@article {pmid41513286,
year = {2025},
author = {Qiao, MN and Bhattarai, P and Yilmaz, E and Rookyard, AW and Das, LN and Zerlin-Esteves, M and Reyes-Dumeyer, D and Lee, AJ and Lantigua, RA and Medrano, M and Mejia, DR and Honig, LS and Brown, LM and Kizil, C and Mayeux, R and Vardarajan, BN},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107767},
doi = {10.1002/alz70856_107767},
pmid = {41513286},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Male ; Female ; tau Proteins/cerebrospinal fluid ; Zebrafish ; Amyloid beta-Peptides/cerebrospinal fluid ; Animals ; Aged ; Neurofilament Proteins/cerebrospinal fluid ; New York City ; Dominican Republic ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; Brain/pathology/metabolism ; },
abstract = {BACKGROUND: We investigated the relationship between the cerebrospinal fluid (CSF) proteome in Alzheimer's disease (AD) and the clinical and biomarker-assisted diagnoses, and with CSF biomarker levels of AD.

METHODS: CSF was collected in 500 individuals of non-Hispanic white, African Americans, and Caribbean Hispanic individuals from Dominican Republic and New York City. CSF biomarkers of AD were measured including p-tau181, Aβ40, Aβ42, total-tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). CSF was depleted of abundant proteins followed by precipitation, cysteine reduction/alkylation, and proteolytic cleavage by trypsin. Peptides were measured using a Q Exactive HF mass spectrometer (Thermo Scientific). Association of individual and co-abundant modules of proteins were tested with the clinical diagnosis of AD, as well as biologically defined AD pathological process based on CSF p-tau181 and other biomarker levels. Results from replicated in 397 participants from the Accelerated Medicine Partnership-Alzheimer's Disease CSF cohort and significantly associated proteins were functionally validated in postmortem human brains and zebrafish models.

RESULTS: CSF levels of 41 proteins were significantly associated with p-tau181 levels after multiple testing correction. Notably phospholipase D3 (PLD3, p = 2.41E-09), APOE (p = 4.25e-08) and osteopontin (OSTP, p = 1.4E-16) were increased and autotaxin (ENPP2, p =  8.39E-09) and ceruloplasmin (CERU, p = 2.72E-07) were decreased among individuals with high p-tau181 levels. These proteins were also associated with CSF Aβ42/Aβ40 ratio and total Tau levels but not with NfL. OSTP was also associated with CSF levels of GFAP (p = 1.32e-05). We did not identify any protein association with clinical AD. Among proteins associated with p-tau181 levels, pathways related to axon development (p = 2.4E-12), axonogenesis (p = 1.45E-11) and regulation of axonogenesis (p = 5.1E-09) were enriched. Immunostaining on postmortem human and zebrafish brains found that ENPP2 expression reduces significantly with AD and amyloidosis, respectively. LPA administration into the zebrafish CSF mitigated Aβ42-induced vascular, neural, and glial changes.

CONCLUSION: Unbiased profiling of circulating CSF proteins identified key proteins associated with β-amyloid and phosphorylated tau pathology. Biologically based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Male
Female
tau Proteins/cerebrospinal fluid
Zebrafish
Amyloid beta-Peptides/cerebrospinal fluid
Animals
Aged
Neurofilament Proteins/cerebrospinal fluid
New York City
Dominican Republic
Glial Fibrillary Acidic Protein/cerebrospinal fluid
Middle Aged
Aged, 80 and over
Brain/pathology/metabolism

@article {pmid41513266,
year = {2025},
author = {Jack, CR and Frisoni, GB},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107828},
doi = {10.1002/alz70856_107828},
pmid = {41513266},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Biomarkers ; Amyloid beta-Peptides ; Brain/pathology ; },
abstract = {BACKGROUND: The IWG and AA diagnostic criteria are major references in the Alzheimer's domain. Although they share analogies, some key differences should be recognized.

METHOD: The original IWG 2024 JAMA Neurology and AA 2024 Alzheimers Dement papers will be used as the major data references.

RESULT: I will outline the similarities and differences between the IWG and the AA criteria for Alzheimer's disease from the point of view of the former. I will discuss similarities regarding: Aim of clinical research on AD and other cognitive disorders, Role of co-pathology, Role of brain reserve, Biomarker use, Indication for anti-β-amyloid, Contra-indication for anti-β-amyloid, and Health care delivery model. I will discuss differences regarding: Core question, Scientific discourse, Knowledge source, Definition of AD, Diagnosis of AD, and Interventions for AD.

CONCLUSION: The differences between the two sets of criteria are not "just semantics". A unified definition of AD is essential to advance the field and improve patient care.},
}

Humans
*Alzheimer Disease/diagnosis
*Biomarkers
Amyloid beta-Peptides
Brain/pathology

@article {pmid41513259,
year = {2026},
author = {Vissel, B},
title = {Anti-amyloid antibodies for Alzheimer's disease are not truly disease modifying.},
journal = {BMJ (Clinical research ed.)},
volume = {392},
number = {},
pages = {s28},
doi = {10.1136/bmj.s28},
pmid = {41513259},
issn = {1756-1833},
}

@article {pmid41513255,
year = {2025},
author = {Rajabli, R and Soltaninejad, M and Collins, DL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107784},
doi = {10.1002/alz70856_107784},
pmid = {41513255},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/diagnosis ; *Magnetic Resonance Imaging ; *Biomarkers ; Male ; Female ; Aged ; *Brain/diagnostic imaging/pathology ; Neuroimaging/methods ; Deep Learning ; },
abstract = {BACKGROUND: Developing diagnostic and prognostic tools for Alzheimer's disease is challenging due to clinical variability across stages. While many studies have focused on case-control classification and conversion prediction, fewer have explored MRI-based prediction of clinical assessment scores, such as the Alzheimer's Disease Assessment Scale (ADAS), despite its potential for measuring disease severity and aiding prognosis. Deep learning could enhance these predictions, but limited labeled data in Alzheimer's disease research constrains model training. To address this, we investigated whether a pretrained, robust brain age prediction model could be fine-tuned to predict clinical scores more effectively.

METHOD: We built an ensemble (n = 5) model to predict brain age from 3D brain MRI. To ensure generalizability, we applied robust preprocessing methods, extensive data augmentation, and regularization techniques, achieving a Mean Absolute Error (MAE) of 3.17 years on average on multiple unseen external test datasets (Rajabli, 2024). We split 11,041 MRIs from the Alzheimer's Disease Neuroimaging Initiative (ADNI1, ADNI2, and ADNI-Go) dataset into a training set (n = 5,536), validation set (n = 2,815), and test set (n = 2,690), ensuring that no subject appeared in more than one set (ADNI is a longitudinal cohort). We then fine-tuned our model to predict ADAS13 on the training set and evaluated it on the validation and test sets.

RESULT: In ADNI, the mean ADAS13 score is 17.92 with a standard deviation of 11.42. We achieved a Mean Absolute Error (MAE) of 5.66, 6.46 and 5.90 on the training, validation and test sets, respectively, for predicting ADAS13. The R[2] score on the test set is 0.58 (r = 0.76, p << 0.01). Figure 1 displays the scatter plot of predicted ADAS13 versus true ADAS13 values for the test set.

CONCLUSION: Using only 50% of the available data for training, we introduced a prediction model which generalized well to the test set, demonstrating the robustness of our model. Our approach required less data while achieving superior results compared to previous methods (such as Bhagwat 2019), paving the way for training more generalizable networks with limited data-a crucial factor for medical imaging datasets.},
}

Humans
*Alzheimer Disease/diagnostic imaging/diagnosis
*Magnetic Resonance Imaging
*Biomarkers
Male
Female
Aged
*Brain/diagnostic imaging/pathology
Neuroimaging/methods
Deep Learning

@article {pmid41513254,
year = {2025},
author = {Windon, CC and Gatsonis, C and Romanoff, J and Hanna, L and Dilworth-Anderson, P and Carrillo, MC and Gareen, IF and Glavin, E and Hillner, BE and March, A and Rissman, RA and Siegel, BA and Smith, K and Whitmer, RA and Weber, CJ and Wilkins, CH and Rabinovici, GD},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107734},
doi = {10.1002/alz70856_107734},
pmid = {41513254},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Positron-Emission Tomography ; Biomarkers/metabolism ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; Aged, 80 and over ; Longitudinal Studies ; Middle Aged ; *Alzheimer Disease/diagnostic imaging ; Prospective Studies ; United States ; Adult ; Medicare ; },
abstract = {BACKGROUND: Amyloid PET use has been associated with change in clinical management among cognitively impaired older adults but various ethnoracial groups were underrepresented in prior studies. New IDEAS examined whether this association exists among cognitively impaired ethnoracially diverse Medicare beneficiaries and beneficiaries presenting with clinically "atypical" (non-memory predominant) presentations of Alzheimer's disease (AD).

METHODS: New IDEAS was a national, multi-site, prospective, longitudinal study that enrolled Medicare beneficiaries with mild cognitive impairment (MCI) or dementia who underwent amyloid PET scan as recommended by their treating dementia specialists at "real-world" clinics. The study examined association between amyloid PET and subsequent change in clinical management within 90 days of PET. Primary endpoint was change in management between pre- and post-PET visits defined as a composite inclusive of change in AD and non-AD drugs and change in counseling about safety and future planning. Proportions of change in management between pre- and post-PET visit by group are reported as well as logistic regression examining association between composite change in management and multiple factors.

RESULTS: Median age of 4363 participants is 75 (range 35-98) years and 55.4% are female, 63.8% having MCI and 65.4% (95% CI 64.0, 66.8) amyloid PET positive. The sample includes 938 (21.5%) Black/African American, 707 (16.2%) Hispanic/Latino, and 2718 (62.3%) other individuals with 1330 (30.5%) participants with atypical presentations of AD (Table 1). Overall change in management occurred in 54.7% (95% CI 51.5, 57.9) of Black/African American, 53.7% (50.1, 57.4) of Hispanic/Latino, and 60.2% (58.3, 62.0) of other individuals. By clinical presentation, 44.1% (40.7, 47.6) of atypical clinical MCI, 52.6% (48.4, 56.7) of atypical dementia, 63.9% (61.8, 66.0) of typical MCI, and 59.9% (56.8, 62.8) of typical dementia participants had an overall change in management (Table 2). Logistic regression demonstrated significant interactions between Black/African American identity and positive amyloid PET scan (OR 1.64, 95% CI 1.14, 2.36; p 0.008) (Table 3).

CONCLUSIONS: New IDEAS demonstrated that amyloid PET use among ethnoracially diverse Medicare beneficiaries and those with atypical and typical clinical presentations of AD leads to changes in clinical management, highlighting the value of this biomarker in a real-world clinical care setting.},
}

Humans
Female
Male
Aged
Positron-Emission Tomography
Biomarkers/metabolism
*Cognitive Dysfunction/diagnostic imaging/metabolism
Aged, 80 and over
Longitudinal Studies
Middle Aged
*Alzheimer Disease/diagnostic imaging
Prospective Studies
United States
Adult
Medicare

@article {pmid41513251,
year = {2025},
author = {Bolton, CJ and Zhang, P and Peterson, AJ and Liu, D and Hohman, TJ and Blennow, K and Zetterberg, H and Jefferson, AL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106533},
doi = {10.1002/alz70856_106533},
pmid = {41513251},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/cerebrospinal fluid ; Aged ; tau Proteins/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Neuropsychological Tests ; *GAP-43 Protein/cerebrospinal fluid ; Cross-Sectional Studies ; Longitudinal Studies ; *Cognitive Dysfunction/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {BACKGROUND: Women are at an increased risk of dementia due to Alzheimer's disease (AD) compared to men, a difference due in part to the role of female sex hormones. Estrogen, in particular, plays a key role in neuroplasticity. However, as women age and estrogen levels decline, high levels of neuroplasticity may be unsustainable. This study investigates the interaction of sex with a marker of neuroplasticity, growth-associated protein-43 (GAP-43), on AD biomarkers and cognitive decline.

METHOD: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n = 161, 72±6 years, 31% female) underwent fasting lumbar puncture and comprehensive neuropsychological assessment at study entry and serially over a mean 6.4-year follow-up period. Cerebrospinal fluid (CSF) levels of GAP-43, b-amyloid1-42 (Ab1-42), tau, and phosphorylated-tau (p-tau) were analyzed in batch. Linear regression models related baseline CSF GAP-43 cross-sectionally and longitudinally to CSF biomarkers and cognition adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE)-e4 status, modified Framingham Stroke Risk Profile, and cognitive status. Follow-up models assessed GAP-43 x sex interactions on AD biomarkers and cognitive outcomes.

RESULT: In cross-sectional analyses, higher GAP-43 was associated with higher levels of all CSF AD biomarkers (p-values<0.0001), worse language performance (b=-0.0005, p = 0.04) and worse visuospatial performance (b=-0.0004, p = 0.005). GAP-43 interacted with sex on CSF tau and p-tau levels (p-values<0.0001) such that associations were stronger in females compared to males. In longitudinal analyses, higher baseline GAP-43 was associated with declining Ab42 levels (b=-0.01, p <0.0001) and declining performance in tasks of language, executive function, and visuospatial abilities (p-values<0.02), indicating greater AD pathology and declining cognition. GAP-43 interacted with sex on longitudinal language, processing speed, executive functioning, and visuospatial performance trajectories (p-values<0.05), such that significant associations were found in women (p-values<0.02) but not men (p-values>0.26).

CONCLUSION: In this cohort of community-dwelling older adults, we found higher baseline levels of GAP-43, indicating increased neuroplasticity, are related to cross-sectional increases in tau pathology, especially in women, and longitudinal decline in cognition, exclusively in women. Findings suggest that differential responses to neuroplasticity in aging could help explain long-recognized sex differences in tau pathology and cognitive decline.},
}

Humans
Female
Male
*Biomarkers/cerebrospinal fluid
Aged
tau Proteins/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Neuropsychological Tests
*GAP-43 Protein/cerebrospinal fluid
Cross-Sectional Studies
Longitudinal Studies
*Cognitive Dysfunction/cerebrospinal fluid
Peptide Fragments/cerebrospinal fluid
Aged, 80 and over

@article {pmid41513247,
year = {2025},
author = {Edwards, NC and Lao, PJ and Alshikho, MJ and Hahm, J and Rizvi, BM and Flores-Aguilar, L and Petersen, M and O'Bryant, SE and Handen, BL and Gutierrez, J and Wilcock, DM and Head, E and Brickman, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105529},
doi = {10.1002/alz70856_105529},
pmid = {41513247},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Biomarkers/blood ; Middle Aged ; Magnetic Resonance Imaging ; *tau Proteins/blood ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging/pathology ; *Down Syndrome/diagnostic imaging/complications ; Adult ; Brain/diagnostic imaging/pathology ; *Cerebrovascular Disorders/diagnostic imaging ; Longitudinal Studies ; White Matter/diagnostic imaging/pathology ; },
abstract = {BACKGROUND: Adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology by age 40, despite few vascular risk factors. MRI shows cerebrovascular disease (CVD) that precedes or begins contemporaneously with markers of AD pathology. We have found that vascular lesions observed on MRI interact with a marker of astrocytosis to promote tau pathology and neurodegeneration. However, it's unclear how CVD and astrocytosis interact with elevated Aβ to influence AD progression. We investigated whether markers of CVD and astrocytosis are linked to longitudinal changes in tau biomarkers and their interaction with Aβ levels.

METHOD: We included 114 participants (mean age[SD]=45.1[6]) from the Alzheimer's Biomarkers Consortium-Down Syndrome with baseline Aβ PET imaging ([11C]PiB or [18F]florbetapir) and three follow-up visits with MRI and plasma biomarker data. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI, and plasma biomarkers (GFAP, p-tau181) were measured at baseline and follow-ups. Centiloid values were derived from Aβ standard uptake value ratio values and standardized across a scale from 0 to 100. Linear mixed effects models first estimated whether baseline WMH volume was associated change in GFAP concentration and whether baseline GFAP was associated with change in p-tau181 concentration. Separate models then tested if each baseline measure interacted with amyloid centiloid values. Models included site, age, sex/gender, and years from baseline as fixed effects and a random effect for participant intercept.

RESULT: Baseline WMH volume predicted an increase in GFAP over time (β=0.22[0.12, 0.31], AIC=-102.84), and baseline GFAP predicted an increase in p-tau181 (β=0.36[0.24, 0.4], AIC=-122.66). However, baseline GFAP did not predict WMH change (β=0.07[-0.1, 0.14], AIC = -25.7) nor did p-tau181 predict GFAP change (β=0.009[-0.18, 0.09], AIC=-33.41). Higher WMH volume predicted increased GFAP, especially in those with higher amyloid levels (β=0.38[0.26, 0.45], AIC=-146.3), and higher GFAP predicted increased p-tau181, particularly in those with higher amyloid levels (β=0.49[0.32, 0.55], AIC=-154.86).

CONCLUSION: Cerebrovascular lesions promote astrocyte-related inflammation, particularly in the context of elevated amyloid pathology, which has a downstream effect on tau pathophysiology in adults with DS. The results support the hypothesis that the interface between CVD and astrocytosis is critical in AD progression in people with DS.},
}

Humans
Male
Female
Biomarkers/blood
Middle Aged
Magnetic Resonance Imaging
*tau Proteins/blood
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
*Alzheimer Disease/diagnostic imaging/pathology
*Down Syndrome/diagnostic imaging/complications
Adult
Brain/diagnostic imaging/pathology
*Cerebrovascular Disorders/diagnostic imaging
Longitudinal Studies
White Matter/diagnostic imaging/pathology

@article {pmid41513243,
year = {2025},
author = {Li, J and Gan, L and Bezgin, G and Chan, T and Hall, BJ and Rahmouni, N and Wang, YT and Aumont, E and Hosseini, SA and Socualaya, KMQ and Trudel, L and Therriault, J and Macedo, AC and Arias, JF and Zheng, Y and Olivia-Lopez, D and Montembeault, M and Li, R and Rosa-Neto, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105624},
doi = {10.1002/alz70856_105624},
pmid = {41513243},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; tau Proteins/metabolism ; Biomarkers/metabolism ; Positron-Emission Tomography ; Aged ; Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/metabolism ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: Growing evidence indicates that the coexistence of visual and auditory impairments increases the risk of developing Alzheimer's disease (AD). However, the mechanisms through which these sensory deficits influence the progression of AD, particularly their impact on amyloid and tau pathology, remain unclear. We hypothesize that alterations in the audio-visual dynamic network play a critical role in mediating the spread of amyloid-related tau pathology during the early stages of AD.

METHOD: This study included multimodal imaging data, including functional MRI, [[18]F]NAV4694 amyloid-PET, and [[18]F]NAV4694 tau-PET, from the TRIAD cohort (n = 216, Table 1). Participants were classified as amyloid-beta (Aβ) positive (A+) or negative (A-) based on established global uptake values of [[18]F]NAV4694 (global standardized uptake value ratio [SUVR] > 1.55). Tau positivity (T+) or negativity (T-) was determined using [[18]F]MK6240, with a temporal meta-ROI SUVR threshold > 1.30. Tau staging was based upon Braak stage classification. Brain dynamics in resting-state fMRI data were analyzed with a multilayer modularity algorithm in MATLAB, focusing on primary sensory and higher-order networks.

RESULT: Module allegiance within the auditory network (AN) and visual networks (VN) was lower in the A+T+ group compared to the A-T- group. Additionally, flexibility within the frontoparietal network (FPN) was increased, while recruitment within the FPN and integration between AN and VN were reduced in the A+T+ group compared to A-T- group (Figure 1). Integration between AN and VN negatively correlated with [[18]F]MK6240 SUVR in Braak stage 1 through 5 and the temporal meta-ROI, as well as with neocortical [[18]F]NAV4694 SUVR. Furthermore, AN-VN integration mediated the relationship between neocortical [[18]F]NAV4694 SUVR and [[18]F]MK6240 SUVR in Braak stage 1 and 2 (Figure 2).

CONCLUSION: Our study suggests that audio-visual network integration during the early stages of tau pathology mediates amyloid-related tau accumulation. This supports a framework in which decline brain network integration may facilitates the early spread of amyloid-driven tau pathology across interconnected brain regions.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/metabolism
Magnetic Resonance Imaging
tau Proteins/metabolism
Biomarkers/metabolism
Positron-Emission Tomography
Aged
Amyloid beta-Peptides/metabolism
*Brain/diagnostic imaging/metabolism
Middle Aged
Cohort Studies

@article {pmid41513241,
year = {2025},
author = {Bieger, A and Borelli, WV and Ferrari-Souza, JP and Brum, WS and Schlickmann, TH and Arnold, D and Pascoal, TA and Souza, DO and Aguzzoli, C and Rosa-Neto, P and Schilling, LP and Zimmer, ER and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107740},
doi = {10.1002/alz70856_107740},
pmid = {41513241},
issn = {1552-5279},
mesh = {Humans ; Male ; *Cognitive Dysfunction/cerebrospinal fluid/pathology/diagnostic imaging ; Female ; Biomarkers/cerebrospinal fluid ; Aged ; tau Proteins/cerebrospinal fluid ; Magnetic Resonance Imaging ; *Hippocampus/pathology/diagnostic imaging ; Atrophy/pathology ; Amyloid beta-Peptides/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/pathology ; Disease Progression ; Longitudinal Studies ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Hippocampal atrophy is a well-established hallmark of Alzheimer's disease (AD), closely associated with cognitive decline and disease progression, even in the earliest symptomatic stages. Despite growing evidence that subfield-specific atrophy patterns could serve as sensitive biomarkers for early diagnosis and tracking disease progression, there remains a significant gap in understanding how these subfields are differentially impacted across different stages of AD. In this study, we explore longitudinal rates of atrophy in hippocampal subfields in individuals with amnestic mild cognitive impairment (MCI).

METHOD: Hippocampal subfields volumes were extracted from volumetric, T1-weighted MRI images from the Alzheimer's Disease Neuroimaging Initiative using Freesurfer (v 7.4.1). We included individuals with MCI who underwent cerebrospinal fluid (CSF) collection and MRI studies at baseline and after 1 year. Participants were categorized according to baseline CSF levels of amyloid and phosphorylated-tau proteins as: A-T-, A+T-, A-T+, and A+T+. Using generalized linear models, we evaluated the effect of biomarker subgroups on hippocampal subfield atrophy rates, controlling for age, sex, and whole hippocampal volume.

RESULT: Table 1 summarizes demographic data for each biomarker group. Using the A-T- group as reference, higher rates of atrophy were observed in the A-T+ group in the subiculum, bilaterally. The A+T- group showed differences in the left presubiculum and in the subiculum, bilaterally. In the A+T+ group, faster atrophy was observed in the bilateral parasubiculum, bilateral subiculum, bilateral presubiculum, bilateral CA1, right CA4, and right dentate gyrus (granule cell and molecular layers) - Figure 1.

CONCLUSION: This study reveals distinct patterns of hippocampal subfield atrophy in amnestic MCI, according to amyloid-beta (A) and phosphorylated tau (T) biomarker profiles. The A-T+ group exhibited a unique pattern of subfield vulnerability, primarily affecting the subiculum, suggesting that tau pathology alone may target specific regions of the hippocampus. In contrast, the A+T+ group showed widespread atrophy across multiple subfields, indicating that combined amyloid and tau pathology leads to more extensive hippocampal degeneration. These findings highlight the potential of subfield-specific atrophy patterns as sensitive biomarkers for differentiating early AD stages and tracking disease progression. Future studies should investigate how these patterns correlate with cognitive decline and their predictive value for dementia conversion.},
}

Humans
Male
*Cognitive Dysfunction/cerebrospinal fluid/pathology/diagnostic imaging
Female
Biomarkers/cerebrospinal fluid
Aged
tau Proteins/cerebrospinal fluid
Magnetic Resonance Imaging
*Hippocampus/pathology/diagnostic imaging
Atrophy/pathology
Amyloid beta-Peptides/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/pathology
Disease Progression
Longitudinal Studies
Aged, 80 and over
Middle Aged

@article {pmid41513238,
year = {2025},
author = {Burns, AP and Fortel, I and Zhan, L and Lazarov, O and Mackin, SR and Demos, AP and Bendlin, BB and Leow, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107724},
doi = {10.1002/alz70856_107724},
pmid = {41513238},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Apolipoprotein E4/genetics ; Magnetic Resonance Imaging ; Biomarkers ; *Alzheimer Disease/genetics/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging/genetics/physiopathology ; *Brain/diagnostic imaging/physiopathology ; Longitudinal Studies ; Aged, 80 and over ; Diffusion Magnetic Resonance Imaging ; Disease Progression ; },
abstract = {BACKGROUND: Excessive neural hyperexcitation has been implicated in early cognitive decline and progression to Alzheimer's disease (AD). Restoring the balance between excitation and inhibition (E/I) with interventions like levetiracetam may offer clinical benefits, particularly for those at heightened risk. Recent cross-sectional studies suggest that female APOE-ε4 carriers may be especially vulnerable to hyperexcitation, but longitudinal evidence remains limited. We therefore investigated whether E/I dysregulation over time differs by sex and APOE-ε4 status in older adults who were cognitively unimpaired at baseline. Figure 1 illustrates the concept of early hyperexcitation preceding AD symptoms.

METHOD: We analyzed multimodal MRI data (resting-state functional MRI and diffusion-weighted imaging) from 106 older adults with at least one cognitively unimpaired scan and three or more longitudinal sessions. Most sessions were rated as clinically unimpaired (CDR = 0), though a subset transitioned to early mild cognitive impairment (CDR = 0.5 or 1). We applied an inverse Ising model regularized by empirical structural connectivity (Figure 2) to derive a whole-brain excitation-inhibition ratio (EIR). Linear mixed modeling tested whether EIR trajectory varied by sex, binary APOE-ε4 status, age at first scan, and time since first scan.

RESULT: A significant three-way interaction (Figure 3) indicated that female APOE-ε4 carriers demonstrate an elevated hyperexcitable EIR trajectory (p = 0.018). Pairwise comparisons further showed higher EIR slopes for female ε4 carriers compared to female non-carriers (p = 0.042). This effect remained significant after adjusting for age, time, and amyloid status, though it was somewhat diminished in participants with fewer longitudinal observations. Regional analyses focusing on default mode and limbic networks found higher baseline excitatory tone in females (p = 0.02), aligning with the global results.

CONCLUSION: These findings provide longitudinal support for a heightened susceptibility to hyperexcitation in female APOE-ε4 carriers, underscoring the importance of sex and genetic risk in preventive and therapeutic strategies for AD. Our multimodal approach integrating structural and functional network data highlights E/I balance as a promising biomarker and treatment target, with levetiracetam representing one potential intervention. Larger studies are needed to confirm how sex- and genotype-specific E/I dysregulation influences dementia risk and therapeutic efficacy.},
}

Humans
Female
Male
Aged
Apolipoprotein E4/genetics
Magnetic Resonance Imaging
Biomarkers
*Alzheimer Disease/genetics/diagnostic imaging
*Cognitive Dysfunction/diagnostic imaging/genetics/physiopathology
*Brain/diagnostic imaging/physiopathology
Longitudinal Studies
Aged, 80 and over
Diffusion Magnetic Resonance Imaging
Disease Progression

@article {pmid41513237,
year = {2025},
author = {Jannati, A and Thompson, K and Toro-Serey, C and Higgins, C and Bates, D and Pascual-Leone, A and Tobyne, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107699},
doi = {10.1002/alz70856_107699},
pmid = {41513237},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/blood ; Aged ; *Alzheimer Disease/diagnosis/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; *Cognitive Dysfunction/diagnosis/diagnostic imaging/metabolism ; *Brain/metabolism/diagnostic imaging ; Neuropsychological Tests ; tau Proteins ; Aged, 80 and over ; },
abstract = {BACKGROUND: Early identification of patients who are likely to have abnormal brain amyloid-beta (Aβ) levels is crucial for identifying patients with Alzheimer's disease (AD) and prioritizing suitable candidates for disease-modifying treatments (DMTs). Therefore, there is an urgent need to develop an efficient, cost-effective, and scalable method for early identification of brain Aβ+ status. This study evaluated the performance of ML-enabled models combining the Digital Clock and Recall (DCR), digital Trail-Making Test-Part B (dTMT-B), and various blood-based biomarkers (BBMs) in predicting brain Aβ-PET status.

METHOD: 930 participants (mean age 72.0±6.7; 56.8% female; 23% minorities) in the Bio-Hermes-001 study were classified as cognitively unimpaired, mild cognitive impairment, or probable Alzheimer's dementia, and 35.1% were Aβ+ on 18F-florbetapir PET scan. Three-class, cross-validated ensemble models combined multimodal process-based features of DCR and dTMT-B performance including drawing metrics, temporal-spatial features of stylus manipulation, speech and acoustic features, APOE status, and BBMs p-tau217, Aβ42/40, p-tau181. All models had <22% indeterminate cases.

RESULT: For predicting Aβ-PET status, the DCR+dTMT-B+P-tau217 model had an AUC=0.943 (NPV=0.946; PPV=0.871), and with APOE added, it achieved AUC=0.954 (NPV=0.963; PPV=0.907). The DCR+dTMT-B+Aβ42/40 model had an AUC=0.929 (NPV=0.936; PPV=0.820), and with APOE added, it achieved AUC=0.948 (NPV=0.952; PPV=0.892). The DCR+dTMT-B+P-tau181 model had an AUC=0.911 (NPV=0.915; PPV=0.774), and with APOE added, it achieved AUC=0.941 (NPV=0.939; PPV=0.831). Addition of Aβ42/40 to the DCR+dTMT-B+P-tau181+APOE model resulted in an AUC=0.949 (NPV=0.960; PPV=0.883).

CONCLUSION: A multimodal model based on DCR, dTMT-B, ±APOE, and various BBMs had excellent performance in predicting Aβ-PET status, at levels comparable to CSF biomarkers of AD. ML-enabled digital cognitive assessments that leverage process-based metrics, such as the DCR and dTMT-B, enable cost-effective integration into clinical workflows to identify patients who are most likely to have Aβ+ PET status, allowing for prioritizing the most suitable candidates for DMTs.},
}

Humans
Female
Male
*Biomarkers/blood
Aged
*Alzheimer Disease/diagnosis/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism
Positron-Emission Tomography
*Cognitive Dysfunction/diagnosis/diagnostic imaging/metabolism
*Brain/metabolism/diagnostic imaging
Neuropsychological Tests
tau Proteins
Aged, 80 and over

@article {pmid41513218,
year = {2025},
author = {Gaona-Partida, PR and Magana-Ramirez, CM and Grill, JD and Gillen, DL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107729},
doi = {10.1002/alz70856_107729},
pmid = {41513218},
issn = {1552-5279},
mesh = {Humans ; Positron-Emission Tomography ; *Biomarkers/metabolism ; *Alzheimer Disease/diagnostic imaging/ethnology/metabolism ; Male ; Female ; Aged ; *Brain/diagnostic imaging/metabolism ; Aged, 80 and over ; Neuroimaging ; Ethnicity ; White People ; },
abstract = {BACKGROUND: In early and preclinical Alzheimer's disease AD clinical trials, amyloid biomarker criteria have resulted in differential ineligibility among racial and ethnic groups. We sought to quantify differences in PET-derived amyloid levels across racial and ethnic groups of similar clinical diagnosis and presumed disease etiology.

METHOD: We utilized data from the Standardized Centralized Alzheimer's and Related Dementias Neuroimaging (SCAN), a newly implemented initiative funded by the National Institute on Aging in conjunction with the National Alzheimer's Coordinating Center (NACC). Our primary outcome was PET-derived amyloid burden using standardized uptake value ratios (SUVRs) shared through the SCAN initiative. Racial and ethnic status were categorized as Non-Hispanic Black (NHB), Non-Hispanic White (NHW), and the remaining participants collated into together (Other), using data obtained from NACC's Uniform Data Set (UDS). We used ordinary least-squares regression to model differences in mean amyloid levels across racial and ethnic groups, with stratification by clinical diagnosis and presumed disease etiology while adjusting for potential confounding factors.

RESULT: We analyzed data on N = 661 NACC participants that had corresponding amyloid PET data available. Table 1 provides basic demographics of the study sample. Figure 1 depicts the distribution of amyloid levels by racial and ethnic group, clinical diagnosis, and presumptive etiology. Table 2 yields the estimated mean differences in SUVR levels by racial and ethnic group stratified by clinical diagnosis and presumptive etiology. After adjustment for potential confounding factors we estimated that NHB participants with cognitive impairment (impaired not MCI or MCI) and probable AD had mean SUVR -0.503 lower than comparable NHW participants (95% CI: (-0.737, -0.270); p-value: <0.001). Among participants with a dementia diagnosis and probable AD the estimated mean difference was -0.242 (95% CI (-0.529,0.045); p-value: 0.099) comparing NHB to NHW.

CONCLUSION: These results add to a growing literature examining amyloid biomarkers across racial and ethnic groups. A limitation of this study is the small sample sizes in several of the groups analyzed. Further research is needed to assess these observed potential differences and the implications to AD trial eligibility and treatment.},
}

Humans
Positron-Emission Tomography
*Biomarkers/metabolism
*Alzheimer Disease/diagnostic imaging/ethnology/metabolism
Male
Female
Aged
*Brain/diagnostic imaging/metabolism
Aged, 80 and over
Neuroimaging
Ethnicity
White People

@article {pmid41513217,
year = {2025},
author = {Zajicek, K and Lapins, A and Mather, MA and Gefen, T and Castellani, RJ and Weintraub, S and Vassar, RJ and Mesulam, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107697},
doi = {10.1002/alz70856_107697},
pmid = {41513217},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/pathology ; Female ; Middle Aged ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; *Frontotemporal Dementia/cerebrospinal fluid/diagnosis ; Diagnosis, Differential ; },
abstract = {BACKGROUND: Most patients clinically diagnosed with dementia due to Alzheimer's disease (AD) are over the age of 65 and exhibit a slowly progressive amnestic clinical syndrome. In contrast, those diagnosed clinically with Frontotemporal Dementia (FTD) tend to have younger age of onset and clinical presentations with behavioral and/or language decline. With the advent of cerebrospinal fluid (CSF) AD biomarkers with high sensitivity and specificity, differentiation between dementia due to AD vs FTD can be made with significantly more confidence during life. Though CSF biomarker testing for AD has excellent diagnostic accuracy for straightforwardly positive or negative results, guidance for interpretation of "borderline" or "indeterminate" results, which is common in clinical practice, is limited.

METHOD: We summarize available clinical, biomarker, and autopsy data for a 56-year-old woman enrolled into the Northwestern University Alzheimer's Disease Research Center with a 3-year history of rapidly progressive decline in language and behavior, borderline cerebrospinal fluid (CSF) biomarkers for AD, but was found to have high level Alzheimer's Disease Neuropathic Change (ADNC) at autopsy.

RESULTS: CSF testing for AD occurred when the patient was in a severe stage of dementia, 1.5 years into the disease process and 15 months before death. Whereas the Aβ42/total tau index (ATI) value fell within the AD range, phosphorylated tau (p-tau) was only borderline elevated (Ab42 = 380 pg/mL, total tau = 414 pg/mL, ATI = 0.62, p-tau = 58.8 pg/mL). Genetic testing was negative for known mutations that cause FTD. The neuropathological findings at autopsy indicated high ADNC. There were incidental Lewy bodies in the brainstem, but no significant FTLD-tau or TDP-43 neuropathologic changes.

CONCLUSION: This case illustrates an atypical, rapidly progressive clinical presentation of autopsy-confirmed AD with CSF biomarkers for AD in the "borderline" range relatively close to death. In clinical practice, cases where biomarkers are "borderline" are not uncommon and pose challenges to differentiating between dementias due to different underlying neurodegenerative diseases. Learning from atypical presentations such as this one may augment diagnostic accuracy and clinical disease management. Further research is needed to establish correspondence of "borderline" or "indeterminate" CSF biomarkers to neuropathological findings seen at autopsy.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnosis/pathology
Female
Middle Aged
tau Proteins/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
*Frontotemporal Dementia/cerebrospinal fluid/diagnosis
Diagnosis, Differential

@article {pmid41513181,
year = {2026},
author = {Vyas, J and Jamenis, AS and Kaku, K and Shah, Y and Miner, KM and Bhatia, TN and Kim, RE and Bai, R and Hamel, E and Leak, RK and Gangjee, A},
title = {Discovery of multitargeting single agents as a novel route to the potential treatment of neurodegenerative diseases.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {133},
number = {},
pages = {130536},
doi = {10.1016/j.bmcl.2026.130536},
pmid = {41513181},
issn = {1464-3405},
abstract = {There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have recently discovered first-in-class novel single agents (compounds 1 and 2) that mildly inhibit clinically important kinases and subtly favor microtubule stability at concentrations that show no evidence of neuronal toxicity in primary neurons, while maintaining their ability to penetrate the CNS in vivo. It is important to note that the effects of these analogs are mild and are predicated on avoiding neurotoxicity. These multitargeting single agents provide a new structural modality with the potential to influence treatments for Parkinson's and Alzheimer's disease and serve as lead compounds for further optimization.},
}

@article {pmid41512968,
year = {2026},
author = {Plubell, DL and Remes, PM and Wu, CC and Jacob, CC and Merrihew, GE and Hsu, C and Shulman, N and MacLean, BX and Heil, L and Poston, KL and Montine, T and MacCoss, MJ},
title = {Development of highly multiplex targeted proteomics assays in biofluids using a nominal mass ion trap mass spectrometer.},
journal = {Molecular & cellular proteomics : MCP},
volume = {},
number = {},
pages = {101506},
doi = {10.1016/j.mcpro.2026.101506},
pmid = {41512968},
issn = {1535-9484},
abstract = {The development of targeted assays that monitor biomedically relevant proteins is an important step in bridging discovery experiments to large scale clinical studies. Targeted assays are currently unable to scale to hundreds or thousands of targets. We demonstrate the generation of large-scale assays using a novel hybrid nominal mass instrument. The scale of these assays is achievable with the Stellar[TM] mass spectrometer through the accommodation of shifting retention times by real-time alignment, while being sensitive and fast enough to handle many concurrent targets. Assays were constructed using precursor information from gas-phase fractionated (GPF) data-independent acquisition (DIA). We demonstrate the ability to schedule methods from orbitrap and linear ion trap acquired GPF DIA library, and compare the quantification of a matrix-matched calibration curve from orbitrap DIA and linear ion trap parallel reaction monitoring (PRM). Two applications of these proposed workflows are shown with a cerebrospinal fluid (CSF) neurodegenerative disease protein PRM assay and with a Mag-Net enriched plasma extracellular vesicle (EV) protein survey PRM assay. In CSF, our assay targets proteins discovered previously to be associated with Alzheimer's disease in a small independent sample set. For the Mag-Net enriched plasma survey assay, we observe that proteins selected based on their measurement robustness are still able to capture differences in abundance across disease groups in a small sample set. These highlight the application of highly multiplex, targeted protein assays in clinical research.},
}

@article {pmid41512910,
year = {2025},
author = {Takieldeen, Y and Yang, HC and Shahid, SS and Ebrahimi, T and Al-Ali, K and Riley, K and Graner, B and Wilcock, DM and Saykin, AJ and Wu, YC and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107738},
doi = {10.1002/alz70856_107738},
pmid = {41512910},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Aged ; *White Matter/diagnostic imaging/pathology ; Biomarkers/metabolism ; tau Proteins/metabolism ; Positron-Emission Tomography ; Pilot Projects ; Magnetic Resonance Imaging ; *Brain/diagnostic imaging/pathology ; Neuroimaging ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism ; },
abstract = {BACKGROUND: White matter hyperintensities (WMHs) in Alzheimer's disease (AD) are often linked to microvascular disease, but emerging evidence suggests AD-specific pathologies also play a role. This pilot study leverages multimodal imaging to examine WMH volume, microstructure, and perfusion, uncovering distinct vascular and AD-related contributions through their associations with amyloid and tau.

METHOD: Thirty cognitively normal (CN), 30 mild cognitive impairment (MCI), and 10 AD participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI3) underwent T1-weighted, fluid-attenuated inversion recovery (FLAIR), T2*-weighted, multi-shell diffusion MRI, arterial spin labeling (ASL) perfusion, amyloid positron emission tomography (PET), tau PET, and vascular risk assessment. WMH volume was extracted using HyperMapp3r algorithm and Lesion Segmentation Tool (LST), and associated with amyloid and tau burden. To address WMH spatial heterogeneity, imaging metrics were assessed across WMHs, perilesional regions, and adjacent normal appearing white matter (NAWM). Adjacent NAWM was chosen over whole-brain NAWM to ensure regional comparability within the same white matter tract and reduce intra-subject variability.

RESULT: WMH volume was higher in AD compared to MCI and CN (Figure 1A), independent of age, sex, and intracranial volume (F(5, 60)=11.28, p <0.001). Amyloid burden (β=0.045, p <0.001) was a predictor of WMH volume, independent of vascular risk, while tau was not. When stratifying by amyloid beta status and vascular risk, WMH burden followed a trend where it was highest in amyloid-positive individuals with high vascular risk (A+V+), followed by amyloid-positive with low vascular risk (A+V-), then amyloid-negative with high vascular risk (A-V+), and lowest in amyloid-negative with low vascular risk (A-V-) (Figure 1B). Across all groups, WMHs showed the most microstructural damage versus perilesion and NAWM, with a consistent trend across metrics. However, the differences were significant for intracellular volume fraction, axial, radial, and mean diffusivity (Figure 2). Significant between-group differences were found in orientation dispersion, mean, and axial diffusivity within WMHs (Figure 3).

CONCLUSION: This study highlights the interplay of vascular and neurodegenerative pathologies in WMH development in AD, with amyloid burden independently contributing to WMH volume and vascular risk amplifying its effects. Future work will examine spatial WMH distribution across amyloid and vascular risk cohorts to clarify their contributions to WMH development and progression.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
*Cognitive Dysfunction/diagnostic imaging/pathology
Aged
*White Matter/diagnostic imaging/pathology
Biomarkers/metabolism
tau Proteins/metabolism
Positron-Emission Tomography
Pilot Projects
Magnetic Resonance Imaging
*Brain/diagnostic imaging/pathology
Neuroimaging
Aged, 80 and over
Amyloid beta-Peptides/metabolism

@article {pmid41512908,
year = {2025},
author = {Valencia, SM and Sanchez, JP and Niño, DFA and Baena, AY and Londono, N and Ramirez, S and Trujillo, SP and Gomez, D and Díaz, DC and Possin, KL and Orrego, NT},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105619},
doi = {10.1002/alz70856_105619},
pmid = {41512908},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Adult ; Cross-Sectional Studies ; *Neuropsychological Tests ; Biomarkers ; *Alzheimer Disease/genetics/diagnosis ; Presenilin-1/genetics ; Colombia ; Middle Aged ; *Cognitive Dysfunction/diagnosis/genetics ; },
abstract = {BACKGROUND: Alzheimer's disease and related dementias are rising at an alarming rate (>300%), leading to human and economic losses, particularly in resource-limited low- and middle-income countries. This exacerbates health disparities and underscores the urgent need for scalable early detection tools to support preventive intervention strategies. Emerging digital cognitive assessment tools, such as TabCAT-BHA, a 15-minute tablet-based battery, offer a practical alternative for identifying early cognitive markers. Colombia's autosomal dominant PSEN1-E280A genetic variant cohort, causative of early-onset familial AD, provides a unique opportunity to examine preclinical cognitive changes associated with the disease. As the need for innovative cognitive markers rises, evidence on their validity is essential for determining their clinical utility. The objective is to evaluate the validity of TabCAT-BHA for detecting cognitive differences between asymptomatic PSEN1-E280A carriers and non-carriers and correlating with established, traditional cognitive tests of the same domains.

METHOD: This cross-sectional study included 135 asymptomatic participants: 79 PSEN1-E280A carriers and 56 non-carriers, mean age: 32.5 years. TabCAT-BHA encompasses memory, executive function, processing speed, visuospatial ability, and language cognitive measures. Neuropsychological paper-pencil assessment was carried out for similar domains through a 25-minute evaluation using widely used tests. Descriptive statistics summarized demographic and cognitive performance. Independent sample t-tests were used to assess cognitive performance differences between groups. Correlation coefficients evaluated concurrent validity between TabCAT-BHA and traditional paper-pencil neuropsychological tests.

RESULTS: Both groups were comparable in terms of sex, age, and educational level. Non-carriers demonstrated a trend toward better performance across all cognitive domains. Statistically significant differences were observed in TabCAT-BHA's memory, visuospatial ability, and language metrics between groups, while traditional evaluations identified differences only in memory tests. Correlation analyses revealed moderate relationships between TabCAT-BHA and traditional tests across same domains, with lower correlations with different domains.

CONCLUSION: TabCAT-BHA detected broader cognitive differences across multiple domains between PSEN1-E280A mutation carriers and non-carriers, underscoring its utility in identifying early cognitive changes during the preclinical stage of AD. Its demonstrated concurrent validity with traditional evaluations further highlights its potential as a scalable, efficient tool for preclinical AD detection, particularly in low- and middle-income countries where resource constraints limit access to traditional diagnostic approaches.},
}

Humans
Male
Female
Adult
Cross-Sectional Studies
*Neuropsychological Tests
Biomarkers
*Alzheimer Disease/genetics/diagnosis
Presenilin-1/genetics
Colombia
Middle Aged
*Cognitive Dysfunction/diagnosis/genetics

@article {pmid41512881,
year = {2025},
author = {Lee, SY and Emanuel, OM and Matusz, EF and Wang, WE and Arias, F and Levy, SA and Velez-Uribe, I and Barker, WW and Rosselli, M and Vaillancourt, DE and Armstrong, MJ and Cid, REC and Loewenstein, DA and Duara, R and Smith, GE and Asken, BM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107710},
doi = {10.1002/alz70856_107710},
pmid = {41512881},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Positron-Emission Tomography ; Biomarkers/blood ; *tau Proteins/blood ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging/blood ; *Sleep Apnea Syndromes/diagnostic imaging/complications/blood ; Aged, 80 and over ; Apolipoprotein E4/genetics ; Middle Aged ; Brain/diagnostic imaging/metabolism ; Aniline Compounds ; Carbolines ; },
abstract = {BACKGROUND: Sleep apnea is a potential risk factor for Alzheimer's Disease (AD). Associations between sleep apnea and elevated AD biomarkers like amyloid beta (Aβ) and p-tau have been reported, but it is unclear if or how sleep apnea influences the connection between the two. The link between sleep apnea and AD also has not been extensively studied in the context of relevant demographic, sociocultural, and common genetic factors. Therefore, we assessed the moderating effects of sleep apnea on the association between Aβ-PET and plasma p-tau217 and whether this moderation differed based on sex, ethnicity, or APOE e4 carrier status.

METHOD: We studied 1Florida ADRC participants (N = 288) with normal cognition, mild cognitive impairment, or dementia (Table 1). Presence or absence of sleep apnea was determined from the National Alzheimer's Coordinating Center Health History. All participants had plasma samples analyzed for p-tau217 (ALZPath) and completed Aβ-PET with [18F] florbetaben or florbetapir. Global standardized uptake value ratio (SUVR; whole cerebellum reference) was calculated and converted to the Centiloid (CL) scale. We used multiple linear regression to assess the interaction of Aβ-PET and sleep apnea status on plasma p-tau217, controlling for age, sex, and CDR sum of boxes. To determine whether sleep apnea moderator effects differed by APOE e4 carrier status, sex, or ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), we employed three-way interactions.

RESULT: Sleep apnea moderated Aβ-PET associations with p-tau217 (β = 0.26, p = .022; Figure 1), such that greater amyloid burden related more strongly to higher plasma p-tau217 in those with sleep apnea versus without. A significant three-way interaction of Aβ-PET x sleep apnea x ethnicity on plasma p-tau217 (β = -0.52, p = .024; Figure 2) revealed that sleep apnea only moderated this association in non-Hispanic/Latino participants. Sleep apnea moderation was not dependent on sex or APOE e4 carrier status.

CONCLUSION: Addressing sleep apnea as a modifiable risk factor may promote slowing or resistance to AD. Larger and longitudinal studies are needed to comprehensively examine sleep apnea in older adults. Exploring sleep apnea effects in more representative samples with consideration of social and structural determinants of brain health will help clarify the role of sleep on AD onset and progression.},
}

Humans
Male
Female
Aged
Positron-Emission Tomography
Biomarkers/blood
*tau Proteins/blood
*Amyloid beta-Peptides/metabolism
*Alzheimer Disease/diagnostic imaging
*Cognitive Dysfunction/diagnostic imaging/blood
*Sleep Apnea Syndromes/diagnostic imaging/complications/blood
Aged, 80 and over
Apolipoprotein E4/genetics
Middle Aged
Brain/diagnostic imaging/metabolism
Aniline Compounds
Carbolines

@article {pmid41512880,
year = {2025},
author = {Agrawal, D and Malo, PK and Krishnamurti, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107723},
doi = {10.1002/alz70856_107723},
pmid = {41512880},
issn = {1552-5279},
mesh = {Humans ; Aged ; Aged, 80 and over ; Female ; Male ; *Speech Perception/physiology ; *Alzheimer Disease/complications ; Biomarkers ; *Hearing Loss/complications ; *Cognitive Dysfunction ; },
abstract = {BACKGROUND: Age related hearing loss (HL) is highly prevalent in older adults and is frequently exacerbated by cognitive decline, such as Alzheimer's disease (AD). While speech communication primarily focusses on segmental content, the prosody- i.e suprasegmental aspects encompassing rhythm, stress and intonation play a critical role in conveying meaning, emotion and syntactic structure. As prosody relies on both auditory and cognitive mechanisms, both of which most of the time are significantly impaired in AD. This study investigates how cognitive impairment affects prosody perception in older adults with HL_AD compared to individuals with HL but no AD.

METHOD: Participants were grouped into two: 1) six older adults (65-85 years) with HL-AD, and 2) six older adults with HL but no AD. The Vocalic Sensitivity Test (VST), which measures prosodic elements such as word stress, grammatical function, emotional prosody, and intonation, was used. The VST involved listening to time-compressed speech and identifying prosodic features. Stimuli were delivered through TDH-39 earphones, and responses were recorded on a laptop with dual raters to ensure reliability. The Mann-Whitney U-test was used to check for the differences in VST scores between the study groups. Median and interquartile range (IQR) are reported, and the statistical significance was based on 10000 samples using the Monte Carlo method at 5% level of significance.

RESULT: Monte Carlo simulated significance levels showed a significant difference between the groups for intonation (control: median (IQR) 8.00 (4.75); HL-AD: 3.50 (2.50); p =  0.032), word stress (control: 8.00 (5.75); HL-AD: 3.50 (2.00); p =  0.044), grammatical function (control: 6.50 (3.50); HL-AD: 3.00 (2.75); p =  0.025) and total VST score (control: 27.00 (12.25); HL-AD: 14.50 (3.75); p =  0.033). However, there was no significant difference for emotional prosody (control: 4.50 (2.75); HL-AD: 3.50 (1.25); p =  0.276).

CONCLUSION: This study reveals that older adults with AD_HL experience considerable difficulty distinguishing prosodic aspects of speech, particularly in word stress, grammatical function, and intonation. Thus improving prosodic perception along with auditory and cognitive abilities is crucial for better communication outcomes, social interaction, and speech comprehension, all of which would improve the quality of life.},
}

Humans
Aged
Aged, 80 and over
Female
Male
*Speech Perception/physiology
*Alzheimer Disease/complications
Biomarkers
*Hearing Loss/complications
*Cognitive Dysfunction

@article {pmid41512865,
year = {2026},
author = {Toda Robert, A and McQuade, A and Koppes-den Hertog, SJ and Erlebach, L and Kronenberg-Versteeg, D and Kampmann, M and Giera, M and van der Kant, R},
title = {Comparative lipidomics of iPSC-derived microglia protocols reveal lipid droplet and immune differences mediated by media composition.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102779},
doi = {10.1016/j.stemcr.2025.102779},
pmid = {41512865},
issn = {2213-6711},
abstract = {Altered microglial lipid metabolism is heavily implicated in Alzheimer's disease (AD) and aging. Recently, protocols were developed to generate human induced pluripotent stem cell-derived microglia-like cells (iMGL) to study microglial function in vitro, including embryoid body-based methods and induced transcription factor (iTF)-dependent approaches. Here, we performed comparative lipidomics on iMGL from these methods and report major differences in multiple lipid classes, including triglycerides (TGs), a storage form of fatty acids implicated in microglial reactivity. TGs are strongly increased in iTF microglia due to the absence of a media supplement (B-27). Supplementing iTF microglia with B-27, or its component L-carnitine, reduces TGs and promotes a homeostatic state. B-27 also renders iTF microglia metabolically responsive to immune stimuli. Overall, our data show that iMGL differentiation methods have a major impact on microglial lipidomes and warrant attention when studying AD and neuroinflammatory processes involving lipids.},
}

@article {pmid41512849,
year = {2025},
author = {King-Robson, J and Soreq, E and Cartlidge, MRE and Harrison, M and Murray-Smith, H and Aimola, L and Poole, M and Ardle, RM and Keshavan, A and Cash, DM and Coath, W and Robinson, L and Sharp, DJ and Schott, JM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105509},
doi = {10.1002/alz70856_105509},
pmid = {41512849},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; tau Proteins/blood ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; Aged ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Sleep/physiology ; Aged, 80 and over ; Cohort Studies ; },
abstract = {BACKGROUND: Sleep and circadian disruption are associated with increased dementia risk. Digital sleep biomarkers may provide an ecologically valid and low-burden means of remote population-level screening for incipient dementia. We explored the feasibility and predictive value of a digital sleep biomarker, developed from data collected using the Withings Sleep Analyzer (WSA), a ballistocardiographic under-mattress pressure sensor which collects sleep and physiological data unobtrusively, to detect Alzheimer-related biomarkers in a presymptomatic cohort.

METHOD: Participants from the Insight 46 study (all born in March 1946) underwent serial assessment, including plasma phosphorylated tau (pTau)217 ALZpath and 18F-Florbetapir β-amyloid PET at age ∼73 and 18F-MK-6240 Tau PET at age ∼77. Amyloid status (-/+) and Tau Braak staging (-/Braak1+/Braak3+) were derived using automated pipelines. The WSA was deployed at age ∼78, installed under participants' mattresses by the study participant/family. Continuous sleep, circadian, and physiological parameters were collected. A leave-one-out cross validation approach was employed to develop models predicting PET status after feature selection (Figure 1). Results were compared to plasma pTau217.

RESULT: n = 161 had both WSA and Tau PET data (12.4% Braak1+, 6.2% Braak3+); n = 153 participants also had β-amyloid PET (25% β-amyloid+ at Centiloid>=12). In total we collected 63,720 nights (174 years) of sleep data, corresponding to a mean±SD of 239.8±108.7 nights/participant (age at collection 78.3±0.2 yrs; 49% female). n = 404 had plasma pTau217. A final trained model identified asymptomatic individuals with Braak3+ tau pathology with area under the receiver operating characteristic curve (AUROC)=0.75; comparable to plasma pTau217 (Figure 2) after iterative feature selection (Figure 3). Trained models were less effective at identifying earlier pathological stages (Tau Braak1+, β-amyloid+).

CONCLUSION: Deploying a remote sleep and circadian monitoring device in a countrywide population-based cohort in their late 70s is feasible. A model based on iterative feature selection was able to identify individuals with significant Tau (Braak3+) pathology with AUROC similar to plasma pTau217. This provides proof-of-concept that digital sleep biomarkers may be useful in identifying individuals at high risk of developing clinical AD. Work is underway to refine the model further, replicate these results in other cohorts, and identify the shortest duration of recording required for robust prediction.},
}

Humans
*Biomarkers/blood
Male
Female
tau Proteins/blood
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
Aged
*Alzheimer Disease/diagnosis/diagnostic imaging
*Sleep/physiology
Aged, 80 and over
Cohort Studies

@article {pmid41512848,
year = {2025},
author = {Singh, S and Rudolph, MD and Bateman, TR and Hughes, TM and Sai, KKS and Craft, S and Gurcan, MN and Popuri, K and Beg, MF and Zhang, L and Ma, D},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107676},
doi = {10.1002/alz70856_107676},
pmid = {41512848},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; *Biomarkers ; Positron-Emission Tomography ; Male ; Disease Progression ; Female ; *Neuroimaging/methods ; *Brain/diagnostic imaging/pathology ; Aged ; Cognitive Dysfunction/diagnostic imaging/pathology ; Deep Learning ; Machine Learning ; Atrophy ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is defined by multi-domain biomarkers according to the revised classification framework. Machine learning models may benefit from an effective combination of multiple modalities. This study aims to incorporate multi-modal neuroimaging data (T1-MRI and amyloid-PET) to improve the predictive power of deep learning models, capturing both the amyloid (A) and atrophy (N) patterns in the brain to derive dementia risk score (DRS) and prediction risk of future progression of dementia at the early stage of the AD.

METHOD: We used the multi-modal neuroimaging data from the ADNI 1,2 and GO datasets (Table 1). The CN and AD subjects were used to train a classification model through 5-fold cross-validation to learn AD-related neuroimaging features and derive the dementia risk scores. The derived models were then applied to subjects who were diagnosed as MCI at their baseline measurements to predict the future risk of progression to dementia. Both T1-MRI and Amyloid-PET data were rigid-registered to the MNI space and skull-stripped. ResNet50 models with initial model weights pre-trained from MedicalNet were fine-tuned to train classification tasks for MRI and PET independently. The resulting single-modal DRS was then averaged to achieve a fused multi-modal DR. The multi-modal DRS was then used to infer the final prediction for future dementia onset. Predictive performance was evaluated via balanced accuracy and AUC.

RESULT: When classifying AD/CN, the balanced accuracy is 94.53% for the MRI-only model, 86.53% for the PET-only model; and 97.29% for the fused model. For predicting future MCI progression, the balance accuracy was 71.17% for MRI-only model, 71.79% for the PET-only model, and 74.59% for the fused model (Table 2, Figure 1).

CONCLUSION: This study underscores the potential of leveraging multi-modal deep learning models toward improving accuracy in AD prediction and tracking progression. Results demonstrated complementary strengths of MRI and PET. The reduced performance on pMCI prediction indicates room for improvement with further fine-tuning process, more advanced multi-modal fusion strategy, as well as the best modality (e.g. FDG-PET and tau-PET). Future plans involve multi-modal fusion at an early stage of the model and further evaluate model generalizability using independent datasets such as NACC data.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
Magnetic Resonance Imaging
*Biomarkers
Positron-Emission Tomography
Male
Disease Progression
Female
*Neuroimaging/methods
*Brain/diagnostic imaging/pathology
Aged
Cognitive Dysfunction/diagnostic imaging/pathology
Deep Learning
Machine Learning
Atrophy

@article {pmid41512820,
year = {2025},
author = {Abdelmoity, O and Wisch, JK and Handen, BL and Christian, BT and Mapstone, M and Rosas, HD and Lai, F and Lee, JH and Krinsky-McHale, SJ and Schmitt, FA and Harp, JP and Hom, CL and Lott, IT and Hartley, SL and Zaman, S and Ptomey, L and Burns, JM and Ibanez, L and Rafii, MS and Head, E and Ances, B},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107707},
doi = {10.1002/alz70856_107707},
pmid = {41512820},
issn = {1552-5279},
mesh = {Humans ; *Down Syndrome/genetics/diagnostic imaging ; *tau Proteins/blood ; Male ; Female ; Biomarkers/blood ; Positron-Emission Tomography ; *Apolipoprotein E4/genetics ; *Alzheimer Disease/genetics/diagnostic imaging ; Middle Aged ; Aged ; Brain/diagnostic imaging/metabolism ; Longitudinal Studies ; Amyloid beta-Peptides/metabolism ; },
abstract = {BACKGROUND: Down syndrome (DS) represents a genetic form of Alzheimer's disease (AD) with an earlier expected symptom onset compared to late onset AD (LOAD). It is thought that the extra copy of the Amyloid Precursor Protein (APP) gene, located on chromosome 21 contributes to the earlier onset due to increased amyloid deposition in the brain. Hyperphosphorylation of tau protein is also thought to be elevated in the beginning stages of AD pathology within DS. Although APOEε4 has been associated with greater AD risk in LOAD, prior cross-sectional investigations into the effects of APOEε4 in DS have suggested that there is no additional impact of APOEε4 on the accumulation of amyloid. We aimed to extend this work by examining the associations between longitudinal plasma pTau217 and amyloid PET as a function of APOEε4 status.

METHOD: Participants with DS were recruited from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. Both p-tau217 (N = 564 results from 223 individuals including 122 that had 3 results each, Lilly MSD) and Amyloid PET ([11C]-PiB or [18F]-AV45) (N = 366 scans with 253 unique participants including 113 that had 2 scans each) were acquired. We analyzed the influence ɛ4 allele carrier status had on changes in pTau217 and amyloid across age using linear mixed-effects modeling, including the age, APOEε4 carrier status and their interaction as covariates. Age was also included as a covariate.

RESULT: Individuals that are carriers of the APOEε4 allele present with similar baseline amyloid and pTau217 values (p = .591 & p = .455 respectively). The rate of amyloid and pTau217 accumulation increased across age similarly for both groups (p = .772 & p = .657 respectively). Although not statistically significant, visual inspection suggests that, with a larger number of participants, individuals between the ages of 45 and 50 who are ɛ4 allele carriers may exhibit elevated pTau217 levels compared to non-carriers.

CONCLUSION: We did not observe increased amyloidosis or tau phosphorylation in APOEε4 carriers with DS. Future studies targeting individuals aged 45-50 are suggested to investigate the potential APOEε4 effect on tau phosphorylation observed in this narrow chronological window, which is close to the average expected age of symptom onset of 52.5 years for DS.},
}

Humans
*Down Syndrome/genetics/diagnostic imaging
*tau Proteins/blood
Male
Female
Biomarkers/blood
Positron-Emission Tomography
*Apolipoprotein E4/genetics
*Alzheimer Disease/genetics/diagnostic imaging
Middle Aged
Aged
Brain/diagnostic imaging/metabolism
Longitudinal Studies
Amyloid beta-Peptides/metabolism

@article {pmid41512538,
year = {2026},
author = {Yao, D and Zhang, N and Yao, Q and Xie, Y and Tian, R and Wu, X and Kuang, W},
title = {Discovery of a novel tau PET tracer: Design, synthesis, radio-labeling, and preclinical evaluations.},
journal = {European journal of medicinal chemistry},
volume = {305},
number = {},
pages = {118542},
doi = {10.1016/j.ejmech.2025.118542},
pmid = {41512538},
issn = {1768-3254},
abstract = {Nitrogen-containing heterocyclic small molecule derivatives have been proved to possess potent affinity with tau aggregates. A series of imidazo[1,2-a]pyridine analogues were designed and synthesized for the screen of potential highly selective tau targeted PET tracers. Structure activity relationship study of these compounds led to the discovery of compound 28, which showed high affinity with tau aggregates (Ki = 0.99 nM). Compound 28 also displayed fast pharmacokinetic properties which are suitable to be developed as PET tracers. Based on the direct SNAr radiofluorination, [18]F-28 was successfully produced with high radiochemical yield. In vitro stability tests and log D7.4 measurement indicated [18]F-28 hold suitable physicochemical parameters for blood-brain-barrier (BBB) penetration and in vivo PET brain imaging. In micro-PET imaging studies, high initial brain uptake was observed with [18]F-28 in normal mice and P301L transgenic mice, as well as a fast clearance from brain. [18]F-28 was also evaluated in non-human primates, which also displayed a fast in and fast out accumulation in the brain. According to the autoradiographic analysis of [18]F-28 with human brain tissues, positive deposits in temporal lobe can be confirmed, which is well agreed with immunohistochemistry results with tau-antibodies. Therefore, the preclinical results revealed compound 28 holds the potential to be developed as a potent and selective tau aggregate targeted PET tracer, and further optimizations and evaluations may still be needed.},
}

@article {pmid41512495,
year = {2026},
author = {Liu, Y and Yao, L and Liu, J and Li, H and Zeng, Y and Xu, Y},
title = {Leveraging hemispheric asymmetry in structural MRI with an attention-guided 3D CNN for early prediction of Alzheimer's conversion.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {197},
number = {},
pages = {108534},
doi = {10.1016/j.neunet.2025.108534},
pmid = {41512495},
issn = {1879-2782},
abstract = {Early identification of mild cognitive impairment (MCI) progressing to Alzheimer's disease (AD) is of paramount importance. Despite the notable advances in deep learning in this domain, current approaches are largely based on global brain analysis and often overlook the hemispheric asymmetry, which is a critical biomarker for AD progression. Although longitudinal studies can capture temporal dynamics, their clinical feasibility is constrained by the need for multiple follow-up visits. To address this issue, we propose HemiNet, a lightweight 3D convolutional neural network based on hemispheric difference analysis, enabling accurate prediction of MCI progression from structural MRI at a single time point. HemiNet is designed with three key modules. First, the asymmetry discrepancy mining strategy is employed to quantify interhemispheric structural differences, derive disease-specific biomarkers, and effectively capture multi-level asymmetry features. Second, the contralateral hemispheric fusion mechanism is designed to adaptively unify bilateral features through discrepancy-aware gating combined with depthwise separable convolution, thus strengthening asymmetry patterns indicative of AD. Finally, the pathology focal attention mechanism is applied with sequential channel-spatial attention to highlight pivotal pathological regions, such as the hippocampus and temporal lobe, thereby enhancing the discriminative capacity of the learned features. Extensive experiments and cross-validation on the ADNI dataset demonstrate that HemiNet achieves an AUC of 84.01% and an accuracy of 78.19% for MCI prediction. This study validates the value of hemispheric asymmetry analysis for early AD detection and presents an efficient, lightweight, and interpretable method for MCI progression prediction from a single scan.},
}

@article {pmid41512461,
year = {2025},
author = {Rodrigues, GB and Ribeiro, IC and da SIlva, MCR and Rizzi, L and Gonçalves, BC and Aventurato, ÍK and Silva, A and Pinheiro, TL and Santos, LE and Felice, FG and Cendes, F and Balthazar, MLF},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107675},
doi = {10.1002/alz70856_107675},
pmid = {41512461},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Aged ; Female ; *Cognitive Dysfunction/blood/diagnostic imaging/physiopathology ; *Amyloid beta-Peptides/blood ; Magnetic Resonance Imaging ; tau Proteins/blood ; *Alzheimer Disease/blood ; *Brain/diagnostic imaging/physiopathology ; Middle Aged ; Neuropsychological Tests ; Peptide Fragments/blood ; *Default Mode Network/physiopathology/diagnostic imaging ; },
abstract = {BACKGROUND: Disruptions in brain network connectivity are strongly associated with the progression of cognitive decline in the Alzheimer's disease (AD) continuum, including mild cognitive impairment (MCI). This study aimed to investigate the relationship between alterations in functional brain connectivity within the default mode network (DMN) in patients with MCI and plasma biomarker levels typically altered in AD (Aβ40, Aβ42, Tau, pTau-181, Aβ42/Aβ40, Aβ42/pTau, Aβ42/tTau, pTau/tTau).

METHODS: Eighteen patients (mean age = 65 years) diagnosed with MCI according to the 2018 NIA-AA and Alzheimer's Association criteria, based on medical and neuropsychological evaluation at the Hospital das Clínicas, University of Campinas (HC-UNICAMP), Brazil, were selected for blood collection and subsequent functional magnetic resonance imaging (fMRI) scans. Plasma samples were stored and analyzed using the automated SIMOA HD-X immunoassay system (Quanterix, Billerica, MA). Resting-state fMRI (RS-fMRI) data were acquired using a 3T Achieva-Intera PHILIPS® scanner. Both imaging data and correlation analyses were processed using the UF2C toolbox within MATLAB and SPM12, with results corrected for false discovery rate (FDR).

RESULTS: Two notable negative correlations were found between the right hippocampus and right precuneus and the Aβ42/Aβ40 ratio (Spearman's correlation: r = -0.76, p =  0.033). No significant correlations were observed for other plasma biomarkers after FDR correction.

CONCLUSION: Since network reorganization is a characteristic feature of MCI and AD, with regions exhibiting increased or decreased activity, the observed inverse relationship between Aβ42/Aβ40 and functional connectivity between the right hippocampus and right precuneus (indicating that an increase in Aβ42/Aβ40 is associated with decreased functional connectivity, and vice versa) supports the disease's underlying pathophysiology. This finding provides a potential avenue for research and diagnostic monitoring. Further studies are needed to explore the functional impact of these alterations and their relevance to disease progression.},
}

Humans
*Biomarkers/blood
Male
Aged
Female
*Cognitive Dysfunction/blood/diagnostic imaging/physiopathology
*Amyloid beta-Peptides/blood
Magnetic Resonance Imaging
tau Proteins/blood
*Alzheimer Disease/blood
*Brain/diagnostic imaging/physiopathology
Middle Aged
Neuropsychological Tests
Peptide Fragments/blood
*Default Mode Network/physiopathology/diagnostic imaging

@article {pmid41512459,
year = {2025},
author = {Lahna, D and Schwartz, D and Roese, NE and Hurworth, J and Woltjer, RL and Mattek, N and Kaye, JA and Silbert, LC},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107686},
doi = {10.1002/alz70856_107686},
pmid = {41512459},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Alzheimer Disease/pathology/diagnostic imaging ; Neuropsychological Tests ; *White Matter/pathology/diagnostic imaging ; Biomarkers ; *Cognitive Dysfunction/pathology ; Aged, 80 and over ; *Brain/pathology ; *Dementia, Vascular/pathology ; },
abstract = {BACKGROUND: MRI-visible white matter (WM) perivascular space (PVS) burden is associated with aging as well as with various disease states, including Alzheimer's Disease (AD) and vascular cognitive impairment (VCI). The objective of this study was to examine relationships between PVS in subcortical WM with tissue pathologies associated with AD and VCI and premortem neuropsychological test performance.

METHOD: 172 subjects received a 1.5T MRI including coronal SPGR and spin echo PD/T2 as part of research at the Oregon Alzheimer's Disease Research Center (OADRC). All participants underwent neuropsychological testing, and a subset (n = 76) had NACC pathology data available (Table 1). MRI volumes were resampled to 1mm isotropic resolution. The T1 was skull stripped, denoised, and registered to a synthetic FLAIR volume generated by taking the product of the PD and T2. Tissue types were segmented (Freesurfer 7.1.1) from the skull stripped and denoised T1 volume. PVS segmentation was accomplished using a local heterogeneity approach on NAWM (non-synFLAIR hyperintense) voxels in T1-weighted volumes with object-level morphology constraints used to identify likely MRI-visible PVS. Multiple linear regressions were performed using PVS burden metrics as independent variables with cognitive tests as dependent variables while controlling for age, sex and brain volume (for PVS predictors) and the time interval between in vivo MRI and death (for pathology predictors) RESULT: Mean age at MRI and death were 86.6 and 96.0 years, respectively. Greater WM PVS burden (count and volume) was related to poorer performance on tests of frontal executive function (Trails B, Category Fluency, digit symbol) and increased pathological markers of both large and small vessel cerebrovascular disease (Table 2). Total PVS was not related to memory (delayed recall), global cognition (MMSE) or AD pathology.

CONCLUSION: In vivo MRI-visible PVS burden within the subcortical WM is associated with a cognitive profile and neuropathologic findings consistent with cerebrovascular disease, supporting its use as a vascular marker in aging studies. Future work should consider longitudinal analysis to confirm the temporal order of increases in MR-visible PVS burden and cognitive decline.},
}

Humans
Male
Female
Magnetic Resonance Imaging
Aged
*Alzheimer Disease/pathology/diagnostic imaging
Neuropsychological Tests
*White Matter/pathology/diagnostic imaging
Biomarkers
*Cognitive Dysfunction/pathology
Aged, 80 and over
*Brain/pathology
*Dementia, Vascular/pathology

@article {pmid41512332,
year = {2025},
author = {Mitchell, SW and Chan, T and Trudel, L and Hosseini, SA and Macedo, AC and Gonçalves, MP and Rahmouni, N and Hall, BJ and Socualaya, KMQ and Therriault, J and Servaes, S and Bezgin, G and Zheng, Y and Aumont, E and Wang, YT and Arias, JF and Real, APB and Jia, WL and Hopewell, R and Hsiao, C and Soucy, JP and Vitali, P and Pascoal, TA and Rosa-Neto, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107705},
doi = {10.1002/alz70856_107705},
pmid = {41512332},
issn = {1552-5279},
mesh = {Humans ; Male ; Biomarkers/metabolism ; Female ; Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aged ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; tau Proteins/metabolism ; *Brain/diagnostic imaging/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Cross-Sectional Studies ; *Tauopathies/diagnostic imaging/metabolism ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Brain and cognitive resilience (BR, CR) reflect the capacity to maintain structural integrity and cognitive function despite pathological tau deposition in Alzheimer's disease (AD). Tau pathology can be characterized in terms of spatial extent of tauopathy (SEOT) or load using standardized uptake value ratio (SUVR). The aim was to compare SEOT and SUVR in their association with BR and CR. To replicate findings from Ossenkoppele et al. (2020) using MK-6240 PET imaging and evaluate demographic, genetic, and imaging factors associated with BR and CR. The objective of this study is to assess the value of SEOT metrics in resilience models and compare their predictive power to standardized uptake value ratio (SUVR) and to evaluate cross sectional interactions between tau pathology, cognitive resilience, and cognitive decline.

METHOD: We assessed 126 amyloid-β-positive participants TRIAD cohort with tau-PET using [[18]F]MK6240 and cognitive assessments (MMSE). SEOT was quantified as the proportion of voxels considered as abnormal relative to young controls. We used Participants recruited from TRIAD cohort, including individuals with mild cognitive impairment (MCI) or AD, positive amyloid-β biomarkers, MK-6240 PET imaging data.

RESULT: Higher Whole Cortex MK SUVR is associated with lower MMSE scores, showing increased tau pathology correlates with cognitive decline. MCI patients maintain higher MMSE scores despite some tau accumulation, while AD patients show greater variability and decline. The negative trend suggests tau deposition contributes to cognitive impairment, but other factors may also play a role. 2. Whole Cortex MK SUVR vs. MMSE the negative correlation between Whole Cortex SEOT and MMSE appears stronger, with a more pronounced decline in cognitive function (MMSE scores) as SEOT increases, suggesting SEOT may be a more sensitive marker of disease progression in AD patients.

CONCLUSION: Whole Cortex SEOT exhibits a stronger negative correlation with MMSE compared to Whole Cortex MK-6240 SUVR, indicating that SEOT may serve as a more sensitive marker of cognitive decline in Alzheimer's disease and mild cognitive impairment. Further research is needed to validate SEOT's potential as a diagnostic or prognostic biomarker in neurodegenerative conditions.},
}

Humans
Male
Biomarkers/metabolism
Female
Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/metabolism
Aged
*Cognitive Dysfunction/diagnostic imaging/metabolism
tau Proteins/metabolism
*Brain/diagnostic imaging/metabolism/pathology
Amyloid beta-Peptides/metabolism
Cross-Sectional Studies
*Tauopathies/diagnostic imaging/metabolism
Neuropsychological Tests

@article {pmid41512324,
year = {2025},
author = {Jannati, A and Thompson, K and Toro-Serey, C and Higgins, C and Bates, D and Pascual-Leone, A and Tobyne, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107677},
doi = {10.1002/alz70856_107677},
pmid = {41512324},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/diagnosis/diagnostic imaging/metabolism ; *Cognitive Dysfunction/diagnosis/diagnostic imaging/metabolism ; Positron-Emission Tomography ; *Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; Neuropsychological Tests ; *Brain/diagnostic imaging/metabolism ; Aniline Compounds ; Aged, 80 and over ; },
abstract = {BACKGROUND: The efficacy of disease-modifying treatments (DMTs) for Alzheimer's disease (AD) hinges on early detection of cognitive impairment and abnormal brain amyloid-beta (Aβ) levels. Moreover, AD clinical trials face significant barriers of high screening failure rates and expensive prescreening. Therefore, there is an urgent need to address these challenges by developing a more efficient and cost-effective method for early AD identification and differentiation from other etiologies. This study evaluated the performance of a combination of Linus Health Digital Clock and Recall (DCR), a 3-minute digital cognitive assessment, and digital Trail-Making Test-Part B (dTMT-B) in detecting cognitive impairment and predicting brain Aβ-PET status.

METHOD: 930 participants (mean age 72.0±6.7; 56.8% female; 23% minorities) in the Bio-Hermes-001 study were classified as cognitively unimpaired (CU), mild cognitive impairment (MCI), or probable Alzheimer's dementia (pAD), and 35.1% were Aβ+ on 18F-florbetapir PET scan. A 3-class, cross-validated machine-learning ensemble model combined multimodal process-based features of DCR and dTMT-B including drawing metrics, temporal-spatial features of stylus manipulation, speech and acoustic features, demographics, and APOE status. All models had <22% indeterminate (Ind.) cases.

RESULT: The DCR+dTMT-B model had AUC=0.906 (NPV=0.816; PPV=0.900) for differentiating HC vs. MCI/pAD vs. Ind., AUC=0.891 (NPV=0.872; PPV=0.808) for differentiating HC vs. MCI vs. Ind., AUC=0.950 (NPV=0.941; PPV=0.870) for differentiating HC vs. pAD vs. Ind., and AUC=0.920 for differentiating MCI vs. pAD vs. Ind. (NPV=0.886; PPV=0.840). For predicting Aβ-PET status, the DCR+dTMT-B model had AUC=0.890 (NPV=0.914; PPV=0.754), whereas the DCR+dTMT-B+APOE model achieved AUC=0.933 (NPV=0.933; PPV=0.815).

CONCLUSION: A multimodal model combining process-based features of DCR and dTMT-B had very good to excellent performance in cognitive-impairment detection and excellent performance in Aβ-PET status prediction, with the DCR+dTMT-B+APOE model performing comparably to CSF biomarkers of AD. This model enables prioritizing the most suitable patients for BBM testing and DMTs, and substantially increases the efficiency of recruitment for AD clinical trials.},
}

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

@article {pmid41512323,
year = {2025},
author = {Trammell, AR and Wingo, AP and Parker, MW and Goldstein, FC and Lah, JJ and Rodriguez, AD and McIntosh, R and Wingo, TS},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107687},
doi = {10.1002/alz70856_107687},
pmid = {41512323},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Female ; Male ; Aged ; Carotid Intima-Media Thickness ; *Alzheimer Disease/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Mounting evidence shows relationships between the cerebrovasculature, cognitive decline, neurodegeneration, and amyloid accumulation that underscores the contribution of cerebrovascular atherosclerotic disease (CA) to the pathogenesis of Alzheimer's disease and related dementias (AD/ADRD). Previously, we identified 114 brain proteins associated with CA as measured by carotid artery intimal media thickness (IMT). That finding suggests that surrogate brain biomarkers of CA may hold promise as sensitive markers for early ADRD detection. Compared to brain tissue, cerebrospinal fluid (CSF) is more accessible and can be collected from living persons. Thus, among the brain proteins profiled, we also profiled 6 (CBR1|P16152, ENDOD1|O94919, MOG|Q16653. PCSK1|P29120, PLP1|P60201, and QDPR|P09417) in CSF. In this follow-up study, we explored the CSF proteome for associations between profiled proteins and CA as measured by carotid artery IMT. Hence, this study aims to explore potential biomarkers of CA and ADRD risk by examining associations between CSF proteins and IMT.

METHOD: All CSF samples and vascular measurements were collected from Emory Goizueta Alzheimer's Disease Research Center research participants. We described the CSF collection steps and multiplex proteomic steps previously.[7] We performed proteomic analysis on 86 CSF samples, followed by linear regression adjusted for age, sex, and cognitive diagnosis (control vs. impaired) to test associations with CA. We applied BoxCox transformation to IMT measures to improve normality and we excluded participants with AD.

RESULT: Data for 83 people were analyzed. The sample's mean age was 65.8 (8.02); 60% were female, 70% were white adults, and 69% were controls. Among white participants, QDPR|P09417 (neurotransmitter production) was associated with higher IMT. For AA participants, PLP1|P60201 (myelin sheath) was associated with higher IMT. In meta-analysis (both groups), QDPR|P09417 and MOG|Q16653 (myelin sheath) were associated with higher mean carotid IMT.

CONCLUSION: Vascular disease can co-occur with AD. Our results show associations between CSF proteins involved in structural integrity and chemical signaling and CA in a sample with impaired and normal cognition. Further, we detected racial differences in these associations. Given these findings among cognitively normal and impaired people, these proteins may have promise as early disease indicators. More extensive study with a larger sample is needed.},
}

Humans
*Biomarkers/cerebrospinal fluid
Female
Male
Aged
Carotid Intima-Media Thickness
*Alzheimer Disease/cerebrospinal fluid
Middle Aged
Aged, 80 and over

@article {pmid41512318,
year = {2025},
author = {Chan, T and Hosseini, SA and Macedo, AC and Trudel, L and Gonçalves, MP and Rahmouni, N and Hall, BJ and Therriault, J and Socualaya, KMQ and Servaes, S and Bezgin, G and Zheng, Y and Wang, YT and Aumont, E and Arias, JF and Real, APB and Jia, WL and Hopewell, R and Hsiao, C and Vitali, P and Pascoal, TA and Rosa-Neto, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107658},
doi = {10.1002/alz70856_107658},
pmid = {41512318},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; Female ; Male ; Aged ; *Alzheimer Disease/cerebrospinal fluid/blood ; *tau Proteins/cerebrospinal fluid/blood ; *Blood-Brain Barrier/metabolism ; *Neurofilament Proteins/cerebrospinal fluid/blood ; Amyloid beta-Peptides/cerebrospinal fluid ; Positron-Emission Tomography ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: Ratio between plasma and cerebrospinal fluid (CSF) biomarkers might inform about the peptide clearance from the central nervous system (CNS) to the peripheral body compartments. However, whether this clearance is linked to blood-brain barrier (BBB) alterations in Alzheimer's disease (AD) remains unclear. In this study, we examined the ratio between plasma and CSF neurofilament light chain (NfL) and p-tau181 and its relationship with BBB permeability in individuals across the AD spectrum.

METHOD: We analyzed data of 102 participants (median age 66 years, 54% female) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Plasma and CSF levels of NfL and p-tau181 were measured using Lumipulse G1200 (Fujirebio). The CSF/serum albumin quotient, a marker of BBB integrity, was calculated, where higher values indicate increased permeability. Mann-Whitney U test compared the biomarker ratios among ATN groups. Spearman's correlation examined the association between the plasma/CSF biomarker ratios and amyloid PET ([18]F-NAV4694) global standardized uptake value ratio (SUVR), and between plasma/CSF biomarker ratios and the albumin quotient.

RESULT: Plasma p-tau181/CSF p-tau181 ratio and plasma NfL/CSF NfL ratio were decreased in A+T+ individuals (Figure 1), suggesting impaired CSF clearance in AD. No significant differences in albumin quotient values were observed among ATN groups. Moreoever, increased amyloid burden on PET correlated with reduced plasma/CSF p-tau181 and NfL ratios (Figure 2), further supporting a link between amyloid pathology and impaired clearance mechanisms. Finally, no significant correlation was found between plasma/CSF p-tau181 and NfL ratios and albumin quotient (Figure 3), suggesting that CSF clearance deficit is independent of BBB integrity.

CONCLUSION: Our results support the concept that impaired CSF clearance contributes to the accumulation of AD biomarkers in the CNS. Moreover, the impaired CSF clearance does not seem to be associated with BBB dysfunction. These results highlight CSF clearance as a potential therapeutic target for AD, emphasizing the need to explore mechanisms that enhance peptide drainage from the CNS.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
Female
Male
Aged
*Alzheimer Disease/cerebrospinal fluid/blood
*tau Proteins/cerebrospinal fluid/blood
*Blood-Brain Barrier/metabolism
*Neurofilament Proteins/cerebrospinal fluid/blood
Amyloid beta-Peptides/cerebrospinal fluid
Positron-Emission Tomography
Middle Aged
Cohort Studies

@article {pmid41512317,
year = {2025},
author = {Barcellos, LFB and Ferrari-Souza, JP and de Jesus Vanni, IJ and Valer, MAA and Bieger, A and Leffa, DT and Lussier, FZ and Brum, WS and Aguzzoli, C and Corin, A and Bastiani, MA and Carello-Collar, G and Borelli, WV and Rahmouni, N and Therriault, J and Trudel, L and Macedo, AC and Ferreira, PCL and Povala, G and Bellaver, B and Souza, DO and Rosa-Neto, P and Pascoal, TA and Zimmer, ER},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107663},
doi = {10.1002/alz70856_107663},
pmid = {41512317},
issn = {1552-5279},
mesh = {Humans ; Male ; Positron-Emission Tomography ; Female ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; Biomarkers/metabolism ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Aged ; Atrophy/pathology ; *Brain/pathology/diagnostic imaging ; Disease Progression ; Plaque, Amyloid/diagnostic imaging/pathology ; Middle Aged ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) diagnostic and staging criteria rely on imaging biomarkers as robust tools for in vivo disease assessment. Among these, cortical brain atrophy is recognized as a key hallmark of disease progression. However, rates of cortical atrophy in preclinical stages remain insufficiently explored within current staging frameworks. In a group of amyloid β-positive (Aβ+) asymptomatic individuals, we investigated the association of the imaging-based biological AD staging framework with longitudinal brain atrophy patterns.

METHODS: We included 162 Aβ+ participants from the A4 Study placebo group with available magnetic resonance imaging (MRI) and positron emission tomography (PET) for amyloid-β (Aβ) plaques ([[18]F]Florbetapir) and tau ([[18]F]Flortaucipir) at baseline, along with a follow-up MRI at least 2 years after baseline. Tau positivity in the medial temporal lobe (TMTL+) and in the neocortex (TNEO+) were determined as tau PET standardized uptake value ratio (SUVR) of 2.5 standard deviations above the mean derived from a separate population (LEARN substudy) of 55 Aβ-negative individuals. Groups were compared using analysis of covariance (ANCOVA) with Tukey's multiple comparison test, adjusting for relevant covariates.

RESULTS: Demographic characteristics of the population are displayed in Table 1. In cross-sectional analysis, we observed that baseline cortical gray matter volumes differed significantly only between A+TNEO+ and A+T- groups (p = 0.042), with no significant differences between other groups (p >0.05 for both; Figure 1a). Longitudinally, A+TNEO+ individuals exhibited greater rates of cortical atrophy compared to A+T- (p <0.001) and A+TMTL+ (p = 0.007), along with A+TMTL+ individuals showing higher rates of cortical atrophy compared to the A+T- group (p = 0.042; Figure 1b). Subsequent regional analyses revealed that the A+TNEO+ individuals showed higher atrophy compared to both A+T- and A+TMTL+ in temporal and parietal regions (Figure 2).

CONCLUSIONS: Our findings reveal that the imaging-based biological AD staging is closely associated with cortical brain atrophy, showing a gradual acceleration in rates of cortical atrophy across stages. Additionally, our results suggest that serial volumetric measurements of temporoparietal brain regions may be sensitive biomarkers of early disease progression. Taken together, our findings provide valuable insights for applying the imaging-based biological AD staging in preclinical AD.},
}

Humans
Male
Positron-Emission Tomography
Female
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
Magnetic Resonance Imaging
Biomarkers/metabolism
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Aged
Atrophy/pathology
*Brain/pathology/diagnostic imaging
Disease Progression
Plaque, Amyloid/diagnostic imaging/pathology
Middle Aged

@article {pmid41512316,
year = {2025},
author = {Guo, G and Sathu, H and Rudolph, MD and Bateman, TR and Hughes, TM and Craft, S and Gurcan, MN and Luo, S and Ma, D},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107666},
doi = {10.1002/alz70856_107666},
pmid = {41512316},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/diagnosis ; Male ; Female ; *Biomarkers ; Magnetic Resonance Imaging ; Aged ; *Cognitive Dysfunction/diagnostic imaging/pathology ; *Neuroimaging/methods ; Atrophy/pathology ; *Cerebral Cortex/diagnostic imaging/pathology ; Neural Networks, Computer ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is the leading cause of dementia. Cortical atrophy patterns derived from T1 MRI are sensitive neuroimaging biomarkers to detect early signs of AD-related neurodegeneration. However, early diagnosis at the prodromal stage is challenging due to the subtle and heterogeneous neuropathological and neurodegeneration patterns over the cortical surface, which cannot be captured by conventional deep learning methods natively. In this study, we developed an explainable cortical graph convolutional network (GCN) that captures the early signs of atrophy patterns in the cortical surface as graph-based features to identify subjects with elevated AD risk.

METHOD: T1 MRI data from the baseline visit of Alzheimer's Disease Neuroimaging Initiative (ADNI; 1645 subjects, 902 Male, 743 Female; stable NC [sNC]: 523, stable [AD]: 339, MCI: 783) dataset was processed through FreeSurfer (v7.4). Five-fold cross-validated models were built using 90% of the CN+AD data as training (stratified by gender and clinical diagnosis), with 10% reserved for independent testing. The dementia risk models were then applied to predict stable mild cognitive impaired (sMCI) vs. progressive MCI (pMCI) to evaluate their performance to predict future risk of dementia onset. A cortical GCN model handles the cortical surface mesh as graphic-based input, where cortical morphological data (thickness and curvature) are defined on each vertex (graph node) and used as predictive features. During training, batch normalization and dropout were applied to each graph convolutional layer to mitigate overfitting and enhance training stability.

RESULT: The cortical GCN classification model achieved a balanced accuracy of 0.736 in differentiating dementia (AD) and cognitively normal (CN) subjects and an average mean balanced accuracy of 0.644 for predicting sMCI from pMCI.

CONCLUSION: This project demonstrated the effectiveness of using cortical GCN to achieve early prediction for future dementia onset for subjects with risk of AD. Future work will focus on independent validation of NACC/ADRC data to evaluate the model's generalizability, as well as enhance the model's explainability through techniques such as Grad-CAM and integrated gradient. These efforts will provide deeper insights into AD's neuroanatomical aspects and contribute to developing more accurate, transparent, and effective diagnostic tools.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/diagnosis
Male
Female
*Biomarkers
Magnetic Resonance Imaging
Aged
*Cognitive Dysfunction/diagnostic imaging/pathology
*Neuroimaging/methods
Atrophy/pathology
*Cerebral Cortex/diagnostic imaging/pathology
Neural Networks, Computer

@article {pmid41512283,
year = {2025},
author = {Morcillo-Nieto, AO and Aranha, MR and Arriola-Infante, JE and Franquesa-Mullerat, M and Zsadanyi, SE and Vaqué-Alcázar, L and Parra, JA and Zhao, Z and Arranz, J and Rodríguez-Baz, Í and Maure-Blesa, L and Videla, L and Barroeta, I and Hoyo, LD and Benejam, B and Fernandez, S and Hernandez, AS and Giménez, S and Alcolea, D and Belbin, O and Lleó, A and Carmona-Iragui, M and Fortea, J and Bejanin, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106414},
doi = {10.1002/alz70856_106414},
pmid = {41512283},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid ; Magnetic Resonance Imaging ; Longitudinal Studies ; *White Matter/pathology/diagnostic imaging ; Middle Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; *Down Syndrome/pathology/diagnostic imaging ; tau Proteins/cerebrospinal fluid ; Aged ; Brain/pathology/diagnostic imaging ; Adult ; Cohort Studies ; },
abstract = {BACKGROUND: Down syndrome (DS) is a genetically determined form of Alzheimer's disease (AD) characterized by a low prevalence of traditional age-related vascular risk factors. Emerging evidence indicates that white matter hyperintensities (WMH) are frequent in DS and linked to small vessel disease and neurodegeneration. However, the temporal dynamics of WMH and their relationship with AD pathology remain unexplored in DS. Using an optimal longitudinal preprocessing pipeline, we aimed to determine the evolution of WMH across the AD continuum in DS and define their associations with baseline clinical and pathological characteristics.

METHOD: Longitudinal study including 47 euploid healthy controls (HC) from the SPIN cohort, and 86 individuals with DS from the DABNI cohort, who underwent 2 to 4 3T-MRI visits (Table 1). The DS cohort included individuals with asymptomatic (aDS, n = 66) and symptomatic AD (sDS; n = 18). WMH were segmented on high-resolution FLAIR images using the longitudinal pipeline from the Lesion Segmentation Toolbox in SPM12. Individuals were classified as WMH Regressor, Stable, and Progressor using a previously proposed threshold (±75 mm[3]/year, Al-Janabi et al., 2019). Non-parametric tests assessed the effect of sociodemographic and genetic factors, AD clinical stage, cerebrospinal fluid (CSF) AD biomarkers (Aβ42/Aβ40 ratio, pTau181, and NfL), WMH volume, and microbleed status on annual WMH volume changes.

RESULT: WMH volume significantly decreased with age in DS (rho=-0.37, p <0.001; Figure 1A-B) but not in HC (p = 0.1). This decrease was more pronounced in sDS than aDS (Figure 1C). Regressor individuals were significantly more frequent in sDS (66.67%) than aDS (13.64%) or HC (12.77%). Sex, APOEε4 status, intellectual disability, and microbleed status did not influence WMH changes (Figure 1D-E-F). CSF-pTau181 and NfL, but not Aβ42/Aβ40 ratio, related to annual WMH changes (Figure 2A-B-C). Additionaly, higher baseline WMH volume correlated with decreasing WMH changes (rho=-0.33, p <0.002, Figure 2E). Sensitivity analyses considering white matter atrophy confirmed the robustness of our findings.

CONCLUSION: WMH decreased more frequently over time in DS compared to the general population, particularly in individuals with symptomatic AD and high baseline WMH volume. This unexpected finding, which cannot be attributed to atrophy, offers novel insights into WMH aetiology in DS and has significant implications for targeted interventions using WMH as an outcome.},
}

Humans
Male
Female
Biomarkers/cerebrospinal fluid
*Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid
Magnetic Resonance Imaging
Longitudinal Studies
*White Matter/pathology/diagnostic imaging
Middle Aged
Amyloid beta-Peptides/cerebrospinal fluid
*Down Syndrome/pathology/diagnostic imaging
tau Proteins/cerebrospinal fluid
Aged
Brain/pathology/diagnostic imaging
Adult
Cohort Studies

@article {pmid41512280,
year = {2025},
author = {Smith, R and Alkhodair, Y and Yadegari, M and DeMarco, ML},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107634},
doi = {10.1002/alz70856_107634},
pmid = {41512280},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Apolipoprotein E4/blood/genetics ; Male ; Female ; *Alzheimer Disease/genetics/blood/diagnosis ; Aged ; Genotype ; Apolipoproteins E/genetics/blood ; },
abstract = {BACKGROUND: Anti-amyloid therapies (AAT) for Alzheimer's disease are associated with the risk of amyloid-related imaging abnormalities (ARIA). APOE4 homozygotes (E4/E4) have the highest risk, followed by APOE4 carriers (E4), making APOE genotyping essential for risk assessment. While APOE4 allelic status is routinely determined via DNA (e.g., by RT-PCR), recently developed automated immunoassays offer an alternative approach by measuring the apolipoprotein E4 (apoE4) concentration in plasma (i.e., proteotyping). In this study, we evaluated the diagnostic accuracy of an apoE4 proteotyping assay (Fujirebio Lumipulse) and its suitability for ARIA risk assessment.

METHOD: This diagnostic accuracy study included 104 plasma samples from unique individuals with known APOE genotypes determined by RT-PCR: E2/E3 = 8, E3/E3 = 45, E2/E4 = 1, E3/E4 = 44, and E4/E4 = 6. Plasma samples were analyzed using Fujirebio's Lumipulse G1200 system with the Lumipulse G ApoE4 and Pan-ApoE assays. These assays measure apoE4 and total apoE protein concentrations, respectively, and their ratio is used to infer E4 allelic status (non-E4, E4, or E4/E4). The assays were further evaluated for precision, potential interferences, and sample stability across freeze/thaw cycles.

RESULT: The plasma proteotyping assay demonstrated 100% accuracy in distinguishing the presence or absence of an E4 allele compared to RT-PCR. It correctly classified all non-E4 individuals (n = 53), all E4/E4 (n = 6), and 41 of 45 E4 heterozygotes (4 heterozygotes were misclassified as E4/E4). The ApoE4 and Pan-ApoE assays had total coefficients of variation of 8.5% and 4.0%, respectively. No significant interference was observed for hemolysate up to ∼5.25 g/L of hemoglobin or for lipemia up to ∼500 mg/dL of intralipid. Additionally, freeze-thaw testing showed no significant impact on assay performance for up to 4 freeze/thaw cycles.

CONCLUSION: The evaluated plasma apoE4 phenotyping assay demonstrated perfect accuracy in detecting the presence or absence of an E4 allele. However, it did not reliably distinguish E4 heterozygotes from homozygotes, with several heterozygotes misclassified as E4/E4. In the context of AAT treatment eligibility and ARIA risk assessment, proteotyping is an accurate method for both ruling in and out the presence of an E4 allele but E4/E4 results specifically should be confirmed via genotyping.},
}

Humans
*Biomarkers/blood
*Apolipoprotein E4/blood/genetics
Male
Female
*Alzheimer Disease/genetics/blood/diagnosis
Aged
Genotype
Apolipoproteins E/genetics/blood

@article {pmid41512277,
year = {2025},
author = {Paez, A and Piñol-Ripoll, G and Dogaheh, SB and Gillman, SO and Dakterzada, F and Carnes, A and Barbe, F and Dang-Vu, TT},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107602},
doi = {10.1002/alz70856_107602},
pmid = {41512277},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/cerebrospinal fluid ; Aged ; *Alzheimer Disease/cerebrospinal fluid ; *Orexins/cerebrospinal fluid ; Polysomnography ; Prospective Studies ; Neuropsychological Tests ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Cognitive Dysfunction/cerebrospinal fluid ; Sleep/physiology ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND: Cerebrospinal fluid (CSF) orexin levels are higher in MCI and AD and associated with sleep deterioration, increasing risk of cognitive decline and Alzheimer's disease (AD) progression. Orexin-A is a key sleep-wake cycle regulator. Dual orexin receptor antagonists improve sleep in AD and insomnia and may reduce tau and Aβ deposition in older adults. However, little research has investigated associations between sleep microarchitecture, orexin, neurodegeneration biomarkers, cognitive decline, or mental health in AD.

METHODS: Using data from a prospective cohort study of mild-to-moderate AD (n = 60, 30-female, mean age-74.7), we analysed non-REM sleep spindles, slow oscillations (SO), and their associations with CSF orexin, AD biomarkers, cognition, and mental health over three years. Participants underwent polysomnography (PSG) and CSF draws at baseline, neuropsychological assessment with the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Neuropsychiatric Inventory (NPI) at baseline and 12 months, and Mini-Mental Status Examination (MMSE) at baseline, 12, 24, and 36 months. PSG was scored along American Academy of Sleep Medicine guidelines. Spindle and SO detection were performed using in-house, open-source software packages developed at Concordia University, following Moelle (2011) recommendations for spindles and Staresina's (2015) recommendations for SO. Associations between SO and spindle characteristics (duration, density, power, amplitude) and orexin, Aβ42 and tau at baseline, and baseline orexin and cognition from baseline to 36 months were investigated with false discovery rate-adjusted generalised linear models, controlling for age, sex, apnea-hypopnea index.

RESULTS: We found previously unreported, predictive associations between SO, duration, density, amplitude, and CSF orexin. Orexin also predicted increased ptau181, total-tau, ptau/Aβ42, total-tau/Aβ42. Increased orexin predicted worse cognitive performance (higher ADAS-cog, lower MMSE) from baseline to 36-months and increased neuropsychiatric symptom severity (NPI) from baseline to 12 months. Orexin also moderates relationships between spindles, SO, cognition, and mental health.

CONCLUSIONS: Orexin levels are associated with neurodegeneration biomarkers and cognitive deterioration in AD and moderate relationships between sleep microarchitecture and cognitive changes over time. Orexin may thus constitute a potential target for sleep-related interventions for cognition in neurodegenerative disorders.},
}

Humans
Female
Male
*Biomarkers/cerebrospinal fluid
Aged
*Alzheimer Disease/cerebrospinal fluid
*Orexins/cerebrospinal fluid
Polysomnography
Prospective Studies
Neuropsychological Tests
Amyloid beta-Peptides/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Cognitive Dysfunction/cerebrospinal fluid
Sleep/physiology
Peptide Fragments/cerebrospinal fluid

@article {pmid41512276,
year = {2025},
author = {Russ, KA and Lane, KA and Gao, S and Unverzagt, FW and Hendrie, HC and Foroud, TM and Dage, JL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107656},
doi = {10.1002/alz70856_107656},
pmid = {41512276},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Biomarkers/blood ; Aged ; Nigeria/epidemiology ; *tau Proteins/blood ; Longitudinal Studies ; Aged, 80 and over ; *Alzheimer Disease/blood/epidemiology/genetics ; Indiana/epidemiology ; Middle Aged ; *Cognitive Dysfunction/blood/epidemiology ; Black or African American ; White ; },
abstract = {BACKGROUND: The Indianapolis-Ibadan Dementia Project (IIDP) is a longitudinal epidemiological study that evaluated subjects in Indianapolis, Indiana and Ibadan, Nigeria for prevalence and incidence of cognitive decline and dementia between 1991-2012. Plasma collected from the 2001 wave is currently stored at the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD). We analyzed the IIDP plasma to assess whether the ability of p-Tau181 to predict disease differed between subjects in these two geographically, culturally, genetically, and environmentally disparate sites.

METHOD: Plasma collected from study participants was analyzed for Alzheimer's disease biomarkers using the Quanterix Simoa HD-X pTau181 v2 Advantage kits. The mean and standard deviation of the log transformed biomarker data using all subjects with normal cognition from 2001 were used to standardize the biomarker prior to statistical analysis. For this analysis, participants with normal cognition during the 2001 wave and at least one follow-up evaluation were included (N = 755 African Americans; N = 864 Nigerians). Incident cognitive impairment status was determined using the last wave the subject was assessed.

RESULT: Using logistic regression models, p-Tau181 was shown to predict incident cognitive impairment in the African American population (Odds Ratio (OR)=1.52, p < 0.0001) but not in the Ibadan population (OR=1.09, p = 0.42) adjusting for age, sex, education, APOE4 genotype and history of stroke. The results from the logistic regression model for incident cognitive impairment/dementia can be seen in Table 1. Mixed effects models assessing cognitive scores showed significant interactions between time and p-Tau181, indicating that higher p-Tau181 is associated with greater decline for total cognitive score (p = 0.0109) and memory cognitive subscale (p = 0.0031) only in the Indianapolis African American population (Table 2).

CONCLUSION: While geographic location has been seen to influence APOE genotype risk, similar investigations of AD biomarkers has been limited. Our data suggest there are differences in etiology that drives cognitive impairment between the African Americans in Indianapolis and the Africans in Ibadan. Additional analyses must be done to determine what drives these differences and the most effective biomarkers or biomarker combinations for differing populations.},
}

Humans
Male
Female
*Biomarkers/blood
Aged
Nigeria/epidemiology
*tau Proteins/blood
Longitudinal Studies
Aged, 80 and over
*Alzheimer Disease/blood/epidemiology/genetics
Indiana/epidemiology
Middle Aged
*Cognitive Dysfunction/blood/epidemiology
Black or African American
White

@article {pmid41512275,
year = {2025},
author = {Aresta, S and Nemni, R and Zanardo, M and Sirabian, G and Capelli, D and Alì, M and Vitali, P and Bertoldo, EG and Fiolo, V and Bonanno, L and Maresca, G and Battista, P and Sardanelli, F and Pizzini, FB and Castiglioni, I and Salvatore, C and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105530},
doi = {10.1002/alz70856_105530},
pmid = {41512275},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers ; *Alzheimer Disease/diagnosis/diagnostic imaging ; Male ; Female ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; Aged ; Neuropsychological Tests ; Magnetic Resonance Imaging ; Disease Progression ; *Artificial Intelligence ; Neuroimaging ; },
abstract = {BACKGROUND: In 2024, eleven European scientific societies/organizations and one patient advocacy association have defined a patient-centered biomarker-based diagnostic workflow for memory clinics evaluating neurocognitive disorders. This study aimed to evaluate the clinical performance of an Artificial Intelligence (AI)-tool applied to neuropsychological assessment and MRI for supporting the staging, clinical profiling, diagnosis, causal hypothesis, and progression of subjects at risk of Alzheimer's disease (AD) following the above-mentioned intersocietal recommendations.

METHOD: This observational, multicentric study enrolled 796 subjects: 705 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, 35 from Centro Diagnostico Italiano (Italy), 26 from IRCCS Policlinico San Donato (Italy), and 30 from IRCCS Bonino Pulejo (Italy). Participants were clinically staged as healthy subjects (HS), subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or AD-dementia at baseline and 24-month follow-up. Patients were clinically profiled into AD clinical syndromes based on cognitive characteristics and structural neuroimaging findings. First-line biomarkers were also measured. The AI-based software TRACE4AD™ automatically processed neuroimaging and neuropsychological test data to extract cognitive and structural findings. The tool staged subjects as HS/SCI, MCI, or moderate-to-severe-dementia (MSD), profiled the causal hypothesis, and predicted conversion risk to AD-dementia. Agreement between AI and human staging was assessed using Cohen's kappa. AI-performance was evaluated by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under curve (AUC), and accuracy.

RESULT: For the staging classification the inter-rater AI-humans agreement was substantial for both HS/SCI vs. rest (Cohen's κ = 0.81) and MCI (κ = 0.70) classification, almost perfect for MSD vs. rest (κ = 0.90) classification. For the causal hypothesis classification, the AI performance vs. biomarker-based diagnosis was: PPV 91%, NPV 100%, and accuracy 91%. For the binary classification of progression to AD-dementia at 24-month, the AI performance was: sensitivity 89%, specificity 82%, accuracy 85%, and AUC 83%.

CONCLUSION: The AI-tool demonstrated its usefulness in supporting the clinical treatment of AD patients by assisting with staging, clinical profiling, diagnosis, hypothesis generation for underlying causes, and predicting the risk of progression to AD-related dementia within 24 months.},
}

Humans
*Biomarkers
*Alzheimer Disease/diagnosis/diagnostic imaging
Male
Female
*Cognitive Dysfunction/diagnosis/diagnostic imaging
Aged
Neuropsychological Tests
Magnetic Resonance Imaging
Disease Progression
*Artificial Intelligence
Neuroimaging

@article {pmid41512267,
year = {2025},
author = {Roberts, PS and Li, CY and Ouellette, DS and Qureshi, N and Spivack, E and Nasmyth, M and Sicotte, NL and Tan, ZS},
title = {Linking data to determine risk for 30-day readmissions in dementia.},
journal = {The American journal of managed care},
volume = {31},
number = {12},
pages = {e371-e377},
doi = {10.37765/ajmc.2025.89842},
pmid = {41512267},
issn = {1936-2692},
mesh = {Humans ; *Patient Readmission/statistics & numerical data ; Male ; Female ; Aged ; Retrospective Studies ; Cross-Sectional Studies ; *Electronic Health Records/statistics & numerical data ; *Dementia/therapy/epidemiology ; Risk Factors ; Aged, 80 and over ; },
abstract = {OBJECTIVE: The demand and the landscape of options for dementia care are growing. Standardization of care for persons with Alzheimer disease and related dementias (ADRD) lacks infrastructure across episodes of care. Use of electronic health records (EHRs) in practice settings yields valuable information that can enhance continuity of patient care. The objective of this study was to use EHR-derived variables to identify risk factors for 30-day readmissions in the ADRD population across episodes of care.

STUDY DESIGN: Cross-sectional, retrospective study of older adults (aged ≥ 65 years) with ADRD discharged from a large urban academic medical center between October 1, 2018, and March 31, 2022.

METHODS: Data extracted across episodes of care from the EHR included demographic characteristics, medical variables, and encounter variables.

RESULTS: A total of 14,101 patients diagnosed with ADRD were included in the study. Factors associated with patients being more likely to experience 30-day hospital readmissions included advanced age, male sex, being a non-English speaker, having more severe comorbidities, staying in the hospital for more than 5 days, having had more than 1 surgical procedure in the prior 6 months, having had 3 or more inpatient admissions in the 6 months prior to index admission, having had more than 3 physician consultations in the prior 6 months, and having been discharged to settings other than home (all P < .05).

CONCLUSIONS: By utilizing the EHR to connect medical and encounter data across episodes of care, health care providers and administrators can gain valuable insight into identifying factors contributing to readmissions, which could be used to improve continuity of care for patients and caregivers, ultimately leading to better outcomes and reduced health care costs.},
}

Humans
*Patient Readmission/statistics & numerical data
Male
Female
Aged
Retrospective Studies
Cross-Sectional Studies
*Electronic Health Records/statistics & numerical data
*Dementia/therapy/epidemiology
Risk Factors
Aged, 80 and over

@article {pmid41512235,
year = {2025},
author = {Singh, A and Denkinger, MN and Dieckhoff, K and Liu, J and Serrano, GE and Beach, TG and Leuzy, A and Atri, A and Reiman, EM and Ashton, NJ},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105227},
doi = {10.1002/alz70856_105227},
pmid = {41512235},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Cerebral Amyloid Angiopathy/blood/diagnosis ; Aged ; *Alzheimer Disease/blood ; Aged, 80 and over ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels leading to increased risk of microbleeds, intracerebral hemorrhages, and progressive cognitive decline. It is estimated that up to 90% of individuals with Alzheimer's disease (AD) exhibit some degree of CAA. Notably, CAA has been identified as a major contributor to the risk of Amyloid-Related Imaging Abnormalities (ARIA), particularly in patients undergoing treatment with anti-amyloid therapies. The use of blood-based biomarkers to accurately detect and assess the severity of CAA is crucial for tailoring treatment plans while reducing the risk of adverse effects.

METHOD: We employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA™) central nervous system panel for an exploratory biomarker quantification in plasma of patients with CAA or no-CAA (presence of cerebral amyloidotic blood vessels) utilizing samples from the Banner Health Brain and Body Donation Program (BBDP) We evaluated the differential protein expression between groups using a linear model. This model was adjusted for age, sex, APOE e4 carrier status and the presence of Alzheimer's amyloid plaque load (AD-status).

RESULT: We selected 251 participants (age: 85±8.2) from the BBDP cohort with a plasma sample taken < 5 years (1.45±1.26) prior to death. At post-mortem each case was classified as CAA+ (n = 140) or CAA- (n = 111). NULISA™ identified several novel proteomic biomarkers which were up-regulated (CRP, IL4, SAA1), and down-regulated (CCL11, PDLIM5, NPY and GDNF) in CAA pathology carriers (Figure 1). We further performed receiver operating characteristic (ROC) curve analysis comparing models and found that a model including age, sex, AD-status, APOE e4 status, CRP and CCL11 had an area under the curve (AUC) of 0.87 (95%CI, 0.83-0.92) to identify the presence of CAA at post-mortem (Figure 2).

CONCLUSION: Blood-based biomarkers capable of identifying CAA could play an important role in improving treatment outcomes by highlighting ARIA risk prior to treatment initiation. We found that plasma proteins related to inflammation, blood brain barrier dysfunction and cytoskeletal stability were significantly changed in participants with confirmed CAA. Further work will be required to replicate these findings in an independent dataset.},
}

Humans
*Biomarkers/blood
Male
Female
*Cerebral Amyloid Angiopathy/blood/diagnosis
Aged
*Alzheimer Disease/blood
Aged, 80 and over

@article {pmid41512232,
year = {2025},
author = {Kang, JW and Vemuganti, V and Jonaitis, EM and Johnson, SC and Asthana, S and Carlsson, CM and Chin, NA and Engelman, CD and Ulland, TK and Rey, FE and Bendlin, BB},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105650},
doi = {10.1002/alz70856_105650},
pmid = {41512232},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Biomarkers/blood ; Aged ; *Alzheimer Disease/diagnosis ; Neuropsychological Tests ; *Imidazoles/blood ; Executive Function/physiology ; Middle Aged ; Aged, 80 and over ; Gastrointestinal Microbiome/physiology ; },
abstract = {BACKGROUND: Among the various modifiable risk factors for AD development, the gut microbiome stands out as a potential therapeutic target, offering opportunities for intervention in the very early stages to potentially prevent disease onset. Notably, specific gut microbial metabolites may critically modulate metabolic and neuroimmune mechanisms shared with type 2 diabetes (T2D) and atherosclerosis-conditions that increase the risk of neurovascular and neurodegenerative disorders. Among these metabolites, imidazole propionate (ImP), a gut bacteria-derived metabolite of histidine, has garnered attention for its potential to cross the blood-brain barrier and exacerbate neurodegenerative processes.

METHOD: Participants included in the analysis were from Wisconsin ADRC and Wisconsin Registry for Alzheimer's Prevention (WRAP) studies. ImP was determined using the Metabolon platform. Three composite tests for measuring executive functions, along with assessments of two other cognitive domains-immediate learning and delayed recall-were used to compute the global composite scores for the three-test version of the Preclinical Alzheimer's Cognitive Composite (PACC3). The PACC3 scores were derived using three distinct measures of executive functions-Animal Naming Test (PACC3-AN, n = 859), Category Fluency Test (PACC3-CFL, n = 1118), and Trail-Making Test B (PACC3-TRLB, n = 1116)-and subsequently transformed into z-scores. Ordinary Least Squares (OLS) multiple linear regression approach was used to evaluate the relationship between levels of ImP and cognitive scores while accounting for covariates such as age and sex in the analysis.

RESULT: Lower cognitive performance was associated with higher levels of plasma ImP while controlling for age and sex, even in cognitively normal individuals before the onset of detectable cognitive symptoms.

CONCLUSION: Despite the modest associations, the significance of predictors suggests these factors warrant further exploration in understanding their combined contribution to ImP levels and broader neurodegenerative mechanisms.},
}

Humans
Male
Female
*Biomarkers/blood
Aged
*Alzheimer Disease/diagnosis
Neuropsychological Tests
*Imidazoles/blood
Executive Function/physiology
Middle Aged
Aged, 80 and over
Gastrointestinal Microbiome/physiology

@article {pmid41512231,
year = {2025},
author = {Dunne, RA and Taghavi, HM and DiGiacomo, P and Maclaren, J and Bell, M and Carlson, ML and Mormino, EC and Henderson, VW and Spincemaille, P and Zhuang, H and Wang, Y and Rutt, BS and Georgiadis, M and Zeineh, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106116},
doi = {10.1002/alz70856_106116},
pmid = {41512231},
issn = {1552-5279},
mesh = {Humans ; Magnetic Resonance Imaging/methods ; Male ; *Cognitive Dysfunction/diagnostic imaging/metabolism/pathology ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Female ; Biomarkers/metabolism ; *Hippocampus/diagnostic imaging/metabolism/pathology ; Aged ; *Iron/metabolism ; Middle Aged ; Disease Progression ; },
abstract = {BACKGROUND: Hippocampal iron, as measured with imaging, biofluids, and histology, has been associated with Alzheimer's disease (AD), its progression, and potentially neuroinflammatory disease mechanisms. With its high sensitivity to tissue magnetic susceptibility, 7T MRI offers the potential to detect abnormal iron deposition within the hippocampus of AD and mild cognitive impairment (MCI) brains in vivo, especially when combined with dedicated methods such as quantitative susceptibility mapping (QSM). We aim to utilize ultra-high resolution 7T MRI and explore conventional and novel source-separated QSM to quantify hippocampal iron deposition in AD, providing insights into the involvement of brain iron in disease progression.

METHOD: We conducted 7T MRI on 19 ADRC human volunteers, including 8 healthy controls (HC), 6 individuals with MCI, and 5 with AD. MR images were acquired using a GE MR950 scanner utilizing optical prospective motion correction. Automatic Segmentation of Hippocampal Subfields generated segmentations of the subiculum and CA1 (Figure 1), which were manually edited in a diagnosis-blind manner, followed by one-pixel erosion. R2* and source-separated QSM (positive susceptibility sources QSM-χ[+], negative QSM-χ[-]) were computed using MEDI and averaged within the subiculum and CA1. Blinded image quality assessments were conducted. Memory composite scores were correlated with iron measurements available in 18 participants. Nonparametric tests quantified hyperintensity gradation in hippocampal QSM/R2* images and assessed the relationship between memory scores and QSM/R2*.

RESULT: We found a significant ordinal increase of R2* according to participant diagnoses (AD>MCI>HC) in the subiculum (p = 0.0445) and combined subiculum-CA1 (p = 0.0232) subfields (examples of negative and positive findings in Figure 2, boxplots in Figure 3-top), suggestive of increased iron. No significant differences were seen in QSM without source separation, QSM-χ[+], or QSM-χ[-]. However, a significant negative association between memory scores and QSM-χ[+] was observed in CA1 (p = 0.0351, Figure 3-bottom).

CONCLUSION: We found elevated iron in the subiculum-CA1 hippocampal subregions in vivo in MCI and AD using 7T MRI, correlating with degraded memory performance. Our noninvasive visualization of microscopic hippocampal iron deposition utilizing ultra-high resolution 7T MRI in vivo corroborates post-mortem data. This translational finding could serve as a novel neuroimaging biomarker for iron-based AD pathology and inflammation.},
}

Humans
Magnetic Resonance Imaging/methods
Male
*Cognitive Dysfunction/diagnostic imaging/metabolism/pathology
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Female
Biomarkers/metabolism
*Hippocampus/diagnostic imaging/metabolism/pathology
Aged
*Iron/metabolism
Middle Aged
Disease Progression

@article {pmid41512227,
year = {2025},
author = {Ersoezlue, E and Hellmann-Regen, J},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105585},
doi = {10.1002/alz70856_105585},
pmid = {41512227},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/blood/pathology/diagnostic imaging ; Aged ; Magnetic Resonance Imaging ; *Cerebral Amyloid Angiopathy/blood/pathology/diagnostic imaging ; Aged, 80 and over ; Cohort Studies ; Brain/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most prevalent causes of dementia, while concomitant diseases such as cerebral amyloid angiopathy (CAA) has a substantial impact on clinical trajectories and therapy, i.e. risk factor for imaging abnormalities under anti-amyloid antibodies. As there are no established biomarkers to identify individual with CAA, we aim to explore potential plasma biomarkers for mechanisms related to CAA in participants in continuum of AD.

METHOD: We included a total of 47 participants from the AD Neuroimaging Initiative study with available plasma biomarkers from a multiplex immunoassay panel (n = 145 analytes from "Biomarkers Consortium MRM data", consisting of proteins related to cancer, cardiovascular disease, metabolic disorders, inflammation, and AD). We stratified the cohort into participants with either T2*-GRE magnetic resonance images (MRI) (n = 21) at baseline or postmortem neuropathological assessment (n = 26). The numbers of definite lobar microbleeds were obtained from central visual readings (Mayo Clinic, Jack Lab), while central neuropathological severity scales for AD (AD neuropathologic change) and CAA (overall neocortical amyloid angiopathy) were included. We defined CAA status as at least two lobar microbleeds in orientation to the Boston criteria and at least moderate density in neuropathology. Plasma analytes were measured twice with a one-year time difference with a maximum of 6.6 years prior to either first MRI or time of death. Non-parametric receiver operating characteristic curves and area under the curve (AUC) values of analytes in differentiation of CAA status.

RESULT: In both cohorts with imaging and NP data, most of the participants exhibited cognitive symptoms and revealed in vivo or neuropathological changes regarding AD (Table-1). Using the imaging, various markers related to inflammation, lipid metabolism, cell adhesion, and sex steroids are found to show a constant increase in CAA (Table-2, Figure 1). Moreover, we identified increases in Clusterin and Complement Factor H levels as well as reduced Alpha-Fetoprotein, characterizing the neuropathological definition of CAA (Table-2, Figure 1).

CONCLUSION: Using both ante-mortem and post-mortem indicators of CAA, several candidate plasma biomarkers of CAA have been found, whereas replications in bigger samples with multiple measurements are crucial to address confounder factors and temporal relationships.},
}

Humans
*Biomarkers/blood
Male
Female
*Alzheimer Disease/blood/pathology/diagnostic imaging
Aged
Magnetic Resonance Imaging
*Cerebral Amyloid Angiopathy/blood/pathology/diagnostic imaging
Aged, 80 and over
Cohort Studies
Brain/pathology/diagnostic imaging

@article {pmid41512221,
year = {2025},
author = {Charles, A and Gallardo, MJJ and Suarez, AC and Sugg, E and Li, P and Hu, K and Gao, L},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107638},
doi = {10.1002/alz70856_107638},
pmid = {41512221},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction/diagnosis ; Biomarkers ; Mental Status and Dementia Tests/statistics & numerical data ; Neuropsychological Tests ; Aged, 80 and over ; },
abstract = {BACKGROUND: Approximately one-third of adults over the age of 65 undergoing surgery experience severe cognitive impairments, including acute confusion, attention deficits, and global cognitive dysfunction. Older adults with greater cognitive impairments are at increased risk for prolonged hospitalization, higher rates of readmission, institutionalization, and long-term cognitive decline, including dementia and Alzheimer's disease. However, the trajectory of postoperative cognitive changes in older adults remains poorly understood. Cognitive assessments such as the Montreal Cognitive Assessment (MOCA) are commonly used in clinical settings but are often interpreted as a single total score, overlooking domain-specific cognitive changes. To address this research gap, this study examines domain-specific cognitive changes in older surgical patients before and after surgery.

METHOD: Seventeen older surgical patients (≥70 years old) undergoing knee, hip, or spine surgery were recruited. Cognitive function was assessed pre- and post-surgery using the Montreal Cognitive Assessment (MOCA). Assessments were captured 1-week before surgery and 1-day post-surgery. A linear mixed-effects model was used to evaluate cognitive function pre- and post-surgery across the following cognitive domains, abstraction, attention, language, orientation, and recall.

RESULT: The analysis revealed an interaction effect between event group (pre- vs. post-surgery) and the MOCA cognitive domains (F(4,126) = 6.97, p < 0.01), indicating that post-operative cognitive functions possibly decline at different rates across cognitive domains. Attention, orientation, and recall demonstrated the strongest effects, where the recall domain showed significant decline following surgery compared to baseline (β = -0.87 (standardized), SE = 0.156, p < 0.01), suggesting a domain-specific vulnerability in memory function.

CONCLUSION: Our findings indicate that postoperative cognitive decline is domain-specific, with memory function exhibiting the greatest vulnerability and possibly a slower recovery trajectory. These results suggest that assessing cognitive domains individually, rather than relying solely on total MOCA scores, may advance early detection of patients at risk for prolonged cognitive impairment. Follow-up studies are warranted to determine whether domain-specific cognitive assessments can serve as predictors of long-term cognitive decline, including postoperative delirium and dementia, ultimately guiding early interventions to improve patient outcomes. This research was supported by AACSF-23-1148490.},
}

Humans
Male
Female
Aged
*Cognitive Dysfunction/diagnosis
Biomarkers
Mental Status and Dementia Tests/statistics & numerical data
Neuropsychological Tests
Aged, 80 and over

@article {pmid41512220,
year = {2026},
author = {Che, Y and Yu, Z and Ji, S and Yang, D},
title = {Decoding TREM2 Signaling Pathways: Linking Macrophage Glycolysis to Inflammatory Diseases in the CNS.},
journal = {Neurology(R) neuroimmunology & neuroinflammation},
volume = {13},
number = {2},
pages = {e200527},
doi = {10.1212/NXI.0000000000200527},
pmid = {41512220},
issn = {2332-7812},
mesh = {Humans ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Signal Transduction/physiology ; *Macrophages/metabolism ; *Neuroinflammatory Diseases/metabolism/immunology ; *Glycolysis/physiology ; Animals ; Neurodegenerative Diseases/metabolism ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a key immunomodulatory receptor broadly expressed on myeloid cells such as macrophages and microglia. It plays versatile roles in neurodegenerative diseases, tissue repair, and tumor immunity by orchestrating glucose metabolism and inflammatory responses. This review systematically summarizes the structural characteristics of TREM2, its ligand-binding mechanisms, and downstream signaling pathways-including the phosphoinositide 3-kinase/protein kinase B(PI3K/Akt), mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and signal transducer and activator of transcription 3 (STAT3) cascades-with a particular focus on its central role in macrophage metabolic reprogramming.In neurodegenerative diseases such as Alzheimer disease, TREM2 contributes to the attenuation of neuroinflammation and slows disease progression by promoting β-amyloid (Aβ) clearance, inhibiting tau hyperphosphorylation, and modulating microglial polarization. Loss-of-function sequence variants, such as R47H, disrupt lipid metabolism, impair phagocytic activity, and destabilize immune homeostasis, thereby significantly increasing disease susceptibility. Furthermore, by enhancing glycolysis and suppressing fatty acid oxidation, TREM2 facilitates macrophage polarization toward a reparative M2 phenotype, promoting neuroregeneration and remyelination in conditions such as spinal cord injury and multiple sclerosis.Within the tumor microenvironment, TREM2 influences tumor progression and therapeutic resistance by modulating the metabolic reprogramming of tumor-associated macrophages (TAMs)-notably through activation of pyruvate kinase muscle isozyme M2 (PKM2)-dependent glycolysis-and promoting an immunosuppressive phenotype. In metabolic disorders such as diabetes and obesity, TREM2 exerts protective effects by inhibiting NLRP3 inflammasome activation and maintaining lipid homeostasis, highlighting its therapeutic potential.This review also outlines the translational prospects of TREM2 as a therapeutic target, including the development of agonists, gene regulatory strategies, and its potential use as a biomarker. Future studies should aim to elucidate the ligand-specific biased signaling and dynamic regulatory networks of TREM2 within tissue microenvironments to advance precision interventions in neuroimmunometabolic diseases.},
}

Humans
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
*Signal Transduction/physiology
*Macrophages/metabolism
*Neuroinflammatory Diseases/metabolism/immunology
*Glycolysis/physiology
Animals
Neurodegenerative Diseases/metabolism

@article {pmid41512209,
year = {2026},
author = {Kek-Laflamme, A and Schaper, FLWVJ and Whittingstall, K and Pennell, PB and Young, GS and Marshall, GA and Larivière, S and Sarkis, RA},
title = {Brain Structural Changes and Cognitive-Clinical Profiles in Late-Onset Unexplained Epilepsy.},
journal = {Neurology},
volume = {106},
number = {3},
pages = {e214575},
doi = {10.1212/WNL.0000000000214575},
pmid = {41512209},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Aged ; Magnetic Resonance Imaging ; *Epilepsy/diagnostic imaging/psychology/pathology/complications ; *Brain/pathology/diagnostic imaging ; Middle Aged ; *Gray Matter/diagnostic imaging/pathology ; Age of Onset ; Neuropsychological Tests ; Prospective Studies ; *Cognition/physiology ; Atrophy ; },
abstract = {BACKGROUND AND OBJECTIVES: Epilepsy incidence peaks in childhood and again after age 55. Up to half of individuals with late-onset epilepsy lack an identifiable cause, but previous imaging studies suggest subtle mesiotemporal atrophy. In this study, we aimed to quantify whole-brain cortical and deep gray matter alterations in late-onset unexplained epilepsy (LOUE) and to examine their associations with cognitive and clinical measures.

METHODS: We prospectively recruited patients with LOUE through Brigham and Women's Hospital and its affiliated sites and compared them with sociodemographically matched healthy older adults from the Harvard Aging Brain Study. Inclusion criteria for LOUE were at least 1 unexplained seizure after age 55, onset within the past 5 years, and no identifiable cortical lesion on MRI. All participants underwent 3T structural MRI and neuropsychological testing. Cortical thickness and deep gray matter volumes were extracted, and linear models were used to compare patients with LOUE and controls. Correlations were computed between structural alterations and demographic, cognitive, and clinical measures.

RESULTS: We included 59 patients with LOUE (mean age 71.2 ± 7.0 years, 49% female) and 53 controls (mean age 70.7 ± 5.2 years, 53% female). Patients with LOUE showed reduced cortical thickness in sensory and mesiotemporal cortices (d = -0.75, 95% CI [-1.14 to -0.37], FDR-corrected p values [pFDR] < 0.05) and reduced deep gray matter volumes in the pallidum and putamen (d = -0.55, 95% CI [-0.93 to -0.17], pFDR < 0.05). These structural reductions correlated with lower performance on a category fluency task (r = 0.31, pFDR = 0.016) and the extended Preclinical Alzheimer's Cognitive Composite (r = 0.37, pFDR = 0.0041). Conversely, patients showed increased thickness in the left inferior frontal gyrus (d = 0.82, 95% CI [0.43-1.20], pFDR < 0.05) and increased thalamic volume (d = 1.13, 95% CI [0.73-1.53], pFDR < 0.05), which were more pronounced in those with focal seizures sparing consciousness (d = -0.62, puncorr = 0.021).

DISCUSSION: Structural brain changes in LOUE are more extensive than previously recognized and are associated with cognitive vulnerability. Although the cross-sectional design and use of independent cohorts limit conclusions about disease progression, the findings suggest that LOUE may fall along a continuum between epilepsy and neurodegenerative disease.},
}

Humans
Female
Male
Aged
Magnetic Resonance Imaging
*Epilepsy/diagnostic imaging/psychology/pathology/complications
*Brain/pathology/diagnostic imaging
Middle Aged
*Gray Matter/diagnostic imaging/pathology
Age of Onset
Neuropsychological Tests
Prospective Studies
*Cognition/physiology
Atrophy

@article {pmid41512186,
year = {2025},
author = {Barragan, EV and Heuer, HW and Nosheny, RL and Camacho, MR and Navarra, K and Aisen, PS and Rahman-Filipiak, A and Roberts, JS and Ajayi, A and Ayo, O and Cho, SJ and Culhane, JE and Germano, KK and Guzman, VA and Higuera, M and Sotelo, M and Byrd, D and Mindt, MGR and Rabinovici, GD and Boxer, AL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107586},
doi = {10.1002/alz70856_107586},
pmid = {41512186},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/blood ; Middle Aged ; Adult ; *Alzheimer Disease/blood/diagnosis ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; United States ; Community-Based Participatory Research ; Surveys and Questionnaires ; },
abstract = {BACKGROUND: Early onset dementia (EOD) affects people at the peak of personal and professional responsibilities and economic productivity. Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) are the most common EOD etiologies, but have not been studied in a sample representative of the general US population. Multiple barriers impede research participation for many groups, but community-engaged research (CER) strategies to enhance recruitment may make research participation more accessible and convenient for all.

METHOD: BEYONDD is an NIH-funded, community-based study focused on understanding the etiology of EOD, uses CER strategies such as remote assessments and return of research results as tools for enhancing sample representativeness. Participants are recruited using social media and local in-person CER strategies and screened via an online platform for eligibility (age 40-64, with concerns about cognitive or behavioral function). Remote completion of online questionnaires, cognitive testing, and an in-home blood draw for standard labs, Aβ42/40 and p-tau217 ratios, and plasma NfL comprise the initial visit. Participants are invited for more comprehensive onsite evaluation at one of 7 BEYOND in-clinic sites, followed by tailored referral to other NIH-funded research programs. Participants can learn their results remotely or in person.

RESULT: Using a novel, CER-based approach for social media ad deployment, BEYONDD has recruited over 1700 potential participants across the US and Puerto Rico; over half (n = 881) completed the online screening survey. Of the 206 participants enrolled in the online procedures, 80% (n = 165) were women and most were Latino (n = 83; 40%) or Black (n = 68; 33%) and over a quarter (n = 74; 36%) reported less than 16 years of education. We have completed over 95 blood draws across 17 states and invited participants for onsite visits. Results have been shared with 22 participants (10 on-site, 12 remotely). Preliminary analyses reveal a high Aβ42/40 positivity rate (∼30%) and the most prevalent routine lab abnormalities include: LDL-Cholesterol (63%), homocysteine (36%), hs-CRP (35%) and HgbA1C (33%). Abnormal p-tau217 ratios (n = 4; 5%) and APS2 scores (n = 3; 4%) have also been identified in this community-based sample.

CONCLUSION: Preliminary results suggest feasibility and acceptability of this innovative CER approach in a more representative sample of the US population.},
}

Humans
Female
Male
*Biomarkers/blood
Middle Aged
Adult
*Alzheimer Disease/blood/diagnosis
tau Proteins/blood
Amyloid beta-Peptides/blood
United States
Community-Based Participatory Research
Surveys and Questionnaires

@article {pmid41512156,
year = {2025},
author = {Geraci, J and Searls, E and Qorri, B and Ho, K and Burk, A and Tsay, M and Cumbaa, C and Pani, L and Alphs, L and Alosco, ML and Mez, J and Au, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107581},
doi = {10.1002/alz70856_107581},
pmid = {41512156},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis/physiopathology ; *Alzheimer Disease/diagnosis ; Aged ; *Biomarkers ; Neuropsychological Tests ; Sleep/physiology ; Machine Learning ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) precision medicine will advance through the application of two key technological advances: 1) digital technologies that can more deeply characterize clinically relevant symptoms and 2) machine learning (ML) approaches the can classify subgroups with shared characteristics that could align with specific treatment plants. This study leverages a digital data collection platform for enhanced characterization and NetraAI, an artificial intelligence (AI) platform to analyze multimodal data to differentiate causal and non-causal subpopulations within a cohort and integrates a "No Call" system to exclude ambiguous data points.

METHOD: We analyzed data from 98 Boston University Alzheimer's Disease Research Center participants and 453 variables derived from digital tasks administered over two months. Eight participants were clinically diagnosed as mild cognitive impairment. Digital measures included sleep metrics (57 measures), clinical scales (324 measures), and cognitive performance assessments (72 GoNoGo and Code Substitution measures). Of the 98 subjects, 81 were cognitively unimpaired and 17 transitioned to MCI during the course of study enrollment.

RESULT: Sleep-derived metrics, including 3% and 4% desaturation thresholds (p = 4×10[-5], p = 7×10[-5]), and periodicity (eLFCnb) (p = 0.008) characterized one population of 8 participants, 7 of whom had been diagnosed with MCI. Incorporating maximum heart rate, another sleep metric, distinguished another subpopulation of 8 subjects (6/8 were diagnosed MCI) with elevated heart rate (p = 10[-10]). We examined 81 cognitively intact (e.g., non-transitioners; Class 0) and 17 MCI transitioners (Class 1) related to Go/No-Go and Code Substitution tasks. Go/No-Go Inter-Trial Intervals (ITI), REM sleep percentage, and maximum apnea duration were key predictors. Shorter, more stable ITI times (inter-trial intervals between tasks), higher REM sleep percentage, and shorter apnea durations were strongly correlated with non-transitioners. A 10-fold cross-validation yielded an average accuracy of 80.89%.

CONCLUSION: Our findings present an ongoing effort on the potential of explainable AI to validate digital measures to identify those with MCI. While the current model effectively identifies prevalent non-transitioners, it remains limited in identifying prevalent transitioners. Future research will focus on refining model sensitivity and balancing classification performance.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis/physiopathology
*Alzheimer Disease/diagnosis
Aged
*Biomarkers
Neuropsychological Tests
Sleep/physiology
Machine Learning
Aged, 80 and over

@article {pmid41512154,
year = {2025},
author = {Nudelman, KN and Russ, KA and Edler, MC and Faber, KM and Dage, JL and Meyer, JS and Oblak, AL and Foroud, TM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107593},
doi = {10.1002/alz70856_107593},
pmid = {41512154},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/genetics/diagnosis ; *Biological Specimen Banks ; *Dementia/genetics ; },
abstract = {BACKGROUND: The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) supports the etiology, early detection, and therapeutic development for Alzheimer's disease and related dementias (ADRD). One of the goals of NCRAD is to continue to offer high-quality biobanking, biospecimens, standardized ADRD biomarkers, and support for investigators utilizing cutting-edge methods and assays to advance ADRD research.

METHOD: NCRAD currently funds sample processing and banking for ADRD studies, and for AD Research Centers (ADRCs), supports generation of APOE genotype, plasma-based ADRD biomarkers, and supplemental GWAS data. Rigorous quality control ensures the highest quality biospecimens are processed, banked, and distributed, including: sample tracking; DNA and RNA quality measurements; hemoglobin contamination assessment; DNA fingerprinting to assess sample quality and identity; and whole genome sequencing (WGS) data generated for all banked induced pluripotent stem cell (iPSC) lines. Genetic and biomarker data is shared with data repositories including the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) and the National Alzheimer's Coordinating Center (NACC).

RESULTS: NCRAD currently banks samples for more than 80 studies, including samples from >130,000 participants with sample types including DNA, RNA, whole blood, plasma, serum, CSF, brain tissue, stool, peripheral blood mononuclear cells (PBMCs), lymphoblast cell lines, fibroblasts, and iPSCs. More than 15,000 samples are from paired visits with more than one sample type available, and many studies bank samples from longitudinal participant visits. The repository distributed 20,000 uniform sample collection kits and received, processed, and stored more than 200,000 new aliquots in 2024. Approximately 440,000 sample aliquots have been distributed to nearly 300 researchers thus far. To date, over 1,000 publications have been generated using NCRAD samples and data.

CONCLUSION: NCRAD has played a key role in development of best practices, protocol development, and uniform sample collection for ADRD studies. NCRAD continues to support cutting-edge research in genetics, genomics, and biomarker research and, more recently, implementation of the Alzheimer's Association Revised Criteria for diagnosing AD by making plasma biomarker data broadly available for ADRC participants. As such, NCRAD has and continues to play a vital part in the advancement of translational ADRD research.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/genetics/diagnosis
*Biological Specimen Banks
*Dementia/genetics

@article {pmid41512146,
year = {2025},
author = {Okamura, N and Ishiki, A and Hiraoka, K and Kobayashi, R and Tomita, N and Mesfin, B and Wu, Y and Harada, R and Kikuchi, A and Takeda, K and Kikuchi, A and Furukawa, K and Watabe, H and Mugikura, S and Kawakatsu, S and Ishii, K and Nihashi, T and Kato, T and Furumoto, S and Tashiro, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107619},
doi = {10.1002/alz70856_107619},
pmid = {41512146},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Positron-Emission Tomography ; Aged ; *Alzheimer Disease/diagnostic imaging/metabolism/blood ; Biomarkers/blood ; *Cognitive Dysfunction/diagnostic imaging/metabolism/blood ; *Brain/diagnostic imaging/metabolism ; Amyloid beta-Peptides/metabolism ; Radiopharmaceuticals ; Middle Aged ; Glial Fibrillary Acidic Protein/blood ; tau Proteins/blood ; Thiazoles ; Aged, 80 and over ; Aniline Compounds ; },
abstract = {BACKGROUND: [[18]F]SMBT-1, a PET tracer targeting monoamine oxidase B (MAO-B), was developed to visualize reactive astrogliosis in the brain. This study investigated [[18]F]SMBT-1 binding in the brains of patients with Alzheimer's disease (AD) and its association with plasma biomarkers.

METHOD: We performed [[18]F]SMBT-1 scans in 35 healthy elderly controls (HCs), 44 patients with mild cognitive impairment (MCI), and 13 patients with Alzheimer's disease (AD). To compare the regional standardized uptake value ratio (SUVR) between the disease groups, 30-minute dynamic scans were conducted 60 min after administration of [[18]F]SMBT-1. PiB PET or flutemetamol PET was performed to confirm the presence of amyloid-β (Aβ) pathology in the brain. Plasma biomarkers (GFAP, pTau-217, NfL) were measured in 38 subjects who underwent SMBT-1 PET.

RESULT: Compared to the amyloid-negative HC and MCI groups, [[18]F]SMBT-1 accumulation was significantly increased in many brain regions, including the temporal, parietal, occipital, cingulate, and parahippocampal gyri, in amyloid-positive MCI and AD patients. These brain regions coincided with regions considered to be frequent sites of reactive astrogliosis in the AD continuum and overlapped with Aβ accumulation. Plasma GFAP was elevated in MCI and AD patients who showed the elevation of [[18]F]SMBT-1 binding in the neocortex.

CONCLUSION: [[18]F]SMBT-1 binding in the neocortex was elevated in patients with MCI and AD in association with Aβ accumulation, which is consistent with the results of plasma GFAP measurements. These findings suggest that [[18]F]SMBT-1 PET is a useful biomarker of reactive astrogliosis in the brain.},
}

Humans
Male
Female
Positron-Emission Tomography
Aged
*Alzheimer Disease/diagnostic imaging/metabolism/blood
Biomarkers/blood
*Cognitive Dysfunction/diagnostic imaging/metabolism/blood
*Brain/diagnostic imaging/metabolism
Amyloid beta-Peptides/metabolism
Radiopharmaceuticals
Middle Aged
Glial Fibrillary Acidic Protein/blood
tau Proteins/blood
Thiazoles
Aged, 80 and over
Aniline Compounds

@article {pmid41512143,
year = {2025},
author = {Tweardy, M and Yoder, KJ and Gerrol, S and Lucero, C},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107041},
doi = {10.1002/alz70856_107041},
pmid = {41512143},
issn = {1552-5279},
mesh = {Humans ; Medicare/statistics & numerical data ; United States/epidemiology ; *Dementia/diagnosis ; *Biomarkers ; Aged ; Male ; Female ; Alzheimer Disease/diagnosis ; Aged, 80 and over ; Insurance Claim Review ; },
abstract = {BACKGROUND: The Center for Medicare and Medicaid Services advocates for cognitive assessments during annual wellness visits. However, traditional screening tools such as the Mini-Mental State Exam require 15 to 20 minutes to administer and interpret, exceeding the average time of an entire primary care visit. With approximately 60 million elderly Americans, manual screening is infeasible. Rather than relying on manually administered tests, a more practical approach may be to leverage existing healthcare data. Given that nearly all healthcare interactions generate insurance claims, claims data may provide a scalable and widely accessible alternative for identifying dementia cases.

METHOD: We analyzed 40 million Medicare claims across 1.9 million individuals over a five year period (2018 - 2022) to develop a model to predict undiagnosed dementia. We took all beneficiaries who had a dementia code (e.g. F00 - Dementia in Alzheimer's disease) in their record as the positive cases, and the first appearance in their record as the incident diagnosis. It takes an average of 4.9 months from initial cognitive complaint to dementia diagnosis. Therefore, we excluded all claims data in the 6 months leading up to diagnosis for the positive cases to ensure we were not taking advantage of claims generated during the diagnostic process. To create our feature set, we extracted literature-based dementia risk factors and comorbidities and broke each beneficiary's claims into separate time periods. Within each period, we counted the number of times each code appeared, and then normalized the counts by the length of the time period. Finally, we trained a gradient-boosted decision tree (XGBoost) to identify whether a set of claims data indicated the beneficiary was "positive" or "negative" for dementia. We evaluated performance using cross-validation.

RESULT: The model achieved an accuracy of 93.9%, with 44.3% sensitivity and 98.8% specificity.

CONCLUSION: Intelligent interpretation of claims data can identify undocumented cases of dementia. Application within a health system could allow physicians to fruitfully focus their attention and spend the time on patients who need it.},
}

Humans
Medicare/statistics & numerical data
United States/epidemiology
*Dementia/diagnosis
*Biomarkers
Aged
Male
Female
Alzheimer Disease/diagnosis
Aged, 80 and over
Insurance Claim Review

@article {pmid41512140,
year = {2025},
author = {Flaherty, R and Sui, YV and Masurkar, AV and Youss, Z and Baete, S and Wisniewski, T and Rusinek, H and Lazar, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107584},
doi = {10.1002/alz70856_107584},
pmid = {41512140},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; Biomarkers ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Neurites/pathology ; Diffusion Magnetic Resonance Imaging ; *Amygdala/diagnostic imaging/pathology ; Anisotropy ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND: Our prior work applying diffusion kurtosis imaging (DKI) to subjective cognitive decline (SCD) showed significantly decreased kurtosis fractional anisotropy (KFA) and significantly increased mean kurtosis (MK) for SCD in bilateral amygdala, an early site for tau tangle pathology[1]. However, the microstructural alterations driving these differences are unclear. Here, we assess associations of MK and KFA with neurite orientation dispersion and density imaging (NODDI) and magnetization transfer imaging (MTI) metrics, which provide a more specific characterization of tissue microstructure.

METHOD: 175 cognitively normal participants from Cam-Can[2] (75 SCD) ages 55-88 were included in the analysis. Participants were defined as SCD if they endorsed problems with their memory and in the control group otherwise. Diffusion images were processed to obtain MK, Radial Kurtosis (RK), Axial Kurtosis (AK) and KFA from DKI and Neurite Density (ND) and Orientation Dispersion (OD), a marker of neurite organization, from NODDI. MTI was used to calculate the Magnetization Transfer Ratio (MTR), a marker of myelin and potentially amyloid aggregation. Mean metric values were calculated for bilateral amygdala (Figure 1). Between-group comparisons were conducted using Wilcoxon rank-sum tests, corrected for multiple testing. Associations between DKI, NODDI, and MTR metrics were examined using linear models corrected for age and sex.

RESULT: SCD had lower KFA, higher MK, and higher RK in the right amygdala (Table 1). KFA had a weak negative correlation with ND, while MK and RK had strong positive correlations (Figure 2A-C). Only MK had a weak positive correlation with OD (Figure 2D-F). Neither KFA, MK, nor RK correlated with MTR (Figure 2G-I).

CONCLUSION: DKI metrics are more sensitive to amygdala changes in SCD than NODDI metrics or MTR. Lower KFA, higher MK, and higher RK were associated with higher ND but not MTR, suggestive of dendritic or glial branching. Higher MK was additionally associated with higher OD, potentially indicating reduced neurite organization. Further analyses on the impact of these amygdala changes on SCD related neuropsychiatric symptoms are needed. References 1. Flaherty R, Sui YV, Li M, et al. Alzheimers Dement. 2024;20(S9):e093982. 2. Shafto MA, Tyler LK, Dixon M, et al. BMC Neurol. 2014;14(1):1-25.},
}

Humans
Male
Female
Aged
Middle Aged
Aged, 80 and over
Biomarkers
*Cognitive Dysfunction/diagnostic imaging/pathology
Neurites/pathology
Diffusion Magnetic Resonance Imaging
*Amygdala/diagnostic imaging/pathology
Anisotropy
Brain/diagnostic imaging

@article {pmid41512131,
year = {2025},
author = {Ponomareva, NV and Andreeva, TV and Kuznetsova, IL and Protasova, M and Malina, D and Kunizheva, S and Kupryanova, D and Petrova, V and Kolesnikova, EP and Mitrofanov, A and Fokin, V and Illarioshkin, SN and Rogaev, EI},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107609},
doi = {10.1002/alz70856_107609},
pmid = {41512131},
issn = {1552-5279},
mesh = {Humans ; Middle Aged ; Aged ; Male ; Female ; *Fatty Acid Elongases/genetics ; Adult ; Aged, 80 and over ; Biomarkers/blood ; *Apolipoprotein E4/genetics ; *Aging/genetics/physiology ; DNA Methylation ; Young Adult ; Genotype ; *Event-Related Potentials, P300/physiology ; Promoter Regions, Genetic ; },
abstract = {BACKGROUND: Aging plays a crucial role in exacerbating the negative impact of the APOE4 genotype on brain function, heightening the risk of Alzheimer disease (AD). Methylation of the ELOVL2 promoter is a robust epigenetic biomarkers of age. ELOVL2 is involved in the production of long-chain polyunsaturated fatty acids, which regulate synaptic plasticity and white matter integrity. P3 component of event-related potentials (ERPs) elicited by the odd-ball paradigm is a reliable marker of cognitive processing. This study investigated the associations between APOE genotype, ELOVL2 methylation and characteristics of the ERP P3 component and verbal memory in non-demented adults during aging METHODS: We examined 75 non-demented volunteers, age range 20-84 years, 44 APOE4- and 31 APOE4+. Methylation of ELOVL2 promoter was measured in the blood. Auditory ERPs were recorded using the odd-ball paradigm, and memory was assessed using the Luria verbal memory test. Informed written consent was obtained from all participants. All subjects underwent a neurological examination.

RESULTS: P3 latency was positively correlated with ELOVL2 methylation, and the correlation remained significant when age was statistically controlled, implying that epigenetic mechanisms might contribute to the prolongation of ERP latency. The correlation between ELOVL2 methylation and P3 latency was higher in APOE4 carriers than in noncarriers. The decrease of verbal memory during aging was more pronounced in APOE4 carriers than in non-carriers. The partial correlation analysis controlling for age revealed a significant correlation between ELOVL2 methylation and verbal memory in APOE4+ carriers only. Moreover, ERP P3 latency was inversely correlated with verbal memory scores, and this correlation was stronger in APOE4+ carriers.

CONCLUSION: Impaired lipid metabolism linked to synaptic dysfunction and deterioration of white matter integrity, driven by age-dependent ELOVL2 methylation, may accelerate the impact of the APOE4 genotype on neurophysiological slowing during aging. These changes may contribute to verbal memory decline in APOE4+ carriers and increase the risk of AD.

FUNDING: This study was supported by Russian Science Foundation (Project 19-75-30039 to TA genotyping; Project 22-15-00448 to NP, VF, EK ERP analysis and MP for genotyping) and by Ministry of Science and Higher Education of the Russian Federation (Agreement 075-10-2021-093 project GEN-RND-2017).},
}

Humans
Middle Aged
Aged
Male
Female
*Fatty Acid Elongases/genetics
Adult
Aged, 80 and over
Biomarkers/blood
*Apolipoprotein E4/genetics
*Aging/genetics/physiology
DNA Methylation
Young Adult
Genotype
*Event-Related Potentials, P300/physiology
Promoter Regions, Genetic

@article {pmid41512123,
year = {2025},
author = {Paez, A and Dogaheh, SB and Gillman, SO and Carnes, A and Dakterzada, F and Barbe, F and Piñol-Ripoll, G and Dang-Vu, TT},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107617},
doi = {10.1002/alz70856_107617},
pmid = {41512123},
issn = {1552-5279},
mesh = {Humans ; Female ; *Biomarkers/cerebrospinal fluid ; Male ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/physiopathology ; Aged ; Chitinase-3-Like Protein 1/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Polysomnography ; Peptide Fragments/cerebrospinal fluid ; Neuropsychological Tests ; Prospective Studies ; Neurogranin/cerebrospinal fluid ; Aged, 80 and over ; Sleep/physiology ; },
abstract = {BACKGROUND: Sleep is essential for brain-health, including clearance of β-amyloid (Aβ), tau, and otherpromising diagnostic markers of neurodegeneration and progression in Alzheimer's Disease (AD): cerebrospinal fluid neurofilament-light chain (NfL), neurogranin-36 (NG-36), and Chitinase-3-like protein-1 (YKL-40). However, it remains unclear which sleep characteristics predict these biomarkers or whether the biomarkers predict cognitive or neuropsychiatric decline after AD onset.

METHODS: Using data from a prospective cohort study of mild-to-moderate AD (n = 60, 30-female, mean age 74.7), we analysed non-rapid eye-movement sleep spindles and slow oscillations (SO) at baseline and their associations with baseline NfL, YKl-40, NG-36, NfL/Aβ42, YKl-40/Aβ42, and whether these biomarkers predict cognition and mental health from baseline to three-years follow-up. Participants underwent baseline polysomnography (PSG) and cerebrospinal fluid draws for amyloid and tau, and neuropsychological assessment at baseline, 12, 24 and 36 months with the Mini-Mental Status Examination (MMSE), and the Alzheimer's Disease AssessmentScale-Cognitive Subscale (ADAS-Cog) and Neuropsychiatric Inventory (NPI) at baseline and 12 months. Spindle and SO detection were performed using in-house, open-source software packages developed at Concordia University. Associations between SO and spindle characteristics (duration, density, power, amplitude), biomarkers, and cognition from baseline to 36 months were investigated with false discovery rate-adjusted robust regression controlling for age, sex, apnea-hypopnea index.

RESULTS: We found previously unreported associations between spindle and SO characteristics, NfL, YKl-40, NG-36, NfL/Aβ42 (β=-.0029, p = 0.001), YKl-40/Aβ42 (β=0.0004, p = 0.003) and cognition in persons with AD. These biomarkers predicted worse cognitive performance (higher ADAS-cog [β=2.28, p = 0.004], lower MMSE scores [β= -2.42, p = 0.01]) from baseline to 36-months, and a significant increase in neuropsychiatric symptom severity (NPI β=16.93 p <0.001). NfL/Aβ42 mediated the effects of spindle activity on cognitive performance on the ADAS-cog (p =  0.041) and MMSE (p = 0.0019). Biomarkers also moderated the relationships between spindle and SO activity on cognition, and spindles and SO moderated the relationships between these biomarkers and cognition.

CONCLUSIONS: Our novel findings demonstrate that spindle and SO activity are associated with NfL, YKl-40, and NG-36, and cognitive decline, constituting predictive, non-invasive biomarkers of neurodegeneration, cognition, and mental health in AD. They may thus provide novel treatment targets for delaying AD progression.},
}

Humans
Female
*Biomarkers/cerebrospinal fluid
Male
*Alzheimer Disease/cerebrospinal fluid/diagnosis/physiopathology
Aged
Chitinase-3-Like Protein 1/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Neurofilament Proteins/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Polysomnography
Peptide Fragments/cerebrospinal fluid
Neuropsychological Tests
Prospective Studies
Neurogranin/cerebrospinal fluid
Aged, 80 and over
Sleep/physiology

@article {pmid41512113,
year = {2025},
author = {Azami, H and McAndrews, MP and Rostaghi, M and Zomorrodi, R and Brooks, H and Blumberger, DM and Fischer, CE and Flint, A and Herrmann, N and Kumar, S and Gallagher, D and Mah, L and Mulsant, BH and Pollock, BG and Rajji, TK and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e105953},
doi = {10.1002/alz70856_105953},
pmid = {41512113},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/physiopathology/diagnosis ; *Alzheimer Disease/physiopathology/diagnosis ; *Electroencephalography ; Aged ; *Biomarkers ; *Depressive Disorder, Major/physiopathology/diagnosis ; *Brain/physiopathology ; Neuropsychological Tests ; Entropy ; Aged, 80 and over ; },
abstract = {BACKGROUND: Multiscale dispersion entropy (MDE) is a nonlinear approach for assessing the complexity of brain activity using electroencephalograms (EEGs). MDE captures EEG dynamics across biologically relevant time scales, with short-scales reflecting high-frequency oscillations and local neuronal activity, and long-scales representing low-frequency oscillations and large-scale network processes. Previous studies suggest that patients with Alzheimer's dementia (AD) have decreased complexity at short time scales compared to those with mild cognitive impairment (MCI) or healthy controls (HCs), and individuals with MCI show reduced complexity compared to HCs. There is also preliminary evidence suggesting that adult patients with acute depression -a high-risk condition for AD- have decreased complexity at a short time scale. Thus, we conducted a study in older participants with AD, MCI, HC, remitted major depressive disorder (rMDD), or rMDD+MCI, hypothesizing reduced short-scale MDE in AD vs. MCI and MCI vs. HC. We also explored MDE at short and long time scales across all diagnostic groups and their relationships with cognitive performance.

METHOD: The study included 44 HC, 46 rMDD, 114 MCI, 71 rMDD+MCI, and 41 AD participants. MDE was generated using resting-state EEG with 24ms as the short time scale and 60ms as the long time scale. Cognition was assessed using the Montreal Cognitive Assessment and a cognitive composite score from a comprehensive neuropsychological battery.

RESULT: MDE at 24ms was decreased in AD vs. MCI and in MCI vs. HCs. rMDD had no impact. At 60ms, only the AD group differed from the other groups. Cognitive performance was associated with MDE at 24ms but not 60ms.

CONCLUSION: This study highlights the value of MDE at a short time scale, related to local neuronal activity, to separate individuals with AD vs. MCI vs. HCs. Reduced complexity in these individuals may underlie their cognitive impairment. In contrast, our study suggests that any MDD impact on complexity is likely related to active depressive symptoms.},
}

Humans
Male
Female
*Cognitive Dysfunction/physiopathology/diagnosis
*Alzheimer Disease/physiopathology/diagnosis
*Electroencephalography
Aged
*Biomarkers
*Depressive Disorder, Major/physiopathology/diagnosis
*Brain/physiopathology
Neuropsychological Tests
Entropy
Aged, 80 and over

@article {pmid41512107,
year = {2025},
author = {Sanborn, V and Drake, JD and Alaimo, H and Teixeira, E and Pracht, JR and Denby, C and Pereira, MG and Wen, S and Quesenberry, PJ and Kreiling, JA and Daiello, LA},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e105183},
doi = {10.1002/alz70856_105183},
pmid = {41512107},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/metabolism ; Female ; Male ; *Cognitive Dysfunction/diagnosis/metabolism ; Longitudinal Studies ; *Alzheimer Disease/diagnosis/metabolism ; *Saliva/metabolism/chemistry ; Aged ; *Extracellular Vesicles/metabolism ; Neuropsychological Tests ; Amyloid beta-Peptides/blood ; MicroRNAs/metabolism ; Aged, 80 and over ; Cohort Studies ; RNA, Messenger/metabolism ; },
abstract = {BACKGROUND: Brain-derived salivary extracellular vesicles (EVs) contain mRNA, miRNA, and protein species which have the potential to be used for molecular characterization of brain health. Prior analysis of salivary EV mRNA identified Alzheimer's disease (AD)- and inflammation-related biomarkers that may be diagnostically useful in this regard, however EV analysis is still in its infancy. The primary objective of this study is to identify a novel biomarker signature for AD using salivary EVs.

METHOD: ExosomeAD is a 60-month longitudinal cohort study enrolling older adults with normal cognition (CN; n = 150) and mild cognitive impairment (MCI; n = 50) at the Rhode Island Hospital Alzheimer's Disease and Memory Disorders Center. Baseline evaluation includes neuropsychological testing, self-report inventories (mood, subjective cognitive impairment, daily functioning), vital signs, and collection of saliva and blood samples. Salivary EVs are being analyzed for mRNA, miRNA, and protein composition and compared with plasma biomarkers of AD risk assessed by PrecivityAD (C2N Diagnostics) testing (plasma Aß42-40 ratio, APOE proteotype, and the Amyloid Probability Score (APS)). Participants complete up to 4 annual follow up visits (cognitive testing, surveys, and saliva/blood sample collection).

RESULT: Currently, 183 participants (CN=163; MCI=20) have been enrolled. Participants in both groups to-date are predominately female (CN, n = 115 (71%); MCI, n = 13 (65%). On average, participants with MCI (Mage=77.7, standard deviation (SD)=5.6) are older than the CN group (Mage=72.1 (5.1)). The group mean Montreal Cognitive Assessment total score in the current sample is lower among those with MCI (M=20.1 (4.1)) vs CN (M=27 (2.2)). MCI participants are more likely to be APOE4 carriers (71.4% vs CN, 31.1%), and have higher median APS (MCIAPS=81.5; CNAPS=17). More than half of participants endorsed family history positive for dementia (CN=60%; MCI=65%).

CONCLUSION: Salivary EVs contain important information about brain health and may be a useful biomarker for AD. However, AD-specific signatures in EVs have not yet been characterized. If successful, the Exosome Study will be first to demonstrate that salivary EV RNA and protein can be used to detect AD and facilitate the development of an inexpensive and noninvasive screening method for use in specialty and primary care settings.},
}

Humans
*Biomarkers/metabolism
Female
Male
*Cognitive Dysfunction/diagnosis/metabolism
Longitudinal Studies
*Alzheimer Disease/diagnosis/metabolism
*Saliva/metabolism/chemistry
Aged
*Extracellular Vesicles/metabolism
Neuropsychological Tests
Amyloid beta-Peptides/blood
MicroRNAs/metabolism
Aged, 80 and over
Cohort Studies
RNA, Messenger/metabolism

@article {pmid41512082,
year = {2025},
author = {Cheng, Y and Medina, A and Korponay, CH and Harper, DG and Nickerson, LD},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e106295},
doi = {10.1002/alz70856_106295},
pmid = {41512082},
issn = {1552-5279},
mesh = {Humans ; Female ; *Alzheimer Disease/diagnostic imaging/psychology/pathology ; Male ; Magnetic Resonance Imaging ; Aged ; *Biomarkers/metabolism ; Neuroimaging/methods ; Positron-Emission Tomography ; tau Proteins/metabolism ; Neuropsychological Tests ; *Brain/diagnostic imaging/pathology ; Aged, 80 and over ; },
abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent in Alzheimer's disease (AD) and may reflect distinct pathophysiological pathways from cognitive decline. While pathological and structural factors relate to NPS, the interplay of amyloid- tau-neurodegeneration remains understudied. Using semi-supervised learning, we identified multi-modal neuroimaging patterns predictive of affective symptoms and hyperactivity.

METHOD: Alzheimer's Disease Neuroimaging Initiative (ADNI-3) data included amyloid PET (A), tau PET (T), and structural MRI (N: cortical thickness, surface area, gray matter volume). Affective symptoms (anxiety/depression) and hyperactivity (agitation, irritability, euphoria, aberrant motor behavior, disinhibition) subsyndromes were derived from Neuropsychiatric Inventory (NPI) composite scores (frequency × severity). SuperBigFlica (SBF), a semi-supervised fusion framework, decomposed modalities into shared latent components while jointly predicting affective /hyperactivity. SBF fused all five modalities, extracting 50 latent components mapped to A-T-N spatial patterns. Transfer learning validated biological relevance via ElasticNet regression predicting age and CDR-SOB. Performance was assessed using Pearson correlation (95% confidence intervals [CI] bootstrapped 5000 iterations).

RESULT: The cohort included 274 participants (192 training, 41 validation, 41 test; mean age 70.8 ± 6.9 years; 55.8% female; 92.7% White). Clinical measures included CDR-SOB (median interquartile range [IQR]: 0 [0,1]) and NPI (median IQR: 0 [0,3]). The SBF model showed good predictive performance for affective symptoms (r=0.34, 95% confidence interval [CI]: 0.03-0.55) and hyperactivity (r=0.38, 95% CI: 0.06-0.72) in an independent test set. Affective symptoms were linked to default mode network (DMN) disruptions, with elevated amyloid (frontal-parietal), elevated tau (middle temporal), and reduced cortical thickness and surface area (frontal-temporal, temporal-parietal), aligning with DMN's role in emotional regulation (Figure 1). Hyperactivity correlated with increased amyloid and reduced gray matter and surface area in DMN and frontoparietal control network. Cingulate atrophy was associated with disinhibition and agitation, supporting its role in behavioral regulation (Figure 2). Transfer learning demonstrated generalizability, with SBF-derived latent representations predicting age (r=0.45, 95% CI: 0.2-0.63) and CDR-SOB (r=0.36, 95% CI: 0.05-0.61), validating the neuroimaging patterns' biological relevance.

CONCLUSION: This study identifies distinct A-T-N signatures for NPS subtyping in AD, with clinical relevance supported by predictive utility. Future work will validate these patterns longitudinally and across datasets.},
}

Humans
Female
*Alzheimer Disease/diagnostic imaging/psychology/pathology
Male
Magnetic Resonance Imaging
Aged
*Biomarkers/metabolism
Neuroimaging/methods
Positron-Emission Tomography
tau Proteins/metabolism
Neuropsychological Tests
*Brain/diagnostic imaging/pathology
Aged, 80 and over

@article {pmid41512036,
year = {2026},
author = {Zhu, B and Liu, Z and Van, R and Wang, H and Kuang, S and Jia, Y and Leon, EC and Yang, F and Zhang, J and Yang, J and Hong, H and Lobo, F and Yu, A and Wang, J and Tanzi, RE and Zhang, C and Mao, X and Shao, Y and Ran, C},
title = {Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {2},
pages = {e2513311123},
doi = {10.1073/pnas.2513311123},
pmid = {41512036},
issn = {1091-6490},
support = {R01AG083759//HHS | NIH (NIH)/ ; R01AG085562//HHS | NIH (NIH)/ ; R01AG055413//HHS | NIH (NIH)/ ; R21AG059134//HHS | NIH (NIH)/ ; R56AG059814//HHS | NIH (NIH)/ ; R21AG078749//HHS | NIH (NIH)/ ; S10OD028609//HHS | NIH (NIH)/ ; CSTB2024NSCQ-MSX0365//CSTC | Natural Science Foundation of Chongqing Municipality ()/ ; 2025MSXM061//CQMHC | Science-Health Joint Medical Scientific Research Project of Chongqing ()/ ; },
mesh = {Animals ; Mice ; *Protein Folding ; alpha-Synuclein/metabolism/chemistry/cerebrospinal fluid ; *Luminescent Measurements/methods ; Humans ; Disease Models, Animal ; *Neurodegenerative Diseases/metabolism/diagnostic imaging ; Parkinson Disease/metabolism ; *Proteostasis Deficiencies ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/metabolism ; Brain/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; *Optical Imaging/methods ; Luminescence ; Mice, Transgenic ; },
abstract = {Protein misfolding in the brain is a key pathological hallmark of neurodegenerative diseases. Optical imaging of misfolded proteins in disease models is essential for elucidating etiology and early diagnosis. However, developing specific optical imaging probes for each misfolded protein is time-consuming and challenging, leaving many pathological targets without effective detection tools, especially for in vivo imaging. Here, we present a dual-mode chemiluminescence strategy that enables both generic and specific detection of misfolded proteins using a single probe platform. In the generic mode, we demonstrate that ADLumin-1, a chemiluminescent probe, enables highly sensitive detection of diverse misfolded proteins in vitro, achieving up to 128-fold higher signal enhancement than Thioflavin T, and allows noninvasive imaging in mice models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. In the specific mode, ADLumin-1 combined with protein misfolding cyclic amplification allows femtomolar-level detection of α-synuclein in cerebrospinal fluid, while integration with a bio-orthogonal chemiluminescence resonance energy transfer technique enables in vivo discrimination of α-synuclein from Aβ. This dual-mode, modular approach offers a practical solution to the current probe limitations, with potential preclinical and clinical applications in neurodegenerative disorders.},
}

Animals
Mice
*Protein Folding
alpha-Synuclein/metabolism/chemistry/cerebrospinal fluid
*Luminescent Measurements/methods
Humans
Disease Models, Animal
*Neurodegenerative Diseases/metabolism/diagnostic imaging
Parkinson Disease/metabolism
*Proteostasis Deficiencies
Amyloid beta-Peptides/metabolism
Alzheimer Disease/metabolism
Brain/metabolism
Amyotrophic Lateral Sclerosis/metabolism
*Optical Imaging/methods
Luminescence
Mice, Transgenic

@article {pmid41512015,
year = {2026},
author = {Pourshafie, N and Alexander, DC and Xu, H and Yang, K and Donahue, G and Lei, X and Zhang, S and Shcherbakova, O and Hogan, C and Gilbert, M and Hoxha, K and Chaboub, L and Lee, VM and Adams, PD and Dani, JA and Bonini, NM and Berger, SL},
title = {ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {2},
pages = {e2503834122},
doi = {10.1073/pnas.2503834122},
pmid = {41512015},
issn = {1091-6490},
support = {RO1AA027202//HHS | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA)/ ; 1F32AG079652-01A1//HHS | NIH | National Institute on Aging (NIA)/ ; na//American Parkinson Disease Association (APDA)/ ; R37 DA053296/DA/NIDA NIH HHS/United States ; #S10 OD026929//HHS | NIH | NIH Office of the Director (OD)/ ; na//Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (Kleberg Foundation)/ ; na//National Institutes of Health | National Institute of General Medical Sciences (NIGMS)/ ; na//National Institutes of Health | National Institute on Aging (NIA)/ ; },
mesh = {Animals ; *tau Proteins/metabolism/genetics ; Mice ; *Neurons/metabolism/pathology ; *Aging/metabolism/genetics ; Hippocampus/metabolism/pathology ; Up-Regulation ; Mice, Transgenic ; Acetylation ; Alzheimer Disease/genetics/metabolism/pathology ; Histones/metabolism ; Humans ; Disease Models, Animal ; Epigenesis, Genetic ; Mice, Knockout ; Memory Disorders/genetics ; },
abstract = {Epigenetic mechanisms, including histone acetylation, regulate learning and memory and underlie Alzheimer's disease and related dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme generating acetyl-CoA, locally regulates histone acetylation and gene expression in neuronal nuclei. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously, we showed that systemic ACSS2 knockout mice, although largely normal in physiology, exhibit memory deficits. Here, we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Additionally, boosting histone acetylation through ACSS2 countered age-related memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. These findings position ACSS2 as a key epigenetic regulator of cognitive aging and ADRD, highlighting its potential for targeted therapeutics to enhance brain resilience and function.},
}

Animals
*tau Proteins/metabolism/genetics
Mice
*Neurons/metabolism/pathology
*Aging/metabolism/genetics
Hippocampus/metabolism/pathology
Up-Regulation
Mice, Transgenic
Acetylation
Alzheimer Disease/genetics/metabolism/pathology
Histones/metabolism
Humans
Disease Models, Animal
Epigenesis, Genetic
Mice, Knockout
Memory Disorders/genetics

@article {pmid41511959,
year = {2025},
author = {Hernández-Villamizar, LF and Braun-Wohlfahrt, LS and Garcia-Escobar, G and De Diego-Osaba, M and Blasco-Forniés, H and Ortiz-Romero, P and Jiménez-Moyano, E and Contador, J and Estragués-Gázquez, I and Manero-Borràs, RM and Navalpotro, I and Grau-Rivera, O and Fernández-Lebrero, A and Del Campo, M and Puig-Pijoan, A and Anastasi, F and Suarez-Calvet, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107568},
doi = {10.1002/alz70856_107568},
pmid = {41511959},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Biomarkers/blood ; Cross-Sectional Studies ; *Cognitive Dysfunction/blood ; *Alzheimer Disease/blood ; Amyloid beta-Peptides/cerebrospinal fluid ; *Aging/blood ; Klotho Proteins ; Aged, 80 and over ; Cohort Studies ; Osteocalcin/blood ; },
abstract = {BACKGROUND: Peripheral blood factors influence brain aging in animal models, but their role in humans, particularly in age-related neurodegenerative diseases like Alzheimer's disease (AD), remains unclear. We investigated whether these blood factors are associated with AD-related biomarkers and cognitive performance in cognitively impaired patients.

METHOD: This cross-sectional study measured 10 age-related blood proteins in 366 participants from the BIODEGMAR cohort (Hospital del Mar, Barcelona), with cognitive impairment (median age of 74.4 years, IQR:70.0-77.5; 57% women; 44% APOE-ε4 carriers; 62,8% were CSF amyloid-positive; Figure 1). Blood proteins and AD-related biomarkers were quantified using ELISAs, MSD, Simoa or Lumipulse platforms. Linear regression models assessed associations with chronological age, and cognitive performance, considering sex and amyloid status as potential modifiers. Benjamini-Hochberg false discovery rate (FDR) correction was applied to adjust for multiple comparisons.

RESULT: Osteocalcin and a-Klotho in blood were higher in women, while β2-microglobulin was higher in men (Figure 2A). Older chronological age was associated with higher β2-microglobulin (β=+0.189, FDR-p=0.002), TIMP2 (β=+0.240, FDR-p=<0.001), and sVCAM1 (β=+0.160, FDR-p=0.008) (Figure 2B). Sex modified associations of CCL19, α-Klotho, and TIMP2 with chronological age (Figure 2C); in men, older age was associated with lower CCL19 (β=-0.204, FDR-p=0.027) and α-Klotho (β=-0.168, p = 0.040), but higher TIMP2 (β=0.382, FDR-p=<0.001). Higher CCL2 and β2-microglobulin were associated with worse cognitive performance in the overall sample (Figure 3A), while higher CCL11 was associated with poorer executive function in women only (β=+0.321, FDR-p=0.030) (Figure 3B). Finally, higher α-Klotho correlated with lower plasma p-tau217, NfL, and with higher CSF Aβ42/p-tau181 in men only (Figure 3C).

CONCLUSION: Sex modulates the relationship between age-related blood factors, and chronological age, cognition, and AD-related biomarkers. α-Klotho was linked to lower AD pathology only in men, while CCL11 was associated with worse executive function in women. These findings highlight sex-specific biological pathways in aging and neurodegeneration.},
}

Humans
Female
Male
Aged
*Biomarkers/blood
Cross-Sectional Studies
*Cognitive Dysfunction/blood
*Alzheimer Disease/blood
Amyloid beta-Peptides/cerebrospinal fluid
*Aging/blood
Klotho Proteins
Aged, 80 and over
Cohort Studies
Osteocalcin/blood

@article {pmid41511941,
year = {2025},
author = {Miyagawa, T and Przybelski, SA and Vernon, C and Min, HK and Forsberg, LK and Fields, JA and McCarter, SJ and Ferman, TJ and Ramanan, VK and Graff-Radford, J and Jones, DT and Savica, R and Reichard, RR and Parisi, JE and Nguyen, AT and Dickson, DW and Murray, ME and Day, GS and Graff-Radford, NR and St Louis, EK and Jain, MK and Kantarci, K and Lowe, VJ and Boeve, BF},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107564},
doi = {10.1002/alz70856_107564},
pmid = {41511941},
issn = {1552-5279},
mesh = {Humans ; Tomography, Emission-Computed, Single-Photon ; Male ; Female ; *Lewy Body Disease/diagnostic imaging/pathology/metabolism ; *Dopamine Plasma Membrane Transport Proteins/metabolism ; Aged ; Biomarkers/metabolism ; Autopsy ; Aged, 80 and over ; Tropanes ; *Brain/diagnostic imaging/pathology/metabolism ; Alzheimer Disease/diagnostic imaging ; },
abstract = {BACKGROUND: Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer's disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time-course [123]I-FP-CIT SPECT (DaT-SPECT) findings in autopsy-confirmed DLB are not well characterized. We previously reported that the DaTQUANT z-score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z-score of -1 as the cutoff value. We sought to examine how DaT-SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials.

METHOD: Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT-SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age-adjusted z-scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare).

RESULT: Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT-SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z-score <-1.0 at their initial scan including in MCI+RBD (-1.76) and iRBD (-1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z-score <-2.0 and one (17%) had z-score of -1.55. All patients (100%) showed DaTQUANT putamen z-score <-2.0 at their last scans.

CONCLUSION: DaTQUANT using cut-off putamen z-score of -1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z-score <-2 at their last scans.},
}

Humans
Tomography, Emission-Computed, Single-Photon
Male
Female
*Lewy Body Disease/diagnostic imaging/pathology/metabolism
*Dopamine Plasma Membrane Transport Proteins/metabolism
Aged
Biomarkers/metabolism
Autopsy
Aged, 80 and over
Tropanes
*Brain/diagnostic imaging/pathology/metabolism
Alzheimer Disease/diagnostic imaging

@article {pmid41511929,
year = {2025},
author = {Imms, P and Chaudhari, NN and Vega, OM and Irimia, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107525},
doi = {10.1002/alz70856_107525},
pmid = {41511929},
issn = {1552-5279},
mesh = {Humans ; Magnetic Resonance Imaging ; *Alzheimer Disease/diagnostic imaging/pathology ; Female ; Male ; Biomarkers ; *Brain/pathology/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Aged ; Neuroimaging/methods ; *Aging/pathology ; *Deep Learning ; Middle Aged ; },
abstract = {BACKGROUND: Traditional brain morphometrics (e.g., regional brain volumes) may not be sensitive to early and subtle neurodegenerations that precede cognitive impairment (CI). Deep learning neural networks (DNNs) leverage neuroimaging data to detect voxel-level deviations from normality. DNNs are trained to predict chronological age (CA) from magnetic resonance images (MRIs), resulting in a global brain age (BA) that estimates the biological age of a brain. The difference between BA and CA reflects the age gap (AG), which is larger in patients with neurodegenerative diseases. Our DNN generates local AGs in specific brain regions, to offer regionally interpretable insights into neurodegeneration.

METHOD: We quantify global and local AGs in 1,320 participants across two large-scale data repositories (i.e., NACC and ADNI). We compare group-level differences in global AG to group-level differences in brain volume across CN adults with and without CI in their future (converters and non-converters, respectively), and individuals with Alzheimer's disease. Additionally, we explore regional-level spatial changes in brain aging across CN adults who will convert in the short-term (ST; 0.5 to 2.5 years), mid-term (MT; 2.5 to 6 years), and long-term (LT; > 6 years).

RESULT: Global AGs, but not brain volumes, are significantly elevated in ST and MT converters and AD subjects compared to non-converters. Compared to non-converters, MT converters' local AGs are significantly higher in temporal, insular, and orbitofrontal regions. As converters approach CI onset (i.e., ST converters), larger AGs propagate to anterior cingulate cortices, lateral temporal and frontal lobes, and parietal regions, before encompassing the rest of the cortex in subjects with AD.

CONCLUSION: Our results challenge the assumption that T1-weighted MRIs cannot reveal temporal dynamics of neurodegeneration. The patterns revealed by local AG maps recapitulate known neurodegenerative patterns of AD observed using imaging techniques that require exposure to radiation (i.e., positron emission tomography). The ability to employ spatiotemporally sensitive biomarkers that are non-invasive and informative of proximity to CI conversion reduces barriers to early detection of Alzheimer's disease.},
}

Humans
Magnetic Resonance Imaging
*Alzheimer Disease/diagnostic imaging/pathology
Female
Male
Biomarkers
*Brain/pathology/diagnostic imaging
*Cognitive Dysfunction/diagnostic imaging/pathology
Aged
Neuroimaging/methods
*Aging/pathology
*Deep Learning
Middle Aged

@article {pmid41511928,
year = {2025},
author = {Doster, S and Price, AN and Sergio, JP and Durkin, M and Strenger, J and Thompson, LI and Stradtman, M and Sinoff, S and Snyder, PJ and Alber, J},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107578},
doi = {10.1002/alz70856_107578},
pmid = {41511928},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; Aged ; *Cognitive Dysfunction/blood/diagnosis ; *Alzheimer Disease/blood/diagnosis ; Middle Aged ; Aged, 80 and over ; *tau Proteins/blood ; *Neurofilament Proteins/blood ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Gait impairments in Alzheimer's disease (AD) and related dementias pose a major fall risk/contribute to morbidity/mortality. The Timed Up and Go (TUG) test is often used to assess mobility, gait changes, and dual-task performance. The TUG-Dual Task (TUG-DT) version adds serial subtraction exercises to evaluate dual-task cost (DTC). For cognitively unimpaired (CU) individuals or those with mild cognitive impairment (MCI), plasma biomarkers like pTau217, pTau181, and neurofilament light chain (NfL) can help assess the risk of AD. This study aimed to explore the relationship between TUG performance and plasma biomarkers in CU and MCI patients.

METHODS: Participants included CU low-risk (n = 75), CU high-risk (n = 87), and CI (n = 32) older adults aged 55-80, mean = .67.28 ± 6.062 years. Cognitive ability was assessed using the Clinical Dementia Rating Scale (CU = 0; CI = 0.5 or 1.0) and the Montreal Cognitive Assessment (CU ≥ 26; 18 ≤ CI ≤ 26). AD-risk was determined by APOE genotyping and family history for CU groups. Plasma biomarkers pTau217, pTau181, and NfL were analyzed from fasting blood draws. Participants completed the TUG and TUG-DT. ANOVAs, ANCOVAs, logistic regression, and generalized additive models (GAMs), were used to analyze the relationship between demographic factors, gait performance, and plasma biomarkers, with model comparisons guiding the final choice of GAMs for their flexibility in handling non-linear relationships.

RESULTS: Step count analysis on the TUG showed that the CU-high-risk and MCI groups performed similarly, while the CU-low-risk group completed significantly fewer steps than both. Plasma biomarkers, particularly pTau181 and NfL, interacted to predict gait performance only in the CU high-risk group.

CONCLUSIONS: The TUG can predict plasma pTau217 levels with high specificity, distinguishing CU individuals not at risk for AD. Additionally, pTau181 and NfL interacted to predict performance on the TUG and TUG-DT in the CU-high-risk group, suggesting subtle gait changes may signal early AD pathology. The CU-low-risk group's reduced step count compared to others indicates preclinical AD might manifest with subtle mobility impairments. These findings support using simple gait tasks like the TUG for AD risk assessment in older adults.},
}

Humans
*Biomarkers/blood
Male
Female
Aged
*Cognitive Dysfunction/blood/diagnosis
*Alzheimer Disease/blood/diagnosis
Middle Aged
Aged, 80 and over
*tau Proteins/blood
*Neurofilament Proteins/blood
Neuropsychological Tests

@article {pmid41511904,
year = {2025},
author = {Crook, MV and Pizarro, EB and Ferrer, GA and Mesquida, MS and Sanchez, ST and Martin, AG and Santos, LN and Bertó, MS and García, DM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107570},
doi = {10.1002/alz70856_107570},
pmid = {41511904},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Biomarkers/blood/cerebrospinal fluid ; Aged ; *Alzheimer Disease/diagnosis/cerebrospinal fluid/blood ; *Glial Fibrillary Acidic Protein/blood ; *Cognitive Dysfunction/diagnosis/cerebrospinal fluid/blood ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Middle Aged ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Fluid biomarkers for Alzheimer's Disease (AD) have demonstrated strong diagnostic performance in clinical practice. However, distinguishing non-AD neurodegenerative from non-neurodegenerative cognitive impairment remains challenging. This study evaluates the utility of plasma glial fibrillary acidic protein (pGFAP) in addressing this diagnostic dilemma.

METHODS: We recruited 160 patients from our memory clinic (July 2022-May 2024) and collected clinical, neuropsychological, and neuroimaging data, along with core AD cerebrospinal fluid (CSF) biomarkers. Plasma GFAP levels were concurrently measured using CMIA assay on the Alinity i series platform (limit of quantification: 3.2 pg/mL; intra-assay CV <5%). Patients with immune-mediated dementia were excluded. After excluding AD patients based on the Aß42/40 or ptau181/Aß42 indexes, 46 non-AD patients remained. Neurologists, blinded to pGFAP results, classified participants either as neurodegenerative or non-neurodegenerative based on clinical and imaging data. Group comparisons were performed using Wilcoxon rank-sum tests, and robust regression models were used to adjust for confounding variables (age and sex).

RESULTS: Among the 46 non-AD patients (69.9% female; median age 71.3 years [IQR: 63.1-76.1], median MMSE score was 27 [IQR: 22-28]), 17 were classified as neurodegenerative (FTD, LBD, LATE) and 29 as non-neurodegenerative, including vascular cognitive impairment. Patients in the neurodegenerative group were older (median age 75 vs. 66 years, p =  0.004), with no significant differences in sex distribution. Median pGFAP levels were significantly higher in the neurodegenerative group (38.8 pg/mL [IQR: 27.8-45.4]) versus the non-neurodegenerative group (21.7 pg/mL [IQR: 16.2-33.2], p =  0.001). ROC analysis yielded an AUC of 0.79 (95% CI: 0.66-0.92) for pGFAP, with a threshold of 35.6 pg/mL achieving 82.8% sensitivity and 64.7% specificity. Positive and negative predictive values were 62.9% and 83.8%, respectively. Robust regression analysis confirmed pGFAP's independent association with neurodegenerative diagnoses (p = 0.015), adjusting for age and sex.

CONCLUSIONS: These findings support the utility of plasma GFAP, measured using a CMIA-based assay, in differentiating neurodegenerative from non-neurodegenerative cognitive impairments. Our real-world cohort analysis underscores the potential of pGFAP for broader clinical application beyond AD.},
}

Humans
Male
Female
Biomarkers/blood/cerebrospinal fluid
Aged
*Alzheimer Disease/diagnosis/cerebrospinal fluid/blood
*Glial Fibrillary Acidic Protein/blood
*Cognitive Dysfunction/diagnosis/cerebrospinal fluid/blood
Amyloid beta-Peptides/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Middle Aged
Neuropsychological Tests

@article {pmid41511900,
year = {2025},
author = {Raikes, AC and Bhattrai, A and Wang, T and Brinton, RD},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107547},
doi = {10.1002/alz70856_107547},
pmid = {41511900},
issn = {1552-5279},
mesh = {Male ; Female ; Animals ; Magnetic Resonance Imaging ; *Alzheimer Disease/genetics/pathology/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Mice ; Disease Models, Animal ; Apolipoproteins E/genetics ; Biomarkers ; Mice, Transgenic ; Genotype ; Atrophy ; Humans ; },
abstract = {BACKGROUND: Whole brain and hippocampal atrophy are key structural features of late-onset Alzheimer's disease (LOAD) and common clinical trial endpoints. The APOE ε4 allele is the strongest genetic risk factor, with ε4/ε4 genotype linked to the greatest atrophy rates. Structural differences in preclinical APOE models remain underreported, limiting assessments of translatability. Here, we considered a humanized APOE (hAPOE) mouse model of AD, and assessed age, sex, and genotype effects on volumetric brain measurements in a voxel-wise manner.

METHOD: High-resolution ex-vivo T2w-RARE MRIs were acquired from male and female hAPOEε3/ε3, ε3/ε4, and ε4/ε4 mice aged 6, 9, 15, and 24 months. Brains were warped to a study-specific template, and voxel-wise analyses were performed on relative Jacobians, reflecting local differences independent of total brain size. The model included mean-centered age, sex, and APOE genotype (ε4/ε4 vs. ε3/ε4; ε3/ε3 vs. ε4+). Significant voxels were thresholded at FDR-corrected p < 0.001 and classified using the Dorr atlas.

RESULT: Significant clusters of voxels were identified for age and sex but not APOE genotype. Age-related volume decreases were observed in cortical regions, cerebellar cortex, striatum, and thalamus, while increases occurred in deep midbrain structures, including the medulla and pons, and white matter tracts such as the corpus callosum. Males had greater volume in midbrain structures, cerebellar cortex, striata, and subcortical gray matter, while females had greater cortical volume, consistent with other rodent models.

CONCLUSION: Our findings leverage a large dataset (n = 159) of high-resolution MRIs in mice spanning 6-24 months (human age range: ∼34-70). Age-related changes indicate cortical contraction and midbrain/white matter expansion. Observed sex differences align with prior mouse studies: females exhibit greater cortical volume, while males show greater subcortical volume. Notably, there were identifiable areas of the hippocampi where volume was smaller in females than males, consistent with human studies. No genotypic effects survived multiple comparison correction, suggesting that age and sex drive volumetric changes rather than APOE and that the ε4 allele in this model does not result in the phenotypic atrophy observed in LOAD. This model reflects aging and neurodegenerative risk rather than disease, providing insights into brain structural dynamics over the lifespan.},
}

Male
Female
Animals
Magnetic Resonance Imaging
*Alzheimer Disease/genetics/pathology/diagnostic imaging
*Brain/pathology/diagnostic imaging
Mice
Disease Models, Animal
Apolipoproteins E/genetics
Biomarkers
Mice, Transgenic
Genotype
Atrophy
Humans

@article {pmid41511895,
year = {2025},
author = {Cullum-Doyle, M and Panizzon, MS and Risbrough, V and Elman, JA and Franz, CE and Kremen, WS and Rissman, RA},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107567},
doi = {10.1002/alz70856_107567},
pmid = {41511895},
issn = {1552-5279},
mesh = {Humans ; Biomarkers/blood ; Male ; Aged ; *Brain Injuries, Traumatic/complications/blood ; *Cognitive Dysfunction/blood/diagnosis ; Longitudinal Studies ; *Cytokines/blood ; Veterans ; *Extracellular Vesicles/metabolism ; Astrocytes/metabolism ; Complement System Proteins/metabolism ; Middle Aged ; },
abstract = {BACKGROUND: Traumatic brain injury (TBI) is a significant risk factor for Alzheimer's disease (AD) and cognitive decline, yet biomarkers identifying persistent neuroinflammation following TBI remain underexplored. Astrocyte-derived small extracellular vesicles (AEVs) from plasma encapsulate inflammatory cytokines and complement proteins, offering a window into chronic neuroinflammatory processes linked to TBI and cognitive dysfunction. Previous studies demonstrate that complement proteins within AEVs predict mild cognitive impairment (MCI) conversion and are elevated in TBI patients years post-injury. This study examines AEV cargo to determine whether inflammatory cytokines and complement proteins serve as biomarkers for cognitive decline in aging veterans with a history of TBI.

METHOD: Participants of the Vietnam Era Twin Study of Aging (VETSA), a longitudinal cohort of male twins (mean age = 68), have extensive cognitive, laboratory, and genetic assessments. Plasma AEVs from biobanked VETSA3 samples were isolated using immunocapture of astrocyte-specific marker GLAST (ACSA-1) and characterized using nanoimaging. We quantified key inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-10) and complement proteins (C4b and C3b) within AEV cargo using ultra-sensitive SIMOA assays. Group differences between TBI-exposed (N≈320) and non-TBI (N≈680) participants were assessed using linear mixed-effects models, accounting for twin clustering. Longitudinal mixed models were applied to evaluate the association of AEV protein cargo with cognitive decline, with MCI classification used as a secondary outcome. ROC analyses examined the predictive utility of AEV biomarkers for MCI diagnosis.

RESULT: AEVs were successfully isolated and characterized, confirming the EV size, shape, and enrichment of astrocyte markers. Preliminary findings suggest significant elevations in C3b and IL-6 in TBI-exposed individuals compared to controls, with higher levels correlating with accelerated cognitive decline. ROC analyses indicate that a combined biomarker panel (IL-6, TNF-α, and C4b) improves the classification of MCI status (AUC > 0.7).

CONCLUSION: These findings highlight the potential of AEV-derived inflammatory and complement proteins as biomarkers of neuroinflammation and cognitive decline in TBI-exposed aging populations. The persistence of inflammatory abnormalities in AEVs years after TBI suggests a chronic neuroinflammatory response that may underlie increased AD risk. Future work will examine interactions between inflammatory and neurodegenerative AEV biomarkers to refine risk prediction models for cognitive impairment in TBI populations.},
}

Humans
Biomarkers/blood
Male
Aged
*Brain Injuries, Traumatic/complications/blood
*Cognitive Dysfunction/blood/diagnosis
Longitudinal Studies
*Cytokines/blood
Veterans
*Extracellular Vesicles/metabolism
Astrocytes/metabolism
Complement System Proteins/metabolism
Middle Aged

@article {pmid41511881,
year = {2025},
author = {Brodman, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107562},
doi = {10.1002/alz70856_107562},
pmid = {41511881},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Amyloid beta-Peptides/blood ; Male ; *Alzheimer Disease/diagnostic imaging/blood/pathology/diagnosis ; Female ; *tau Proteins/blood ; Positron-Emission Tomography ; Aged ; Glial Fibrillary Acidic Protein/blood ; Brain/diagnostic imaging/pathology ; },
abstract = {BACKGROUND: Plasma biomarkers are critical for early detection and treatment of Alzheimer's disease (AD). We assessed plasma biomarker association and classification capacity against neuroimaging measures.

METHOD: In the racially diverse Human Connectome Project (HCP; n = 218, 15% Aβ-PET-positive) Aβ-PET and cortical thickness (neurodegeneration) were related to plasma biomarkers (p-tau181, p-tau217 [Janssen and ALZpath], p-tau231, GFAP, NfL, Aβ42/Aβ40).

RESULT: Plasma p-tau217 accurately identified abnormal Aβ-PET (: AUC=0.9145, 95% CI=[0.8367, 0.9923]) followed by GFAP and Aβ42/40 ratio (GFAP (AUC=0.8529, 95% CI = [0.7485, 0.9573], Aβ42/40 (AUC = 0.7962, 95% CI = [0.6581, 0.9346]). All biomarkers performed poorly to identify cortical thickness, but were increased according to combined Aβ-PET-neurodegeneration profiles. Correlations of p-tau217, p-tau181, and Aβ42/40 with Aβ-PET were stronger in self-identified non-Hispanic Whites vs. Black/African Americans.

CONCLUSION: Plasma biomarkers identify brain Aβ pathology in the community. However, consideration of potential racial/ethnic differences in brain-to-blood biomarker correlations should be critically examined and addressed to enable widespread cross-population applications.},
}

Humans
*Biomarkers/blood
*Amyloid beta-Peptides/blood
Male
*Alzheimer Disease/diagnostic imaging/blood/pathology/diagnosis
Female
*tau Proteins/blood
Positron-Emission Tomography
Aged
Glial Fibrillary Acidic Protein/blood
Brain/diagnostic imaging/pathology

@article {pmid41511875,
year = {2025},
author = {Rosso, LM and Ferrari-Souza, JP and Beltrami, LB and Povala, G and Leffa, DT and Lussier, FZ and Brum, WS and Aguzzoli, C and De Bastiani, MA and Bieger, A and Carello-Collar, G and Borelli, WV and Therriault, J and Macedo, AC and Rahmouni, N and Souza, DO and Bellaver, B and Ferreira, PCL and Rosa-Neto, P and Pascoal, TA and Zimmer, ER},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107489},
doi = {10.1002/alz70856_107489},
pmid = {41511875},
issn = {1552-5279},
mesh = {Humans ; Positron-Emission Tomography ; Aged ; Male ; Female ; *Alzheimer Disease/genetics/diagnostic imaging/metabolism ; *tau Proteins/metabolism ; Middle Aged ; *Apolipoprotein E4/genetics ; Aged, 80 and over ; *Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; Aniline Compounds ; *Brain/diagnostic imaging/metabolism ; Stilbenes ; Cohort Studies ; Carbolines ; Ethylene Glycols ; },
abstract = {BACKGROUND: Trials in preclinical Alzheimer's disease (AD) are becoming increasingly important, as AD pathological changes appear decades before dementia onset. Amyloid-beta (Aβ) pathology and the apolipoprotein E ε4 (APOEε4) carriership jointly accelerate tau tangle accumulation. However, the utility of assessing both variables to enhance participant selection for AD trials using tau positron emission tomography (PET) as outcome has not yet been explored. Here, we investigated the implications of considering APOEε4 status for participant selection in tau-targeting trials for preclinical AD.

METHOD: We analyzed 96 cognitively unimpaired (CU) individuals (aged 57-90 years) from the ADNI cohort that underwent clinical assessments, APOE genotyping, PET for Aβ ([[18]F]Florbetapir or [[18]F]Florbetaben) and tau ([[18]F]Flortaucipir) at baseline, along with a 2-year follow-up. Aβ positivity was determined as global [[18]F]Florbetapir SUVR >1.11 or [[18]F]Florbetaben SUVR >1.08. We calculated the sample size required for a hypothetical clinical trial testing a 25% drug effect, with 80% power at alpha level 0.05, to reduce tau-PET accumulation in the medial temporal lobe (MTL) and neocortex (NEO), along with the total trial costs.

RESULT: Table 1 reports the demographic information of the study population. Figure 1 shows enrichment strategies for the selection of participants in a clinical trial aiming at tau PET reduction in CU individuals. In comparison to using only Aβ positivity, the use of APOEε4 genotyping together with Aβ positivity for population enrichment would reduce the sample size and total costs, respectively, by 28% and 34% in trials targeting tau PETMTL, and by 24% and 36%, respectively, in trials targeting tau PETNEO (Figure 2).

CONCLUSION: Our findings suggest that combining APOEε4 status with Aβ positivity may be a cost-effective strategy for enriching participant selection in AD tau-targeting trials focusing on asymptomatic individuals, reducing required sample sizes and trial costs.},
}

Humans
Positron-Emission Tomography
Aged
Male
Female
*Alzheimer Disease/genetics/diagnostic imaging/metabolism
*tau Proteins/metabolism
Middle Aged
*Apolipoprotein E4/genetics
Aged, 80 and over
*Biomarkers/metabolism
Amyloid beta-Peptides/metabolism
Aniline Compounds
*Brain/diagnostic imaging/metabolism
Stilbenes
Cohort Studies
Carbolines
Ethylene Glycols

@article {pmid41511868,
year = {2025},
author = {Bhattrai, A and Raikes, AC and McLean, JW and Brinton, RD},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107527},
doi = {10.1002/alz70856_107527},
pmid = {41511868},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/diagnostic imaging ; Female ; Male ; Mice ; Amyloid beta-Protein Precursor/genetics ; Biomarkers/metabolism ; Apolipoprotein E4/genetics ; Mice, Transgenic ; *Brain/metabolism/diagnostic imaging ; Positron-Emission Tomography ; Disease Models, Animal ; Apolipoproteins E/genetics ; Humans ; Fluorodeoxyglucose F18 ; Blood Glucose/metabolism ; },
abstract = {BACKGROUND: Late-onset Alzheimer's disease (LOAD) affects approximately 95% of the clinical dementia population aged 65 and older, influenced by genetics, age and sex. Apolipoprotein e4 (APOE4) is the strongest genetic risk factor, in addition to other prominent risk genes such as amyloid precursor protein (APP). APOE4 confers a 15-fold higher risk in females compared to males. Preclinical research often uses familial AD risk factor gene mouse models, which impact <5% of the clinical population, limiting clinical translatability. Herein, we investigated the impact of a single strong AD risk factor gene (APP) combined with LOAD-specific risk factors on brain and peripheral bioenergetics.

METHOD: Aged (23-25 months) humanized APP/APOE (APP carrier) and hAPOE (APP non-carrier) mice with ε3/3, ε3/4 and ε4/4 genotype underwent metabolic and body composition screening including fasting blood glucose (FBG) and ketone (FKB) measurement, EchoMRI, and 18F-FDG-PET. Cerebral FDG-PET standardized uptake values (SUVR) were normalized to pons. For analysis, mice were classified as APOE4 carriers and non-carriers, based on the presence of an ε4 allele. All data were analyzed with APP carrier x APOE carrier x sex analyses of variance followed by post-hoc Bonferroni correction.

RESULT: APP carriers had significantly lower SUVR compared to non-carriers. Irrespective of genetic model, females had lower brain glucose uptake than males. APP carriers, irrespective of genotype, additionally had lower FBG than non-carriers with a trend towards sex differences. Finally, APP carriers had higher FKB levels than non-carriers, with female APP carriers having higher FKB levels than all non-carriers.

CONCLUSION: In a mouse cohort at a comparative human age of ∼70 years, lower brain SUVR in APP carriers coupled with lower FBG indicates bioenergetic deficits and the inability to meet energetic demands via glycolysis. This bioenergetic profile is also observed in clinical populations. Greater FKB in APP carriers suggests a shift toward utilizing fatty acids to meet bioenergetic demands. These results highlight the downstream metabolic impact of hAPP in the presence of hAPOE in these aged mice, providing important evidence for the interplay between AD genetic risk factors and bioenergetic dysfunction.},
}

Animals
*Alzheimer Disease/genetics/metabolism/diagnostic imaging
Female
Male
Mice
Amyloid beta-Protein Precursor/genetics
Biomarkers/metabolism
Apolipoprotein E4/genetics
Mice, Transgenic
*Brain/metabolism/diagnostic imaging
Positron-Emission Tomography
Disease Models, Animal
Apolipoproteins E/genetics
Humans
Fluorodeoxyglucose F18
Blood Glucose/metabolism

@article {pmid41511860,
year = {2025},
author = {Franquesa-Mullerat, M and Morcillo-Nieto, AO and Arriola-Infante, JE and Zsadanyi, SE and Vaqué-Alcázar, L and Aranha, MR and Arranz, J and Rodríguez-Baz, Í and Maure-Blesa, L and Videla, L and Barroeta, I and Hoyo, LD and Benejam, B and Fernandez, S and Hernandez, AS and Giménez, S and Alcolea, D and Lleó, A and Carmona-Iragui, M and Fortea, J and Bejanin, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e106416},
doi = {10.1002/alz70856_106416},
pmid = {41511860},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Cross-Sectional Studies ; Aged ; Middle Aged ; *Cerebrovascular Circulation/physiology ; Amyloid beta-Peptides/cerebrospinal fluid ; Adult ; *Down Syndrome/diagnostic imaging/pathology ; *Brain/diagnostic imaging/pathology/blood supply ; Spin Labels ; tau Proteins/cerebrospinal fluid ; Cognitive Dysfunction/diagnostic imaging ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND: Down Syndrome (DS) represents a high-risk group for Alzheimer's disease (AD) due to chromosome 21 triplication, which drives amyloid precursor protein overproduction. While brain atrophy in DS has been widely studied, the underlying brain perfusion changes remain poorly understood. This study leverages MRI pseudo-continuous arterial spin labeling (pCASL) to explore early cerebral blood flow (CBF) alterations along the AD continuum in DS and compares these changes to the perfusion patterns seen in sporadic AD (sAD) METHOD: We performed a cross-sectional analysis including 32 euploid cognitively unimpaired individuals (eCU, age= 56.8yo, 68.7% female), 37 adults with DS (age= 42.64y; females= 37.83%, 40.5% symptomatic including n = 8 prodromal AD and n = 7 dementia) and 24 sAD patients (age 74.2yo, 50% female, 16 MCI and 8 in dementia stage) from the SPIN and DABNI cohorts that underwent 3T-MRI. pCASL images were preprocessed using ASLprep. Analyses explored the effects of demographic variables (age, sex), clinical stages, and AD biomarkers (including cerebrospinal fluid [CSF] Aβ1-42/Aβ1-40 ratio, pTau-181, and hippocampal volume) on global and regional CBF.

RESULT: Age-related decreases in cerebral blood flow (CBF) were observed in prefrontal regions in eCU, parietal structures in DS, and temporal lobes in sAD (Figure 1 A-D). Females had higher perfusion than males in eCU and sAD, but not in DS (Figure 1 E-H). In DS, CBF was reduced in temporal-parietal regions in asymptomatic individuals, extending to frontal areas in symptomatic cases, resembling sAD patterns (Figure 2). Symptomatic DS showed significantly lower CBF in lateral parietal regions than asymptomatic DS. Temporoparietal CBF correlated negatively with CSF-pTau-181 and positively with CSF-Aβ1-42/Aβ1-40 ratio and hippocampal volume, with the strongest association seen with hippocampal volume (Figure 3) CONCLUSION: Brain perfusion is significantly altered in adults with DS along the AD continuum, with changes detectable even before clinical symptoms. Hypoperfusion primarily affects temporoparietal and frontal regions at the symptomatic stage, closely resembling patterns seen in sAD. Notably, perfusion in the parietal areas differentiates asymptomatic from symptomatic DS and correlates strongly with key AD biomarkers. These findings highlight the potential of pCASL to detect early functional changes in this high-risk population.},
}

Humans
Female
Male
Biomarkers/cerebrospinal fluid
*Alzheimer Disease/diagnostic imaging/pathology
Magnetic Resonance Imaging
Cross-Sectional Studies
Aged
Middle Aged
*Cerebrovascular Circulation/physiology
Amyloid beta-Peptides/cerebrospinal fluid
Adult
*Down Syndrome/diagnostic imaging/pathology
*Brain/diagnostic imaging/pathology/blood supply
Spin Labels
tau Proteins/cerebrospinal fluid
Cognitive Dysfunction/diagnostic imaging
Peptide Fragments/cerebrospinal fluid

@article {pmid41511852,
year = {2025},
author = {Pytel, D and Ivey, BT and Jenkins, DP and Ackerman, M and Belk, J and Mitchell, C and Davis, L and Waugh, ML and Moss, MA and Liu, C and Ding, F and Longo, JF and Carroll, SL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107504},
doi = {10.1002/alz70856_107504},
pmid = {41511852},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Amyloid beta-Peptides/cerebrospinal fluid ; Female ; Male ; Aged ; *Vitreous Body/metabolism ; Neurofilament Proteins/cerebrospinal fluid ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Aged, 80 and over ; Dementia ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) and AD-Related Dementias (ADRDs) represent a growing public health challenge, underscoring the urgent need for accessible and reliable biomarkers for early diagnosis, progression monitoring, and therapeutic response assessment. The search for reliable and accessible biomarkers remains a critical challenge in advancing early diagnosis and precision medicine. Vitreous humor (VH), a transparent ocular fluid in close anatomical and physiological connection with the central nervous system (CNS), represents a promising yet underutilized biofluid for biomarker discovery. Recent studies suggest that VH has potential as a proxy for brain neuropathology. We hypothesize that VH may also provide useful biomarker potential for other neurodegenerative diseases. We analyzed postmortem paired biosamples from VH, cerebral spinal fluid (CSF) and blood plasma from individuals with AD and other ADRDs to test this hypothesis.

METHOD: Postmortem blood plasma, CSF, and VH samples (n = 133) were obtained from the Carroll A. Campbell, Jr. Neuropathology Laboratory at the Medical University of South Carolina. Samples were tested for Aβ40, Aβ42, GFAP, and NfL. Relative concentrations were measured using the Simoa Neurology 4-Plex E (N4PE+) Advantage PLUS assay with a 4- fold dilution for blood plasma, 25-fold dilution for VH and 400-fold dilution for CSF on HD-X analyzer (Quanterix, MA). All samples were processed per manufacturer's instructions in the immunoassay kits; we are currently analyzing the same samples for p-Tau217. Artificial intelligence (AI) predictive modeling (including neural networks) using retrospective and prospective cohorts is being used to ensure accuracy and reliability.

RESULT: Our findings reveal biomarker signatures (Aβ40, Aβ42, GFAP, and NfL) in the VH of AD and ADRDs. Moreover, we highlight the potential of these biomarkers for early disease detection and differentiation of AD from ADRD subtypes. We analyzed the relationship between VH biomarkers, blood plasma, CSF, clinical, and neuropathological measures.

CONCLUSION: VH may be a valuable source for biomarker discovery in neurodegenerative disease such as AD, diffuse Lewy body disease and frontotemporal dementia (FTD). We anticipate that integration of VH and other biomarkers with AI-driven data analysis will enhance diagnostic capabilities, ultimately supporting neurology and memory care clinicians in the future.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Amyloid beta-Peptides/cerebrospinal fluid
Female
Male
Aged
*Vitreous Body/metabolism
Neurofilament Proteins/cerebrospinal fluid
Glial Fibrillary Acidic Protein/cerebrospinal fluid
Aged, 80 and over
Dementia

@article {pmid41511811,
year = {2025},
author = {Pillai, JJ and Reid, RI and Weigand, SD and Cogswell, PM and Vemuri, P and Algeciras-Schimnich, A and Knopman, DS and Radford, JG and Petersen, R and Jack, CR},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e105668},
doi = {10.1002/alz70856_105668},
pmid = {41511811},
issn = {1552-5279},
mesh = {Humans ; Aged ; Male ; Female ; Biomarkers/blood ; *Cognitive Dysfunction/blood/diagnostic imaging/pathology ; Middle Aged ; Aged, 80 and over ; *Neurofilament Proteins/blood ; *Glial Fibrillary Acidic Protein/blood ; *Alzheimer Disease/blood/diagnostic imaging/pathology ; Diffusion Magnetic Resonance Imaging ; Temporal Lobe/diagnostic imaging/pathology ; },
abstract = {BACKGROUND: Plasma neurofilament light chains (NfL) and glial fibrillary acidic protein (GFAP) are blood-based biomarkers of axonal injury and astrocytic activation, respectively, that are elevated in those with Alzheimer's disease (AD) and mild cognitive impairment (MCI) relative to cognitively unimpaired (CU) individuals. Neurite orientation dispersion and density imaging (NODDI) is a multishell diffusion MRI method capable of evaluating tissue microstructure at the axonal and dendritic level. We evaluated associations between temporal cortex orientation dispersion index (ODI), neurite density index (NDI) and isotropic volume fraction (ISOVF) and plasma NfL and GFAP concentrations.

METHOD: We included Mayo Clinic Study of Aging (MCSA) participants (ages 60-95 years) with diagnoses or CU (n = 356) or MCI (n = 60), and Alzheimer's Dementia Research Center (ADRC) participants with dementia (n = 51). NODDI imaging was obtained on a 3T Siemens Prisma scanner with 2 mm isotropic resolution. NfL and GFAP were measured using the Simoa® Neurology 4-Plex E Advantage kit. We fit separate linear regression models within each MCALT_ADIR122 cortical ROI with regional NODDI as the primary predictor and log-transformed plasma concentration as the outcome. Models were adjusted for age, sex, BMI, cortical thickness (or hippocampal & amygdalar volume) and total intracranial volume.

RESULT: The Table displays demographic data. Figures 1 and 2 show the relationship of NDI and ISOVF measures to plasma NfL concentrations across participants in individual ROIs (similar findings were noted with GFAP). A significant inverse relationship between NfL concentrations and NDI was observed in hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus as well as all temporal neocortical regions except the superior temporal gyrus (p <0.001) (Figure 1), whereas higher NfL concentrations were associated with higher ISOVF in all regions (p <0.001) (Figure 2). Fewer significant associations were also seen with ODI. After adjusting for age, cortical thickness/volume and other confounds, significant associations with NDI remain, particularly in hippocampal and amygdalar regions.

CONCLUSION: NODDI-derived measures (NDI and ISOVF) within the temporal lobe cortical regions demonstrate significant associations with plasma biomarkers of axonal and astrocytic dysfunction that are elevated during cognitive decline. This association provides preliminary validation of the utility of NODDI in assessing cortical microstructural changes associated with cognitive decline.},
}

Humans
Aged
Male
Female
Biomarkers/blood
*Cognitive Dysfunction/blood/diagnostic imaging/pathology
Middle Aged
Aged, 80 and over
*Neurofilament Proteins/blood
*Glial Fibrillary Acidic Protein/blood
*Alzheimer Disease/blood/diagnostic imaging/pathology
Diffusion Magnetic Resonance Imaging
Temporal Lobe/diagnostic imaging/pathology

@article {pmid41511749,
year = {2025},
author = {Honig, LS and Kang, MS and Lamoureux, J and Marder, K},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107531},
doi = {10.1002/alz70856_107531},
pmid = {41511749},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; Aged ; *Lewy Body Disease/cerebrospinal fluid/diagnosis ; Amyloid beta-Peptides/cerebrospinal fluid ; Longitudinal Studies ; Alzheimer Disease/cerebrospinal fluid/diagnosis ; *alpha-Synuclein/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Aged, 80 and over ; Cohort Studies ; Middle Aged ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND: Dementia with Lewy bodies (DLB) can be a challenging diagnosis clinically. Accurate Alzheimer's disease (AD) diagnosis has been improved by cerebrospinal fluid (CSF), molecular-imaging, and recently, blood-based, biomarkers. But only very recently has the advent of α-synuclein seed-aggregation-assays (SAA), been available as a DLB diagnostic biomarker. DLB and AD pathologies co-occur, so characterization is particularly important, with accompanying therapeutic implications. We report results of a cohort, enrolled in a longitudinal DLB study, the performance and stability of CSF SAA biomarker status, and its relation to demographics and AD biomarkers.

METHOD: As part of the NINDS-supported PDBP program, DLB patients were annually followed: thirty had CSF, and of those 13 had at least 2 separate CSF sampling. CSF samples were analyzed in blinded fashion by Amprion (San Diego, CA) using the SAAmplify™-αSYN test, and at Columbia for AD biomarkers using the Quanterix HD-X platform.

RESULT: For the 30 clinically-diagnosed DLB participants, 23 (77%) were SAA-positive. Eight participants had two, and five participants three CSF samples each. Testing was stable over time: the 3 SAA-negative participants remained negative, and 10 SAA-positive remained positive. Comparison of 23 SAA-positive and 7 SAA-negative individuals revealed no significant differences in age (71.1±7.6 vs 73.8±6.3 yr), male sex (91% vs 100%), nonwhite ethnicity (8/23 vs 0/7), or APOE4 carrier status (8/23 vs 1/7). Likewise there were no significant difference in CSF, and plasma, biomarker levels for Aβ40, Aβ42, total-tau, phosphotau181, NfL, or Aβ42/Aβ40, tau/Aβ42, or phosphotau181/Aβ42 ratios. Overall, about 15-30% of both groups met AD-positive criteria depending on which biomarker was used. One of 30 cases, which was CSF SAA-negative, had an autopsy, and showed no DLB pathology, but only AD pathology, with substantia nigra neurofibrillary degeneration.

CONCLUSION: Determination of DLB status using CSF SAA test in this clinical DLB cohort revealed high (77%) positivity. Repeated CSF evaluations revealed that SAA measurements, whether negative or positive, remained consistent over 1-2 years. For the few individuals who were SAA negative, there was no evidence of increased Alzheimer pathology by CSF biomarkers, although the one SAA negative case that came to autopsy was also negative for Lewy body pathology.},
}

Humans
*Biomarkers/cerebrospinal fluid
Male
Female
Aged
*Lewy Body Disease/cerebrospinal fluid/diagnosis
Amyloid beta-Peptides/cerebrospinal fluid
Longitudinal Studies
Alzheimer Disease/cerebrospinal fluid/diagnosis
*alpha-Synuclein/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Aged, 80 and over
Cohort Studies
Middle Aged
Peptide Fragments/cerebrospinal fluid

@article {pmid41511710,
year = {2025},
author = {Cohen, B and Goldsmith, N and Story, C and Yerokhin, V and Arciero, P and Needham, V and Panos, S and Warner, G and Anderson-Hanley, C},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e106286},
doi = {10.1002/alz70856_106286},
pmid = {41511710},
issn = {1552-5279},
mesh = {Humans ; *Cognitive Dysfunction/blood ; Biomarkers/blood ; Pilot Projects ; Aged ; Male ; Female ; COVID-19 ; *Brain-Derived Neurotrophic Factor/blood ; Dried Blood Spot Testing ; Alzheimer Disease/blood ; Neuropsychological Tests ; Aged, 80 and over ; Caregivers ; Executive Function/physiology ; },
abstract = {BACKGROUND: Clinical trials to ameliorate mild cognitive impairment (MCI) and stave off Alzheimer's and related dementias (ADRDs) can benefit from facile methods for tracking biomarker correlates linking interventions (e.g., exercise) with neuropsychological outcomes (e.g., executive function). Brain-derived neurotrophic factor (BNDF) has been found to be related to cognitive function (Shamida et al., 2014), and to mediate the impact of exercise interventions (Leckie et al., 2014). Serum is standard for measuring BDNF, but dried blood spot sampling (DBSS) was piloted with older adults to increase sample collection in a national RCT conducted remotely during the COVID pandemic (affording self-collection in the comfort of home with return by mail). While two pediatric studies have reported analyzable BDNF via DBSS correlating with executive function (Ghassabian et al., 2017; Skogstrand et al., 2019), this is the first known report with older adults.

METHOD: Pilot analyses of DBSS samples were from MCI patients and caregivers (n = 7; ave age = 73). Participants were enrolled in a clinical trial to evaluate the neuropsychological benefit of long-term use of a pedal-n-play neuro-exergame: iPACES (an interactive Physical and Cognitive Exercise System). Executive function was assessed at baseline via videoconference: Stroop C (interference trial; 40 stimuli) and Trails B (alternating numbers and letters). Participants collected their own DBSS and returned them by mail where they were stored (-18C). Eluants from the extraction of each 3 mm punch from DBSS cards were frozen at -80°C until analysis for BDNF (quantified using standard ELISAs).

RESULT: Measures of executive function (Stroop C and Trails B) were found to correlate moderately with BDNF (r = -.69 and r = -.56; see Figures), such that higher levels of BDNF were associated with better cognitive performance (faster response times).

CONCLUSION: Feasibility of at-home DBSS collection was shown for older adult participants (including MCI) in a remote clinical trial and pilot analyses of DBSS cards returned in the mail yielded sufficient BDNF from punches for analyses. Furthermore, higher levels of BDNF correlated with better executive function thus providing preliminary validation of this novel approach. Results should be replicated in a larger sample.},
}

Humans
*Cognitive Dysfunction/blood
Biomarkers/blood
Pilot Projects
Aged
Male
Female
COVID-19
*Brain-Derived Neurotrophic Factor/blood
Dried Blood Spot Testing
Alzheimer Disease/blood
Neuropsychological Tests
Aged, 80 and over
Caregivers
Executive Function/physiology

@article {pmid41511709,
year = {2025},
author = {Anastassiadis, C and Thapa, S and Vasilevskaya, A and Cortez, K and Dimal, NP and Tsang, M and Couto, B and Tang-Wai, DF and Fox, S and Kovacs, GG and Lang, AE and Kivisäkk, P and Hyman, BT and Arnold, SE and Ingelsson, M and Tartaglia, C},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107533},
doi = {10.1002/alz70856_107533},
pmid = {41511709},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; *Alzheimer Disease/cerebrospinal fluid ; Aged ; Middle Aged ; tau Proteins/cerebrospinal fluid ; Cohort Studies ; Amyloid beta-Peptides/cerebrospinal fluid ; *Frontotemporal Lobar Degeneration/cerebrospinal fluid ; Frontotemporal Dementia/cerebrospinal fluid ; Supranuclear Palsy, Progressive/cerebrospinal fluid ; Inflammation/cerebrospinal fluid ; },
abstract = {BACKGROUND: Although immune dysregulation has been reported in many neurodegenerative diseases (NDDs), our understanding of shared vs disease-specific features is still lacking. Here, we analyze a large panel of inflammatory markers in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD)-related syndromes.

METHOD: The cohort included 26 healthy controls (HC); 90 biomarker-positive AD patients (including 57 young-onset); 25 progressive supranuclear palsy (PSP) patients; and 16 patients clinically diagnosed with semantic variant primary progressive aphasia or frontotemporal dementia with motor neuron disease (FTD+/-MND group). Their CSF samples were tested for inflammation (737 proteins, Olink proximity extension assay) and neurodegeneration biomarkers (NfL, Aβ42, ptau181, total tau). All analyses were corrected for age, sex, and plate.

RESULT: ANCOVAs showed alterations in distinct subsets of proteins in NDDs compared to HC: the AD group was characterized by increased levels of inflammatory markers, while the opposite was seen in PSP. The smaller FTD+/-MND cohort only showed differences in four proteins (Figure 1). Gene-set enrichment analysis (GSEA) highlighted the implication of cell signaling pathways (including the transmembrane receptor protein tyrosine kinase signaling (q<.05) and response to growth factor (q<.10) pathways) in PSP compared to HC. Principal component analysis (PCA) revealed a limited overlap between NDDs and HC (Figure 2). Differences between diagnoses were best captured by PC2 (10% variance). Among the biomarkers, ptau181 was the strongest correlate of PC1 (24% variance) and PC2 (q<.0001). In preliminary investigations of astrocytic contributions to these differences, YKL-40 levels (astrocytic reactivity) were measured for 22 PSP subjects. YKL-40 and ptau181 were associated with the levels of distinct sets of proteins (after correcting for disease duration and age at onset). In patients with low vs high YKL40, pathways related to white blood cell function (e.g. lymphocyte and neutrophil chemotaxis, chemokine binding) were the top differentially expressed pathways (q<.01).

CONCLUSION: There are distinct inflammatory patterns in AD, PSP, and FTD+/-MND. AD is characterized by increases in inflammatory marker levels, while in PSP the opposite is seen. These differences appear to be related to ptau181-related pathology. Future directions include assessing the contributions of known mediators of neuroinflammation, such as astrocytic reactivity, APOE genotype, and age at onset, to these differences.},
}

Humans
*Biomarkers/cerebrospinal fluid
Male
Female
*Alzheimer Disease/cerebrospinal fluid
Aged
Middle Aged
tau Proteins/cerebrospinal fluid
Cohort Studies
Amyloid beta-Peptides/cerebrospinal fluid
*Frontotemporal Lobar Degeneration/cerebrospinal fluid
Frontotemporal Dementia/cerebrospinal fluid
Supranuclear Palsy, Progressive/cerebrospinal fluid
Inflammation/cerebrospinal fluid

@article {pmid41511689,
year = {2026},
author = {Shah, M and Patel, K and Kulkarni, U and Yadav, MR and Patel, A and Nagani, A},
title = {Advances in 1,3,4-thiadiazole-based cholinesterase inhibitors: toward novel therapeutics for Alzheimer's disease.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {41511689},
issn = {1573-501X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which cholinergic dysfunction plays a central role. Inhibition of acetylcholinesterase and butyrylcholinesterase remains a validated therapeutic approach for managing AD symptoms. Over the past decade (2015-2025), 1,3,4-thiadiazole derivatives have gained considerable attention as promising scaffolds for cholinesterase inhibition owing to their favorable electronic configuration, hydrogen-bonding potential, and metabolic stability. This review comprehensively analyzes recent progress in the synthesis and biological evaluation of 1,3,4-thiadiazole-based cholinesterase inhibitors, with an emphasis on structure-activity relationship trends supported by molecular docking insights. Substitution with electron-withdrawing or heteroaryl groups has been found to enhance the binding affinity toward AChE and BuChE, while some derivatives also exhibit activity against carbonic anhydrase, α-glucosidase, α-amylase, and antioxidant systems, reflecting scaffold versatility. This review further highlights the docking interactions with catalytic residues that validate the observed experimental potency. Finally, key limitations and future directions are discussed, emphasizing rational structure modification, computationally guided design, and green synthetic approaches to develop brain-penetrant and pharmacologically optimized 1,3,4-thiadiazole-based anti-Alzheimer's agents.},
}

@article {pmid41511604,
year = {2026},
author = {Babaker, MA and Alazabi, NI and Yousef, EM and Haredy, SA and Algohary, AM and Mansour, DF and Ahmed-Farid, OA},
title = {Taurine Mitigates Spironolactone-Induced Hyperkalemia and Cognitive Dysfunction: A Biochemical and Histological Study in a Rat Model.},
journal = {Applied biochemistry and biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s12010-025-05513-9},
pmid = {41511604},
issn = {1559-0291},
abstract = {Spironolactone (SPR), a widely used potassium-sparing diuretic, frequently causes hyperkalemia, leading to significant cardiovascular and neurological complications. Taurine, a semi-essential amino acid with known antioxidant and neuroprotective effects, was hypothesized to mitigate these adverse effects. This study investigated taurine's efficacy against SPR-induced hyperkalemia and associated cognitive dysfunction in a rat model. Adult male Sprague-Dawley rats were treated for four weeks with SPR, SPR + galantamine (an AChE inhibitor widely used in the treatment of Alzheimer's disease), or SPR + varying concentrations of taurine, followed by assessment of cognitive, biochemical, and histopathological alterations. SPR administration significantly increased serum potassium levels (~7.5 mEq/L), induced cognitive deficits, disrupted neurotransmitter balance (e.g., altered GABA and glutamate levels), and caused reactive astrocytic swelling in key brain regions. Taurine demonstrated a dose-dependent protective effect against SPR-induced neurotoxicity by mitigating hyperkalemia and associated cognitive impairments. Biochemically, taurine restored neurotransmitter balance by increasing GABA and reducing the excitotoxic glutamate levels. Histological analysis further confirmed taurine's neuroprotective effects, showing preserved cortical structures and reduced astrogliosis, especially at the highest concentration (5%). Our correlation analysis reveals complex regulatory mechanisms underlying neurotransmitter balance in the brain. These findings suggest taurine as a promising therapeutic agent for alleviating SPR-induced neurological side effects. Further studies are needed to explore taurine's long-term effects and clinical applications in managing hyperkalemia-related cognitive dysfunctions.},
}

@article {pmid41511498,
year = {2026},
author = {Hwang, H and Park, D and Kim, J},
title = {Structural Assessment of Fibrillated Beta Amyloid to Reveal the Potential Epitopes for Alzheimer's Disease.},
journal = {Cell biochemistry and biophysics},
volume = {},
number = {},
pages = {},
pmid = {41511498},
issn = {1559-0283},
}

@article {pmid41511473,
year = {2025},
author = {Rajabli, R and Soltaninejad, M and Collins, DL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107437},
doi = {10.1002/alz70856_107437},
pmid = {41511473},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Magnetic Resonance Imaging ; *Brain/diagnostic imaging/pathology ; Aged ; Biomarkers ; *Alzheimer Disease/diagnostic imaging/pathology ; Middle Aged ; *Aging/pathology ; Aged, 80 and over ; Neuroimaging ; },
abstract = {BACKGROUND: Brain Age Gap (BAG), the difference between age estimated from brain MRI and chronological age, is a potential feature for quantifying an individual's overall level of neurodegeneration. As a global measure, BAG can be used to examine differences in the extent of neurodegeneration across various groups. In this study, we apply BAG to amyloid positive subjects and investigate potential sex differences in different diagnostic groups.

METHOD: We trained five different models on UK Biobank (UKBB) and the Mayo Clinic Study of Aging (MCSA) data, with an age range of [45, 89] and nearly balanced sex distribution, to build an ensemble model for predicting brain age from T1w images. To ensure the model's generalization within the training age range, we used robust image preprocessing methods, massive data augmentation, and model regularization techniques (Rajabli 2024). Using our brain age prediction model, without further fine-tuning, we estimated BAG on Alzheimer's Disease Neuroimaging Initiative (ADNI) samples.

RESULT: We estimated the brain age gap for all cognitively normal subjects, regardless of amyloid status, and found no significant sex difference (-0.24 ± 3.85 for males, -0.05 ± 4.04 for females), indicating that our model is not biased toward either sex. As shown in previous studies and reaffirmed by our model, BAG increases along the AD trajectory (Figure 1). After correcting for age and the ADAS13 cognitive score, we found a residual statistically significant sex difference (p < 0.05) in BAG estimations, with amyloid-positive female brains appearing older than their male counterparts across all diagnostic groups except MCI, as determined by an ANCOVA test. Table 1 summarizes the statistical analysis.

CONCLUSION: We showed that female brains appear older than male brains in most diagnostic groups. While we corrected for age and ADAS13 within each group, this finding may suggest that females have greater cognitive reserve than males.},
}

Humans
Male
Female
Magnetic Resonance Imaging
*Brain/diagnostic imaging/pathology
Aged
Biomarkers
*Alzheimer Disease/diagnostic imaging/pathology
Middle Aged
*Aging/pathology
Aged, 80 and over
Neuroimaging

@article {pmid41511471,
year = {2025},
author = {Mhatre-Winters, I and Sammoura, FM and Cirillo, P and Barahona, AJ and Han, Y and Krigbaum, N and Factor-Litvak, P and Link, B and Go, YM and Jones, DP and Cohn, B and Richardson, JR},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e106002},
doi = {10.1002/alz70856_106002},
pmid = {41511471},
issn = {1552-5279},
mesh = {Animals ; *Amyloid beta-Peptides/blood/metabolism ; *Biomarkers/blood ; Mice ; Male ; *Alzheimer Disease/pathology/blood ; Female ; Mice, Transgenic ; Humans ; *Dichlorodiphenyl Dichloroethylene/toxicity ; *Brain/pathology/metabolism ; Disease Models, Animal ; Pregnancy ; *Peptide Fragments/blood ; *Prenatal Exposure Delayed Effects ; },
abstract = {BACKGROUND: Environmental factors, including pesticides, are increasingly associated with an increased risk of Alzheimer's disease (AD). Although banned in 1972, DDT remains persistent due to its long half-life, bioaccumulation, and residual dumpsites. However ubiquitous, its metabolite, dichlorodiphenyldichloroethylene (DDE), is considered non-neurotoxic. We previously reported that serum DDE levels were nearly 4x higher in AD patients compared to healthy individuals. Here, we assessed: i) effects of subchronic DDE exposure on serum Aβ-42/40, brain Aβ pathology, and cognition in 5xFAD mice, and ii) impact of prenatal DDE exposure on midlife plasma Aβ-42/40 in humans.

METHOD: Six-week-old male 5xFAD mice were exposed to 3 mg/kg p,p'-DDE or corn oil every 3 days for 90 days. At 4.5 months, mice were sacrificed post-behavioral testing; brains were drop-fixed for staining, hippocampi dissected, and serum collected for biochemical assays. For prenatal p,p'-DDE exposure, offspring born into the Child Health and Development Studies (CHDS) were recruited in 2010 for follow-up (∼50 years), completing cognitive tests and providing blood samples. Plasma Aβ-42/40 ratio in midlife was measured using the Quanterix N3PA kit (N = 160).

RESULT: In DDE-exposed 5xFAD mice, MSD analysis showed significantly elevated Guanidine-HCl (GuHCl)-soluble Aβ42 (∼100-fold) and formic acid (FA)-soluble Aβ42 (∼5-fold), indicating increased insoluble Aβ. Serum Aβ-42/40 was significantly reduced by 31% in DDE-exposed mice and was correlated with elevated brain Aβ42 in the GuHCl (r = -0.42) and FA fractions (r = -0.40). DDE-exposed mice displayed working memory deficits, performing 20% worse in Y-maze, which correlated with low serum Aβ-42/40 (r = 0.42). In the CHDS cohort, higher prenatal DDE was associated with lower midlife Aβ-42/40. In logistic models, the Odds Ratio for estimating lower Aβ-42/40 was 2.6 and 3.2 for DDE tertiles 2 and 3, respectively. The test for trend across DDE tertiles was significant (p = 0.04). Higher prenatal DDE was also associated with lower midlife Wechsler Digit Symbol Substitution Task score (β = -0.0221).

CONCLUSION: These findings show that DDE is an active metabolite of DDT and has lasting neurological effects on the amyloid system and cognition. This translational evidence highlights the role of early-life environmental exposures in AD risk and opportunities for early interventions to prevent disease progression.},
}

Animals
*Amyloid beta-Peptides/blood/metabolism
*Biomarkers/blood
Mice
Male
*Alzheimer Disease/pathology/blood
Female
Mice, Transgenic
Humans
*Dichlorodiphenyl Dichloroethylene/toxicity
*Brain/pathology/metabolism
Disease Models, Animal
Pregnancy
*Peptide Fragments/blood
*Prenatal Exposure Delayed Effects