma pTau217 as a tool for Aβ screening and stratification in clinical trials for alpha-synucleinopathies such as dementia with Lewy bodies and Parkinson's disease.},
}

Humans
*Biomarkers/blood/cerebrospinal fluid
Male
Female
Aged
*Amyloid beta-Peptides/blood/cerebrospinal fluid
tau Proteins/blood/cerebrospinal fluid
*alpha-Synuclein/cerebrospinal fluid/blood
*Alzheimer Disease/blood/diagnosis/cerebrospinal fluid
Middle Aged
Peptide Fragments/blood/cerebrospinal fluid
Glial Fibrillary Acidic Protein/blood/cerebrospinal fluid
Neurofilament Proteins/blood
Cohort Studies
Aged, 80 and over

@article {pmid41451930,
year = {2025},
author = {Ishiki, A and Oyama, C and Miyazawa, I and Tomita, N and Furukawa, K},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e105340},
doi = {10.1002/alz70858_105340},
pmid = {41451930},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Japan ; Neuropsychological Tests/statistics & numerical data ; *Cognitive Dysfunction/diagnosis/psychology ; *Dementia/diagnosis/psychology ; Aged, 80 and over ; *Alzheimer Disease/diagnosis/psychology/drug therapy ; },
abstract = {BACKGROUND: In Japan, Lecanemab could be administered to patients with early Alzheimer's disease in September 2023. Since the diagnosis of the disease would need to be made earlier than before, it was expected that patient referrals from primary care physicians to Dementia Disease Center specialists would increase. This study aims to determine if the patient population that visited the Dementia Disease Center changed before and after the launch of Lecanemab in Japanese setting.

METHOD: Patients visiting our Dementia Disease Center in a city in eastern Japan from January 2022 to August 2024 with a chief complaint of cognitive impairment were included in the study. We analyzed whether there were differences in age, neuropsychological test results, last diagnosis, and severity of cognitive impairment between the periods before and after January 2023, when Lecanemab became available at our hospital.

RESULT: The total patients examined were 409 (age 79.1±7.4, 62.6% female), 90.3% were diagnosed with dementia and Mild Cognitive Impairment (MCI), 56% were diagnosed with AD and MCI due to AD. There were no significant differences in age (Before 78.9±7.7 vs. after 79.75±6.5), MMSE (20.8±5.8 vs. 21.0±5.3), or FAST stage (4.1±1.0 vs. 3.9±0.9) between before and after the launch of Lecanemab.

CONCLUSION: Early diagnosis is important for the administration of anti-amyloid-β drugs, although early diagnosis has not increased after the launch of Lecanemab. Facilitated collaboration between primary care physicians and specialists is needed to ensure that the appropriate treatment is given to the appropriate patient.},
}

Humans
Female
Male
Aged
Japan
Neuropsychological Tests/statistics & numerical data
*Cognitive Dysfunction/diagnosis/psychology
*Dementia/diagnosis/psychology
Aged, 80 and over
*Alzheimer Disease/diagnosis/psychology/drug therapy

@article {pmid41451891,
year = {2025},
author = {Calio, ML and Santos, LE and Mosini, AC and Foresti, ML and De Felice, FG and Mello, LEM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103686},
doi = {10.1002/alz70856_103686},
pmid = {41451891},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Brain Injuries, Traumatic/blood/drug therapy ; tau Proteins/blood ; Ubiquitin Thiolesterase/blood ; *Glial Fibrillary Acidic Protein/blood ; Middle Aged ; Aged ; Neurofilament Proteins/blood ; Alzheimer Disease/blood ; Adult ; },
abstract = {BACKGROUND: Traumatic Brain Injury (TBI) is a significant risk factor for Alzheimer's Disease (AD). However, the mechanisms connecting TBI to AD pathology remain unclear. Identifying blood-based biomarkers of neuronal and astrocytic injury is crucial for advancing precision diagnostics and intervention by predicting neurodegeneration. This study evaluates serum biomarkers using the ultra-sensitive Single Molecule Array (SIMOA) platform to explore their association with TBI severity, sex-specific responses and potential relevance to AD.

METHODS: We conducted a subanalysis of 123 patients enrolled in the phase III NCT01048138 clinical trial at HCFMUSP. Participants with acute TBI were randomized to receive either biperiden or placebo. Serum samples were collected and analyzed at multiple time points for biomarkers including Tau, NfL, GFAP, and UCHL1 using SIMOA. Biomarker profiles were compared across treatment groups, TBI severity, sex, age and time post-injury. Additional analyses explored their relevance to AD-related neurodegenerative process.

RESULTS: GFAP and NfL emerged as the most reliable biomarkers, strongly correlating with age, sex, TBI severity and temporal progression post-injury. Intriguingly, elevated levels of these biomarkers in the acute phase post-TBI were associated with astrocytic and axonal injury, which are critical in AD pathology. UCHL1 levels are also associated with trauma severity, sex, and time post-injury, but less significantly than NfL and GFAP. Women exhibited higher levels of levels Tau, GFAP and UCHL1 but lower NfL levels compared to men, suggesting a potential sex-specific response. Age-stratified analyses revealed increased NfL and GFAP levels in older patients, emphasizing the impact of age on astrocytic activation. While biperiden treatment did not significantly alter biomarker levels across the overall cohort, exploratory analyses also revealed possible sex-specific trends in treatment response.

CONCLUSIONS: Our findings underscore the feasibility of serum biomarkers such as GFAP and NfL to bridge the understanding of the molecular link between TBI and AD. The SIMOA technology enables precise quantification of biomarkers, providing valuable knowledge into the time window from the moment of TBI to the development of AD, allowing for the analysis of long-term neurodegeneration. These results reinforces the importance of personalized approaches to diagnosis and therapeutic monitoring.},
}

Humans
*Biomarkers/blood
Male
Female
*Brain Injuries, Traumatic/blood/drug therapy
tau Proteins/blood
Ubiquitin Thiolesterase/blood
*Glial Fibrillary Acidic Protein/blood
Middle Aged
Aged
Neurofilament Proteins/blood
Alzheimer Disease/blood
Adult

@article {pmid41451887,
year = {2025},
author = {Lynch, SY and Jia, J and Miles, N and Boiser, J and Buhl, DL and Graff, O and Zadikoff, C},
title = {ABBV-552 in patients with mild Alzheimer's disease: a randomized phase IIb trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70994},
doi = {10.1002/alz.70994},
pmid = {41451887},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Aged ; Female ; Middle Aged ; Aged, 80 and over ; Double-Blind Method ; Treatment Outcome ; Dose-Response Relationship, Drug ; Mental Status and Dementia Tests ; },
abstract = {INTRODUCTION: This proof-of-concept, dose-finding phase IIb trial evaluated treatment with ABBV-552 compared with placebo in participants with clinically diagnosed mild Alzheimer's disease (AD).

METHODS: Participants aged 50 to 90 years with a Mini-Mental State Examination score of 20 to 26 and a global Clinical Dementia Rating score of 0.5 to 1.0 were randomized 1:1:1:1 to placebo or ABBV-552 (1, 5, or 15 mg) daily. The primary endpoint was the change from baseline in the 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 14) at week 12.

RESULTS: Two hundred sixty-three participants were randomized. The least-squares mean difference (vs placebo) in change from baseline at week 12 in ADAS-Cog 14 total score (95% confidence interval) for ABBV-552 1 mg was -0.02 (-1.87, 1.83), nominal p = 0.9819; 5 mg, -0.42 (-2.25, 1.42), nominal p = 0.6545; 15 mg, 0.25 (-1.58, 2.08), nominal p = 0.7860. Treatment-emergent adverse events occurred in 48.5% of ABBV-552 recipients versus 42.2% in the placebo group; no safety concerns were identified.

DISCUSSION: ABBV-552 did not demonstrate a meaningful difference versus placebo on the primary endpoint.

HIGHLIGHTS: ABBV-552 is a small molecule that modulates the SV2A receptor in neurons ABBV-552 may enhance synaptic efficiency leading to improved cognition in patients with Alzheimer's disease (AD) Participants with mild AD were treated with either placebo, 1 mg, 5 mg, or 15 mg of ABBV-552 covering an estimated 35% to 80% SV2A receptor occupancy in a phase II randomized clinical trial Results failed to show efficacy over placebo as measured by ADAS-Cog 14 at week 12 ABBV-552 was generally safe and well tolerated.},
}

Humans
*Alzheimer Disease/drug therapy
Male
Aged
Female
Middle Aged
Aged, 80 and over
Double-Blind Method
Treatment Outcome
Dose-Response Relationship, Drug
Mental Status and Dementia Tests

@article {pmid41451871,
year = {2025},
author = {Yang, T and Huhe, H and Williams, SP and Kaur, S and Ay, YA and Davis-Gilbert, ZW and Cary, GA and Paisie, C and Butler, RR and Wiley, J and Betarbet, R and Fu, H and Duong, D and Seyfried, NT and Leal, K and Carter, GW and Edwards, A and Levey, AI and Capener, JL and Drewry, DH and Hossain, MA and Oh, HJ and Axtman, AD and Sukoff Rizzo, SJ and Longo, FM and , },
title = {PAK1 inhibitor NVS-PAK1-1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71033},
doi = {10.1002/alz.71033},
pmid = {41451871},
issn = {1552-5279},
support = {//PhRMA Foundation/ ; //The SGC is a registered charity that receives funds from Bayer AG, Boehringer Ingelheim/ ; //NIH grants NIA U54AG065187/ ; //Applebaum Foundation Fund/ ; //Archer Fund/ ; //Jean Perkins Foundation/ ; },
mesh = {Animals ; *Dendritic Spines/drug effects/pathology/metabolism ; *p21-Activated Kinases/antagonists & inhibitors/metabolism ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; Mice, Transgenic ; *Alzheimer Disease/pathology/metabolism/drug therapy ; *Neurons/drug effects/metabolism ; Hippocampus/drug effects/pathology ; Disease Models, Animal ; Mice ; Female ; Humans ; Dibenzazepines ; Pyrrolidines ; },
abstract = {INTRODUCTION: Synaptic spine loss in Alzheimer's disease (AD) contributes to cognitive decline. p21-activated kinase 1 (PAK1), a regulator of spine integrity, is aberrantly activated in AD. We investigated whether PAK1 inhibition might preserve dendritic spines in vitro and in vivo.

METHODS: Oligomeric amyloid beta (oAβ) or tau (oTau) were applied to hippocampal neurons ± NVS-PAK1-1, a selective PAK1 inhibitor. NVS-PAK1-1 was orally administered to 5xFAD mice. The effects of NVS-PAK1-1 treatment on PAK1 activity, spine density, and the proteome were assessed using phospho-PAK1 (pPAK1) western blotting, Golgi staining, and mass spectrometry for proteomic analyses.

RESULTS: NVS-PAK1-1 prevented oAβ and oTau-induced spine loss in vitro. In 5xFAD mice, NVS-PAK1-1 demonstrated brain exposure after oral administration and reduced PAK1 activation, prevented spine loss, and partially normalized synaptic proteomic signatures in females in absence of alterations in brain or plasma Aβ.

DISCUSSION: PAK1 inhibition enhances spine resilience in AD models, supporting its therapeutic potential.

HIGHLIGHTS: p21-activated kinase 1 (PAK1) inhibitors prevent oligomeric amyloid beta (oAβ) and oligomeric tau-induced spine loss and dendritic degeneration in cultured mouse hippocampal neurons. NVS-PAK1-1, a selective PAK1 inhibitor, protects against oAβ-induced spine loss in a dose-dependent manner (EC50 = 2 nM). Oral administration of NVS-PAK1-1 achieves brain penetration and bioavailability in normal CD-1 mice, and target engagement in 5xFAD mice. Chronic NVS-PAK1-1 treatment mitigates spine loss in the somatosensory cortex of 6-month-old 5xFAD female mice. Chronic treatment with NVS-PAK1-1 restores proteomic abundance of actin cytoskeleton and dendritic spine-associated proteins, including cofilin 2 and pyruvate dehydrogenase kinases, downstream of PAK1 in young 5xFAD female mice showing spine resilience. Clinical oncology trials with other PAK1 inhibitors support potential repurposing or novel compound development for Alzheimer's disease trials.},
}

Animals
*Dendritic Spines/drug effects/pathology/metabolism
*p21-Activated Kinases/antagonists & inhibitors/metabolism
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism/toxicity
Mice, Transgenic
*Alzheimer Disease/pathology/metabolism/drug therapy
*Neurons/drug effects/metabolism
Hippocampus/drug effects/pathology
Disease Models, Animal
Mice
Female
Humans
Dibenzazepines
Pyrrolidines

@article {pmid41451867,
year = {2025},
author = {Grundman, M and Catalano, S and Hamby, ME and Devins, T and Iaci, J and Caggiano, AO},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106858},
doi = {10.1002/alz70859_106858},
pmid = {41451867},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Alzheimer Disease/drug therapy ; Middle Aged ; *Drug Development ; Aged, 80 and over ; Double-Blind Method ; tau Proteins/blood ; Amyloid beta-Peptides ; Treatment Outcome ; },
abstract = {BACKGROUND: Zervimesine (CT1812) is an experimental oral, small-molecule drug candidate in development for Alzheimer's disease (AD) and dementia with Lewy bodies. Zervimesine is designed to protect neuronal synapses by preventing the binding of amyloid beta (Aβ) oligomers.

METHOD: The Phase 2 COG0201 'SHINE' clinical trial measured tolerability and clinical effects of zervimesine in adults with amyloid-positive mild-to-moderate AD (MMSE 18 to 26). The study enrolled 153 individuals at 30 U.S. and international sites. Participants were randomized 1:1:1 to receive placebo or one of two doses (100 or 300mg) of oral zervimesine daily for 26 weeks. Patients were assessed using a traditional battery of symptomatic assessments (ADAS-Cog, MMSE, ADSC-ADL and CGIC). A pre-specified analysis evaluated treatment effect relative to placebo based on median plasma p-tau217 value.

RESULT: In the full mITT population in SHINE, zervimesine-treated participants (n=101) declined 39% less on ADAS-Cog 11 and 70% less on MMSE relative to placebo (n=49). Participants with plasma p-tau217 levels below the median of 1.0 pg/mL had an even more robust response. Zervimesine-treated patients with sub-median levels of plasma p-tau217 (n=45) experienced 95% less cognitive decline on ADAS-Cog 11 and 108% less decline on MMSE vs placebo (n=24). We will present for the first time at AAIC the distribution of plasma p-tau217 by MMSE severity in SHINE and demonstrate that this enhanced response was similar for patients with MMSE 22-26 and MMSE 18-21, encompassing the full range of baseline severity in this study.

CONCLUSION: Results from the SHINE study provide compelling evidence that zervimesine has the potential to slow cognitive decline in patients with AD. Participants with lower disease burden, as measured by plasma p-tau217 experienced a more pronounced treatment effect. Importantly, this benefit was observed in people across the mild-to-moderate MMSE spectrum. While preliminary, these results suggest that having a lower disease burden as measured by plasma p-tau217 may provide a therapeutic window to still treat patients in the moderate MMSE range. SHINE was supported by a grant from the National Institute of Aging (R01AG058660).},
}

Humans
Male
Female
Aged
*Alzheimer Disease/drug therapy
Middle Aged
*Drug Development
Aged, 80 and over
Double-Blind Method
tau Proteins/blood
Amyloid beta-Peptides
Treatment Outcome

@article {pmid41451852,
year = {2025},
author = {Ackley, SF and Flanders, M and Chen, R and Wang, J and Shah, SJ},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106785},
doi = {10.1002/alz70859_106785},
pmid = {41451852},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Drug Development ; Positron-Emission Tomography ; Aged ; *Cognitive Dysfunction/drug therapy/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Aniline Compounds ; Ethylene Glycols ; },
abstract = {BACKGROUND: Amyloid removal has been used as surrogate outcomes in clinical trials of Alzheimer's disease (AD) drugs, leading to approvals of aducanumab and lecanemab under the Accelerated Approval Program. While well-established epidemiologic and econometric methods exist to formally evaluate amyloid's validity as a surrogate outcome, their application has been hindered by restricted access to individual-level data from anti-amyloid drug trials. The newly available individual-level data from the A4 trial of solanezumab offers a unique opportunity to demonstrate how these untapped approaches can improve our understanding of the impact of amyloid removal on cognitive decline.

METHOD: We used data on 815 A4 study participants (Alzheimer's Clinical Trial Consortium A4/LEARN) with complete follow-up measures for florbetapir PET imaging and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score. We estimated cognitive change using the trajectory of the CDR-SB score over 4.5 years. Instrumental-variable (IV) methods were used to evaluate the causal effect of amyloid reduction on cognitive changes using randomization as an instrument for amyloid reduction. Causal mediation analysis was conducted to estimate the extent to which changes in amyloid mediated the cognitive effects of solanezumab. Analyses were adjusted for sex, APOE-ε4 carrier status, and baseline age, cognition, and amyloid.

RESULT: Average between-group differences in amyloid change and cognitive trajectory were -0.05 (SD 0.16) SUVr and 0.002 (SD 0.028) CDR-SB points per month, respectively. Non-linear effects of amyloid on cognition were not supported (figure 1). The IV-estimated effect of a 1 SUVr reduction on monthly CDR-SB change was -0.041, 95% CI: (-0.096, 0.014) (figure 2). Mediation analysis suggests that amyloid change mediates 23% of solanezumab's effect on cognitive change, 95% CI: (-125%, 253%) (figure 2).

CONCLUSION: Using epidemiologic and econometric methods to analyze individual-level data from trials of amyloid-targeting drugs will improve our understanding of amyloid as a surrogate outcome for cognition. In this instance, results are imprecise because solanezumab did not effectively remove amyloid. However, reproducing these analyses using individual-level data from effective anti-amyloid trials has the potential to shape treatment strategies and inform use of surrogate outcomes in future approval processes.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging
Male
Female
*Antibodies, Monoclonal, Humanized/therapeutic use
*Drug Development
Positron-Emission Tomography
Aged
*Cognitive Dysfunction/drug therapy/diagnostic imaging
Amyloid beta-Peptides/metabolism
Aniline Compounds
Ethylene Glycols

@article {pmid41451848,
year = {2025},
author = {Chan, D and Zheng, M and Geigenmuller, U and Pantazis, D and Becker, A and Quay, MJ and Ruiz, E and Philips, R and Zhang, X and Hahn, N and Yee, S and Jackson, BL and Boyden, ES and Brown, EN and Tsai, LH and Leclerc, G},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e107067},
doi = {10.1002/alz70859_107067},
pmid = {41451848},
issn = {1552-5279},
mesh = {Humans ; Magnetoencephalography ; Male ; Female ; Magnetic Resonance Imaging ; Acoustic Stimulation/methods ; *Brain/physiology ; *Drug Development ; *Gamma Rhythm/physiology ; Alzheimer Disease/therapy ; Middle Aged ; },
abstract = {BACKGROUND: Non-invasive gamma-frequency light and sound stimulation at 40Hz has shown promise as a possible disease modifying therapeutic for the treatment of Alzheimer's disease (AD). However, human neural substrates generating a gamma frequency response to Gamma Entrainment Using Sensory (GENUS) stimulation have never been shown. Here, we aim to show brain regions that generate gamma frequency oscillations in response to GENUS stimulation.

METHODS: We conducted an observational trial in cognitively typical subjects (n=16) undergoing magnetoencephalography (MEG) while receiving 40Hz light and sound stimulation with the GENUS device. Neurophysiological data recorded with MEG was mapped on individual T1 structural magnetic resonance (MR) images to deduce source localization of 40Hz oscillation potentiation in the brain.

RESULTS: Source localization in response to GENUS light and sound stimulation shows induced 40Hz oscillations in the appropriate sensory cortices as well as in brain regions important for associative, executive and higher order memory functions, memory consolidation, spatial orientation, and integration of sensory processes. Induced 40Hz oscillations are maximal with synchronized 40Hz light and sound stimulation as compared to light or sound stimulation alone. Interestingly, when 40Hz light and sound are anticorrelated, 40Hz oscillations are significantly reduced in the auditory and visual cortices as compared to when 40Hz light and sound are synchronized.

CONCLUSIONS: For the first time, we provide evidence of target engagement and sources of gamma wave generation in the brain that are important for sensory processing, associative and executive memory functions and areas affected by AD pathology when humans are undergoing 40Hz GENUS light and sound stimulation. This data set can serve as a resource for exploring responses of neural substrates of 40Hz visual and auditory stimulation.},
}

Humans
Magnetoencephalography
Male
Female
Magnetic Resonance Imaging
Acoustic Stimulation/methods
*Brain/physiology
*Drug Development
*Gamma Rhythm/physiology
Alzheimer Disease/therapy
Middle Aged

@article {pmid41451827,
year = {2025},
author = {Castroflorio, E and Cabot, J and Suau, M and Fernández-García, P and Lladó, V and Escriba, PV and Torres, M},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106958},
doi = {10.1002/alz70859_106958},
pmid = {41451827},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Mice, Transgenic ; Cell Proliferation/drug effects ; *Docosahexaenoic Acids/pharmacology ; Cell Differentiation/drug effects ; *Neurons/drug effects ; Neurogenesis/drug effects ; Disease Models, Animal ; Neural Stem Cells/drug effects ; },
abstract = {BACKGROUND: Lipids are fundamental to neuronal function, and disruptions in lipid homeostasis are increasingly recognized as key contributors to neurodegenerative diseases such as Alzheimer's disesase. While lipid dysregulation is known to alter protein function, the therapeutic potential of lipid-based interventions remains largely unexplored.

METHODS: Neurospheres culture, immunocytochemistry, immunohistochemistry, inmunofluorescence labeling, confocal microscopy, western-blot, qPCR.

RESULTS: Here, using 5xFAD mice and primary neurospheres, we investigate the effects of a hydroxylated derivative of docosahexaenoic acid (DHA-H) and its metabolite heneicosapentaenoic acid (HPA) on neuronal proliferation and differentiation. We show that DHA-H and HPA enhance proliferation, as evidenced by increased expression of Ki-67, Sox2, and Nestin, alongside BrdU incorporation in vitro. Confocal microscopy and Western blot analyses further reveal upregulation of neuronal differentiation markers, including Doublecortin, NeuroD1, and PSA-NCAM. In vivo, treatment of WT and 5xFAD mice promotes neuronal progenitor cell proliferation in the dentate gyrus, as indicated by elevated staining of phospho-Histone H3 levels. Moreover, we identify GPR37 as a potential receptor mediating these effects, with its expression upregulated following treatment. This is accompanied by alterations in MAPK and mTOR signaling pathways, uncovering key mechanisms underlying neuroproliferation and differentiation in Alzheimer's disease models.

CONCLUSION: These findings highlight the potential of lipid-based interventions in restoring neurogenesis and neuronal maturation in neurodegenerative conditions.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
Mice
Mice, Transgenic
Cell Proliferation/drug effects
*Docosahexaenoic Acids/pharmacology
Cell Differentiation/drug effects
*Neurons/drug effects
Neurogenesis/drug effects
Disease Models, Animal
Neural Stem Cells/drug effects

@article {pmid41451766,
year = {2025},
author = {Chang, JW},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103281},
doi = {10.1002/alz70856_103281},
pmid = {41451766},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/therapy/metabolism ; Positron-Emission Tomography ; Aged ; *Blood-Brain Barrier/diagnostic imaging/metabolism ; Prospective Studies ; Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; Magnetic Resonance Imaging ; Neuropsychological Tests ; *Plaque, Amyloid/diagnostic imaging/metabolism ; Middle Aged ; },
abstract = {BACKGROUND: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is safe and potentially beneficial in patients with Alzheimer's disease (AD) for the removal of amyloid-beta (Aβ) plaques. However, the optimal BBB opening intervals and number of treatment sessions for clinical improvement remain undefined. Th METHOD: In this open-label prospective study, 6 patients with AD were enrolled from June 2022 to July 2023. FUS mediated BBB opening was performed three times at 2-month intervals targeting the bilateral frontal lobes. 18F-florbeta ben positron emission tomography (FBB-PET) was performed before the first procedure and after the third procedure. Patients were administered neuropsychological and neuropsychiatric evaluations.

RESULT: All 6 participants completed the study without any acute treatment-related adverse events. An extensive area of BBB opening (mean 43.1 cm3), more than twice as large as the opening volume (mean 20 cm3) in the authors' previ ous study, was confirmed by contrast-enhanced MRI. FBB-PET scans demonstrated a 14.9-Centiloid average decrease in Aβ plaques in 4 of the 6 participants (67%), but the Aβ plaques increased in 2 participants after BBB opening, com pared with baseline. No significant changes were observed in the Korean version of the Mini-Mental State Examination in either group. Caregiver-Administered Neuropsychiatric Inventory scores improved in 5 of 6 participants (83%), indicat ing an improvement in neuropsychiatric symptoms.

CONCLUSION: This study confirmed the safety and efficacy of more frequent and extensive bilateral frontal BBB opening over multiple sessions in patients with AD. Furthermore, this is the first clinical trial to demonstrate improvement in neuropsychiatric symptoms through BBB opening alone, without concurrent administration of antibody medications.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/therapy/metabolism
Positron-Emission Tomography
Aged
*Blood-Brain Barrier/diagnostic imaging/metabolism
Prospective Studies
Biomarkers/metabolism
Amyloid beta-Peptides/metabolism
Magnetic Resonance Imaging
Neuropsychological Tests
*Plaque, Amyloid/diagnostic imaging/metabolism
Middle Aged

@article {pmid41451751,
year = {2025},
author = {Moreira, JA},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106341},
doi = {10.1002/alz70859_106341},
pmid = {41451751},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antioxidants/therapeutic use/administration & dosage ; *Drug Development ; Female ; Male ; Aged ; Oxidative Stress/drug effects ; },
abstract = {BACKGROUND: Alzheimer's disease is the most common form of dementia, accounting for 60% to 70% of cases. (1) Current research indicates that oxidative stress is the principal cause of pathology linked to Alzheimer's disease. (2-6) Neuronal degeneration in this disorder is considered to be caused by the secondary effects of an increase in oxidation and lower mitochondrial bioenergetics with the lack of energy ending in neuronal death. (2-6) A reduction in ATP levels is caused by mitochondrial malfunctions that are characterized by decreased electron transport rates in complex I, III and IV of the mitochondrial respiration, increased oxidative stress - reactive oxidative species, decrease in glucose utilization associated to decrease activity and expression of Pyruvate Dehydrogenase Complex (PDH), elevation in glycolysis and loss in metabolic capabilities are early AD pathophysiological findings (2-6) Rationality: Infusion therapy of intravenous and/or intraspinal cranio-cervical injections of antioxidant biosupplements (NAD, Alpha Lipoic Acid, Glutathione, Vitamin C) may serve to counteract the oxidation and inflammation that occurs in Alzheimer's disease by increasing the redox potential inside the mitochondria, which facilitate the production of neurotransmitters and reverse the loss of brain energy production at the chemical level, halting the cognitive deficit progression.

METHOD: In the first month, fifty (50) patients received two initial biosupplements infusion treatments, which was then followed by a monthly infusion throughout the year. Intravenous biosupplements (NAD, Alpha Lipoic Acid, Vitamin C, and Glutathione) were administered. MOCA and ADAS- cog were measured at baseline and after one year receiving treatment.

RESULT: Twenty-seven (27) of the fifty patients showed no signs of deterioration, eighteen (18) showed mild improvement at the end of the year on MOCA and ADAS-cog. Five (5) patients showed mild deterioration. No side effects were observed.

CONCLUSION: Clinical symptoms of Alzheimer's disease can be medically controlled with an appropriate intravenous bionutritional antioxidant combination as a treatment by improving the energy production of the brain. A clinical trial with a larger population should be considered.},
}

Humans
*Alzheimer Disease/drug therapy
*Antioxidants/therapeutic use/administration & dosage
*Drug Development
Female
Male
Aged
Oxidative Stress/drug effects

@article {pmid41451707,
year = {2025},
author = {Liu, YA},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103383},
doi = {10.1002/alz70856_103383},
pmid = {41451707},
issn = {1552-5279},
mesh = {Animals ; Macaca mulatta ; Male ; Tomography, Optical Coherence ; Female ; Biomarkers ; *Retina/pathology/diagnostic imaging ; Visual Acuity ; Decision Making/physiology ; },
abstract = {BACKGROUND: Retinal layer thinning measured by optical coherence tomography (OCT) has been proposed as a noninvasive biomarker for central nervous system degeneration, including Alzheimer's disease (AD). Non-human primates (NHPs), whose brains and retinas closely resemble those of humans, offer a promising model for preclinical testing. However, no studies have assessed the relationship between retinal layer thickness and cognitive decline in NHPs.

METHODS: At the California National Primate Research Center, we evaluated 110 adult rhesus macaques aged 19.54 ± 3.28 years (range 11-30; 14 males, 96 females). Biobehavioral assessments investigated included visual acuity, decision-making, working memory, spatial memory, problem-solving, and social learning. OCT scans of both eyes were obtained and analyzed using customized software to measure peripapillary and macular layer thicknesses within different circular regions centered on the fovea of the early treatment of diabetic retinopathy study (EDTRS) grid. Pearson correlation and multiple linear regression were used to assess relationships between retinal and optic nerve layer thickness and cognitive scores.

RESULTS: Behavioral studies revealed that older monkeys demonstrated improved decision-making in food choice tests but worsened problem-solving in food retrieval tasks. Visual acuity, spatial memory, and social learning behaviors remained unchanged with age. Retinal layer thickness measurements were very similar to human data and there was no age or behavior-related changes. The behavioral data demonstrated a much larger variability compared to retinal OCT measurements.

CONCLUSIONS: Rhesus macaques showed aging behaviors and retinal layer measurements similar to humans. Although behavioral testing poses challenges, retinal imaging was highly reproducible. A larger, longitudinal study pairing behavioral assessments with retinal measurements is needed to determine if the retina could serve as a noninvasive biomarker of cognitive function in preclinical NHP research.},
}

Animals
Macaca mulatta
Male
Tomography, Optical Coherence
Female
Biomarkers
*Retina/pathology/diagnostic imaging
Visual Acuity
Decision Making/physiology

@article {pmid41451692,
year = {2025},
author = {Alladi, S and Mondal, SM and Arshad, F and Ramakrishnan, S and Govindaraj, S and Sastry, PN and Kumar, S},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106469},
doi = {10.1002/alz70859_106469},
pmid = {41451692},
issn = {1552-5279},
mesh = {Humans ; Male ; *Cognitive Dysfunction/drug therapy ; Female ; Retrospective Studies ; *Alzheimer Disease/drug therapy ; Aged ; *Drug Development ; Biomarkers ; Aged, 80 and over ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Mental Status and Dementia Tests ; Middle Aged ; },
abstract = {BACKGROUND: Lecanemab, a monoclonal antibody targeting amyloid, has been approved as disease-modifying treatment for Alzheimer's disease (AD) and is gradually gaining regulatory approvals across the globe. However, its accessibility and applicability in low-and middle-income countries (LMICs) remains limited due to constraints in biomarker availability, cost effectiveness concerns and underrepresentation of diverse cohorts in clinical trials. This study aimed to evaluate the eligibility of patients with Mild cognitive impairment (MCI) and AD from Cognitive Disorders Clinic (CDC) for treatment with lecanemab, based on clinical, and imaging criteria used in clinical trials.

METHOD: A retrospective review of patients diagnosed dementia was conducted using data from the CDC registry. Patients with MCI and AD dementia were included based on the Lecanemab drug trial's inclusion criteria. Cognitive assessments including Mini Mental Status Examination (MMSE), Clinical Dementia Rating (CDR) scales and MRI were reviewed. Eligibility was assessed by applying the appropriate use criteria for Lecanemab to all patients with MCI/AD. Plasma and Brain amyloid biomarkers were not available for the patients.

RESULT: Of the 1448 patients with dementia seen in CDC from May 2016 to May 2021, 643 (44.4%) were clinically diagnosed with MCI (n=252, 17.4%)/AD (n=350, 24.2%). Applying the CDR criteria excluded 43 MCI and 165 AD cases. An additional 20 MCI and 10 AD cases were excluded based on age criteria. Applying the MMSE criteria excluded 28 MCI and 132 AD cases. Additionally, 18 MCI cases were excluded due to the presence of cerebral microbleeds. The primary exclusion factors included, advanced disease stage (40%), and contraindications such as significant comorbidities (30%) and microbleeds 102 (20%). Thus, out of the total 1,448 dementia patients, 134 (9.25 %) and of 643 patients with clinical AD or MCI, 134 (20.8%) were potentially eligible treatment with Lecanemab.

CONCLUSION: A substantial proportion (80.75%) of dementia patients from LMICs may be ineligible for lecanemab due to diagnostic and resource limitations. However, 20.8% of clinically diagnosed AD could potentially be eligible with biomarker testing. Efforts to enhance biomarker availability, early detection, and cost-effective strategies are crucial to enable equitable access to emerging AD therapies in LMICs.},
}

Humans
Male
*Cognitive Dysfunction/drug therapy
Female
Retrospective Studies
*Alzheimer Disease/drug therapy
Aged
*Drug Development
Biomarkers
Aged, 80 and over
*Antibodies, Monoclonal, Humanized/therapeutic use
Mental Status and Dementia Tests
Middle Aged

@article {pmid41451676,
year = {2025},
author = {Carlsson, CM and Zylstra, H and Cronin, K and Cole, A and Beckman, E and Eierman, AC and Wilson, RE and Chappell, RJ and Gleason, CE and Zetterberg, H and Johnson, SC and Asthana, S and Hulle, CAV},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106943},
doi = {10.1002/alz70859_106943},
pmid = {41451676},
issn = {1552-5279},
mesh = {Humans ; Male ; *Eicosapentaenoic Acid/analogs & derivatives/therapeutic use ; Veterans ; Female ; Aged ; Double-Blind Method ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; *Drug Development ; Middle Aged ; Vascular Endothelial Growth Factor A/cerebrospinal fluid ; United States ; },
abstract = {BACKGROUND: Veterans Affairs (VA)-eligible US military Veterans have increased susceptibility to Alzheimer's disease (AD) dementia, possibly due to vascular contributions to AD pathology. The omega-3 fatty acid eicosapentaenoic acid (EPA) has beneficial anti-inflammatory and anti-atherogenic properties, reduces clinical cardiovascular events, and has been associated with reduced risk for dementia. It is unclear if treatment with high-dose EPA icosapent ethyl (IPE) improves cerebrospinal fluid (CSF) markers of vascular and metabolic health in adults at risk for AD.

METHOD: The Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid Study (BRAVE-EPA, NCT02719327) recruited 131 cognitively unimpaired VA-eligible Veterans from the Madison VA Hospital to participate in an 18-month, placebo-controlled, double-blind randomized controlled trial of icosapent ethyl (IPE, Vascepa®, Amarin Corp.) 4g daily vs placebo. At baseline, month 9, and month 18, participants had cerebrospinal fluid (CSF) collected, MRI, and cognitive testing. In an exploratory analysis, CSF samples were analyzed at the University of Wisconsin ADRC Biomarker Lab using the multiplex NUcleic acid-linked Immuno-Sandwich Assay (NULISA)seq CNS disease panel kit according to manufacturer instructions. NULISAseq CNS disease panel includes measures of the vascular endothelial growth factor (VEGF) family, reflecting endothelial function, angiogenesis, vascular permeability, inflammation, and oxidation. ANOVA was used to test the ratio of 18 mo/baseline NULISA protein quantification (NPQ) for each biomarker.

RESULT: Of the 131 recruited Veterans (ages 50-76), 86 had CSF available at both baseline and month 18 for NULISA analyses. Baseline participant characteristics are noted in Table 1. This cognitively unimpaired sample was predominantly male, White, and demonstrated a breadth of vascular risk and educational attainment. Compared to placebo, 18 months of IPE therapy did not alter CSF biomarkers of vascular or metabolic health or a marker of AD pathology (pTau-217)(Table 2, p-value range 0.10 - 0.98).

CONCLUSION: In this cohort of cognitively unimpaired VA-eligible Veterans, IPE did not alter NULISA CSF biomarkers of vascular and metabolic health or AD pathology (pTau-217). While EPA has previously been shown to improve VEGF-mediated inflammatory and atherogenic processes, further studies are needed to clarify the potential role of IPE or other omega-3 fatty acids to alter AD risk through vascular risk modification.},
}

Humans
Male
*Eicosapentaenoic Acid/analogs & derivatives/therapeutic use
Veterans
Female
Aged
Double-Blind Method
*Alzheimer Disease/drug therapy/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
*Drug Development
Middle Aged
Vascular Endothelial Growth Factor A/cerebrospinal fluid
United States

@article {pmid41451659,
year = {2025},
author = {Gabelle, A and Sabbagh, MN and Grimmer, T and Villa, L and Gordon, E and Borrot, M and Gueddou, A and Guizard, N and Courreges, O and Jin, K and Chezem, WR and Lopez-Talavera, JC and Missling, CU},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106459},
doi = {10.1002/alz70859_106459},
pmid = {41451659},
issn = {1552-5279},
mesh = {Humans ; *Drug Development/methods ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Magnetic Resonance Imaging ; Patient Reported Outcome Measures ; Precision Medicine ; Brain/diagnostic imaging ; Neuroimaging ; },
abstract = {BACKGROUND: There is a critical need to establish robust Real-World Evidence (RWE) platform for monitoring both clinically relevant benefits and potential mid/long-term side effects of Alzheimer's disease (AD) drugs at an individual level, with the ambition to enhance personalized medicine in AD. However, there are no standards for digital post-market approval continuous monitoring of drug safety and efficacy. Oral blarcamesine, a novel convenient scalable precision medicine treatment was submitted and accepted for Marketing Authorisation Application (MAA) review by the European Medicines Agency. To innovate the monitoring of blarcamesine, we built a patient-centric, digital multimodal platform based on three pillars consisting of digital Patient Reported Outcomes (PRO), digital clinical and cognitive assessments, and automated MRI Brain Imaging exams.

METHOD: The digital PRO includes regularly administered surveys via wearable device data to provide a comprehensive view of treatment impact. The digital clinical and cognitive assessment integrates interactive applications for clinical and cognitive training and performance tracking and historical comparisons. The brain imaging pillar implements automated MRI image quality control and automated monitoring of brain volume changes using the QyScore ® neuroimaging analysis platform from Qynapse.

RESULT: Such a platform would enable continuous, real-time data collection from patients, facilitating more precise tracking of drug efficacy, patient individual responses, and the emergence of potential side effects.

CONCLUSION: This post-market approval continuous monitoring platform may benefit all stakeholders, including patients, clinicians, regulators, service providers and payors. This modularly digital platform can be customized to fit also other post-market approval monitoring.},
}

Humans
*Drug Development/methods
*Alzheimer Disease/drug therapy/diagnostic imaging
Magnetic Resonance Imaging
Patient Reported Outcome Measures
Precision Medicine
Brain/diagnostic imaging
Neuroimaging

@article {pmid41451645,
year = {2025},
author = {Kay, DG and Grady, KP and Wahlert, AJ and McFadden, M},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e107255},
doi = {10.1002/alz70859_107255},
pmid = {41451645},
issn = {1552-5279},
mesh = {Humans ; *Galantamine/analogs & derivatives/pharmacokinetics/administration & dosage/therapeutic use/adverse effects ; *Cholinesterase Inhibitors/pharmacokinetics/administration & dosage/therapeutic use ; Male ; Female ; *Drug Development ; Dose-Response Relationship, Drug ; *Alzheimer Disease/drug therapy ; Aged ; Middle Aged ; Adult ; Delayed-Action Preparations ; },
abstract = {BACKGROUND: ZUNVEYL (benzgalantamine, galantamine benzoate gluconate), is a pharmacologically inactive prodrug of galantamine. ZUNVEYL was FDA approved in 2024 for BID dosing for the treatment of mild to moderate Alzheimer's dementia, via the 505(b)(2) regulatory pathway, relying on FDA's previous finding of safety and efficacy for the listed drugs (LDs) Razadyne® (galantamine hydrobromide tablets), and Razadyne® ER (galantamine hydrobromide extended-release capsules). When dosed as a delayed-release (DR) tablet, ZUNVEYL bypasses the stomach and, is absorbed in the small intestine potentially reducing the gastrointestinal side effects common for acetylcholinesterase inhibitors. Consequently, ZUNVEYL may offer advantages over the other acetylcholinesterase inhibitors by reducing gastrointestinal adverse effects which limit patient compliance. Here we report the outcome of a study designed to assess the dose proportionality of ZUNVEYL DR tablets over a dosage range of 5-15 milligrams.

METHODS: This was an open-label, balanced, randomized, three-arm, three-treatment, single-dose parallel study to evaluate the pharmacokinetics and dose proportionality of ZUNVEYL DR tablets of 5, 10 and 15 mg strength in healthy adult subjects (N=42), under fasting conditions. The study protocol underwent ethics review and was conducted under GCP conditions.

RESULTS: The dose proportionality of ZUNVEYL based on the plasma analysis of galantamine derived from ZUNVEYL (Table 1), and the pharmacokinetic profiles of all three doses (Figure 1) are presented below. Fifteen milligrams of ZUNVEYL administered to drug naïve subjects, provoked one gastrointestinal adverse event (1/14), a lower incidence than that expected with an equivalent dose of Galantamine hydrobromide.

CONCLUSIONS: ZUNVEYL was well-tolerated, no serious adverse events were observed. Statistical analysis confirmed the dose proportionality for Cmax, AUC0-t, & AUC0-∞ over the entire 5 mg to 15 mg dose range for ZUNVEYL. The studies demonstrating bioequivalence, under fed and fasted (abstract #107030), and steady state (abstract #107147) conditions, and dose proportionality studies, lead to the conclusion that one ZUNVEYL 5 mg DR tablet is equivalent to one galantamine hydrobromide 4 mg immediate release tablet.},
}

Humans
*Galantamine/analogs & derivatives/pharmacokinetics/administration & dosage/therapeutic use/adverse effects
*Cholinesterase Inhibitors/pharmacokinetics/administration & dosage/therapeutic use
Male
Female
*Drug Development
Dose-Response Relationship, Drug
*Alzheimer Disease/drug therapy
Aged
Middle Aged
Adult
Delayed-Action Preparations

@article {pmid41451626,
year = {2025},
author = {Javaid, H and Saddique, MN and Musani, A and Jha, A and Noor, M and Arfan, M and Cheema, U and Aqeel, M and Cheema, S},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e103458},
doi = {10.1002/alz70858_103458},
pmid = {41451626},
issn = {1552-5279},
mesh = {Humans ; *Psychomotor Agitation/drug therapy/etiology/psychology ; *Thiophenes/therapeutic use ; Quality of Life ; *Alzheimer Disease/psychology/complications/drug therapy ; *Quinolones/therapeutic use ; *Dementia/psychology ; },
abstract = {BACKGROUND: Agitation is one of the most distressing neuropsychiatric symptoms in patients with dementia due to Alzheimer's disease (AD), significantly impacting patients' quality of life and increasing caregiver burden. Current management options for agitation in AD remain limited, with many treatments associated with modest efficacy and considerable safety concerns. Brexpiprazole, a serotonin-dopamine activity modulator, has recently emerged as a potential therapeutic option for this challenging clinical scenario. This systematic review and meta-analysis aim to evaluate the efficacy and safety of brexpiprazole in managing agitation associated with dementia in AD.

METHOD: A comprehensive literature search was conducted across PubMed, Cochrane, Scopus, Embase and ClinicalTrials.gov from inception up to January 2025. We pooled dichotomous outcomes as risk ratio (RR) and continuous outcomes as mean differences (MD) with 95% confidence intervals (CI), using random-effects models. Heterogeneity was assessed using I[2] and X[2] statistics. A p-value of <0.05 was considered statistically significant. All the calculations were performed using RevMan 5.4.

RESULT: This meta-analysis included 4 studies involving 1440 patients (944 vs. 496) suffering from agitation associated with dementia in AD. Brexpiprazole demonstrated a significant reduction in the Cohen-Mansfield Agitation Inventory (CMAI) score (MD: -3.94 [95% CI: -6.21 to -1.67], p <0.001) and Neuropsychiatric Inventory-Nursing Home (NPI-NH) score (MD: -0.67 [95% CI: -1.08 to -0.26], p = 0.002) from baseline, with the greatest improvement observed at the 2-3 mg dose. There was statistically significant change in SAS score (MD: 0.38, [95% CI: 0.18 to 0.58], p = 0.0002) but no difference in Mini-Mental State Examination (MMSE) score (MD: -0.26 [95% CI: -0.53 to 0.01], p = 0.06) and Clinical Global Impression-Severity (CGI-S) score (MD: -0.16 [95% CI: -0.34 to 0.01], p = 0.06) from the baseline with brexpiprazole. There was no difference between two groups regarding serious adverse events (p = 0.57), dizziness (p = 0.49), extrapyramidal effects (p = 0.18) and mortality (p = 0.22).

CONCLUSION: Brexpiprazole significantly reduces agitation symptoms in Alzheimer's disease, as shown by improvements in CMAI and NPI-NH scores, with no significant cognitive or safety concerns. While promising, limitations include moderate heterogeneity and short follow-up durations. Future studies should focus on long-term effects, quality of life, and identifying optimal patient subgroups for treatment.},
}

Humans
*Psychomotor Agitation/drug therapy/etiology/psychology
*Thiophenes/therapeutic use
Quality of Life
*Alzheimer Disease/psychology/complications/drug therapy
*Quinolones/therapeutic use
*Dementia/psychology

@article {pmid41451623,
year = {2025},
author = {Dirks, B and Friend, SM and Howell, BM and Murphy, CM and Zhang, PM and Feng, X and Pathak, SS},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106556},
doi = {10.1002/alz70859_106556},
pmid = {41451623},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/complications ; Biomarkers/blood/cerebrospinal fluid ; *Drug Development ; Aged ; Male ; *Psychotic Disorders/drug therapy ; Female ; Amyloid beta-Peptides ; tau Proteins/blood ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is diagnosed and staged based on biological criteria that utilize biomarkers. However, biomarker data are sparse in patients with psychosis and significant cognitive decline. Here we present screening metrics based on study biomarker requirements in patients diagnosed using 2011 National Institute on Aging-Alzheimer Association (NIA-AA) criteria for AD and International Psychogeriatrics Association (IPA) criteria for psychosis. Patients were enrolled in the context of the ACP-204 Alzheimer's disease psychosis (ADP) clinical development program. ACP-204 is a potent inverse agonist and antagonist of serotonin 2A (5-HT2A) receptors.

METHODS: ACP-204-006 is intended to enroll patients with ADP into a master protocol [ACP-204-006 (NCT06159673)]. This includes Part 1, one phase 2 efficacy and dose-confirming study, and Parts 2A and 2B, two independent phase 3 confirmatory efficacy studies, for ACP-204 in ADP. Each study has the same design (6-week double-blind treatment); patients may participate in only a single Part (Figure 1). In addition to meeting clinical criteria for ADP, participants must have confirmed plasma or historical biomarker positivity. Blood samples collected at screening were tested for Amyloid Probability Score (APS), APS2, and phosphorylated tau at threonine 217 (p-tau217) ratio using commercially available blood tests with diagnostic algorithms to predict amyloid brain status. These include amyloid beta (Aβ)42/40 ratios and p-tau217 ratios.

RESULTS: In Part 1 (currently ongoing), between February 6, 2024, and December 27, 2024, 322 adults were screened, of whom 75 (aged 59-89 years) met NIA-AA and IPA criteria. Of these, 23 met clinical criteria for ADP but were not positive for APS or APS2, despite meeting historical biomarker requirements. We will present detailed biomarker results on the population, including apolipoprotein E (apoE) proteotype, Aβ42/40 ratio, and p-tau217 ratio. Clinical presentation and related information will be detailed as well.

CONCLUSIONS: Biomarkers, rather than syndromic presentation, are recommended as a mechanism by which to define AD biologically. Since biomarker data from patients presenting with clinical symptoms consistent with Alzheimer's disease dementia and psychosis are sparse, we present biomarker data in a rigorously phenotyped population. These results can also inform the design and execution of clinical trials in ADP in the future.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis/complications
Biomarkers/blood/cerebrospinal fluid
*Drug Development
Aged
Male
*Psychotic Disorders/drug therapy
Female
Amyloid beta-Peptides
tau Proteins/blood
Aged, 80 and over

@article {pmid41451613,
year = {2025},
author = {Coskun, EP and Elam, MG and Clewett, L and Bojarski, L and Curtis, A and Harper, M and George, R and Shaffer, A and Amry, M and Shrestha, S and Jicha, GA},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106302},
doi = {10.1002/alz70859_106302},
pmid = {41451613},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Development ; *Cognitive Dysfunction/drug therapy ; *Clinical Trials as Topic ; *Patient Selection ; },
abstract = {BACKGROUND: Recruitment and engagement are major challenges for clinical trials in the area of Alzheimer's disease and related dementias (ADRD). This problem may be exacerbated by the recent FDA approval of anti-amyloid therapies and their introduction into standard clinical practice. A better understanding of the barriers to research engagement may increase research productivity resulting in shorter trials that can move the needle forward at a faster rate. This study sought to explore the pipeline from prescreening participants for clinical trials of mild cognitive impairment (MCI) and early Alzheimer's disease (AD) in order to provide insights into the major current barriers for research engagement in this era of disease modifying therapies.

METHOD: The present data analyzes the recruitment and engagement pipeline for two current clinical trials of experimental medications for the treatment of MCI and early AD. Descriptions of reasons for screen failure along the pipeline are presented based on summary categorization in order to better understand the barriers to clinical trial recruitment at present.

RESULT: Over the last year, 490 potential research participants were prescreened for clinical trial engagement, with 45 moving on to consent (<10%), and only 8 of these eventually being enrolled (<20%), demonstrating an overall success rate for clinical trial engagement at only 1.6% in the current study. Approximately 23% of participants were to clinical trial engagement, and another 20% of potential participants failed to engage in pursuit of alternate treatments, including nearly 10% due to pursuit of recently approved anti-amyloid therapy treatments. Thirty-eight percent of potential participants screen-failed for medical conditions and exclusionary medications, of which nearly one-half were not related to safety and or primary outcome measures. Less than 5% of potential participants could not participate due to trial logistics (travel, need for a study partner, duration and or frequency of visits).

CONCLUSION: This data suggests that increasing the pipeline of potential research participants for clinical trials should focus on continued efforts to destigmatize clinical trial engagement, adapt inclusion/exclusion criteria to allow concomitant disease-modifying therapies, and eliminate unnecessary exclusion criteria if it does not affect safety and or primary outcome measures.},
}

Humans
*Alzheimer Disease/drug therapy
*Drug Development
*Cognitive Dysfunction/drug therapy
*Clinical Trials as Topic
*Patient Selection

@article {pmid41451598,
year = {2025},
author = {Putcha, D and Properzi, MJ and Papp, KV and Johnson, KA and Sperling, RA and Rentz, DM and Amariglio, RE},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e106551},
doi = {10.1002/alz70857_106551},
pmid = {41451598},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Positron-Emission Tomography ; Neuropsychological Tests ; *Cognitive Dysfunction/diagnostic imaging ; tau Proteins/metabolism ; *Alzheimer Disease/diagnostic imaging ; Aged, 80 and over ; *Brain/diagnostic imaging/metabolism/pathology ; Middle Aged ; Self Report ; },
abstract = {BACKGROUND: The presence of Subjective Cognitive Decline (SCD) in cognitively unimpaired (CU) individuals represents a significant risk factor for progression from preclinical to the symptomatic stage of Alzheimer's disease (AD). Studies on SCD to date have focused on memory concerns as a risk factor for developing amnestic AD dementia. However, AD pathology underlies a heterogeneous phenotypic spectrum, including a visual variant of AD-Posterior Cortical Atrophy (PCA)-thought to comprise 5-15% of AD dementia cases. We do not yet have a method for identifying individuals at the preclinical stage of AD who go on to develop PCA.

METHOD: Self-report responses on the Everyday Cognition Scale (ECOG) from 253 CU participants (mean age = 72.1 ± 8.9) in the Harvard Aging Brain Study were analyzed. We explored associations between total participant responses on the visuospatial subscale, objective cognitive tests, and amyloid PET positivity. An exploratory whole-cortex tau PET general linear model was conducted to examine the association between subjective visuospatial decline and emerging tau burden in the neocortex.

RESULT: Four percent of participants (N = 9) endorsed "at least occasional problems" or more averaged across the 7-item ECOG visuospatial subscale. These individuals did not differ from the rest of the sample on age, sex, education, or MMSE. ECOG visuospatial scores across the whole CU group were unrelated to MMSE or objective visuospatial cognition. ECOG visuospatial scores were higher in PiB+ individuals compared to PiB- individuals (t = 3.4, p = 0.001). Subjective visuospatial concerns were associated with right-hemisphere predominant tau in temporoparietal and prefrontal cortices, largely overlapping with regions associated with subjective memory concerns and with tau epicenters reported in preclinical AD.

CONCLUSION: A subset of CU individuals endorsed subjective visuospatial decline, a cognitive domain that does not typically decline in healthy aging. The positive relationships observed between subjective visuospatial decline and biomarkers of amyloid and tau suggest that the ECOG can be a useful tool in capturing subtle visuospatial decline in addition to early memory concerns in preclinical AD. Developing methodology to predict the development of atypical AD variants has significant implications for optimizing early diagnosis and treatment of this disease.},
}

Humans
Male
Female
Aged
Positron-Emission Tomography
Neuropsychological Tests
*Cognitive Dysfunction/diagnostic imaging
tau Proteins/metabolism
*Alzheimer Disease/diagnostic imaging
Aged, 80 and over
*Brain/diagnostic imaging/metabolism/pathology
Middle Aged
Self Report

@article {pmid41451570,
year = {2025},
author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106694},
doi = {10.1002/alz70859_106694},
pmid = {41451570},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Retrospective Studies ; *Alzheimer Disease/epidemiology/drug therapy/prevention & control ; *Anti-Inflammatory Agents/therapeutic use ; *Drug Development ; Middle Aged ; *Inflammation/drug therapy ; Aged, 80 and over ; Incidence ; Propensity Score ; Adrenal Cortex Hormones/therapeutic use ; },
abstract = {BACKGROUND: Inflammation is a critical factor in the onset and progression of neurodegenerative diseases, including Alzheimer's Disease (AD). Notably, inflammatory processes are evident in AD as early as the prodromal stages. Despite this, the role of anti-inflammatory treatments (aIT) in modifying AD risk remains unclear. This study aimed to evaluate the impact of aIT on AD incidence and to characterize patients who subsequently developed AD after drug exposure (non-responders) and those who did not (responders).

METHOD: A retrospective analysis was conducted using an insurance claims dataset, including patients 60 years and older. The anti-inflammatory drugs included in the study were oral corticosteroids, non-selective COX-1 and 2 inhibitors, and COX-2 selective inhibitors. Propensity score matching was applied to minimize bias by adjusting for age, gender, Charlson Comorbidity Index (CCI), and comorbidities. The final cohort included 225,742 patients, who were surveyed for a diagnosis of AD at least 1 year after their first prescription for an oral anti-inflammatory drug, independently of their inflammation-related medical condition. The analysis assessed different aIT classes, treatment durations, and a responder analysis to identify patient characteristics associated with AD risk. Characterization of patients included demographic characteristics, comorbidity burden, and co-treatment profiles.

RESULT: The propensity score matched group included 112,871 patients exposed to aIT and 112,871 patients with no exposure to any aIT. aIT use was associated with a significant decrease in the risk of AD diagnosis (RR [95%CI]: 0.35 [0.33-0.37]; P<.001), driven by a significantly reduced risk in patients undergoing aIT for at least a year. There were no statistically significant differences in AD risk reduction when comparing women to men. Patients aged 75 to 79 years and those with longer aIT exposure (6 years or longer) exhibited the greatest risk reduction. COX inhibitors were associated with superior AD risk reduction compared to corticosteroids.

CONCLUSION: This study supports the association between aIT and a reduced risk of AD. Key factors influencing this relationship included patient age, treatment duration, and the drug class used. These nuanced findings can guide future interventions targeting neuroinflammation in AD prevention.},
}

Humans
Male
Female
Aged
Retrospective Studies
*Alzheimer Disease/epidemiology/drug therapy/prevention & control
*Anti-Inflammatory Agents/therapeutic use
*Drug Development
Middle Aged
*Inflammation/drug therapy
Aged, 80 and over
Incidence
Propensity Score
Adrenal Cortex Hormones/therapeutic use

@article {pmid41451556,
year = {2025},
author = {Haynes, KA and Cope, ZA and Williams, SG and Nepali, U and Little, G and Doolen, S and Doud, EH and da Silva, L and Quinney, SK and Eldridge, K and Burton, CP and Persohn, SA and Pandey, RS and Carter, GW and Sasner, M and Lamb, BT and Oblak, AL and Territo, PR and Rizzo, SJS},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e105982},
doi = {10.1002/alz70859_105982},
pmid = {41451556},
issn = {1552-5279},
mesh = {Animals ; Mice ; *Alzheimer Disease/drug therapy ; *Drug Development ; Female ; Male ; Amyloid beta-Peptides/metabolism ; *Antibodies, Monoclonal, Humanized/pharmacology/pharmacokinetics/therapeutic use ; Mice, Transgenic ; Disease Models, Animal ; Brain/metabolism/drug effects ; Plaque, Amyloid/drug therapy ; },
abstract = {BACKGROUND: While there is ongoing support to position amyloid-targeting antibody-based therapeutics as standard-of-care treatments for Alzheimer's disease (AD), their benefits and limitations are debated. Despite significant reductions in amyloid with treatment, the disease continues to progress, and clinical trial data have now clearly demonstrated differential effects of sex. Given that females have a higher risk of AD, it is prudent to understand and predict beneficial effects and limitations in both sexes. The present studies aimed to characterize a murinized chimeric Aducanumab ([ch]Aducanumab) through the MODEL-AD Preclinical Testing Core (PTC) Drug Screening Pipeline. We evaluated the pharmacokinetic (PK), pharmacodynamic (PD), and behavioral effects of chronic administration to 5XFAD mice in comparison to murine IgG2a kappa control antibody (IgG) and saline.

METHODS: 5XFAD mice with significant plaque accumulation were chronically dosed IP once weekly [ch]Aducanumab and compared to IgG and saline controls. Brain and plasma levels of [ch]Aducanumab were analyzed using an attomolar sensitive, targeted mass spectrometry parallel reaction monitoring assay. Pre- and post-treatment plasma Aβ, terminal soluble and insoluble brain Aβ, and in vivo 18F-AV-45 and 18F-FDG PET were quantified and cross-referenced for the presence of anti-drug antibodies. Behaviors and cognitive function were tested in a behavioral battery.

RESULTS: Both [ch]Aducanumab and IgG were effective in attenuating plasma and brain Aβ with more robust effects on Aβ lowering in males than in females, and dose-dependent levels of [ch]Aducanumab were detectable in plasma and brain homogenate. Reduction of Aβ plaques did not correspond to significant improvements in performance on cognitive tasks or healthspan measures. The variability in PD responses within [ch]Aducanumab treatment groups was cross-referenced to individual data for the presence of anti-drug antibodies.

CONCLUSIONS: Sex-dependent differential clearance of amyloid plaques with monoclonal antibody treatment has been observed translationally across species. The interaction with IgG may contribute to both the amyloid-lowering effects and possibly to the reported adverse events. Results from this study will inform future MODEL-AD PTC evaluations of novel therapeutics, particularly those combined with or following anti-Aβ immunotherapies once amyloid is lowered and the disease continues to progress, and importantly to identify and predict differential effects of sex.},
}

Animals
Mice
*Alzheimer Disease/drug therapy
*Drug Development
Female
Male
Amyloid beta-Peptides/metabolism
*Antibodies, Monoclonal, Humanized/pharmacology/pharmacokinetics/therapeutic use
Mice, Transgenic
Disease Models, Animal
Brain/metabolism/drug effects
Plaque, Amyloid/drug therapy

@article {pmid41451546,
year = {2025},
author = {Wood, E and Azage, M and Dratch, L and Mim, R and Ofidis, D and Trieu, P and Syeda, A and Broaddus, E and Milinski, S and Egleston, BL and Vaishnavi, S and Bradbury, AR},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e107211},
doi = {10.1002/alz70858_107211},
pmid = {41451546},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Alzheimer Disease/genetics/psychology/therapy ; *Apolipoproteins E/genetics ; *Genetic Counseling ; Genetic Testing ; Genotype ; Middle Aged ; *Patient Education as Topic/methods ; Aged, 80 and over ; },
abstract = {BACKGROUND: APOE genotyping is recommended for patients considering anti-amyloid antibody therapy (AAT). It is also recommended that genetic testing for Alzheimer's disease (AD) should be conducted with the support of genetic counseling, as genetic information can raise questions and has implications beyond the initial clinical indication. The advent of AAT has caused an increased demand for both genetic testing and counseling for AD clinical care. Digital tools are a possible solution to meet this demand.

METHOD: Utilizing prior research and clinical experience, a custom chatbot was designed to provide educational information on AD and the APOE gene as a quality improvement project. The chatbot also provided the option to request assistance from a genetic counselor. Electronic health records were queried for patients who received APOE genotype results as part of a work-up for potential treatment with AAT. The chatbot was deployed to the patient's mobile phone number of record. Descriptive statistics were used to analyze utilization of the chatbot. Exit interviews were conducted by telephone with a subset of patients as part of rapid-cycle-testing.

RESULT: The APOE educational chatbot was launched to 369 patients, with 201 (54.5%) engaging with the chat (Table 1). Of those who engaged, 85 (45.7%) accessed the educational content in part or full, and 7% sent individual questions through the chat and/or requested genetic counseling given remaining informational needs. Engagement and access varied by genotype: e4 homozygotes had 66.7% engagement, 53.8% access, e4 heterozygotes had 47.4% engagement, 45.7% access, and non-carriers had 44.9% engagement, 42.4% access. Exit interviews (n = 22) revealed high patient value and constructive suggestions for improving the chatbot.

CONCLUSION: Engagement with a chatbot for APOE education was consistently high across all APOE result types, suggesting that patients receiving APOE genetic testing for the consideration of AAT have interest in APOE information regardless of genotype. Patient feedback was positive and constructive, supporting patient value and providing direction for changes to improve utilization. AD clinic populations may find chatbots to be an acceptable method for receiving genetic education about APOE and requesting additional support from a genetic counselor when needed.},
}

Humans
Male
Female
Aged
*Alzheimer Disease/genetics/psychology/therapy
*Apolipoproteins E/genetics
*Genetic Counseling
Genetic Testing
Genotype
Middle Aged
*Patient Education as Topic/methods
Aged, 80 and over

@article {pmid41451475,
year = {2025},
author = {Verastegui, G and Bustamante-Paytan, D and Montesinos, R and Custodio, N and Tosto, G},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e105516},
doi = {10.1002/alz70858_105516},
pmid = {41451475},
issn = {1552-5279},
mesh = {Humans ; *Dementia/diagnosis/psychology/therapy ; *Neuropsychological Tests ; },
abstract = {In the coming decades, the number of dementia cases is projected to increase worldwide. This public health issue will significantly impact low- and middle-income countries, such as those in Latin America, due to their aging populations. Proper diagnosis and identification of these patients require a comprehensive assessment, including neuropsychiatric, laboratory, and imaging evaluations, supported by neuropsychological assessments. However, despite the necessity of neuropsychological evaluations to identify impairments in one or more higher cognitive functions-facilitating the differentiation between various types of dementia-the availability of trained personnel to administer these assessments correctly is limited. This shortage leads to undiagnosed cases or inaccurate results in clinical studies. Here, we describe and propose a structured virtual training model for future raters assessing dementia patients, based on the training conducted at the Instituto Peruano de Neurociencias as part of the GLASS-AD (Global Latinos Sequencing Study for Alzheimer's Disease) study (Grant number: U01-AG081817). The primary objective of this training was to ensure that raters could accurately administer neuropsychological tests, thereby guaranteeing the validity of results. The training was structured into several phases: (1) Virtual sessions provided a theoretical explanation of neuropsychological tests, organized by cognitive domains. (2) Participants submitted evidence of their practical application of the material, using cognitively healthy individuals simulating cognitive impairment symptoms. (3) Expert neuropsychologists reviewed the trainees' submitted videos, providing feedback and corrections. (4) Participants then resubmitted a video with the corrected test administration for approval and certification. (5) Finally, a follow-up evaluation was scheduled six months later, requiring the submission of a new video to verify the quality and consistency of test administration. Standardizing training is essential to ensure that personnel are adequately prepared, improving the identification and diagnosis of dementia patients. This facilitates timely treatment and the development of strategies to mitigate the disease's impact on families and communities while also helping reduce the costs associated with patient care, especially in LMICs.},
}

Humans
*Dementia/diagnosis/psychology/therapy
*Neuropsychological Tests

@article {pmid41451474,
year = {2025},
author = {Darwish, M and Feng, X and Dirks, B and Raether, B and Pathak, SS},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e105732},
doi = {10.1002/alz70859_105732},
pmid = {41451474},
issn = {1552-5279},
mesh = {Humans ; Male ; Double-Blind Method ; Female ; Aged ; Middle Aged ; Adult ; *Drug Development ; Dose-Response Relationship, Drug ; *Antipsychotic Agents/pharmacokinetics ; *Alzheimer Disease/drug therapy ; *Serotonin 5-HT2 Receptor Antagonists/pharmacokinetics/administration & dosage ; Area Under Curve ; },
abstract = {BACKGROUND: ACP-204, a potent inverse agonist/antagonist of 5-HT2A receptors, is under investigation for the treatment of Alzheimer's disease psychosis (ADP). Frail elderly patients with ADP are vulnerable to adverse effects of antipsychotics and potential age-related differences in drug pharmacokinetics (PK) and pharmacodynamics. We investigated the PK, safety, and tolerability of ACP-204 in healthy elderly and adult participants at the proposed clinical dose (60 mg).

METHOD: In this single-center, phase 1, double-blind, multiple ascending dose study, healthy elderly and adult participants were randomized to receive ACP-204 oral doses up to 60 mg and 120 mg, respectively. Steady-state plasma samples were collected daily up to 10 days of dosing. The maximum observed drug concentration at steady state (Cmax-ss) and the area under the concentration-time curve over the 24-h dosing interval at steady state (AUCτ) were compared. Due to demonstrated linearity data, the 60-mg dose was selected as a representative of the PK parameters for the comparison. Safety was evaluated at each visit and during follow-ups.

RESULT: Seven healthy adult participants in 1 cohort and 17 elderly participants in 3 cohorts received 60 mg of ACP-204. Data from the elderly were pooled for steady-state PK evaluation. Median Tmax-ss was ∼5-6 h in elderly and ∼4-6 h in adult cohorts. Decline from peak was monophasic, with mean t1/2 of 19.8 and 17.8 h, respectively. In elderly participants, Cmax-ss and AUCτ were higher than those of the adults by 1.14-fold and 1.20-fold, respectively. The geometric least squares mean of the AUCτ for elderly vs adult participants was 1892 h*ng/mL vs 1575 h*ng/mL at 60 mg. The geometric mean ratio (elderly/adults) of the AUCτ was 120.17% (90% CI, 86.31%, 167.32%) (Table 1). Plasma ACP-204 concentrations are shown in Figure 1. Safety profiles were similar between age groups (Table 2).

CONCLUSION: The PK profiles were qualitatively similar over the studied dose ranges in healthy elderly and adult participants with minimal difference in exposure parameters 14% and 20% for Cmax,ss and AUC τ, respectively. ACP-204 was generally safe and well tolerated across age groups, with no unexpected safety findings.},
}

Humans
Male
Double-Blind Method
Female
Aged
Middle Aged
Adult
*Drug Development
Dose-Response Relationship, Drug
*Antipsychotic Agents/pharmacokinetics
*Alzheimer Disease/drug therapy
*Serotonin 5-HT2 Receptor Antagonists/pharmacokinetics/administration & dosage
Area Under Curve

@article {pmid41451455,
year = {2025},
author = {Wang, R and Chen, Q and Hu, N and Kuang, W and Li, Y and Lv, S and Tian, R and Li, L and Gao, H and Tang, Y and Qin, L and Feng, S and Cai, H and Yang, F and Luo, C and Guo, M},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e105423},
doi = {10.1002/alz70859_105423},
pmid = {41451455},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Retrospective Studies ; Aged ; *Alzheimer Disease/drug therapy/diagnostic imaging ; China ; *Drug Development ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/drug therapy/diagnostic imaging ; Middle Aged ; Positron-Emission Tomography ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) poses a significant public health challenge in China. Recent advancements in disease-modifying therapies, particularly lecanemab, have brought new therapeutic opportunities. In China, nationwide implementation of lecanemab in clinical practice was launched in June 2024. The study aims to investigate the characteristics of patients receiving lecanemab treatment and explore ways to improve patient recruitment and Amyloid-related imaging abnormalities (ARIA) monitoring.

METHOD: We retrospectively reviewed patients who received lecanemab treatment at West China Hospital from June 2024 to January 2025 (n=101). Patients interested in lecanemab treatment were screened by a multidisciplinary team (MDT) comprising experts from Neurology, Psychiatry, Geriatrics, Radiology, and Nuclear Medicine. Requirement for referral to the MDT clinic included a diagnosis of mild cognitive impairment (MCI) or mild dementia confirmed by amyloid PET, no evidence of disease other than AD being the primary cause of cognitive impairment, and the ability to undergo MRI scans. ARIA was monitored by comparing MRI scans from the same 3T scanner, interpreted by the same radiologist. In case of suspected adverse reactions, urgent MRI scans were promptly arranged.

RESULT: As of January 2025, 101 patients have received at least one lecanemab infusion at West China Hospital (mean age: 66.32 ± 10.69; 30.69% male). Three patients received additional lecanemab treatment in Hainan prior to June 2024 via an early access program. Amyloid PET scans confirmed AD in all patients, 48 also underwent Tau PET (47.52%), and 50 had CSF testing (49.51%). Sixty-one patients had MCI (60.40%) and forty had mild dementia (41.67%). Fifty-four were ApoE ε4 heterozygotes (53.47%), and nine were ApoE ε4 homozygotes (8.91%). Forty-three patients received intravenous prophylactic medications to prevent infusion reactions (42.57%), and seven patients experienced infusion reactions (6.93%). Ten patients (9.90%) had asymptomatic ARIA (8 with ARIA-H, 2 with ARIA-E). ARIA was observed at various infusion stages, with five cases in ApoE ε4 heterozygotes and five in noncarriers.

CONCLUSION: Careful selection by MDT and amyloid PET confirmation ensured optimal recruitment. High-field MRI and consistent radiologist interpretation facilitated ARIA detection. Our experience provides insights into establishing specialized medical frameworks for the safe and widespread administration of lecanemab.},
}

Humans
Male
Female
Retrospective Studies
Aged
*Alzheimer Disease/drug therapy/diagnostic imaging
China
*Drug Development
Magnetic Resonance Imaging
*Cognitive Dysfunction/drug therapy/diagnostic imaging
Middle Aged
Positron-Emission Tomography
Aged, 80 and over

@article {pmid41451451,
year = {2025},
author = {Guia, IL and Eslick, S and Kanduri, S and Poudel, P and Hone, E and Martins, RN},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e102434},
doi = {10.1002/alz70856_102434},
pmid = {41451451},
issn = {1552-5279},
mesh = {Humans ; Aged ; *Biomarkers/blood ; Male ; Female ; Tomography, Optical Coherence ; Middle Aged ; *Amyloid beta-Peptides/blood ; Aged, 80 and over ; *Retina/pathology/diagnostic imaging ; *Alzheimer Disease/blood/pathology/diagnostic imaging ; Neurofilament Proteins/blood ; Positron-Emission Tomography ; Peptide Fragments/blood ; Glial Fibrillary Acidic Protein ; },
abstract = {BACKGROUND: Retinal deposits of amyloid beta (Aβ) have been identified in the eye and has shown to have a greater impact on retinal thickness than age-related effects. Therefore, retinal thickness could serve as a diagnostic marker, warranting further investigation as demand for accessible Alzheimer's disease (AD) screening grows. This study aims to evaluate correlations between blood-based AD biomarkers and retinal thickness across different eye regions in amyloid-negative and amyloid-positive individuals.

METHOD: Optical coherence tomography (OCT) and AD plasma biomarkers NFL, Aβ42, Aβ40, GFAP were analysed in cognitively normal individuals (MMSE >24) aged 58-84 years, who previously undertook Positron Emission Tomography (PET) amyloid imaging. A centiloid (CL) cut-off score of 20 was used to subgroup recruited participants into amyloid-positive (n = 5) and amyloid-negative (n = 5). Data was analysed in reference to eye (LE/RE), image location (optic disc, macula) and ETDRS (early treatment diabetic retinal study) regions. R software was used to calculate Spearman correlation coefficients, with a significance level of p < 0.05.

RESULT: Comparing correlation coefficients across both groups demonstrated the amyloid-negative group having strong negative correlations between CL scores and total retinal thickness in only the peripapillary region (r = -0.71 to -0.97, p =  <0.05), where the amyloid-positive group had negative correlations in both macular and peripapillary regions (r = -0.71 to -1, p =  <0.05). The amyloid-negative group exhibited strong positive correlations with macular (r = 0.8 to 0.94, p =  <0.05) and outer disc peripapillary (r = 0.7, p =  <0.05) thickness to the Aβ42/Aβ40 ratio. The amyloid-positive groups retinal thicknesses across various regions had stronger negative associations of GFAP and NFL (r = -0.7 to -0.9, p =  <0.05) than the amyloid-negative group (r = -0.63 to -0.8, p =  <0.05).

CONCLUSION: These findings suggest that total retinal thickness in the macular and peripapillary regions via OCT may correlate with AD biomarkers. Increased retinal thickness were associated with increased Aβ42/AΒ40 ratio and decreased retinal thickness associated with higher brain amyloid CL scores, and blood-based GFAP and NFL biomarkers. Further study in larger cohorts is required to validate results.},
}

Humans
Aged
*Biomarkers/blood
Male
Female
Tomography, Optical Coherence
Middle Aged
*Amyloid beta-Peptides/blood
Aged, 80 and over
*Retina/pathology/diagnostic imaging
*Alzheimer Disease/blood/pathology/diagnostic imaging
Neurofilament Proteins/blood
Positron-Emission Tomography
Peptide Fragments/blood
Glial Fibrillary Acidic Protein

@article {pmid41451443,
year = {2025},
author = {Li, Y and Gohel, D and Pieper, AA and Cummings, JL and Cheng, F},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e105583},
doi = {10.1002/alz70859_105583},
pmid = {41451443},
issn = {1552-5279},
mesh = {*Sildenafil Citrate/pharmacology/therapeutic use ; Animals ; Humans ; *Alzheimer Disease/drug therapy ; Mice ; Female ; Male ; *Drug Development ; Induced Pluripotent Stem Cells/drug effects ; *Phosphodiesterase 5 Inhibitors/pharmacology/therapeutic use ; Mice, Transgenic ; Disease Models, Animal ; Brain/drug effects ; Aged ; Neurons/drug effects ; },
abstract = {BACKGROUND: We previously identified Sildenafil (a phosphodiesterase type 5 (PDE5) inhibitor) as a candidate drug in Alzheimer's Disease (AD) using an in silico network medicine approach. However, the clinically meaningful effect size and mechanism-of-action of sildenafil in AD treatment is still unclear.

METHOD: To further investigate the real-world effect of sildenafil on AD incidence, we conducted new patient data analyses using both the MarketScan® Medicare with Supplemental database (n=7.23 million older subjects) and the OPTUM database (n=11.52 million older subjects). We utilized AD patient-induced pluripotent stem cells (iPSC)-derived neuron and cerebral organoid models (both female and male familial and sporadic AD patients) to explore the mechanism-of-action of sildenafil's protective effects on AD. Additionally, we treated 5xFAD, a transgenic AD mouse model, with 15 mg/kg sildenafil for 3 months. Finally, we conducted behavioral tests, immunofluorescence staining on mouse brain sections, and single-cell RNA-seq to evaluate sildenafil's efficacy and brain target engagement.

RESULT: Sildenafil usage is significantly associated with reduced likelihood of AD across all four new drug cohorts (bumetanide, furosemide, spironolactone, and nifedipine). Compared to spironolactone, sildenafil was linked with a 46% and 30% reduced prevalence of AD in MarketScan (HR = 54%, 95% CI 0.32-0.66, p-value = 3.33x10-5) and OPTUM (HR = 70%, 95% CI 0.49-1.00, p-value = 0.05), respectively. In AD patient iPSC-derived neuron models, sildenafil treatment reduces phosphorylated tau (pTau181 and pTau231), phosphorylated GSK-3b, and CDK5. Sildenafil treatment in mice significantly improved novel object recognition and performance on the Morris water maze and contextual fear conditioning test. Immunostaining revealed significantly decreased amyloid plagues in the isocortex and interbrain of the sildenafil-treated mice, supporting its therapeutic effects in AD from real-world patient data and iPSC model findings. RNA-seq analysis (bulk and single-cell) identified brain target engagements and potential cell type-specific pharmacodynamics pathway for potential treatment of AD.

CONCLUSION: Evidence from real-world data, patient iPSC-derived cellular and brain organoids, and in vivo transgenic mouse model observations suggest that sildenafil is a potential repurposable treatment for AD. However, future clinical trials are necessary to test and confirm the causal relationship of sildenafil in prevention and treatment of AD.},
}

*Sildenafil Citrate/pharmacology/therapeutic use
Animals
Humans
*Alzheimer Disease/drug therapy
Mice
Female
Male
*Drug Development
Induced Pluripotent Stem Cells/drug effects
*Phosphodiesterase 5 Inhibitors/pharmacology/therapeutic use
Mice, Transgenic
Disease Models, Animal
Brain/drug effects
Aged
Neurons/drug effects

@article {pmid41451442,
year = {2025},
author = {Yang, X and Gong, Z and Tian, F and Ha, K and Lyalikov, D and Sun, Z and Kim, C and Nguyen, T and Xu, Y and Kamb, J and Chen, A and Xiao, M and Masurkar, AV and Wisniewski, T and Chen, S},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e105359},
doi = {10.1002/alz70859_105359},
pmid = {41451442},
issn = {1552-5279},
mesh = {Animals ; Mice ; Mice, Transgenic ; *Anxiety/drug therapy ; *Alzheimer Disease/drug therapy ; *Amyloid beta-Peptides/pharmacology ; *Drug Development ; Disease Models, Animal ; *Brain/drug effects ; Male ; *Peptide Fragments/pharmacology ; },
abstract = {BACKGROUND: Anxiety is a common symptom of Alzheimer's disease (AD). It has been recently established that anxiety is associated with AD pathology characterized by amyloid-β (Aβ) plaques and neurofibrillary tangles. Our laboratory has demonstrated that acute administration of Aβ12-28P, a synthetic peptide with the potential to competitively inhibit toxic Aβ oligomers, resulted in improved cognitive function in old transgenic AD mice. However, whether inhibiting Aβ toxicity by Aβ12-28P also alleviates anxiety in AD mice remains unknown.

METHOD: Middle-aged (12-15 months old) and old (18-24 months old) APP/PS1 dE9 mice were intraperitoneally injected with Aβ12-28P, while control mice received an equivalent volume of saline. Behavioral tests, including open field test and elevated plus maze, were conducted 2 hours post-injection to assess the acute effect of Aβ12-28P or saline on the anxiety of animals. We further performed in vivo fiber photometry to investigate anxiety-associated neural dynamics across multiple brain regions, such as ventral CA1 (vCA1), medial prefrontal cortex (mPFC), basal amygdala (BA), and lateral hypothalamic area (LHA). Adeno-associated virus expressing GCaMP8f was injected into target brain regions, above which an optic fiber was implanted. Four weeks later real-time calcium transients were recorded during anxiety tests.

RESULT: In middle-aged AD mice, Aβ12-28P administration exerted acute anxiolytic effects in the open field test (n = 8 drugged versus 8 non-drugged, p < 0.05). Furthermore, anxiety was also significantly alleviated by Aβ12-28P in old AD mice in both the open field (n = 17 drugged versus 14 non-drugged, p < 0.0001) and elevated plus maze (n = 11 drugged versus 12 non-drugged, p < 0.05) tests. We further compared the neural activity patterns in brain regions, such as vCA1, mPFC, BA, and LHA, with or without Aβ12-28P treatment by fiber photometry. Our data suggested significant modification of anxiety-associated neural dynamics in these brain regions by Aβ12-28P administration.

CONCLUSION: These results suggest that Aβ12-28P has an acute anxiolytic effect in both middle-aged and old AD mice. Our finding opens the possibilities to apply the strategy of targeting Aβ pathology for alleviating neuropsychiatric AD symptoms, such as anxiety, and provide insights into a brain region-specific mechanism behind this therapeutic strategy.},
}

Animals
Mice
Mice, Transgenic
*Anxiety/drug therapy
*Alzheimer Disease/drug therapy
*Amyloid beta-Peptides/pharmacology
*Drug Development
Disease Models, Animal
*Brain/drug effects
Male
*Peptide Fragments/pharmacology

@article {pmid41451427,
year = {2025},
author = {Nam, B and Huang, D and Shin, HW and Lee, EJ and Phan, N and Yun, SW and Park, VT},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e103256},
doi = {10.1002/alz70858_103256},
pmid = {41451427},
issn = {1552-5279},
mesh = {Humans ; Aged ; Female ; Male ; Middle Aged ; *Caregivers/psychology/education ; Aged, 80 and over ; *Asian/psychology ; *Dementia/psychology/therapy/ethnology/nursing ; Adult ; *Advance Care Planning ; *Health Knowledge, Attitudes, Practice ; Surveys and Questionnaires ; Republic of Korea/ethnology ; },
abstract = {BACKGROUND: Older Korean adults traditionally engage in indirect communication and are uncomfortable with topics such as advance care planning and treatment options for health conditions such as Alzheimer's disease and related dementias (ADRD). The overarching goal of a national, culturally tailored, bilingual (English, Korean) community engagement project called, Koreans Invested in Making Caregivers Health Important (KIMCHI), is to educate and promote community discussions on aging and caregiving topics, such as advanced care planning/directives among older Korean Americans with ADRD and their caregivers.

METHOD: Seven in-person workshops were hosted in collaboration with two community organizations that serve Korean Americans: Somang Society and Asian American Resource and Information Network, Inc. Pre- and post-workshop assessments measured knowledge (10 items), attitudes (7 items), and behaviors (6 items) on advance directives, where participants answered on an "agree-disagree-neutral" scale. Paired-sample t-tests were conducted to assess mean (M) changes. Participants also completed a satisfaction survey to evaluate the workshop.

RESULT: There were 204 participants (aged 25-92 years; M=67; SD=11.4) who were mostly female (75%) and foreign-born (98%) and who reported limited English proficiency (87%). Nearly a third (32.4%) were ADRD caregivers or knew or worked with someone who has ADRD. Post-test results showed significant changes in attitudes (pre: M=10.29; post: M=9.76; t(203)=0.53, p < .05) and behaviors (pre: M=9.79; post: M=10.71; t(203)=0.92, p < .05) regarding advanced planning and directives. Knowledge scores showed no significant change (pre: M=12.62; post: M=12.50; t(203)=0.36, p = .47), though the knowledge pre-test score was notably high. High satisfaction was reported, with 96.1% of participants expressing overall satisfaction, 90.7% learned something new about advanced directives, 94.1% found the presentations culturally relevant and applicable, and 76% expressed interest in learning more about ADRD.

CONCLUSION: Findings demonstrate the potential of culturally tailored, community-based interventions to improve Korean Americans' attitudes and behaviors toward understanding and engaging in advanced care planning, including making informed decisions about end-of-life care. Future studies should further tailor content for diverse learning needs, including real-life case examples, and ensure more representation in research studies for the Korean American community.},
}

Humans
Aged
Female
Male
Middle Aged
*Caregivers/psychology/education
Aged, 80 and over
*Asian/psychology
*Dementia/psychology/therapy/ethnology/nursing
Adult
*Advance Care Planning
*Health Knowledge, Attitudes, Practice
Surveys and Questionnaires
Republic of Korea/ethnology

@article {pmid41451412,
year = {2025},
author = {Li, S and Qian, W and Zhang, Z and Chen, Y and Hou, X and Min, B and Zhou, H and Zhu, X and Ling, J and Yang, W and Cao, S},
title = {Comprehensive safety assessment of donepezil: pharmacovigilance analysis based on the FDA adverse event reporting system.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1655216},
pmid = {41451412},
issn = {1664-2295},
abstract = {BACKGROUND: Alzheimer's disease (AD) has a growing global prevalence, and the need for safe and effective treatments is urgent. Donepezil is commonly used therapeutic agents for AD but has safety controversies. The objective of this study was to thoroughly evaluate donepezil's adverse event profile using actual data.

METHODS: In this study, reports of donepezil-related adverse events were collected from the first quarter of 2004 to the fourth quarter of 2024 through the FAERS database. The association of donepezil-induced adverse events was disproportionality analyzed using Reporting odds Ratios (ROR) and Proportional Reporting Ratio (PRR) and Bayesian Confidence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS), among other methods.

RESULTS: A total of 26,120 ADRs with donepezil as the "first suspect" were retrieved during the reporting period. The most common AEs included nausea, vomiting, syncope, and dizziness, which were consistent with the labeling of the medication and clinical trials. Unintended major AEs such as fall, hypotension, tremor, cognitive disorder, mania, and the highest signal of pleurothotonus were also detected. The reports also collected were characterized by a high proportion of female patients (51.3%) and the time of AE induction within 30 days (41%).

CONCLUSION: Donepezil treatment needs to focus on cardiovascular and neurological adverse events, especially for women, elderly patients, or patients with co-morbidities, cardiac monitoring and dose adjustment should be strengthened. Clinics need to balance efficacy and risk, develop individualized dosing regimens, and explore novel therapeutic strategies to improve long-term safety.},
}

@article {pmid41450657,
year = {2025},
author = {Zhao, Y and Xi, E and Wang, Z and Gao, N and Sun, H and Zhu, G},
title = {Nanoamplifier Agents Transiently Rise the Metabolism of β‑Amyloid Peptide in Urine for the Early Diagnosis of Alzheimer's Disease.},
journal = {JACS Au},
volume = {5},
number = {12},
pages = {6169-6178},
pmid = {41450657},
issn = {2691-3704},
abstract = {Alzheimer's disease (AD) is the most common form of dementia without effective treatment. Therefore, early diagnosis for timely treatment and delayof the onset of AD are critical. At present, detecting β-amyloid (Aβ) in cerebrospinal fluid is still the most important clinical method. However, the invasive detection method is harmful and difficult to promote. Recent research has shown that Aβ was found not only in blood and cerebrospinal fluid, but also in urine, which could be used for noninvasive testing. Compared with blood/cerebrospinal fluid, the background proteins in urine are very low, but unfortunately the content of Aβ is even lower. Therefore, if the concentration of Aβ is increased with the background proteins maintained at the low level, urine could be an ideal noninvasive early detection target for AD. Gold nanoparticles (AuNP) with ultrasmall size (<6 nm) could be rapidly metabolized by the kidneys and excreted with urine, and easily regulated by the metabolic pathway between kidneys and liver by changing their size. After screening, we found 3 nm AuNP had the highest renal metabolic efficiency, and by modifying with kidney targeting peptides and Aβ antibody 6E10, the complex system (P6-Au) acted as a "Aβ-targeting renal metabolic carrier", which both metabolized rapidly through the kidneys and increased the concentration of Aβ in urine. After tail vein injection of P6-Au, the Aβ content in the urine of 5×FAD transgenic mice increased by more than 20 times within the next 24 h, which resulted in the diagnosis time being advanced from the ninth month to the fifth month and provided a new approach for early detection of AD.},
}

@article {pmid41450541,
year = {2025},
author = {Chen, C and Shao, Q and Zhou, S},
title = {Exploring the Mahuang Fuzi Xixin Decoction's mechanism for treating Alzheimer's disease using molecular docking and network pharmacology.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1688316},
pmid = {41450541},
issn = {1663-4365},
abstract = {OBJECTIVE: Explore the potential mechanism of Mahuang Fuzi Xixin Decoction (MFXD) in the treatment of Alzheimer's disease (AD) using network pharmacology, molecular docking approaches, and test its efficacy by in vitro experiments.

METHODS: Active components of MFXD were screened from TCMSP, BATMAN-TCM, and TCMID, with corresponding targets obtained from SwissTargetPrediction and TCMSP. AD-related differential genes were retrieved from GEO. Intersection targets were identified via Venn diagrams, followed by GO/KEGG enrichment analyses, PPI network construction, and molecular docking. In vitro validation experiments were carried out using PC12 cells induced by Aβ25-35 to simulate the pathological state of AD. For the detection of cell viability, the CCK-8 assay was employed to evaluate the protective effect of MFXD and its active components on damaged PC12 cells. Western blot analysis was used to determine the protein expression levels of key molecules involved in AD-related signaling pathways, including phosphorylated p-NF-κB p65, NF-κB p65, p-GSK-3β, GSK-3β, MMP-9, p-Tau, and Tau. Additionally, the ELISA was utilized to measure the secretion level of TNF-α in the supernatant of Aβ25-35-induced PC12 cells, so as to assess the anti-inflammatory effect of MFXD.

RESULTS: Thirty-seven active components and 230 targets of MFXD were identified, along with 4913 AD-related differentially expressed genes from GEO dataset GSE122063, yielding 47 intersection targets. GO annotation enriched these targets in processes like reactive oxygen species metabolism, components like extracellular matrix, and functions like neurotransmitter binding; several pathways were enriched in the KEGG analysis, such as TNF signaling pathway, calcium signaling pathway, and NF-κB signaling pathway. The intersection target PPI network identified MMP9, EGFR, FOS as core targets. Molecular docking results indicated that quercetin binds to the three core targets (MMP9, EGFR, FOS), while luteolin binds preferentially to EGFR and MMP9. In vitro, Aβ25-35-induced PC12 cells treated with quercetin/luteolin had concentration-dependent viability increases (all P < 0.001); 15% MFXD-containing serum restored viability to ≥ 95% (P < 0.001 vs. AD model, comparable to DHCL). Western blot showed AD model had elevated p-NF-κB p65/NF-κB p65, MMP9/β-actin, p-Tau/Tau and reduced p-GSK-3β/GSK-3β (all P < 0.05); MFXD reversed these (all P < 0.05), while DHCL only inhibited p-NF-κB p65/NF-κB p65. ELISA showed MFXD and DHCL both reduced AD model's TNF-α (all P < 0.001).

CONCLUSION: MFXD potentially exerts anti-AD effects through a multi-component, multi-target, multi-pathway approach. Its key active components (quercetin, luteolin) may act by modulating the core target MMP9. Also, MFXD can simultaneously regulate several pathways, such as the TNF signaling pathway, Calcium signaling pathway, and NF-κB signaling pathway, and target Tau protein-related pathology by restoring the phosphorylation level of GSK-3β to suppress abnormal hyperphosphorylation of Tau, and thereby alleviating pathological damage in AD.},
}

@article {pmid41450326,
year = {2025},
author = {Llibre-Guerra, JJ and Zhou, J and Schneider, LSS and Andreozzi, E and Clifford, DB and Banerjee, S and Wang, G and McDade, E and Reyderman, L and Bateman, RJ},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e105299},
doi = {10.1002/alz70859_105299},
pmid = {41450326},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; *tau Proteins/immunology ; Male ; Female ; Double-Blind Method ; Middle Aged ; *Drug Development ; Aged ; Biomarkers ; Disease Progression ; Adult ; },
abstract = {BACKGROUND: Dominantly Inherited Alzheimer's disease (DIAD) is a rare form of AD that has its onset typically at 30-50 years old. DIAD has a small prevalence (∼1%), but shares pathophysiology with the more prevalent late-onset sporadic form of AD. The aim of the Dominantly Inherited Alzheimer Network -Trials Unit (DIAN-TU) is to find solutions to treat or prevent DIAD and to potentially apply these solutions to all forms of AD. Herein, we describe the baseline characteristics from the DIAN-TU-001 Tau NexGen arm evaluating the anti-tau therapy etalanetug with background lecanemab therapy.

METHODS: DIAN-TU-001 is a phase II/III multicenter randomized, double-blind, placebo-controlled platform trial of potential disease modifying therapies utilizing biomarker, cognitive, and clinical endpoints in DIAD. The purpose of this study is to assess the safety, tolerability, biomarker, cognitive and clinical efficacy of investigational products in participants with an AD-causing mutation by determining if treatment with the anti-tau antibody (etalanetug) slows the rate of progression of cognitive/clinical impairment or improves disease-related biomarkers. Baseline characteristics are summarized descriptively for both cohorts (Cohort 1: Symptomatic Population (CDR=0.5-1); Cohort 2: Asymptomatic Population (CDR=0)).

RESULTS: As of a data cutoff of December 3, 2024, 243 participants were screened and 197 randomized in DIAN-TU-001 Tau NexGen trial (Cohort 1: 97; Cohort 2: 100). Baseline characteristics of Cohort 1 and Cohort 2 were similar except for cognitive values, all of which varied as expected per the differing CDR study entry criteria for the two cohorts. Mean age (standard deviation [SD]) was 47.8 (8.6) and 43.4 (8.4) years in Cohort 1 and 2, respectively. At baseline, mean CDR-SB values (SD) were 3.7 (2.1) for Cohort 1 and 0.1 (0.3) for Cohort 2. APOE4 carrier frequency is consistent with that of the general population, with 25.8% and 21.0% carriers in Cohorts 1 and 2, respectively. The most common gene type in each group was PSEN1 (Cohort 1:78.4%; Cohort 2:85.0%).

CONCLUSIONS: The baseline characteristics for DIAN-TU-001 Tau NexGen trial were consistent with clinical features of asymptomatic and symptomatic DIAD. These characteristics were also generally consistent between Cohort 1 and Cohort 2 with the exception of clinical, and cognitive scores.},
}

Humans
*Alzheimer Disease/drug therapy/genetics
*tau Proteins/immunology
Male
Female
Double-Blind Method
Middle Aged
*Drug Development
Aged
Biomarkers
Disease Progression
Adult

@article {pmid41450296,
year = {2025},
author = {Smith, J and Mummery, CJ and Cummings, JL and Rabinovici, GD and Salloway, S and Sperling, RA and Zetterberg, H and Thanasopoulou, A and Lane, C and Delmar, P and Klein, G and Croney, R and Wojtowicz, J and Hofmann, C and Kulic, L and Garren, H},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e104294},
doi = {10.1002/alz70859_104294},
pmid = {41450296},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Development ; *Plaque, Amyloid/drug therapy ; Randomized Controlled Trials as Topic ; Double-Blind Method ; Clinical Trials, Phase III as Topic ; *Antibodies, Monoclonal, Humanized/therapeutic use ; },
abstract = {BACKGROUND: Developing potent therapies that reduce amyloid plaques has been shown as one means of producing clinical benefit in the early stages of symptomatic Alzheimer's disease (AD). Trontinemab is a novel amyloid-targeting Brainshuttle™ antibody specifically engineered for efficient transferrin receptor 1-mediated transport across the blood-brain barrier. Trontinemab has demonstrated robust and rapid mean amyloid plaque removal of 107 centiloids after 28 weeks of 3.6 mg/kg treatment in the Phase Ib/IIa Brainshuttle AD study (n=12; NCT04639050), coupled with a low incidence of amyloid-related imaging abnormalities (ARIA). Based on the results from the Brainshuttle AD study, to be presented at AAIC 2025 by Kulic et al., a pivotal program with trontinemab in early AD will be discussed.

METHOD: TRONTIER 1 and 2 are two identically designed global, randomized, double-blind, placebo-controlled, parallel-group Phase III studies designed to investigate the efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of trontinemab following intravenous infusion in participants with early AD who have confirmed amyloid pathology. A pre-screener study, Traveller, based on a brief clinical assessment and a plasma biomarker will also be initiated to enable broader community outreach and extend access to these trials to more diverse populations.

RESULT: The primary endpoint is the change from baseline on the Clinical Dementia Rating - Sum of Boxes at 18 months' treatment duration. Secondary outcome measures include assessments of cognition, function, behavioral symptoms, and quality of life. PD effects of trontinemab will be evaluated using amyloid and tau positron emission tomography, magnetic resonance imaging, and fluid biomarkers. Additional important objectives include assessment of safety, PK, and immunogenicity.

CONCLUSION: The recent Phase Ib/IIa interim results suggest that rapid and robust amyloid plaque clearance and fluid biomarker changes may be achieved with low ARIA incidence. The overall favorable safety and interim biomarker results to date support the rationale for moving into the pivotal Phase III studies TRONTIER 1 and TRONTIER 2. These studies will provide the opportunity to assess whether treatment with trontinemab slows disease progression in people living with early symptomatic AD.},
}

Humans
*Alzheimer Disease/drug therapy
*Drug Development
*Plaque, Amyloid/drug therapy
Randomized Controlled Trials as Topic
Double-Blind Method
Clinical Trials, Phase III as Topic
*Antibodies, Monoclonal, Humanized/therapeutic use

@article {pmid41450269,
year = {2025},
author = {Cunningham, NP and Tremblay-Mercier, J and Baril, AA and Dang-Vu, TT and Lim, A and Geddes, MR and Badawy, M and Poirier, J and Ducharme, S and Villeneuve, S and , },
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e105733},
doi = {10.1002/alz70859_105733},
pmid = {41450269},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Sleep Initiation and Maintenance Disorders/drug therapy/therapy ; Aged ; Double-Blind Method ; Middle Aged ; *Orexin Receptor Antagonists/therapeutic use ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; *Cognitive Behavioral Therapy/methods ; *Alzheimer Disease/prevention & control ; tau Proteins/blood/cerebrospinal fluid ; Aged, 80 and over ; *Drug Development ; Biomarkers/blood/cerebrospinal fluid ; *Pyridines/therapeutic use ; *Pyrimidines/therapeutic use ; },
abstract = {BACKGROUND: Poor sleep is a modifiable factor associated with the development and progression of Alzheimer's Disease (AD). Pharmacological treatments and Cognitive Behavioural Therapy for Insomnia (CBT-I) which promote sleep have the potential to improve AD risk profile. In addition, prior research suggests that Dual Orexin Receptor Antagonists (DORAs), which are prescribed more and more to treat insomnia, could also help to decrease tau phosphorylation and concentrations of beta-amyloid (Aβ) in the cerebrospinal fluid.

OBJECTIVE: To study the impact of Lemborexant, a DORA, with or without CBT-I on AD blood biomarkers and on cognitive performance in a population at risk of developing AD dementia.

METHOD: We will conduct a double-blind randomized clinical trial in men and women aged 50 to 90 years old with symptoms of insomnia. 220 participants will be screened and randomized into 4 treatment groups over 12 months: Lemborexant, Lemborexant plus CBT-I, placebo, or placebo plus CBT-I. All participants will receive education on sleep hygiene measures.

PRIMARY OUTCOMES: Change in (1) plasma p-tau181 and (2) modified Preclinical Alzheimer's Cognitive Composite score from baseline to 12-months.

SECONDARY OUTCOMES: Change in (1) plasma p-tau217, (2) CSF Aβ 42/40 and CSF p-tau181, and (3) objective sleep measures measured with electroencephalogram (EEG) recording from baseline to 12-months.

ANTICIPATED RESULTS: We anticipate that Lemborexant will be associated with a reduction in plasma p-tau181 over time compared to placebo. Lemborexant will improve sleep and cognitive performance compared to placebo, and the addition of CBT-I will accentuate the beneficial effect on sleep and cognition but not on AD biomarkers.

CONCLUSION: This study will grant us an opportunity to deepen our understanding of the therapeutic potential of sleep interventions and the influence of DORAs on AD prevention.},
}

Humans
Male
Female
*Sleep Initiation and Maintenance Disorders/drug therapy/therapy
Aged
Double-Blind Method
Middle Aged
*Orexin Receptor Antagonists/therapeutic use
Amyloid beta-Peptides/cerebrospinal fluid/blood
*Cognitive Behavioral Therapy/methods
*Alzheimer Disease/prevention & control
tau Proteins/blood/cerebrospinal fluid
Aged, 80 and over
*Drug Development
Biomarkers/blood/cerebrospinal fluid
*Pyridines/therapeutic use
*Pyrimidines/therapeutic use

@article {pmid41450262,
year = {2025},
author = {Manchanayake, DNH and Jayarathne, HSM and Sadagurski, M},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e104072},
doi = {10.1002/alz70859_104072},
pmid = {41450262},
issn = {1552-5279},
mesh = {Animals ; Mice ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Male ; *Drug Development ; Female ; Disease Models, Animal ; *Canagliflozin/pharmacology/therapeutic use ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Mice, Transgenic ; Brain/drug effects/pathology ; Amyloid beta-Peptides/metabolism ; Hippocampus/drug effects/pathology ; },
abstract = {BACKGROUND: Aging is the primary risk factor for numerous chronic diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). Current therapeutic options for AD provide limited efficacy, thus requiring novel interventions that target key molecular pathways associated with aging and neurodegeneration. Pharmacological approaches targeting these pathways have shown promise in delaying aging and extending lifespan. A diabetes drug, Canagliflozin (Cana), an FDA-approved sodium-glucose cotransporter 2 (SGLT2) inhibitor, has previously demonstrated lifespan extension in genetically diverse UM-HET3 male mice (14%) without effects in females. In aged male mice, Cana also exhibited neuroprotective properties, including improved central insulin responsiveness, reduced neuroinflammation, and enhanced locomotor activity and exploratory behavior. These results suggest that Cana has a potential for mitigating age-associated brain pathologies.

METHOD: To investigate this potential, we used a well-established model of AD, 5XFAD mice and fed them diet containing Cana (180 ppm) from 3 months of age. At 6-7 months of age, we conducted metabolic assessments and a panel of behavioral assays, followed by brain histological analysis to assess amyloid-beta (Aβ) burden, neuroinflammation, and hippocampal function.

RESULT: Cana treatment significantly improved glucose tolerance in both male and female 5XFAD mice. However, only male 5XFAD mice exhibited notable improvements in cognitive performance, including enhanced spatial memory in behavioral assays. Importantly, Cana treatment markedly reduced hippocampal Aβ plaque burden and attenuated neuroinflammation in male 5XFAD mice.

CONCLUSION: Our study highlights a novel role for SGLT2i in alleviating AD-related pathologies. Moreover, for the first time, our findings emphasize SGLT2i as promising candidates for repurposing in the treatment of neurodegenerative diseases.},
}

Animals
Mice
*Alzheimer Disease/drug therapy/pathology/metabolism
Male
*Drug Development
Female
Disease Models, Animal
*Canagliflozin/pharmacology/therapeutic use
*Sodium-Glucose Transporter 2 Inhibitors/pharmacology
Mice, Transgenic
Brain/drug effects/pathology
Amyloid beta-Peptides/metabolism
Hippocampus/drug effects/pathology

@article {pmid41450232,
year = {2025},
author = {Tallon, C and Pradel, S and Yakabi, K and Breyak, E and Gajera, C and Posakony, J and Block, G and Daggett, V},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e104011},
doi = {10.1002/alz70859_104011},
pmid = {41450232},
issn = {1552-5279},
mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Microglia/drug effects/metabolism ; Mice ; Mice, Transgenic ; *Drug Development ; Plaque, Amyloid/pathology/drug therapy/metabolism ; Disease Models, Animal ; Humans ; Macrophages/drug effects/metabolism ; Brain/drug effects/pathology/metabolism ; },
abstract = {BACKGROUND: Recent advancements in the understanding of the molecular pathophysiology of amyloid-β (Aβ) in Alzheimer's disease (AD) have identified soluble oligomers as the dominant toxic form of Aβ correlating with cognitive decline. These toxic oligomers have been observed to adopt a nonstandard secondary structure: α-sheet. SOBIN-01, has been specifically designed to target the α-sheet structure of toxic oligomers.

METHOD: Using biolayer interferometry we determined the binding affinity of SOBIN-01 to the monomeric random coil, α-sheet, and β-sheet forms of Aβ. We then examined the efficacy of fluorescently labeled α-sheet Aβ uptake in vitro in cultured microglia and macrophage cells with SOBIN-01 treatment. Finally, we measured the in vivo effects of SOBIN-01 on Aβ plaque accumulation by treating 3-month-old Tg2576 AD mice for 12 months.

RESULT: The biolayer interferometry studies demonstrated that SOBIN-01 binds tightly and preferentially to α-sheet oligomers over both random coil monomers and β-sheet protofibrils, with a 2.4x10[4]- and 1.2x10[5]-fold change, respectively. We observed enhanced phagocytosis of fluorescently labeled α-sheet Aβ in a dose-dependent manner from 0.1-10 μM SOBIN-01 in both microglia and macrophages, with a 1.9- and 3.4-fold change with 10 μM treatment, respectively. We then examined whether SOBIN-01 would have effects on Aβ accumulation in the Tg2576 AD mouse model and observed a significant reduction in the percent plaque area in the brains of SOBIN-01 treated animals.

CONCLUSION: SOBIN-01 is a highly specific peptide that targets the α-sheet conformation of Aβ and leads to enhanced phagocytosis by microglia and macrophage cells. In vivo SOBIN-01 demonstrated a significant reduction in plaque area in Tg2576 AD mice. Together, these data suggest that SOBIN-01 targets and stimulates the clearance of Aβ toxic oligomers.},
}

Animals
*Amyloid beta-Peptides/metabolism
*Alzheimer Disease/drug therapy/pathology/metabolism
Microglia/drug effects/metabolism
Mice
Mice, Transgenic
*Drug Development
Plaque, Amyloid/pathology/drug therapy/metabolism
Disease Models, Animal
Humans
Macrophages/drug effects/metabolism
Brain/drug effects/pathology/metabolism

@article {pmid41450230,
year = {2025},
author = {Dos Santos Silva, KG and Souza, VF and Alves, GLF and Oliveira, CR},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103969},
doi = {10.1002/alz70859_103969},
pmid = {41450230},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Genistein/therapeutic use/pharmacology ; Randomized Controlled Trials as Topic ; *Drug Development ; Prodromal Symptoms ; *Phytoestrogens/therapeutic use ; Amyloid beta-Peptides/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease, the most prevalent cause of dementia globally, imposes a tremendous public health burden, with cases projected to triple by 2050. Among potential therapeutic avenues, genistein - a phytoestrogen with antioxidant and anti-inflammatory Properties - has garnered attention for its role in modulating amyloidβ deposition and promoting neuronal survival. This systematic review aims to evaluate its efficacy in the prodromal phase of Alzheimer's disease, a critical window for intervention.

METHOD: This study is a systematic review of randomized clinical trials on the effect of genistein in the prodromal phase of Alzheimer's disease. The search strategy involved an active search in the Medline and Lilacs databases, using the term "Genistein" associated with "Alzheimer's disease" by the Boolean operator "AND." Filters were applied for randomized clinical trials published in English and Spanish, with articles dated up to 15 years ago. Trials were included if they evaluated genistein in participants diagnosed with prodromal Alzheimer's disease according to standardized criteria (e.g., Dubois). The identified articles were assessed by two independent reviewers. Risk of bias was assessed using the Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2.0).

RESULT: In total, three (3) clinical trials were evaluated (Figure 1). The study by Gleason et al. (2015) revealed an association between plasma levels of isoflavones and speed, dexterity and verbal fluency (Figure 2). The analysis of beta-amyloid deposition carried out in the study by Viña et al. (2022) showed that patients treated with genistein did not increase their uptake in the anterior cingulate gyrus after treatment (p = 0.878), while those treated with placebo increased it (p = 0.036). Finally, the study by Wang et al (2020) shows that Genistein preserved cognitive function in verbal learning and executive function.

CONCLUSION: Genistein has been shown to improve cognitive function and reduce beta-amyloid deposition in patients with prodromal Alzheimer's disease. However, small sample sizes and variability in dosages limit the generalizability of these findings. Future trials with larger cohorts and standardized protocols are needed to validate these results.},
}

Humans
*Alzheimer Disease/drug therapy
*Genistein/therapeutic use/pharmacology
Randomized Controlled Trials as Topic
*Drug Development
Prodromal Symptoms
*Phytoestrogens/therapeutic use
Amyloid beta-Peptides/metabolism

@article {pmid41450221,
year = {2025},
author = {Zetterberg, H},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103313},
doi = {10.1002/alz70856_103313},
pmid = {41450221},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/metabolism ; *Alzheimer Disease/metabolism/pathology/diagnostic imaging ; Male ; Aged ; Female ; *Nerve Tissue Proteins/metabolism ; *Brain/metabolism/pathology ; Aged, 80 and over ; *Membrane Glycoproteins/metabolism ; Synapses/metabolism ; Middle Aged ; Mass Spectrometry ; },
abstract = {BACKGROUND: SV2A levels are decreased in Alzheimer's disease (AD) brains, as revealed by Positron Emission Tomography (PET). Whether this decrease is due to synapse loss or SV2A protein loss remains unclear, hindering treatment development and interpretation of SV2A PET as a biomarker for neurodegenerative diseases. To address this, we examined synaptic enriched fractions and crude homogenates from post-mortem brain tissue.

METHODS: Targeted mass spectrometry was performed on individual post-mortem entorhinal cortex (EC), cerebellum, and centrum semiovale tissue from control (Braak stage 0-II; n = 23), early-AD (Braak III-VI; n = 21) and AD (Braak V-VI; n = 25) cases. Detergent soluble proteins from total homogenate and synaptoneurosome fractions were digested, desalted and quantified with high flow liquid chromatography and selected reaction monitoring on a 6495 Triple Quadrupole LC/MS system (Agilent Technologies). A panel of 31 synapse associated proteins was measured including SV2A, neurogranin, AP2B1, complexin-1 and -2, synaptophysin, SNAP-25, syntaxin-1A and B, β-synuclein, and NPTX1, NPTX2 and NPTXR. Quality control samples, consisting of homogenate pools, were injected periodically to monitor assay performance.

RESULTS: We found SV2A enriched in the synaptoneurosome fractions compared to total homogenates and lower levels were evident in centrum semiovale as expected. Furthermore, SV2A levels correlated strongly with synaptophysin and previously described interaction partner synaptotagmin-1 and the SNARE complex proteins. Preliminary analysis showed no significant differences between control, early AD and AD groups in the amount of SV2A protein in the synaptoneurosome fraction, and indicate a trend toward reduction of SV2A protein in AD total homogenates.

CONCLUSIONS: These data are consistent with the reduction in SV2A PET signal in AD reflecting loss of synapses rather than loss of protein in remaining synapses. These data form part of the SV2A PET Project, a program of the FNIH Biomarker Consortium which together aim to understand the biological underpinnings of the change in SV2A PET signal in AD.},
}

Humans
*Biomarkers/metabolism
*Alzheimer Disease/metabolism/pathology/diagnostic imaging
Male
Aged
Female
*Nerve Tissue Proteins/metabolism
*Brain/metabolism/pathology
Aged, 80 and over
*Membrane Glycoproteins/metabolism
Synapses/metabolism
Middle Aged
Mass Spectrometry

@article {pmid41450198,
year = {2025},
author = {Soria-Lopez, J and Bueno, L and Gaudia, J and Ochoa-Cipes, S and Romero, U and Asencio, C and McGehrin, K and Hall, J and Huisa, B},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e104139},
doi = {10.1002/alz70858_104139},
pmid = {41450198},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/drug therapy/psychology/diagnosis ; Aged ; Aged, 80 and over ; California ; },
abstract = {BACKGROUND: Disease-modifying therapies, such as anti-amyloid monoclonal antibodies, have emerged as treatment options to slow cognitive and functional decline in early Alzheimer's Disease (AD). These therapies require careful implementation in community clinics, with considerations including patient selection, timely access to therapy, and monitoring for adverse events. Therefore, the development of Key Performance Indicators (KPIs) is crucial to ensure the effective delivery of these novel treatments and to improve outcomes in real-world settings.

METHODS: We developed a clinical program for diagnosing and treating early AD within community clinics in Southern California. Patients confirmed to have early-stage AD were offered access to disease-modifying therapy with anti-amyloid monoclonal antibody, administered through in-clinic based infusion centers. Additional patients were enrolled and monitored while receiving treatment at external infusion centers. KPIs relevant to patient care were identified. Demographic and clinical data were analyzed using non-parametric statistical tests and regression analyses to assess the utility of these KPIs in guiding clinical practice.

RESULTS: Between April 2023 and December 2024, a total of 506 patients were enrolled in the program. Among them, 108 received treatment, 140 were pending treatment, and 258 were disqualified. Key metrics included: Negative AD Biomarker Rate: Percentage of patients with negative AD specific biomarker results as the reason for disqualification of treatment. Treatment Rate: Percentage of eligible patients receiving therapy, analyzed independently of insurance coverage. Door-to-Treatment Time: Time from first clinical evaluation to first infusion treatment. Dropout Rate: Proportion of patients discontinuing therapy. Rates of Amyloid Related Imaging Abnormalities (ARIA) CONCLUSIONS: The evaluation and treatment of early Alzheimer's disease with anti-amyloid monoclonal antibody therapy is both feasible and safe within community neurology clinics. Streamlined triaging, simplified care coordination, and rigorous quality and safety monitoring are critical for success. Monitoring key performance indicators-including 1) Negative AD Biomarker Rate, 2) Treatment Rate, 3) Door-to-Treatment time, 4) Dropout Rate, and 5) ARIA rates-facilitates the standardization and scalability of care delivery. These KPIs offer a structured approach to optimizing treatment outcomes and broadening access to disease-modifying therapies in real-world settings.},
}

Humans
Male
Female
*Alzheimer Disease/drug therapy/psychology/diagnosis
Aged
Aged, 80 and over
California

@article {pmid41450183,
year = {2025},
author = {Raychaudhuri, U and Tang, C and Singh, H and Seyedmohammadlou, M and Park, SJ and Rose, MF and Spada, AR},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e104518},
doi = {10.1002/alz70859_104518},
pmid = {41450183},
issn = {1552-5279},
mesh = {Animals ; Mice ; Disease Models, Animal ; *Drug Development ; *Tauopathies/drug therapy/genetics ; Mice, Transgenic ; Maze Learning/drug effects ; Male ; Alzheimer Disease/drug therapy ; tau Proteins/metabolism/genetics ; },
abstract = {BACKGROUND: Elevated levels of ptau (phosphorylated tau) is directly correlated with neurodegeneration and neuropathogenesis in Alzheimer's disease(AD). The presence of ApoE allele is a significant genetic risk factor for the progression of AD. PPAR-δ, a nuclear receptor highly expressed in CNS neurons, regulates metabolic processes that helps boost mitochondrial function and improve quality protein control; processes that deteriorate as neurodegeneration progresses. This makes PPAR-δ an appealing candidate for neurodegenerative diseases such as Alzheimer's. Here we access the effect of PPAR-delta agonist, T3D, on a mouse model of tauopathy P301S/E4 against a saline control group.

METHOD: T3D was administered intraperitoneally at 50mg/kg/day, 3 days a week from ∼4 to ∼11 month of age. Neurological testing was performed every alternate month. Behavior studies such as Object Recognition Memory test (ORM), Object Location Memory (OLM), and Y maze studies were conducted at 7, 9 and 11 months.

RESULT: The weight of T3D-959 treated mice appear to deteriorate less compared to saline treated mice. Not much difference was seen in the overall neurological exam scores. In behavioral studies, T3D-959 treated mice subjected to OLM performed the long-term memory task significantly better compared to saline treated mice. Significant superior performance of the T3D-959 treated mice were observed at 11 months of age (p=0.02, n=5 per group, two-tailed t-test; error bars = s.e.m.), indicative of better long-term hippocampal memory function upon treatment with T3D-959. There was no significant difference in the ORM and Y-maze test.

CONCLUSION: OLM testing evaluates dorsal hippocampus long term memory function and is transcription based. Y-maze is non-transcription based and studies short-term memory function and spatial recognition. Several relevant brain regions, including the entorhinal cortex and ventromedial prefrontal cortex, are required for ORM. Significantly higher discrimination index (DI) scores were observed with OLM testing at 11 months of age in the T3D-959 treatment group compared to saline, which demonstrates that T3D rescues hippocampal long term memory function better than saline. This is a potentially important finding that indicates that T3D-959 can impact the hippocampus to preserve long term memory function.},
}

Animals
Mice
Disease Models, Animal
*Drug Development
*Tauopathies/drug therapy/genetics
Mice, Transgenic
Maze Learning/drug effects
Male
Alzheimer Disease/drug therapy
tau Proteins/metabolism/genetics

@article {pmid41450130,
year = {2025},
author = {Wu, XY and Li, LY and Park, E and He, C and Abbasi, AZ and Ahmed, T and Fraser, PE and Rauth, AM and Henderson, JT},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103999},
doi = {10.1002/alz70859_103999},
pmid = {41450130},
issn = {1552-5279},
mesh = {Animals ; *Brain-Derived Neurotrophic Factor/pharmacology/administration & dosage ; Mice ; *Alzheimer Disease/drug therapy ; *Neuroprotective Agents/pharmacology ; Mice, Transgenic ; Neurons/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; Amyloid beta-Peptides ; Humans ; Hippocampus/drug effects ; },
abstract = {BACKGROUND: Up to date, Alzheimer's disease (AD) has very limited disease-modifying treatment. With respect to neuroprotection, brain-derived neurotrophic factor (BDNF) has been shown to promote the survival and synaptic plasticity of glutamatergic and GABAergic neurons in brain regions associated with cognitive and emotive decline relevant to AD. However, the poor blood-brain barrier (BBB) permeability and pharmacokinetic properties of BDNF limit its utilization as a neuroprotective treatment. Herein we aim to design a new BDNF nanocarrier system using a novel BBB-permeable terpolymer (BDNF-TPN) and investigate its neuroprotective effect in neurones and AD mice.

METHOD: Bioactivity of the BDNF-TPN was first evaluated in vitro using the SH-SY5Y cell differentiation assay. The protective effects of BDNF-TPN on primary murine hippocampal neurons were assessed following exposure to Aβ. The BDNF delivery and expression in the brain following IV injection were examined by ELISA and confocal microscopy. The biodistribution and safety were evaluated via hematologic, clinical biochemical, immunotoxicity and histology tests in APP transgenic TgCRND8 AD mice and CD-1 mice. The effects of the treatment were evaluated in AD mice via immunohistochemistry, ELISA and behavioral test after 4-week IV treatment (weekly, 1 mg BDNF/kg b.w.).

RESULT: The BDNF-TPN maintained BDNF bioactivity and rescued Aβ42 toxified primary neurons in vitro. Biomarker studies demonstrated BDNF-mediated neuroprotective signaling in transgenic mice following IV treatment using BDNF-TPN. Compared to free BDNF, BDNF-TPN significantly reduced reactive microglia and astrocytes and apoptosis of neurons. The pAKT level increased more than 2-fold in BDNF-TPN-treated group compared to vehicle and free BDNF treated groups. Synaptophysin, a marker for synaptic plasticity and integrity, was profoundly increased. The improved hippocampal-dependent contextual learning in the AD mice was observed. There was not detectable toxicity following the BDNF-TPN treatment.

CONCLUSION: Our findings suggest BDNF-TPN is a promising treatment for reducing neuroinflammation, apoptosis and programmed cell death in AD mouse brains, while improving synaptic plasticity and cognitive function. Reference 1. Zhang W, et al. Sig Transduct Target Ther 2023, 8, 267. 2. He C, et al. Nano Today. 2020;35:100965. 3. Park E, et al. Advanced Science. 2023, 10(12):2207238. 4. Park E, et al. Biomaterials. 2025 Jan 24:123142.},
}

Animals
*Brain-Derived Neurotrophic Factor/pharmacology/administration & dosage
Mice
*Alzheimer Disease/drug therapy
*Neuroprotective Agents/pharmacology
Mice, Transgenic
Neurons/drug effects
Blood-Brain Barrier/metabolism/drug effects
Disease Models, Animal
Amyloid beta-Peptides
Humans
Hippocampus/drug effects

@article {pmid41450125,
year = {2025},
author = {Lee, L and Hempel, E and Leach, JM and Kern, R},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e105986},
doi = {10.1002/alz70859_105986},
pmid = {41450125},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Male ; Female ; *Drug Development ; Aged ; Caregivers/psychology ; Treatment Outcome ; Neuropsychological Tests ; },
abstract = {BACKGROUND: The OVERTURE (NCT03556280) randomized controlled trial (RCT) evaluated Spectris[TM] in mild-moderate Alzheimer's disease (AD)[1], and collected functional and cognitive outcomes using several validated, clinically relevant instruments. Spectris was associated with significant improvements in ADCS-ADL and MMSE relative to sham treatment. Linking validated clinical trial measures with outcomes most important to patients and their caregivers is crucial in understanding how well therapies may address patient and family treatment goals. Recent, published studies revealed 42-concepts that matter most to patients and caregivers in their management of AD (What Matters Most [WMM]).[2] This research approach revealed specific symptoms, impacts and outcomes most important to patients and caregivers. For example, the desire to maintain independence (eg. taking medications correctly), physical and mental health (eg. not feeling down or depressed), and safety were identified as extremely important.[2] The 42-items were mapped to individual queries within assessments commonly used in AD clinical trials.[2] Herein, we report the results of active and sham treated participants on WMM concepts mapped to instruments used in the Overture study.

METHOD: Individual items in the ADCS-ADL, MMSE, ADAS-Cog, CDR and NPI collected in the Phase 2 Overture study were mapped to each of the 42-WMM concepts (except #7), adapted from previously described studies.[3] Mean changes from baseline at Month 6 of each WMM were compared between active and sham groups using T-Test. An overall score encompassing all improvement measures was also compared (active vs sham) by T-Test.

RESULT: Of the 42 WMM concepts described in the literature, 41 were evaluable using instruments used in the Overture study. Twelve of 41 individual WMM concepts (29%) evaluated demonstrated a statistically significant difference (p < 0.05) in favor of active treatment. An exploratory evaluation of mean change from baseline summarizing improvements of the 41 individual components was -0.59 for active compared to -15.12 for sham treated participants (p=0.0006).

CONCLUSION: Consideration of outcomes important to patients and their caregivers are important in assessing overall efficacy of AD therapies. Initial analysis of 41 WMM components explored the feasibility of developing a WMM scale demonstrated through application of Overture data, a step towards developing patient-centric scales.},
}

Humans
*Alzheimer Disease/drug therapy/psychology
Male
Female
*Drug Development
Aged
Caregivers/psychology
Treatment Outcome
Neuropsychological Tests

@article {pmid41450116,
year = {2025},
author = {Chambers, L and Sivananthan, S and Whate, A and Raju, K and Ménard, A},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e103688},
doi = {10.1002/alz70858_103688},
pmid = {41450116},
issn = {1552-5279},
mesh = {Humans ; *Dementia/therapy/psychology ; *Delivery of Health Care ; Canada ; },
abstract = {Dementia care pathways are important tools that help standardize care, improve patient outcomes, and support both clinicians and individuals living with dementia. We analyzed dementia strategies in countries with healthcare systems similar to Canada's. Our research reviewed WHO member states' dementia plans, reports from Alzheimer's Disease International, and other global databases. We focused on countries with federated health systems, similar resources, and comparable insurance models. We assessed strategies based on governance, funding, accountability, and clearly defined goals. Strong leadership and governance are essential for effective implementation of dementia care pathways. A central organization should oversee coordination while ensuring all levels of government have clear roles and responsibilities. A well-structured implementation plan should outline key initiatives, target populations, and measurable outcomes. Adequate funding, staffing, and infrastructure are necessary to support these efforts. While long-term financial investment is critical, having a trained workforce with the capacity to implement changes is equally important. Collaboration across different levels of government and stakeholder buy-in are also essential to ensure success. Accurate data systems help track progress, enabling real-time monitoring and public reporting. Regular evaluations allow for adjustments and improvements. Canada must develop a strong implementation plan to provide effective dementia care pathways. By learning from other countries, setting clear targets, and improving coordination, Canada can improve dementia care, treatment, and prevention nationwide.},
}

Humans
*Dementia/therapy/psychology
*Delivery of Health Care
Canada

@article {pmid41450101,
year = {2025},
author = {do Prado Mascarenhas, FA and Santos, ACC and Rodrigues, TS and Malta, SM and Bernardes, LMM and Silva, MH and Zanon, RG and Ueira-Vieira, C and Mendes-Silva, AP},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103660},
doi = {10.1002/alz70859_103660},
pmid = {41450101},
issn = {1552-5279},
mesh = {Humans ; *Amyloid beta-Peptides/metabolism ; Cell Survival/drug effects ; *Neurons/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Development ; *Kefir ; Peptide Fragments/pharmacology ; Plaque, Amyloid/pathology ; Cell Line, Tumor ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in older adults. The amyloidogenic hypothesis, the leading theory explaining this condition, describes the extracellular buildup of amyloid beta (Aβ) peptides. Kefir, a fermented dairy product, has gained prominence in the literature due to its health benefits, including modulating the intestinal microbiota. This modulation is particularly relevant as the gut-brain axis plays a critical role in influencing neuronal survival and inflammatory processes. In this study, we evaluate the effect of four kefir peptides with high homology to the human Aβ 1-42 peptide domain on neuron viability using an in vitro model of Aβ aggregation.

METHODS: Four kefir peptides (PW, M11, M20, and M25) were selected from our previous in silico findings and synthesized. We used the human neuronal cell line, SH-SY5Y, to standardize two experimental approaches to evaluate the effect of kefir peptides on cell viability before and after senile plaque formation. Amyloid beta peptide [886 μM] was diluted to 1 μM and followed by two models, one of incubation together with kefir peptides and then added to the cells, and another of incubation and addition to the cells, promoting senile plaque formation, to later be treated with kefir peptides. After the treatment period, cell viability was evaluated by the AlamarBlue assay (Invitrogen®) and oxidative stress by DCFH-DA staining (Cayman Chemical®). Statistical analysis by Student's t-test (GraphPad Prism v9.0) (p ≤ 0.05).

RESULTS: Peptides M11, M20 and M25 significantly increased neuronal viability when administered simultaneously with amyloid beta before senile plaque formation, while PW did not show a significant effect. Regarding viability after senile plaque formation, all peptides studied showed an increase when compared to the control groups. Both peptides also showed potential to attenuate intracellular oxidative stress when administered before or after senile plaque formation.

CONCLUSIONS: In general, kefir peptides increased neuronal viability and attenuated intracellular oxidative stress before and after senile plaque formation. These findings suggest that kefir peptides may offer neuroprotective benefits in the context of Alzheimer's disease.},
}

Humans
*Amyloid beta-Peptides/metabolism
Cell Survival/drug effects
*Neurons/drug effects
*Alzheimer Disease/drug therapy/metabolism
*Drug Development
*Kefir
Peptide Fragments/pharmacology
Plaque, Amyloid/pathology
Cell Line, Tumor

@article {pmid41450094,
year = {2025},
author = {Martens, YA and Samsel, J and Curtis, ME and Park, Y and Li, Z and Chen, K and An, G and Li, M},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e107093},
doi = {10.1002/alz70859_107093},
pmid = {41450094},
issn = {1552-5279},
mesh = {Humans ; *Amyloid beta-Peptides/metabolism/immunology ; *Alzheimer Disease/drug therapy/pathology ; *Drug Development ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; Animals ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in aged individuals. Given the central role of Aβ aggregation in AD, therapeutic strategies have focused on targeting Aβ to promote its clearance. Recent advances highlighted the need for antibodies with high selectivity for aggregated forms of Aβ, such as soluble Aβ (sAβ) aggregates and fibrils, while minimizing binding to monomeric Aβ. Monoclonal antibodies which selectively target aggregated forms of Aβ or amyloid aggregates which contain pyroglutamate modified Aβ have shown promising results in clinical trials, leading to their FDA approval despite the concerns for increased risks for vascular-related side effects in certain groups of patients. However, there remains an ongoing need for more potent binding agents that selectively target aggregated forms of Aβ peptides and can be used for the diagnosis, prevention, and treatment of AD and other disorders characterized by Aβ aggregation.

METHOD: Here, we describe the development of SNP234, a highly selective monoclonal antibody against sAβ aggregates that is more potent than currently available anti-amyloid therapeutic antibodies. Its binding affinities to different species of Aβ were assessed using direct and competition binding assays. Human AD brain sections were used to assess its binding to endogenous, disease-associated Aβ plaques. The antibody-mediated Aβ clearance activity of SNP234 was also investigated.

RESULT: SNP234 was one of several novel antibodies identified with high selectivity, exhibiting sub-nanomolar affinity, for sAβ aggregates while maintaining low binding to monomer Aβ. It displayed excellent developability profiles amicable for subQ formulation. SNP234 binds robustly to disease-associated amyloid and is efficacious in removing human amyloid plaques.

CONCLUSION: SNP234 demonstrates high selectivity against toxic form of Aβ and promotes efficient removal of disease-associated Aβ. These findings support further development of SNP234 as a potential next generation best-in-class anti-amyloid immunotherapy agent with subcutaneous administration.},
}

Humans
*Amyloid beta-Peptides/metabolism/immunology
*Alzheimer Disease/drug therapy/pathology
*Drug Development
*Antibodies, Monoclonal/therapeutic use/pharmacology
Animals

@article {pmid41450078,
year = {2025},
author = {Sabbagh, MN and Gabelle, A and Grimmer, T and Villa, L and Gordon, E and Borrot, M and Gueddou, A and Guizard, N and Courreges, O and Jin, K and Chezem, WR and Lopez-Talavera, JC and Missling, CU},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106527},
doi = {10.1002/alz70859_106527},
pmid = {41450078},
issn = {1552-5279},
mesh = {Humans ; *Receptors, sigma/genetics ; *Drug Development ; *Alzheimer Disease/drug therapy/genetics ; Sigma-1 Receptor ; *Precision Medicine ; },
abstract = {BACKGROUND: Precision Medicine represents a transformative approach in treating Alzheimer's disease (AD), focusing on tailoring interventions based on individual genetic, molecular, clinical and environmental profiles in addition to confirm clear Mechanism of Action (MoA). This strategy aims to optimize treatment outcomes by identifying patient subgroups that are most likely to benefit or benefit at a higher degree from specific therapies, thus reducing inefficacies and potentially adverse effects associated with generalized treatment regimens.

METHOD: Blarcamesine, a selective modulator of the Sigma-1 receptor (SIGMAR1), has garnered attention due to its role in autophagy, cellular stress response, protein homeostasis, and neuroprotection. Recent clinical studies have confirmed its effects in the majority of AD patients who carry the homozygous wild-type (WT) SIGMAR1 genotype (∼70% of the whole population) (Hampel et al., 2020).

RESULT: In the Phase IIb/III ANAVEX2-73-AD-004 trial, a clear MoA of oral once daily blarcamesine, a pre-specified efficacy analysis confirmed the importance of SIGMAR1 to clinical response. While all trial participants improved significantly versus placebo after 48 Weeks, 36.3% for ADAS-Cog13 and 27.6% for CDR-SB, respectively, a further, also significant, improvement was observed in the prespecified analysis of SIGMAR1 carriers. Compared to the ITT group, participants carrying the SIGMAR1 WT gene observed further improvement versus placebo of 49.8% and 33.7% for the primary and secondary key endpoints ADAS-Cog13 and CDR-SB, respectively (Macfarlane et al., 2025).

CONCLUSION: Thus, the specificity of blarcamesine to this genotype underscores the importance of understanding clear MoA and potential for further improved personalized medicine in AD treatment, as therapies targeting individual molecular profiles could achieve more substantial and sustained benefits. While Precision Medicine holds great promise for improving the treatment paradigm of AD by offering more personalized, likely more effective therapies, it also introduces challenges related to potential cost, data privacy, ethical concerns, and inequities in access. Addressing these issues is crucial to ensure that the benefits of Precision Medicine can be realized for all patients.},
}

Humans
*Receptors, sigma/genetics
*Drug Development
*Alzheimer Disease/drug therapy/genetics
Sigma-1 Receptor
*Precision Medicine

@article {pmid41450074,
year = {2025},
author = {Botton, LP and da Silva, MRA and de Oliveira Felício, A and Bahlis, BS and Faresin, E and Garrafiel, FN and Lazzaretti, FJ and Patatt, J and Aguzzoli, C and Schilling, LP},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e107388},
doi = {10.1002/alz70858_107388},
pmid = {41450074},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Retrospective Studies ; Aged ; *Frontotemporal Dementia/drug therapy/psychology/mortality ; *Antipsychotic Agents/therapeutic use ; Middle Aged ; *Benzodiazepines/therapeutic use ; },
abstract = {BACKGROUND: Frontotemporal dementia (FTD) is characterized by a progressive decline in behavior, executive functions, and/or language. Besides the inexistence of disease-modifying treatments for FTD, benzodiazepines, typical antipsychotics, and Alzheimer's drugs are avoided due to ineffectiveness or harm. This study aims to identify the most commonly prescribed medications following an FTD diagnosis and compare clinical outcomes.

METHOD: We conducted a retrospective study using data from TriNetX, a global health research network dataset from real-world clinical settings. We included 150 individuals diagnosed with probable FTD within the last five years from 42 health centers, excluding those with other neurodegenerative conditions. All individuals underwent neuroimaging. We conducted logistic regression models and Kaplan-Meier analysis to investigate the association and survival between medications and clinical outcomes.

RESULT: Results showed that 144 (96%) patients came from U.S. healthcare centers. 100 individuals (67%) either received no pharmacological treatment post-diagnosis or received medications not included in the analysis (Table 1). Benzodiazepines were the most prescribed drug class (25 individuals) and the most frequent first-line treatment, followed by atypical antipsychotics (12) and Alzheimer's medications (9). All patients who received Alzheimer's medications had them prescribed as a first line of treatment strategy. Logistic models indicated an elevated risk of either hospitalization, emergency department visit, or critical care needs for individuals treated with benzodiazepines, typical antipsychotics, or Alzheimer's drugs (OR 4.1; 95% CI: 1.8-8.9, p = 0.0002) compared to those individuals not on these treatments. Survival analysis further revealed a significant difference in survival between groups (HR 3.05 95% CI: 1.886-4.931, p <0.0001; Figure 2).

CONCLUSION: Individuals treated with benzodiazepines, typical antipsychotics, or Alzheimer's medications present a higher risk of hospitalization or critical care needs and poorer survival outcomes. Altogether, these findings suggest that these medications may be associated with adverse healthcare outcomes and reduced survival in this population. Better-informed prescribing practices could lead to more effective patient care, brain health equity, and improved outcomes in FTD treatment.},
}

Humans
Male
Female
Retrospective Studies
Aged
*Frontotemporal Dementia/drug therapy/psychology/mortality
*Antipsychotic Agents/therapeutic use
Middle Aged
*Benzodiazepines/therapeutic use

@article {pmid41450072,
year = {2025},
author = {Dayley, CW and Dickson, SP and Hendrix, K and Mallinckrodt, C and Hendrix, SB},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103871},
doi = {10.1002/alz70859_103871},
pmid = {41450072},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Disease Progression ; *Drug Development ; Treatment Outcome ; },
abstract = {BACKGROUND: Clinical trials aim to address three critical questions: the statistical significance of a treatment effect, the magnitude of that effect, and whether that effect is clinically meaningful. Symptomatic treatment effects can be assessed with actual point changes, or standardized changes (Cohen's D) on clinical scales. However, in the context of progressive diseases like Alzheimer's Disease (AD), the percentage slowing approach can clarify the interpretation of treatment effects. This metric assesses the rate of disease progression observed in the placebo arm and the extent to which treatment slows that progression.

METHOD: We extracted placebo progression data from early, mild, and moderate AD studies for ADAS-Cog scores up to 18 months. Theoretical percent slowing effects were applied to the observed progression rates. This allowed us to evaluate the absolute and standardized treatment differences within each population for similar disease slowing, highlighting how the magnitude of these effects varies depending on disease stage.

RESULT: Assuming an equal percent slowing across the populations, much larger point differences (170%) were seen in the moderate AD population compared to the early AD population (see Figure). The mild AD population demonstrates a slight increase in progression when compared to the early AD population. Despite these differences in progression, all three populations exhibit a comparable increase in the variance of change over the 18-month observation period, meaning that the Cohen's D values are dramatically different in these scenarios. The contrast of these results originates from the difference in disease progression between the different populations. As such, using percent slowing to evaluate treatment efficacy in the slow development phase provides a clearer picture of the true underlying story.

CONCLUSION: Observed treatment effects must always be interpreted in the context of the specific population in which they are measured or they may be misinterpreted. Using rate of placebo progression to standardize a treatment effect allows evaluation of disease slowing effects in early disease. Without this change of perspective, we are likely to undervalue disease-modifying treatment effects that may significantly improve the lives of patients in early stage, and overvalue symptomatic effects that are often observed in later stages.},
}

Humans
*Alzheimer Disease/drug therapy
Disease Progression
*Drug Development
Treatment Outcome

@article {pmid41450068,
year = {2025},
author = {Tutubala, TE and , },
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106679},
doi = {10.1002/alz70859_106679},
pmid = {41450068},
issn = {1552-5279},
mesh = {Nanoparticles/chemistry ; *Drug Development ; Blood-Brain Barrier/drug effects/metabolism ; Poloxamer/chemistry ; Polyesters/chemistry ; Chitosan/chemistry ; Humans ; *Neuroprotective Agents ; *Alzheimer Disease/drug therapy ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) presents a significant challenge due to limited treatment options that only provide symptomatic relief. A promising approach is the development of multifunctional agents capable of halting AD's degenerative processes. One such agent, the edaravone-N-benzyl pyridium hybrid (EBPD), designed by our group, has demonstrated neuroprotective properties. However, EBPD faces solubility, stability, and blood-brain barrier (BBB) permeability issues. To address these challenges, this study aims to synthesize and characterize EBPD encapsulated in chitosan (CS)-coated polycaprolactone (PCL) and Poloxamer 188 (P188) nanoparticles (NPs), aiming to enhance EBPD stability, solubility, and BBB permeability for AD treatment.

METHOD: PCL-EBPD and P188-EBPD CS-coated NPs were prepared using emulsion-solvent evaporation and self-assembly methods, respectively, and characterized for size, polydispersity index(PDI), and zeta potential using Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM), High-performance liquid chromatography (HPLC) was used to determine drug concentration, drug load, and encapsulation efficiency. Further characterization, including chemical interactions, thermal stability, and crystallinity, was performed using Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and Powder X-ray Diffraction (PXRD), respectively.

RESULT: DLS analysis revealed PCL-EBPD-CS and P188-EBPD-CS NPs had sizes of 400-600 nm, PDI values of 0.154-0.3, and zeta potentials of +15 - +17 mV, indicating uniform distribution, stability, and potential for enhanced BBB penetration. SEM analysis confirms smooth, uniform surfaces, suggesting reduced immune recognition and efficient encapsulation. HPLC analysis confirm EBPD 's tautomeric nature, while FTIR analysis showed successful encapsulation without chemical interactions. DSC analysis indicated thermal stability and PXRD analysis confirmed the amorphous nature of encapsulated EPD, with changes in the angle θ supporting disrupted crystallinity.

CONCLUSION: In conclusion, NPs were successfully synthesized and characterized, demonstrating stability, efficient EBPD encapsulation, and potential for BBB permeation. Future studies will evaluate drug release, loading efficiency, cytotoxicity, and BBB permeability using bend5 cells to validate their therapeutic potential for AD treatment.},
}

Nanoparticles/chemistry
*Drug Development
Blood-Brain Barrier/drug effects/metabolism
Poloxamer/chemistry
Polyesters/chemistry
Chitosan/chemistry
Humans
*Neuroprotective Agents
*Alzheimer Disease/drug therapy

@article {pmid41450039,
year = {2025},
author = {Evans, EE and Fisher, TL and Mishra, V and Balch, L and Gersz, EE and Howell, A and Kirk, R and Gil-Moore, M and Mallow, CL and Foster, A and Porsteinsson, AP and Feigin, A and Zauderer, M},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103679},
doi = {10.1002/alz70859_103679},
pmid = {41450039},
issn = {1552-5279},
mesh = {Humans ; Animals ; *Drug Development ; *Alzheimer Disease/drug therapy ; Mice ; *Semaphorins/antagonists & inhibitors ; },
abstract = {BACKGROUND: Semaphorin 4D (SEMA4D, CD100) and its receptors Plexin B1, B2 have been identified in multiple transcriptomic/genomic studies as a key signaling pathway associated with reactive gliosis and disease risk in Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis, and vascular dementia. Our lab has reported that SEMA4D protein is upregulated in diseased neurons and activates astrocytes via receptor binding, resulting in downregulation of metabolic transporters and release of inflammatory cytokines. In a completed randomized Phase 2 study in HD (NCT02481674), SEMA4D blocking antibody pepinemab prevented metabolic decline in glucose uptake (FDG-PET) reduced plasma GFAP, biomarkers of astrogliosis, and slowed cognitive decline employing multiple cognitive scales. Mechanistic and clinical studies investigate pepinemab effects on changes associated with reactive gliosis, neuroinflammation, and cognitive decline.

METHOD: Effects of SEMA4D blockade on neuropathology, behavior, and vascular integrity were evaluated in a mouse model of HD (Hu97/18) and an in vitro brain chip model. In the phase 1b/2 SIGNAL-AD trial (NCT04381468), 50 individuals with mild AD dementia (MMSE 17-26) were treated for 12 months with pepinemab (40 mg/kg) or placebo, Q4W, IV infusion. Key objectives included safety, cognition, and biomarker assessments.

RESULT: In preclinical disease models, SEMA4D blocking antibody reduced astrocyte and microglial activation markers, increased synaptic markers, and improved deficits in spatial learning and memory. In a human brain chip model, pepinemab restored α-synuclein-induced disruption of vascular integrity. Evaluation of amyloid-induced damage in the brain chip model is ongoing. In SIGNAL-AD, pepinemab was well-tolerated and meaningful improvements in cognitive assessments were observed in the MCI-early AD subgroup (>70% slowing of cognitive decline in CDR-SB, iADRS, and ADAS-Cog13). O-link proteomic analysis of CSF revealed treatment-related reductions in biomarkers associated with reactive astrocytes (GFAP), microglia clearance (LILRB4, MARCO), and tau pathology (GAP-43 and SNAP25).

CONCLUSION: Given the many physiological parallels between glial activation and inflammatory processes in HD and AD, results from these studies suggest that preventing astrocyte activation and reducing brain inflammation and associated vascular disruption with pepinemab treatment could be an attractive alternative or complement to anti-Aβ antibodies and support the broad application of glial regulators to treat cognitive dysfunction and neurodegenerative disease.},
}

Humans
Animals
*Drug Development
*Alzheimer Disease/drug therapy
Mice
*Semaphorins/antagonists & inhibitors

@article {pmid41450009,
year = {2025},
author = {Gareri, P and Pagano, L and Lercara, E and Covello, LB and Rocca, F and Gareri, I and Armeli, C},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e102220},
doi = {10.1002/alz70858_102220},
pmid = {41450009},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Caregivers/psychology ; Aged ; *Dementia/psychology/nursing ; Activities of Daily Living/psychology ; Aged, 80 and over ; Stress, Psychological/psychology ; *Cost of Illness ; },
abstract = {BACKGROUND: There is a growing interest in assessing the impact that Alzheimer's disease has on the family and the caregiver's burden. Our study aimed to identify the most common types of burden and the tools currently used to assess the burden of caring for a person with dementia.

METHOD: Eighty patients with dementia were assessed. The MMSE was used for the cognition score, ADL and IADL for function assessment, the NPI score for behavioral disorders, and the CBI scale for caregiver stress.

RESULT: Patients' mean age was 77.4 ± 4.7 years. They had a mean MMSE score of 15.5 ± 3.7, mean ADL was 3.4 ± 2.8, and mean IADL was 3.5 ± 2.1. Behavioral disorders were present in 77.5% of cases, mainly insomnia, psychomotor restlessness, wandering, and aggressiveness. The most exposed caregiver population comprised women;80% of them were housewives, wives, daughters, or daughters-in-law. The caregiver's task changed according to the stages of the disease and included emotional support for the most complex activities of daily life and management of behavioral disorders. Among these, severe insomnia increased stress, frustration, anxiety, and depression in the caregiver.

CONCLUSION: The main complaint of caregivers is the lack of support from the National Health Service. The results of this study suggest that it would be useful to encourage interventions that make daycare and treatment centers more accessible to older people with dementia. The solutions for reducing the caregiver's stress could be enhancing assistance, strengthening home care, territorial social and healthcare networks, and promoting psychological assistance to the caregiver who is at risk of burnout.},
}

Humans
Female
Male
*Caregivers/psychology
Aged
*Dementia/psychology/nursing
Activities of Daily Living/psychology
Aged, 80 and over
Stress, Psychological/psychology
*Cost of Illness