@article {pmid41501511,
year = {2025},
author = {Natarajan, SG and S, M and Issac, TG},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106720},
doi = {10.1002/alz70856_106720},
pmid = {41501511},
issn = {1552-5279},
abstract = {BACKGROUND: The presence of ApoE4 allele is known to be the most important genetic risk factor for Late Onset Alzheimer's Disease (LOAD). Hyperhomocysteinemia (HHcy), a cardiovascular risk factor, is also being extensively studied for its role in increasing the risk of cognitive decline in the elderly. The current study aims to explore if any interaction exists between HHcy and ApoE4 allele with respect to their association with cognition.

METHOD: The study recruited 750 participants from the Tata Longitudinal Study of Ageing (TLSA), an ongoing cohort study of individuals aged ≥ 45 years. The Computerised Assessment of Adult Information Processing (COGNITO) neuropsychological battery was used to assess cognitive performance. Homocysteine levels were quantified using chemiluminescence immunoassays. ApoE genotype was determined using Polymerase Chain Reaction (PCR) amplification followed by Sanger sequencing. Generalised Linear Model (GLM) was used to study the interaction between HHcy and ApoE4 allele on cognition.

RESULT: The GLM identified that the HHcy/ApoE4 non-carriers had impaired performance in reading and sentence comprehension (B=-0.190; p = 0.047) and form matching (B=-0.335; p = 0.029) tasks. Such impairment was not observed in the HHcy/ApoE4 carriers group. In the name-face association task, only the HHcy/ApoE E4 carriers group (B=-0.672; p = 0.037) had lower scores when compared to the reference group. In episodic memory immediate recall task, both HHcy/ApoE E4 non-carriers (B=-0.323; p = 0.015) and HHcy/ApoE E4 carriers (B=-0.423; p = 0.040) groups had lower scores.

CONCLUSION: The results suggest that the association of HHcy with impairment in memory-related tasks was seen irrespective of ApoE4 carrier status, but is exaggerated in ApoE4 carriers. In tasks related to language and visuo-spatial abilities, the ApoE4 carriers had no association with the scores even if they had HHcy. Thus, the study results imply that HHcy affects cognitive functioning, but ApoE4 allele modulates the relationship only in non-memory domains.},
}

@article {pmid41501404,
year = {2025},
author = {Vanderlip, CR and Adams, JN},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105308},
doi = {10.1002/alz70856_105308},
pmid = {41501404},
issn = {1552-5279},
abstract = {BACKGROUND: Hippocampal hyperexcitability is an early feature of Alzheimer's disease (AD) that may drive pathology. However, current models of AD risk focusing on the A/T/N framework (Aβ /Tau/Neurodegeneration) do not include hyperexcitability as a key disease biomarker. Here, we investigated a candidate hyperexcitability ("H") biomarker from resting-state fMRI (rsfMRI) - the amplitude of low-frequency fluctuations (ALFF), which reflects the intensity of spontaneous brain activity - to determine if it provides sensitive information about AD progression.

METHOD: We analyzed 386 older adults spanning the AD spectrum (277 cognitively normal, CN; 84 Aβ+ mild cognitive impairment, MCI; 25 Aβ+ AD dementia) from ADNI who underwent rsfMRI, Aβ-PET (18F-FBP/18F-FBB), and tau-PET (18F-FTP) within a year. ALFF was quantified from rsfMRI in the hippocampus as the primary "H" candidate, as well as the retrosplenial cortex, which served as a control region. Aβ-PET (18F-florbetapir or 18F-Florbetaben) global Centiloids (CL) and Aβ+ status (>20 CL), tau-PET (18F-Flortaucipr) in the medial temporal lobe (MTL) composite (entorhinal and amygdala mean SUVR), and hippocampal volume were used as A/T/N biomarkers, respectively. Relationships between ALFF, A/T/N biomarkers, and diagnosis were examined, controlling for age, sex, and education.

RESULT: Hippocampal and retrosplenial ALFF were elevated in individuals with MCI compared to CN individuals (Figure 1). Higher hippocampal ALFF significantly correlated with increased MTL tau in Aβ+ individuals, whereas there was no relationship with retrosplenial ALFF (Figure 2A-B). Further, among Aβ+ individuals, those with high hippocampal ALFF (A+H+) had greater MTL tau than those with high Aβ alone (A+H-), demonstrating hippocampal hyperexcitability in the context of Aβ is related to elevated tau pathology (Figure 2C). Finally, ROC analyses revealed that adding hippocampal ALFF to a basic A/T/N biomarker model improved diagnostic discrimination (Figure 3), suggesting hippocampal ALFF captures cognitive impairment beyond the A/T/N framework.

CONCLUSION: These findings indicate that hippocampal ALFF, a proxy of hippocampal hyperexcitability, serves as a valuable biomarker of AD. Planned analyses include assessing the sensitivity of hippocampal ALFF for longitudinal prediction of AD pathology and phenoconversion from CN to MCI or dementia. Future frameworks of AD should incorporate "H" biomarkers of hyperexcitability to further understand disease progression and risk.},
}

@article {pmid41500978,
year = {2025},
author = {Jo, T},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105659},
doi = {10.1002/alz70856_105659},
pmid = {41500978},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis ; *Biomarkers ; Male ; Polymorphism, Single Nucleotide ; Female ; Whole Genome Sequencing ; Aged ; Apolipoproteins E/genetics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and memory impairment. Early and accurate detection is critical for clinical intervention. While machine and deep learning approaches have been widely used to predict AD progression, recent work emphasizes quantifying predictive uncertainty in high-stakes medical contexts. However, many studies focus on limited genetic regions (e.g., APOE), highlighting the need for broader whole-genome sequencing (WGS) analyses.

METHOD: We obtained 1,050 WGS datasets (443 cognitively normal, 607 AD-diagnosed) from ADNI, ADNI-WGS-2, and ADSP-FUS1-ADNI-WGS-2. SNPs were extracted from a region containing the APOE gene on chromosome 19, then divided into fixed-size windows ("tokens") for a Transformer-based classification model. Monte Carlo (MC) Dropout was applied during training and inference to enable multiple forward passes, providing predictive variance. Models with and without MC Dropout were compared using accuracy (ACC), area under the curve (AUC), F1 score, sensitivity, specificity, expected calibration error (ECE), and reliability diagrams. Predictions were further stratified into "Uncertain" (top 25% variance) and "Certain" (bottom 75%) to examine accuracy differences.

RESULT: Stratification by predictive variance revealed that the Uncertain group, with 53 samples, had an accuracy of 0.5472, while the Certain group, with 157 samples, had 0.6497. This indicates that Monte Carlo Dropout-derived variance effectively captures higher uncertainty. The Monte Carlo Dropout model showed a slight increase in accuracy from 0.6143 to 0.6238 and in area under the curve from 0.6644 to 0.6832 compared with baseline, but calibration worsened when the expected calibration error rose from 0.1024 to 0.1858. Sensitivity and specificity shifted from 0.7417 to 0.6833 and from 0.4444 to 0.5444, while the F1 score decreased from 0.6873 to 0.6749.

CONCLUSION: These findings demonstrate the feasibility of using MC Dropout within a Transformer-based WGS framework to estimate predictive uncertainty in AD classification. Variance-based stratification effectively flagged samples with lower confidence. However, MC Dropout did not consistently improve calibration or overall accuracy, indicating a need for refining dropout settings, Transformer hyperparameters, and potentially Bayesian time-series methods. Future work should also explore complementary approaches to balance classification accuracy with reliable uncertainty estimates.},
}

Humans
*Alzheimer Disease/genetics/diagnosis
*Biomarkers
Male
Polymorphism, Single Nucleotide
Female
Whole Genome Sequencing
Aged
Apolipoproteins E/genetics

@article {pmid41500964,
year = {2025},
author = {Machado, LS and Povala, G and Pola, I and Vizlin-Hodzic, D and Rosa-Neto, P and Blennow, K and Zimmer, ER and Zetterberg, H and Benedet, AL and Ashton, NJ},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106436},
doi = {10.1002/alz70856_106436},
pmid = {41500964},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Male ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging ; Female ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging ; *Astrocytes/metabolism ; Proteomics ; Positron-Emission Tomography ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Aged, 80 and over ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: Astrocytes are highly involved in Alzheimer's disease (AD) pathophysiology. GFAP, an astrocyte-enriched protein, increases in response to amyloid (Aβ) pathology and is used as a fluid biomarker of astrocyte reactivity in AD. However, GFAP does not fully reflect the astrocytic dynamics in response to the disease. Thus, we aimed to identify novel astrocyte biomarkers in CSF that contribute to the understanding of the pathological changes in AD.

METHOD: We analyzed CSF proteomic data from 728 individuals in the ADNI cohort (SomaLogic). A pre-defined list of 30 astrocyte-enriched genes was contrasted with the available ADNI CSF proteomic data, resulting in eight proteins of interest, including GFAP. We examined their CSF levels across cognitively unimpaired (CU), mild cognitively impaired (MCI), and AD individuals (Figure 1a). The proteins levels in CSF were further investigated in CU and cognitively impaired (CI) individuals who were also categorized according to their Aβ status (ptau181/Aβ42 ratio cut-off=0.028, Figure 1b). Voxelwise models assessed associations between the selected proteins and [[18]F]Florbetapir-PET, a biomarker of Aβ deposition, in a subset of the individuals (n = 461), and CU and CI individuals separately. Models also included age and sex, and RFT was used for multiple comparisons correction in the imaging analyses.

RESULT: CSF NCAN was significantly reduced in AD individuals compared to CU and MCI (Figure 1a). Further analysis revealed elevated CSF GPC5 levels in Aβ-positive CI (CI Aβ+) compared to Aβ-negative CU (CU Aβ-) and CI (CI Aβ-) groups. In contrast, CSF LRIG1 and NCAN were only increased in CI+ compared to CI- individuals (Figure 1b). Positive associations were observed between CSF GPC5, LRIG1, and NCAN, and [[18]F]Florbetapir-PET, with GPC5 showing the most widespread cortical associations, particularly in CI individuals (Figure 2).

CONCLUSION: This study identifies GPC5, LRIG1, and NCAN as CSF astrocyte biomarkers altered across AD cognitive status and amyloid pathology. GPC5, in particular, showed the most widespread cortical association with Aβ deposition, consistent with its role in synaptic maturation and stabilization. Given that GPC5 is highly expressed in cortical astrocytes, these findings highlight its potential as a novel astrocytic biomarker in AD. Further validation will be conducted in an external cohort.},
}

Humans
*Biomarkers/cerebrospinal fluid
Male
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging
Female
Aged
Amyloid beta-Peptides/cerebrospinal fluid
*Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging
*Astrocytes/metabolism
Proteomics
Positron-Emission Tomography
Glial Fibrillary Acidic Protein/cerebrospinal fluid
Aged, 80 and over
Middle Aged
Cohort Studies

@article {pmid41500961,
year = {2025},
author = {Kindler, C and Gillis, G and Bhalerao, GV and Andersson, JLR and McCarthy, P and Miklitz, C and Stoecker, T and Petzold, GC and Griffanti, L and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105620},
doi = {10.1002/alz70856_105620},
pmid = {41500961},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Magnetic Resonance Imaging ; *Alzheimer Disease/diagnostic imaging/pathology ; *Frontotemporal Dementia/pathology/diagnostic imaging/physiopathology ; Aged ; Middle Aged ; Biomarkers ; *Basal Nucleus of Meynert/diagnostic imaging/pathology/physiopathology ; Aphasia, Primary Progressive ; },
abstract = {BACKGROUND: The nucleus basalis of Meynert (NBM) is crucial for learning, attention, and memory. While its involvement in Alzheimer's disease (AD) has been widely reported, the role in frontotemporal dementia (FTD) remains unclear. Here we examined NBM functional connectivity (FC) as well as NBM and cortical volume changes in AD, healthy controls (HC), and FTD subtypes: behavioral variant FTD (bvFTD), unclassified primary progressive aphasia (PPA), progressive nonfluent aphasia (PNFA), semantic dementia (SemD), and progressive logopenic aphasia (PLA).

METHOD: Resting-state fMRI and T1-weighted scans were collected from HC (n = 66), individuals with AD (n = 50), bvFTD (n = 63), PLA (n = 18), PPA (n = 20), PNFA (n = 32), and SemD (n = 15). We performed seed-based FC analyses in FSL with left and right NBM as seeds. We compared HC with AD (cluster-based threshold z > 2.3, p < 0.05). Significant clusters were used to extract mean FC for the other groups. We then compared FC values and normalized NBM volumes across HC and FTD subtypes using the Kruskal-Wallis test, followed by Bonferroni-corrected pairwise comparisons where applicable. Voxel-based morphometry (VBM) was conducted to explore cortical atrophy patterns.

RESULT: HC showed stronger NBM connectivity than AD in the hippocampus/parahippocampal gyrus, frontal pole, paracingulate cortex, precuneus, and lateral occipital cortex (Figure 1, left NBM results). Across HC and FTD subtypes, we found significant group differences for the paracingulate (H = 36.15, p < 0.001) and lateral occipital cortex (H = 18.25, p =  0.003). Connectivity was higher in bvFTD, PPA, and LPA than in HC, with the strongest effect for bvFTD in the paracingulate cortex (r = 0.48) and moderate effects across other contrasts (r = 0.28-0.42, all p < 0.020). Volumetric analyses indicated no significant group differences in NBM volumes but distinct cortical atrophy patterns: PNFA, PLA, and PPA exhibited temporal- frontal atrophy similar to AD, while bvFTD showed predominantly frontal and SemD primarily temporal atrophy.

CONCLUSION: Differential functional connectivity of the NBM and distinct cortical atrophy patterns were observed between HC and AD and between HC and FTD subtypes. Ongoing analyses on subgroup comparisons and integration of cognitive assessments aim to elucidate these relationships and their clinical implications.},
}

Humans
Male
Female
Magnetic Resonance Imaging
*Alzheimer Disease/diagnostic imaging/pathology
*Frontotemporal Dementia/pathology/diagnostic imaging/physiopathology
Aged
Middle Aged
Biomarkers
*Basal Nucleus of Meynert/diagnostic imaging/pathology/physiopathology
Aphasia, Primary Progressive

@article {pmid41500848,
year = {2025},
author = {Prabha, PK and Jain, A and Dadoo, N and Charan, S and Medhi, B and Prakash, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105361},
doi = {10.1002/alz70856_105361},
pmid = {41500848},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis ; *Biomarkers/blood ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Cholesterol/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition marked by memory loss, cognitive decline, and eventually motor and behavioural dysfunction. Most AD drug trials have failed due to the lack of early intervention, which is crucial for treatment effectiveness. Though early diagnosis remains challenging owing to blood-brain barrier, blood-based biomarkers are being explored due to their non-invasive nature. Genes involved in cholesterol and lipid metabolism, such as APOE, APOJ, ABCA7, and SORL1, have also been observed to increase AD risk.

METHODS: Clinical studies of polymorphisms in cholesterol homeostasis pathway involving participants clinically diagnosed with Alzheimer's Disease of any form as per set criteria of diagnosis for AD were included after comprehensive search across PubMed, Embase, Scopus and Web of Science. Independent reviewers extracted data from the included studies which included information like general information, participants, study methods, polymorphisms studied, outcomes, results, conclusion, etc. Any discrepancies or doubts was resolved by a third reviewer.

RESULT: A total of 1870 studies were identified based on the designed search strategy, which reduced to 216 after removal of duplicates, with 45 studies considered suitable for the final meta-analyses. The risk of AD was significantly associated in random effect model for SNP rs3846662 (HMGCR; OR = 1.16, 95% CI = 0.99, 1.35, I[2] = 59%, p = 0.06), rs11136000 (CLU; OR = 1.15, 95% CI = 1.08, 1.22, I[2] = 0%, p = 0.83), rs754203 (CYP46A1; OR = 1.10, 95% CI = 0.92, 1.33, I[2] = 87%, p < 0.01), and rs3851179 (PICALM; OR = 1.18, 95% CI = 1.05, 1.33, I[2] = 77%, p < 0.01).

CONCLUSION: The selected SNPs were found to be significantly associated with the risk of AD, with risk alleles for rs3846662, rs11136000, rs754203, and rs3851179 being G, C, T, C alleles respectively with an OR of 1.16, 1.15, 1.10, and 1.18 respectively. Therefore, these can be considered to be AD biomarkers.},
}

Humans
*Alzheimer Disease/genetics/diagnosis
*Biomarkers/blood
Polymorphism, Single Nucleotide
Genetic Predisposition to Disease
Cholesterol/metabolism

@article {pmid41500846,
year = {2025},
author = {Sewell, KR and Solis-Urra, P and Huang, H and Grove, G and Kramer, AF and McAuley, E and Burns, JM and Hillman, C and Vidoni, ED and Marsland, A and Kang, C and Wan, L and Oberlin, L and Erickson, KI},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106538},
doi = {10.1002/alz70856_106538},
pmid = {41500846},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/blood ; Aged ; *tau Proteins/blood ; Magnetic Resonance Imaging ; *Brain/diagnostic imaging/pathology ; *Alzheimer Disease/blood ; *Neurofilament Proteins/blood ; Neuropsychological Tests ; *Cognition/physiology ; *Aging ; Middle Aged ; },
abstract = {BACKGROUND: The development of Alzheimer's disease (AD) involves accumulation of brain pathology; however, some individuals appear to maintain cognitive and day-to-day function in the presence of neuropathology better than others. One likely contributor to this resilience is the maintenance of structural brain integrity to a greater extent than expected based on age-related norms, i.e., a younger 'brain age'. In this study we examined whether brain age moderated the association between AD-related blood biomarkers and cognitive function.

METHOD: We utilized baseline data from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE) study. Cognitively unimpaired older adults (n = 648, aged 69.9±3.8, 71% female) completed a comprehensive cognitive assessment and an MRI scan where T1-weighted images were used to calculate brain age using brainageR. The difference between chronological age and brain age was used to calculate the brain-predicted age difference (brain-PAD). Assays were completed for plasma-based biomarkers phosphorylated tau (p-tau) 217 and neurofilament light (NfL) measured on the SIMOA platform.

RESULT: After covarying for age, sex, site, BMI, image quality and education, brain-PAD moderated the association of p-tau217 with episodic memory (β=-0.09, SE = 0.04, p = .017), processing speed (β=-0.07, SE = 0.04, p = .046), working memory (β=-0.10, SE = 0.04, p = .005), and executive function/attentional control (β=-0.08, SE = 0.04, p = .035), but not visuospatial processing. The direction of these interactions was such that the association between higher p-tau217 and poorer cognitive performance was strongest in those with higher brain-PAD (i.e., accelerated brain aging). We do not find evidence of a significant moderation effect of brain-PAD on the association between NfL and cognitive performance in any domain (all p >.05).

CONCLUSION: Our results suggest that maintenance of structural brain integrity (slower brain aging) may help protect against cognitive deficits in the face of AD pathology (i.e., p-tau217) in cognitively unimpaired individuals. These results provide support for the concept of brain maintenance, however, should be further tested in samples across the AD trajectory (i.e., mild cognitive impairment and AD). Understanding these mechanisms could inform strategies to promote resilience and delay AD-related cognitive decline in aging populations.},
}

Humans
Female
Male
*Biomarkers/blood
Aged
*tau Proteins/blood
Magnetic Resonance Imaging
*Brain/diagnostic imaging/pathology
*Alzheimer Disease/blood
*Neurofilament Proteins/blood
Neuropsychological Tests
*Cognition/physiology
*Aging
Middle Aged

@article {pmid41500842,
year = {2025},
author = {Khan, S and Soliman, MT and Murray, S and Szabo, J and Llanos, M and Kim, H and Mir, E and Santoyo-Alanis, D and Kingsley, C and Swain, J and Mulholland, MM and Hopkins, WD and Wisniewski, T and Veraart, J and Zaim-Wadghiri, Y and Scholtzova, H},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105980},
doi = {10.1002/alz70856_105980},
pmid = {41500842},
issn = {1552-5279},
mesh = {Animals ; *Brain/pathology/diagnostic imaging ; Biomarkers ; Saimiri ; Male ; Diffusion Magnetic Resonance Imaging ; Female ; Aging/pathology ; Disease Models, Animal ; *Cerebral Amyloid Angiopathy/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; },
abstract = {BACKGROUND: Amyloid related imaging abnormalities (ARIA) have emerged as indicators of potentially serious side effects in therapeutics for Alzheimer's disease (AD). Squirrel monkeys (SQMs) are a unique non-human primate (NHP) model for studying ARIA, due to their propensity of naturally developing age dependent cerebral amyloid angiopathy (CAA). Previously, we reported the sporadic occurrence of ARIA, manifesting as vasogenic edema (ARIA-E) and cerebral microhemorrhage (ARIA-H) in geriatric SQMs. Our initial studies demonstrated that quantitative R2* (1/T2*) mapping can serve as a noninvasive and effective imaging biomarker for monitoring gray and white matter (GM/WM) age-related and region-specific changes associated with SQM neuropathology. In the current project, we extended this work by echo-averaging the multi-gradient-echo (MGE) dataset to generate 3D-anatomical images used to assess in-vivo brain volumetric changes across the SQM lifespan. Additionally, we examined a subset of SQMs using multi-shell diffusion-weighted-imaging (DWI) to evaluate changes in microstructural tissue integrity.

METHOD: SQMs underwent 2D-T2-w Turbo-Spin-Echo RARE/FLAIR MRI scans, alongside multi-shell DWI. Diffusion metrics including mean diffusivity (MD), fractional anisotropy (FA), and mean kurtosis (MK) were calculated. Brain volumetrics were quantified as a function of age using the Jacobian of local deformation fields from in-vivo MGE scans. Coronal brain sections were examined to characterize histopathological features of MRI abnormalities.

RESULT: Multi-shell DWI revealed abnormal propagation along the WM tract, which went undetected using conventional ARIA-E criteria. The microstructural changes depicted on DWI were accompanied by alterations in MD, FA, and MK. Histologically, affected regions visible only in DWI showed differentiated pathology from conventional ARIA-E regions, accompanied by dystrophic microglia, reactive astrocytosis, disruption of myelin integrity, and extensive fibrinogen extravasation. Comparing young to geriatric SQMs, deformation masks revealed age-related volumetric decreases in PFC, putamen, nucleus caudate, and thalamus. When comparing middle-aged to geriatric SQMs, negative volumetric correlations with age were observed in putamen and thalamus, WM regions, and to a lesser extent, PFC.

CONCLUSION: This study advocates for the use of multiparametric MRI methodologies to achieve a more sensitive and specific interpretation of imaging abnormalities potentially linked to age-associated cerebrovascular dysfunction. These findings highlight the SQM model as an ideal environment for studying neuroimaging biomarkers of AD and CAA.},
}

Animals
*Brain/pathology/diagnostic imaging
Biomarkers
Saimiri
Male
Diffusion Magnetic Resonance Imaging
Female
Aging/pathology
Disease Models, Animal
*Cerebral Amyloid Angiopathy/pathology/diagnostic imaging
Magnetic Resonance Imaging

@article {pmid41500832,
year = {2025},
author = {Piura, YD and Lachner, C and Algeciras-Schimnich, A and Figdore, D and Bornhorst, JA and Aduen, P and Schecter, L and Graff-Radford, NR and Day, GS},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105551},
doi = {10.1002/alz70856_105551},
pmid = {41500832},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/blood ; *tau Proteins/blood ; Positron-Emission Tomography ; Aged ; *Alzheimer Disease/blood/diagnosis/diagnostic imaging ; Hispanic or Latino ; Black or African American ; Middle Aged ; *Cognitive Dysfunction/blood/diagnosis/diagnostic imaging ; Amyloid beta-Peptides ; White ; },
abstract = {BACKGROUND: Black and Latino Americans experience a disparate dementia burden yet remain underrepresented in dementia research, including clinical trials designed to slow or prevent symptomatic Alzheimer's disease (AD). Accessible and non-invasive AD blood biomarkers may improve identification and recruitment of underrepresented participants into AD clinical trials. There is a clear need to assess the performance of emergent plasma AD biomarkers for the detection of AD neuropathology in cognitively normal Black and Latino Americans.

METHOD: Cognitively normal Black and Latino participants underwent cognitive evaluations and PET (amyloid-PiB, tau-flortaucipir) imaging at Mayo Clinic in Florida. Plasma p-tau217 was measured using Fujirebio Lumipulse assays. We evaluated the diagnostic performance of a p-tau217 threshold (≥0.186 pg/mL) known to identify non-Hispanic White participants with cognitive impairment and "positive" amyloid PET scans (>25 Centiloids). Next, we derived an optimized threshold to identify participants with "positive" amyloid PET using Youden's method.

RESULT: The cohort included 58 Black (55%) and 47 Latino-White (45%) well-educated (mean 16.1±2.3 years) individuals, with mean age 64.7±8.8 years, and slight female bias (63%). Plasma p-tau217 concentrations increased with age (rho=0.269, p = 0.004) and declined with MoCA scores (rho=-0.225, p = 0.027). Sixty-nine participants completed amyloid- and tau-PET imaging. Plasma p-tau217 concentrations increased with amyloid- (rho=0.254, p = 0.044) but not with tau-PET standardized uptake value ratio (rho=0.127; p = 0.334). p-tau217 concentrations were ≥0.186 pg/mL in 10/69 participants (14%), including 3/3 amyloid- and tau-PET positive (A+T+) participants, 3/8 A+T- participants (sensitivity: 55%), and 4/58 A-T- participants (specificity 93%). An optimized p-tau217 threshold of ≥0.118 pg/mL identified 10/11 A+T± participants (sensitivity 91%), and 16/58 A-T- participants (specificity 73%). In A-T- participants, estimated glomerular filtration rate was lower in participants with 'false positive' elevations in plasma p-tau217 (mean difference: 67 vs 81 ml/min/1.73m[2], p = 0.004), emphasizing the need for caution when interpreting plasma p-tau217 concentrations in patients with decreased kidney function.

CONCLUSION: Plasma p-tau217 thresholds validated in participants with symptomatic AD (≥0.186 pg/mL) failed to identify early AD neuropathology in 5/8 cognitively normal Black and Latino participants. Optimized thresholds are required to improve detection of preclinical AD in Black/Latino individuals.},
}

Humans
Female
Male
*Biomarkers/blood
*tau Proteins/blood
Positron-Emission Tomography
Aged
*Alzheimer Disease/blood/diagnosis/diagnostic imaging
Hispanic or Latino
Black or African American
Middle Aged
*Cognitive Dysfunction/blood/diagnosis/diagnostic imaging
Amyloid beta-Peptides
White

@article {pmid41500828,
year = {2025},
author = {Alves, IDS and Aranha, MR and de Paula Faria, D and De Almeida Mantovani, DB and de Oliveira, LC and da Costa Leite, C and Nunes, DM and Bejanin, A and Buchpiguel, CA and Fortea, J and Coutinho, AM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106085},
doi = {10.1002/alz70856_106085},
pmid = {41500828},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Magnetic Resonance Imaging ; Atrophy/pathology ; Retrospective Studies ; Adult ; Biomarkers/cerebrospinal fluid ; *Down Syndrome/pathology/diagnostic imaging ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Positron-Emission Tomography ; *Brain/pathology/diagnostic imaging ; Young Adult ; },
abstract = {BACKGROUND: Down syndrome (DS) is considered a genetic form of Alzheimer's disease (AD) and is characterized by early neurodegeneration and cortical atrophy. Subjective scale-based visual evaluation of brain atrophy is widely used in clinical neuroradiology. This study aims to evaluate brain atrophy scales in DS individuals from a young age and investigate its relationship with cortical amyloid status.

METHODS: A bi-centric retrospective analysis was conducted at Hospital das Clínicas, Brazil, and Hospital de la Santa Creu i Sant Pau, Spain, using 3T Magnetic resonance imaging (MRI) data from individuals aged 18 years or older. Amyloid status was classified as positive (A+) or negative (A-) based on [11C]PiB-PET-amyloid scans obtained within 30 days of MRI or cerebrospinal fluid analysis, with a positive result defined as an Aβ42/40 ratio < 0.062. MRI was independently analyzed by two expert neuroradiologists, who assigned scores for medial temporal atrophy (MTA), entorhinal cortex atrophy (ERICA), posterior cortical atrophy (Koedam scale), and global cerebral atrophy (GCA) for each hemisphere. The inter-rater agreement was satisfactory, and the average (right-left) from the more experienced neuroradiologist was used. Individuals were then separated into two groups (younger and older than 45).

RESULTS: 106 individuals were initially evaluated, and 25 were excluded from the final analysis (total included N = 81). The mean age of participants was 42.7 years (19-64 years). The sample consisted of 64 DS individuals (35% females) and 17 non-DS controls (58% females). Thirty individuals were A+, all of them DS individuals. DS individuals exhibited higher atrophy scales, however, reaching statistical significance only for the MTA scale (hippocampal atrophy) in the ≥ 45-year-old group (tables 1 and 2); such atrophy was linked to higher A+ prevalence (p-value < 0.05). Furthermore, higher A+ prevalence was observed in DS overall (p-value < 0.05), including younger participants under 45 (Figure 1).

CONCLUSIONS: The MTA scale detected early-stage hippocampal atrophy in DS, which was also linked to amyloid deposition since early adulthood, highlighting the use of this scale as a proxy for AD pathology in DS.},
}

Humans
Female
Male
Magnetic Resonance Imaging
Atrophy/pathology
Retrospective Studies
Adult
Biomarkers/cerebrospinal fluid
*Down Syndrome/pathology/diagnostic imaging
Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
Positron-Emission Tomography
*Brain/pathology/diagnostic imaging
Young Adult

@article {pmid41500825,
year = {2025},
author = {Foster, E and Herbert, C and Vosmeier, A and Hottle, S and Apostolova, LG and Brosch, JR and Clark, DG and Farlow, MR and Mathew, S and Unverzagt, F and Wang, S and Gao, S and Yates, CW and Pisoni, D and Saykin, AJ and Risacher, SL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107173},
doi = {10.1002/alz70856_107173},
pmid = {41500825},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Biomarkers/metabolism ; *Alzheimer Disease/diagnostic imaging/diagnosis ; Magnetic Resonance Imaging ; tau Proteins/metabolism ; Positron-Emission Tomography ; *Speech Perception/physiology ; Neuroimaging ; Aged, 80 and over ; Middle Aged ; Amyloid beta-Peptides/metabolism ; },
abstract = {BACKGROUND: Hearing loss is linked to dementia, yet its relationship with Alzheimer's disease (AD) biomarkers remains unclear. This study examines associations between performance on auditory and speech perception measures with neuroimaging measures of neurodegeneration (N; cortical volume), amyloid (A), and tau (T) to aid early AD detection.

METHOD: 121 participants from the Indiana Alzheimer's Disease Research Center underwent auditory testing and neuroimaging. Auditory assessments included CUNY sentences, Speech-in-Noise (QuickSiN), and Letter Number Sequencing (LNS). Neuroimaging measures included MRI-based cortical volume extracted with Freesurfer v6 (N), cortical Centiloid value from amyloid PET (A), and bilateral mean meta-temporal tau standardized uptake value ratio from tau PET (T). A one-way ANCOVA was used to compare differences in auditory tests between diagnostic groups, while partial Pearson correlations were used to assess associations of auditory tests with A/T/N biomarkers, covaried for age, sex, and total intracranial volume (N only).

RESULT: The sample (age=71.90±6.6; 63.9% female) included 49 cognitively normal older adults, 40 with subjective cognitive decline, 23 with mild cognitive impairment (MCI) due to AD, 7 with MCI due to other conditions, and 2 with AD. Significant diagnostic differences were observed in SNR loss on QuickSiN (p = .006) and CUNY subtests, including AV words (p <.001), AV sentences (p = .037), and A words (p = .002). Cortical amyloid correlated with SNR loss (r=.231, p = .045) and CUNY subscores, including auditory (Au) words (r=-.272, p = .018) and word gain (r=-.250, p = .031). LNS raw scores correlated with cortical volume (r=-.311, p = .008). Associations were found between cortical volume and CUNY audiovisual (AV) words (r=.254, p = .023), A words (r=.395, p < .001), and sentence gain (r=-.261, p = .020), but not with SNR loss. Meta-temporal tau SUVR was associated with CUNY A words (r=-.294, p = .021), A sent (r=-.276, p = .031), word gain (r=.303, p = .016), and LNS raw scores (r=-.276, p = .036), but not with SNR measures.

CONCLUSION: Findings suggest that auditory and speech perception tests are associated with neuroimaging biomarkers of AD, supporting the potential utility of hearing assessments as early screening tools for AD-related pathology. Further research with larger sample sizes is warranted to strengthen these findings and explore their clinical implications.},
}

Humans
Female
Male
Aged
Biomarkers/metabolism
*Alzheimer Disease/diagnostic imaging/diagnosis
Magnetic Resonance Imaging
tau Proteins/metabolism
Positron-Emission Tomography
*Speech Perception/physiology
Neuroimaging
Aged, 80 and over
Middle Aged
Amyloid beta-Peptides/metabolism

@article {pmid41500818,
year = {2025},
author = {Hazelton, JL and Bella, GD and Barttfeld, P and Dottori, M and Gonzalez-Gomez, R and Migeot, J and Moguilner, S and Legaz, A and Hernandez, H and Prado, P and Cuadros, J and Maito, MA and Fraile-Vazquez, M and Gadea, MLG and Çatal, Y and Miller, BL and Piguet, O and Northoff, G and Ibanez, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104944},
doi = {10.1002/alz70856_104944},
pmid = {41500818},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/physiopathology ; Electroencephalography ; Aged ; *Frontotemporal Dementia/physiopathology ; *Interoception/physiology ; Biomarkers ; Middle Aged ; *Brain/physiopathology ; Electrocardiography ; *Allostasis/physiology ; Heart Rate/physiology ; },
abstract = {BACKGROUND: Dysfunctional allostatic-interoception, altered processing of bodily signals in response to environmental demands, occurs in behavioural-variant frontotemporal dementia (bvFTD) patients. Previous research, however, has focused on static measures of interoception (e.g., heart-evoked potential, HEP). These measures do not capture the dynamic nature of interoception, unlike intrinsic neural timescales. Intrinsic neural timescales refers to the temporal durations over which information is processed within the spatiotemporal hierarchy of the brain, with shorter timescales representing more rapid processing. We hypothesised that longer intrinsic neural timescales of interoception would occur in bvFTD patients, evidencing dysfunctional allostatic-interoception.

METHOD: One-hundred and twelve participants (31 bvFTD patients, 35 Alzheimer's disease patients, AD and 46 healthy controls) completed a well-validated task measuring cardiac-interoception and exteroception. Simultaneous EEG and ECG were recorded. Intrinsic neural timescales were measured via the autocorrelation window (ACW) of broadband EEG signals from each heartbeat and a time-lagged version of itself. Spatiotemporal clustering analyses identified clusters with significant between-group differences in each condition. HEP modulation analyses were also conducted and covaried for to investigate potential relationships between HEP and ACW. Voxel-based morphometry was used to target the allostatic-interoceptive network. Neuropsychological tests of cognition and social cognition were assessed.

RESULT: In bvFTD patients, longer interoceptive-ACWs than controls were observed in the bilateral fronto-temporal and parietal regions (Figure 1). In AD patients, longer interoceptive-ACWs than controls were observed in central and occipitoparietal brain regions (Figure 1). No differences were observed during exteroception. In bvFTD patients only, longer interoceptive-ACW was linked to worse sociocognitive performance. Our interoceptive-ACW results, remained the same when accounting for HEP modulation. Structural neural correlates of interoceptive-ACW in bvFTD involved the anterior cingulate, insula, orbitofrontal cortex, hippocampus, and angular gyrus (Figure 2). No structural differences emerging in AD.

CONCLUSION: Our findings suggest a core allostatic-interoceptive deficit occurs in people with bvFTD, captured by altered brain dynamics of intrinsic neural timescales. In AD, it is possible that a more generalised disruption of brain oscillation occurs. Altered interoceptive intrinsic neural timescales may provide a neurobiological mechanism underpinning the complex behaviours observed in bvFTD patients. Our findings support synergistic models of brain disease and can inform clinical practice.},
}

Humans
Male
Female
*Alzheimer Disease/physiopathology
Electroencephalography
Aged
*Frontotemporal Dementia/physiopathology
*Interoception/physiology
Biomarkers
Middle Aged
*Brain/physiopathology
Electrocardiography
*Allostasis/physiology
Heart Rate/physiology

@article {pmid41500793,
year = {2025},
author = {Gaur, A and Chen, JJ and Wong, M and Kang, Y and Tahoulas, D and Gallagher, D and Herrmann, N and Lanctôt, KL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105493},
doi = {10.1002/alz70856_105493},
pmid = {41500793},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/blood ; Exosomes/metabolism ; Synaptosomal-Associated Protein 25/cerebrospinal fluid ; Nerve Tissue Proteins/cerebrospinal fluid ; C-Reactive Protein ; },
abstract = {BACKGROUND: Alzheimer's dementia (AD) is a neurodegenerative condition characterized by progressive cognitive decline. Synaptopathy-defined as loss and dysfunction of existing synapses-is a hallmark pathological feature of AD and can directly contribute to underlying cognitive deficits. In this study, we meta-analyzed several cerebrospinal fluid (CSF) and blood exosomal biomarkers associated with synaptopathy in AD and healthy controls (HCs).

METHOD: Original peer-reviewed articles that reported synaptic biomarker concentrations in CSF or blood exosomes were reviewed. Specifically, synaptosome associated protein-25 (SNAP-25), growth associated protein-43 (GAP-43), neuronal pentraxin receptor (NPTXR), neuronal pentraxin-1 (NPTX-1), neuronal pentraxin-2 (NPTX-2), complexin-2, syntaxin-1B, syntaxin-7, and vesicle-associated membrane protein-2 (VAMP-2) in AD and HCs were included for meta-analysis. A random-effects model was used to determine standardized mean differences (SMDs) and 95% confidence intervals (CIs). Heterogeneity was quantified using I[2].

RESULT: The meta-analysis included 43 study cohorts. In CSF, concentrations of SNAP-25 (NAD/NHC = 394/539, SMD [95% CI] = 1.08 [0.73, 1.42], p < 0.001; I[2] = 81.43%), GAP-43 (NAD/NHC = 851/557, SMD [95% C] = 1.02 [0.69, 1.34], p < 0.001; I[2] = 83.97%), and VAMP-2 (NAD/NHC = 398/490, SMD [95% CI] = 0.32 [0.05, 0.60], p = 0.02; I[2] = 64.91%) were elevated, and NPTXR (NAD/NHC = 575/470, SMD [95% CI] = -0.68 [-0.96, -0.40], p < 0.001; I[2] = 75.59%), NPTX-1 (NAD/NHC = 344/333, SMD [95% CI] = -0.48 [-0.64, -0.31], p < 0.001; I[2] = 9.05%), and NPTX-2 (NAD/NHC = 462/496, SMD [95% CI] = -0.78 [-1.02, -0.54], p < 0.001; I[2] = 66.43%) were decreased in AD compared to HCs. In blood exosomes, SNAP-25 (NAD/NHC = 161/159, SMD [95% CI] = -1.05 [-1.28, -0.82], p < 0.001; I[2] = 0%) and GAP-43 (NAD/NHC = 110/110, SMD [95% CI] = -1.66 [-2.43, -0.88], p < 0.001; I[2] = 77%) concentrations were decreased in AD.

CONCLUSION: This study found that several synaptic biomarkers were significantly altered in AD in CSF and blood exosomes. There was significant heterogeneity for most comparisons (with the exception of CSF NPTX-1 and blood exosome SNAP-25) that remains to be explored. Nonetheless, further review of the identified biomarkers may provide fundamental insight into AD pathophysiology and disease trajectory.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/cerebrospinal fluid/blood
Exosomes/metabolism
Synaptosomal-Associated Protein 25/cerebrospinal fluid
Nerve Tissue Proteins/cerebrospinal fluid
C-Reactive Protein

@article {pmid41500721,
year = {2025},
author = {Park, C and Wharton, W and Hu, WT and Huang, H and Kehoe, PG and Miners, JS and Verble, DD and Zetterberg, H and Hammerschlag, BL and Trotti, LM and Benameur, K and Butts, B},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106513},
doi = {10.1002/alz70856_106513},
pmid = {41500721},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; Middle Aged ; Female ; Male ; Aged ; *Alzheimer Disease/cerebrospinal fluid/genetics ; Amyloid beta-Peptides/cerebrospinal fluid ; *Stress, Psychological/cerebrospinal fluid ; Black or African American ; tau Proteins/cerebrospinal fluid ; Vascular Cell Adhesion Molecule-1/cerebrospinal fluid ; White People ; Cohort Studies ; Inflammation ; Matrix Metalloproteinase 2/cerebrospinal fluid ; Apolipoproteins E/genetics ; White ; },
abstract = {BACKGROUND: Studies suggest a chronic stress-activated pathway in the development of Alzheimer's disease (AD) and cognitive decline, underscoring the need to better understand mechanisms of stress and downstream impacts. Inflammation and vascular dysfunction caused by subjective stress may contribute to pathology in AD. Here, we investigated how stress relates to AD biomarkers and cognition in a cohort of B/AA (Black/African Americans) and NHW (non-Hispanic White) participants in the NIH-funded ASCEND study.

METHOD: Cognitively normal, middle-aged (45-65 years) B/AA and NHW adults with a parental history of AD were enrolled in a 2-year observational study. CSF was collected for measurement of Aβ and tau, MMPs (MMP-2), and markers of vascular function (sPDGFRβ, VCAM-1) and inflammation (IL-7). At the same visit, blood was collected for APOE genotyping and inflammatory markers (IL-12), in addition to the Digit Span for measurement of cognition. The 10-question Perceived Stress Scale (PSS) assessed perceived stress.

RESULT: Participants (N = 50, mean age 58 ± 7 years) were mostly female (66%), well-educated (84% college or higher), 36% earning ≥ $40K, 30% B/AA, and 48% APOE ε4 positive. PSS was positively correlated with IL-7 (r=.392, p = .024), IL-12 (r=.375, p = .021), MMP-2 (r=.333, p = .029), VCAM-1 (r=.352, p = .033), and Aβ1-42 (r=.328, p = .032), and negatively correlated with the number correct on backwards Digit Span (r=-.365, p = .009). Linear models showed sPDGFRβ was positively associated with MMP-2 (r=.409, p = .008) and VCAM-1 (r=.473, p = .005).

CONCLUSION: Higher perceived stress was associated with higher central and systemic inflammation in a cohort of cognitively normal, middle-aged individuals at risk for AD. Stress was associated with CSF markers of MMP-2, linked with early AD pathology, and VCAM-1, which is involved in vascular dysfunction. SPDGFRβ in CSF was also positively correlated with MMP-2 and VCAM-1, suggesting that these processes may elicit blood brain barrier breakdown. The correlation between stress and Aβ1-42 reflects that participants were cognitively unimpaired, but higher stress related to lower digit span scores suggests that working memory and executive function are impacted. A larger sample size is required for more robust data analysis. More research is needed examining mechanisms of stress to lower AD risk, particularly in diverse populations at high risk for AD.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
Middle Aged
Female
Male
Aged
*Alzheimer Disease/cerebrospinal fluid/genetics
Amyloid beta-Peptides/cerebrospinal fluid
*Stress, Psychological/cerebrospinal fluid
Black or African American
tau Proteins/cerebrospinal fluid
Vascular Cell Adhesion Molecule-1/cerebrospinal fluid
White People
Cohort Studies
Inflammation
Matrix Metalloproteinase 2/cerebrospinal fluid
Apolipoproteins E/genetics
White

@article {pmid41500702,
year = {2025},
author = {Oomens, JE and Wilson, RE and Reyes, RER and Jonaitis, EM and Chin, NA and Zetterberg, H and Johnson, SC},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105805},
doi = {10.1002/alz70856_105805},
pmid = {41500702},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/blood ; *Cognitive Dysfunction/blood/diagnosis ; *tau Proteins/blood ; Aged ; *Alzheimer Disease/blood/diagnosis ; Cohort Studies ; Disease Progression ; Registries ; Middle Aged ; Wisconsin ; Aged, 80 and over ; },
abstract = {BACKGROUND: As the evidence base supporting the accuracy and reliability of plasma pTau217 assays continues to grow, attention has shifted towards establishing their diagnostic and clinical utility. The aim of the current study was to examine the association between plasma pTau217 levels and conversion to MCI in a preclinical cohort.

METHOD: We selected 1943 participants from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin ADRC for whom Quanterix HD-X plasma pTau217 data was available. Participants were classified as being plasma pTau217 negative (≤ 40 pg/ml, n = 1402) or positive (> 40 pg/ml, n = 541), with the positive group also being subdivided into moderately positive (> 0.40 & ≤ 0.63 pg/ml, n = 308) and strongly positive (> 0.63 pg/ml, n = 233). Incident MCI was defined using varying levels of stringency and definitions included (1) conversion from CDR 0 to CDR 0.5 at two consecutive visits (n = 197, median 3 visits, mean FU 3.4 years; definition 1), (2) a clinical diagnosis of MCI from multidisciplinary consensus review (n = 1076, median 5 visits, mean FU 5.6 years; definition 2) and (3) performance below the 7[th] conditional centile on the PACC-3 for two consecutive visits (n = 948, median 3 visits, mean FU 6.6 years; definition 3).

RESULT: The mean age of the included participants was 63 years (SD8.1). 68% of participants were female, 35% of participants were APOE e4 carrier and 83% of participants were non-Hispanic white. Rates of conversion in the total cohort were < 1% per year (1.5% overall; average time to conversion 5.1 years) for definition 1, 1.1% per year (6.4% overall; average time to conversion 7.3 years) for definition 2 and <1.0% per year (3.9% overall; average time to conversion 5.7 years) for definition 3. Rates of conversion in the subset of pTau217 positive participants ranged from <1.0% to 4.7% per year (Table 1). Those with strongly positive plasma levels showed the highest rates of conversion (Table 1).

CONCLUSION: Rates of conversion to MCI in this largely preclinical cohort ranged from < 1% to 1.9% per year in the total cohort and from <1% to 4.7% per year in the subset of participants that were plasma pTau217 positive.},
}

Humans
Female
Male
*Biomarkers/blood
*Cognitive Dysfunction/blood/diagnosis
*tau Proteins/blood
Aged
*Alzheimer Disease/blood/diagnosis
Cohort Studies
Disease Progression
Registries
Middle Aged
Wisconsin
Aged, 80 and over

@article {pmid41500699,
year = {2025},
author = {Darchi, S and Pinter, Y and Sadeh, T},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105272},
doi = {10.1002/alz70856_105272},
pmid = {41500699},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnosis/psychology ; Aged ; *Cognitive Dysfunction/diagnosis ; *Natural Language Processing ; Biomarkers ; *Social Media ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Natural Language Processing (NLP) has shown promise in identifying linguistic markers of MCI and Alzheimer's Disease (AD). Prior studies have achieved classification accuracy of 80%-85% but were often limited by cross-sectional designs and reliance on curated texts like novels and speeches. Social media data offer a more ecologically valid, continuous assessment of linguistic changes. This study explores whether cognitive decline can be detected through online activity on Reddit, contributing to developing a more complex model capable of detecting early changes indicative of cognitive deterioration from online activity.

METHOD: We applied a Self-Disclosure approach, commonly used in research for identifying self-reports of various mental illnesses. We identified self-reported AD cases on Reddit and extracted their posts. Data from 42 Reddit users (20 diagnosed with AD, 22 matched controls) were collected and analyzed to examine both online engagement patterns and linguistic shifts over time.

RESULT: We analyzed the texts using an automatic scoring method based on DistilBERT. This method measures the amount of two types of details in a text: internal details (episodic information) and external details (repetitions and metacognitive statements). A two-way MANOVA showed a significant group effect on word usage (F(2, 4243) = 41.90, p < .001). Follow-up analyses revealed that this effect was driven by internal words, with control using significantly more internal words than diagnosed individuals (F(1, 4244) = 52.78, p < .001; mean difference = -13.30). No significant differences were found for external words between the groups (F(1, 4244) = 0.09, p = .76). An analysis of LIWC psychological categories found that patients and controls differed in their language. Most interestingly, compared to controls, patients displayed increased use of past tense, emotional, function, and social words. The controls used more analytic language reflecting logical, formal thinking, cognitive processes such as reasoning and analysis.

CONCLUSION: Significant differences in online activity and language patterns between AD patients and controls suggest that analyzing social media activity can provide valuable insights into cognitive decline. By leveraging such linguistic and behavioral markers, future models may enable early detection of dementia in a scalable and non-invasive manner.},
}

Humans
Male
Female
*Alzheimer Disease/diagnosis/psychology
Aged
*Cognitive Dysfunction/diagnosis
*Natural Language Processing
Biomarkers
*Social Media
Aged, 80 and over
Middle Aged

@article {pmid41500650,
year = {2025},
author = {Tirambulo, CVG and Merlini, S and Paul, M and Lizarraga, C and Brinton, RD and Vitali, F},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105280},
doi = {10.1002/alz70856_105280},
pmid = {41500650},
issn = {1552-5279},
mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; *Alzheimer Disease/blood/genetics/diagnosis ; Aged ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Middle Aged ; Apolipoprotein E4/genetics ; Registries ; Risk Factors ; },
abstract = {BACKGROUND: Individuals in the early stages of Alzheimer's disease (AD) constitute a heterogeneous group, with diverse risk factor profiles such as chromosomal sex, apolipoprotein E (APOE) genotype, and comorbidities, evolving over distinct time courses. Within a prodromal phase that can extend for one to three decades, opportunities and challenges exist in identifying crucial tipping points in progression and opportunities for prevention.

METHOD: Our study aimed to identify subgroups within the 389 individuals at high-risk for AD (65.6±6.4 years old, 67.1% female, 38.8% APOE ε4 carriers) from the Wisconsin Registry for Alzheimer's Prevention data, 2001-2022. We analyzed prospectively collected data covering patient characteristics (age, sex, race, and APOE ε4 carrier status), medical history (history of diabetes, hypertension, and hyperlipidemia), plasma biomarkers (amyloid-β (Aβ) 40, Aβ42, Aβ40/42 ratio, phosphorylated tau (p-tau) 181, and p-tau 217), and blood laboratory parameters (insulin, glucose, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol). Employing classical clustering methodologies (CCMs, k-means (KMs), KMs with principal component analysis, hierarchical clustering (HC), and HC with dynamic time warping) to inform the unsupervised deep embedded clustering (DEC) algorithm, we evaluated cluster membership and assessed clinical validity. Variable contributions to the predicted cluster membership were assessed using SHapley Additive exPlanations values.

RESULT: Our DEC findings demonstrated promising results by identifying more distinct risk profile patterns for each cluster (n = 6) compared to CCMs (n = 2); achieving a more evenly distributed partitioning of participants into clusters with increased stability, measured by Jaccard and entropy scores; and validating the clinical recognizability based on laboratory values, plasma biomarkers, physician cognitive diagnoses, and Preclinical Alzheimer Cognitive Composite scores. Cluster characterization revealed participants in cluster 6 (n = 44) were most at-risk for AD, consisting of female APOE ε4 carriers with elevated p-tau levels. Conversely, cluster 4 (n = 57) was the least at-risk, youngest cluster, comprising females with fewer comorbid conditions and the lowest AD biomarker levels. Cluster 3 (n = 81) represented the control population.

CONCLUSION: Going forward, these outcomes will enable a robust pipeline for integrating electronic medical record data, empowering diverse patient characterization, and better identify those at risk to implement personalized preventative treatment within heterogeneous populations at risk for AD.},
}

Humans
Female
*Biomarkers/blood
Male
*Alzheimer Disease/blood/genetics/diagnosis
Aged
Amyloid beta-Peptides/blood
tau Proteins/blood
Middle Aged
Apolipoprotein E4/genetics
Registries
Risk Factors

@article {pmid41500595,
year = {2025},
author = {Hara, N and Kamada, M and Yamaguchi, H and Uenishi, T and Tanizawa, Y and Ueda, K and Osaga, S and Hatakeyama, N},
title = {[Survey on peer support programs for family members and other caregivers of people with dementia in Japan].},
journal = {Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics},
volume = {62},
number = {4},
pages = {409-421},
doi = {10.3143/geriatrics.62.409},
pmid = {41500595},
issn = {0300-9173},
mesh = {Humans ; *Caregivers/psychology ; *Dementia/nursing ; Surveys and Questionnaires ; *Family/psychology ; *Social Support ; *Peer Group ; Japan ; Male ; Female ; Aged ; Middle Aged ; },
abstract = {OBJECTIVE: Peer support, including family associations and dementia cafés, helps reduce the psychological burden on patients with dementia and their caregivers. By considering various aspects of peer support, this study aimed to determine its psychological impact on caregivers, efficacy, and related challenges.

METHOD: In June 2023, we conducted a web-based questionnaire survey of caregivers of people with dementia.

RESULTS: Among 3,318 respondents, 29.3% were aware of peer support, but only 14.0% participated. The important determinants of participation were low time-related and psychological barriers. Among the participants, 46.4% learned about peer support from a care manager, which is a significantly higher proportion than from other sources (p<0.001). The question of whether the means of obtaining information was "psychologically positive" was answered positively by more peer support participants (62.4%) than by non-participants (individuals who obtained information outside of peer support; 59.5%; p=0.390). Participation was rated as "psychologically positive" by a significantly higher proportion (93.9%) of caregivers still participating in peer support than by those who no longer participated (55.9%; p<0.001). Reasons for continued participation included ease of participation and enjoyment.

DISCUSSION AND CONCLUSION: The survey revealed a positive psychological impact of peer support, which was higher among those who continued to participate. Caregivers of people with dementia need to be informed about the availability and efficacy of peer support soon after a dementia diagnosis. To ensure the continuous provision of support, the convenience and design of peer support needs to be improved in response to various care needs.},
}

Humans
*Caregivers/psychology
*Dementia/nursing
Surveys and Questionnaires
*Family/psychology
*Social Support
*Peer Group
Japan
Male
Female
Aged
Middle Aged

@article {pmid41500584,
year = {2025},
author = {Orukari, IE and Wang, Y and Chen, Y and Wang, B and Friedrichsen, KA and Flores, S and Nai, YH and Jones, LA and Rahmani, F and Okafor, JN and Rajamanickam, J and Lee, JM and Ford, AL and Brier, MR and Tu, Z and Benzinger, TLS and An, H},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105981},
doi = {10.1002/alz70856_105981},
pmid = {41500584},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Positron-Emission Tomography ; Biomarkers/metabolism ; Aged ; *White Matter/diagnostic imaging/pathology ; Middle Aged ; *Alzheimer Disease/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; *Brain/diagnostic imaging/metabolism ; Sphingosine-1-Phosphate Receptors/metabolism ; *Cognitive Dysfunction/diagnostic imaging ; Aniline Compounds ; },
abstract = {BACKGROUND: White matter hyperintensities (WMHs) are associated with both Alzheimer's Disease (AD) and vascular contributions to cognitive impairment & dementia (VCID). Both neuroinflammation and amyloid-β are hypothesized to contribute to WMH development, yet exact mechanisms are unknown. We have developed [[11]C]CS1P1, a novel PET probe targeting the S1PR1 receptor in the brain, a receptor which has been previously associated with neuroinflammation. In this study, we characterized [[11]C]CS1P1 PET and PiB Centiloid in human subjects with early AD/VCID.

METHOD: We enrolled 23 subjects (≥50 years old) with varying numbers of cerebrovascular risk factors (i.e. hypertension, hyperlipidemia, diabetes, stroke, and tobacco use), and had a CDR ≤0.5. Subjects had MPRAGE MRI scans for anatomic segmentation; FLAIR MRI scans for segmentation of WMHs; [[11]C]CS1P1 dynamic PET scans for quantifying S1PR1 activity (Figure 1); and PiB scans for assessing Centiloid. A Centiloid ≥20 defined PiB positivity. MRI scans were co-registered to [[11]C]CS1P1 PET scans, and kinetic modeling was performed for grey matter (GM), normal appearing white matter (NAWM), and WMH regions of interests (ROIs). Relative WMH volumes were normalized to whole brain volume and log-transformed to indicate WMH burden (logrVWMH). Linear regression was performed to determine the relationship between logrVWMH and [[11]C]CS1P1 PET volume of distribution (VT) in all ROIs. A stepwise multiple linear regression model was performed to evaluate the association between logrVWMH and [[11]C]CS1P1 VT and PiB Centiloid with age, sex, and cerebrovascular vascular risk factors as covariates.

RESULT: [[11]C]CS1P1 VT in the WMH ROI significantly correlated with logrVWMH (R[2]= 0.3044, p-value= 0.0063, Figure 2). Patients with high WMH [[11]C]CS1P1 VT and PiB positivity had high logrVWMH. The stepwise multiple linear regression model demonstrated logrVWMH are significantly associated with WMH [[11]C]CS1P1 VT and PiB Centiloid (adjusted R[2]= 0.417, p-value= 0.00176, Figure 3) after controlling for age, sex, and cerebrovascular risk factors. [[11]C]CS1P1 VT in the NAWM or GM ROIs did not correlate with logrVWMH.

CONCLUSION: A novel metric of neuroinflammation, [[11]C]CS1P1, and amyloid-β are independently associated with WMH burden. Future studies are needed to evaluate whether neuroinflammation and amyloid deposition synergistically or additively contribute to WMH burden in AD/VCID.},
}

Humans
Male
Female
Positron-Emission Tomography
Biomarkers/metabolism
Aged
*White Matter/diagnostic imaging/pathology
Middle Aged
*Alzheimer Disease/diagnostic imaging/metabolism
Magnetic Resonance Imaging
*Brain/diagnostic imaging/metabolism
Sphingosine-1-Phosphate Receptors/metabolism
*Cognitive Dysfunction/diagnostic imaging
Aniline Compounds

@article {pmid41500562,
year = {2025},
author = {Chen, G and McKay, NS and Joseph-Mathurin, N and Massoumzadeh, P and Gordon, BA and Liu, J and LaMontagne, PJ and Keefe, SJ and Schindler, SE and Hassenstab, JJ and Cruchaga, C and Morris, JC and Benzinger, TLS},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105116},
doi = {10.1002/alz70856_105116},
pmid = {41500562},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Biomarkers/cerebrospinal fluid ; Magnetic Resonance Imaging ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/pathology/diagnostic imaging ; Aged ; *Hippocampus/pathology/diagnostic imaging ; *Cognitive Dysfunction/cerebrospinal fluid/pathology/diagnostic imaging/diagnosis ; Neuropsychological Tests/statistics & numerical data ; *Lateral Ventricles/pathology/diagnostic imaging ; Cohort Studies ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Biomarkers are essential for the early detection of Alzheimer disease (AD) to develop effective treatments. As neurons die, hippocampal shrinkage and lateral ventricle expansion occur. Measuring hippocampal volume is challenging due to its small size, while lateral ventricle volume is easier to quantify. Our previous research showed that baseline and longitudinal changes in lateral ventricle volume predicted cognitive decline in a research cohort. However, its utility as a biomarker in clinical populations remains underexplored. This study investigated whether lateral ventricle volume predicts cognitive decline in clinical patients with memory complaints who underwent Clinical Dementia Rating (CDR©), neuropsychometric, cerebrospinal fluid (CSF) and imaging assessments between 1990 and 2018.

METHOD: This study included 344 participants from the OASIS4 clinical cohort (https://sites.wustl.edu/oasisbrains/home/oasis-4/) who had at least two cognitive assessments and corresponding MRI scans. Lateral ventricle and hippocampal volumes were extracted using FreeSurfer (5.3) software and adjusted for intracranial volume. Cognitive performance was measured using a composite score based on z-scores from Verbal Fluency, Trailmaking B Seconds, and Digit Symbol Errors-tests commonly used to study early AD-related changes. A random coefficient model examined whether baseline lateral ventricle volume predicted cognitive decline, controlling for age, sex, and education. Linear regression analyzed correlations between baseline hippocampal volume and baseline lateral ventricle volume, and the relationship between baseline lateral ventricle volume and changes in cognitive composite scores.

RESULT: Demographic characteristics of the participants at baseline were presented in Table 1. Baseline lateral ventricle volume was a significant predictor of the cognitive decline as measured by the cognitive composite scores (Table 2, p =  0.01). Additionally, baseline lateral ventricles volume is significantly correlated with the rate of changes in cognitive composite scores (Figure 2A, R[2]=0.0368, p = 0.0003) and baseline hippocampal volume (Figure 2B, R[2] = 0.1631, p < 0.0001).

CONCLUSION: These findings suggest that the lateral ventricle volume may be used as a robust and easily measurable imaging biomarker in clinical setting. Its significant predictive value for cognitive decline, along with its strong association with hippocampal volume in a clinical cohort, highlights its potential for monitoring AD progression. This translates our research findings into real-world populations.},
}

Humans
Male
Female
*Biomarkers/cerebrospinal fluid
Magnetic Resonance Imaging
*Alzheimer Disease/cerebrospinal fluid/diagnosis/pathology/diagnostic imaging
Aged
*Hippocampus/pathology/diagnostic imaging
*Cognitive Dysfunction/cerebrospinal fluid/pathology/diagnostic imaging/diagnosis
Neuropsychological Tests/statistics & numerical data
*Lateral Ventricles/pathology/diagnostic imaging
Cohort Studies
Aged, 80 and over
Middle Aged

@article {pmid41500544,
year = {2025},
author = {Turney, IC and Huber, BD and Ryan, CP and Avila, JF and Lao, PJ and Rentería, MA and Mazen, J and Belsky, DW and Manly, JJ and Brickman, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104877},
doi = {10.1002/alz70856_104877},
pmid = {41500544},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Magnetic Resonance Imaging ; Middle Aged ; Aged ; *Biomarkers ; *Aging/pathology ; *Alzheimer Disease/diagnostic imaging/pathology ; *Brain/pathology/diagnostic imaging ; *White Matter/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: Advanced biological is associated with cumulative physiological damage resulting from chronic exposure to environmental and social stressors. The Weathering Hypothesis posits that such exposure-especially in marginalized populations-accelerates biological aging, contributing to health disparities and elevated Alzheimer's disease and related dementias (AD/ADRD) risk. Midlife is a pivotal period for brain aging, marked by structural changes such as increased white matter hyperintensity (WMH) volume and reduced cortical thickness (CT). However, the interplay among advanced biological aging, MRI-based brain aging markers, and social determinants of health across racially/ethnically diverse populations remains poorly understood. Understanding these dynamics is essential for addressing disparities in brain health and AD/ADRD outcomes.

METHOD: We examined the association between biological age acceleration (GrimAge) and ADRD-related MRI measures (WMH volume and CT) in 681 racially/ethnically diverse adults aged 45-65 years from the Offspring Study of Racial and Ethnic Disparities in Alzheimer's Disease. Linear regression models assessed the relationships between biological age acceleration and MRI outcomes, adjusting for age, sex, and estimated intracranial volume. Stratified analyses explored associations within racial/ethnic groups. Interaction terms tested the moderating effects of years of education and cardiovascular disease (CVD) burden on these associations.

RESULT: In this diverse midlife cohort (66% women; 69% Latinx, 22% Black, 7.5% White; mean age=54±11 years; mean education=13.3 ±3.4 years), accelerated aging was significantly associated with increased WMH volume (β=0.014, 95%CI [0.003,0.025]), but not cortical thickness (β=0.562, 95%CI [0.003,0.025]). The relationship between biological age and WMH was amplified in participants with greater CVD burden (β=0.028, 95%CI [0.011,0.045]). Participants with higher education, Latinx, or White showed less biological age acceleration. Stratified analyses revealed that the association between biological age acceleration and greater WMH volume was marginally strongest in Black (β=0.013, 95%CI [-0.008,0.033]) and Latinx participants (β=0.014, 95%CI [0.001,0.028]), compared with White participants.

CONCLUSION: Accelerated biological aging is associated with increased WMH volume and may contribute to disparities in brain health, particularly among individuals with greater cardiovascular burden. These results highlight the need for targeted, multifaceted interventions that account for sociocultural and biological influences to reduce brain health disparities and promote equity in ADRD outcomes.},
}

Humans
Female
Male
Magnetic Resonance Imaging
Middle Aged
Aged
*Biomarkers
*Aging/pathology
*Alzheimer Disease/diagnostic imaging/pathology
*Brain/pathology/diagnostic imaging
*White Matter/pathology/diagnostic imaging

@article {pmid41500543,
year = {2025},
author = {Ikanga, JN},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105508},
doi = {10.1002/alz70856_105508},
pmid = {41500543},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/genetics/blood ; *Biological Specimen Banks ; Aged ; Female ; Male ; Africa South of the Sahara ; Middle Aged ; },
abstract = {BACKGROUND: The use of biobanking and fluid biomarkers in Western countries has revolutionized Alzheimer's disease (AD) and dementia research. This study presents preliminary efforts in biobanking and plasma biomarkers by the Recruitment and Retention for Alzheimer's Disease Diversity in the Alzheimer's Disease Sequencing Project (READD-ADSP). The project aims to recruit 5000 African participants (both AD patients and cognitively unimpaired controls) to generate genomic and biomarker data to better characterize AD neurobiology in Africa, focusing on countries that constitute the African Dementia Consortium.

METHODS: Blood samples from older adults over 50 years old from more than 10 countries in Sub-Saharan Africa (SSA) are collected, separated into fractions, and transported to the African Coordinating Centre in Ibadan, Nigeria. There, DNA extraction and long-term biospecimen storage are carried out. Plasma and DNA aliquots are sent to the John P. Hussman Institute for Human Genomics at the University of Miami for genotyping, whole genome sequencing, and biomarker analysis. Innovative solutions were devised to mitigate challenges encountered so far.

RESULTS: Significant challenges related to blood collection from many participants in SSA arise due to conceptions of blood and the transportation of samples out of Africa. The stepwise creation and development of the READD-ADSP biobanking network have been guided by global best practices and regulatory standards. Challenges were encountered in the process of establishing the READD-ADSP biobanking, and home-grown solutions were developed. Preliminary analyses of plasma AD biomarkers have been conducted, including core AD, non-specific, and neuroinflammation AD biomarkers. Initial genotyping results show the prevalence of APOE in these populations. Additionally, some associations between these plasma biomarkers with cognitive functions and neuroimaging data have been identified.

CONCLUSION: The READD-ADSP biobanking experience demonstrates the feasibility of establishing a successful African biobanking network and offers lessons to researchers in low-resource settings on how collaborative efforts between the global north and global south enhance cutting-edge team science to tackle aging-associated brain disorders in low- and middle-income countries. This network is an important infrastructure to support AD/ADRD research in Africa and highlights the need to build local infrastructure for biomarker and genotyping, genomics, and other omics analyses.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/genetics/blood
*Biological Specimen Banks
Aged
Female
Male
Africa South of the Sahara
Middle Aged

@article {pmid41500540,
year = {2025},
author = {Patel, AG and Nehete, PN and Salaymeh, N and Nehete, BP and Karimi, S and Debure, L and Zhang, Q and Wang, F and Pytka, LM and Shao, Y and Mulholland, MM and Hopkins, WD and Wisniewski, T and Scholtzova, H},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105057},
doi = {10.1002/alz70856_105057},
pmid = {41500540},
issn = {1552-5279},
mesh = {*Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/blood ; Male ; Humans ; Female ; Chitinase-3-Like Protein 1/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Animals ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Cross-Sectional Studies ; S100 Calcium Binding Protein beta Subunit/cerebrospinal fluid ; },
abstract = {BACKGROUND: Current immunotherapeutic approaches for Alzheimer's disease (AD) are limited in their effectiveness and face complications associated with cerebral amyloid angiopathy (CAA), such as amyloid-related imaging abnormalities (ARIA). Our earlier published work using a TLR9 agonist, CpG-ODN, to modulate the innate immune system for treating AD, has benefited from the use of non-human primates (NHP), squirrel monkeys (SQMs), which naturally develops AD pathology, including extensive age-dependent CAA. In this study, we further the development of this model by characterizing trajectories of biofluid biomarkers and cognitive changes across the SQM lifespan, the dynamics that have never been described before.

METHOD: Plasma and CSF biomarkers of AD pathogenesis (Ab), neurodegeneration (NfL, GFAP, neurogranin), cerebrovascular dysfunction (MMPs), and inflammation (YKL-40/CHI3L1, sTREM2, S100B) were characterized cross-sectionally using SIMOA and Luminex immunoassays. New age cohorts were supplemented into our dataset. A touchscreen-based Automated Cognitive Testing System (ACTS) was implemented within SQM cohorts to assess behavioral performance.

RESULT: Our current work represents continuation of our comprehensive cross-sectional study on aging and CAA/AD pathogenesis in SQMs. By applying simple linear regression models, we observe age-associated decreases in plasma Aβ40, Aβ42, and Aβ42/Aβ40 ratio. Additionally, CSF levels of NfL, GFAP, and plasma YKL-40, sTrem2 demonstrated significant linear increases across disease continuum. Segmented regression analyses revealed changepoints in CSF Aβ40, Aβ42, Aβ42/Aβ40 ratio and plasma MMP3, that were followed by a significant decrease in slope. Plasma concentrations of NfL, GFAP, neurogranin, and S100B significantly increased with age after the estimated changepoint. We are further exploring SQM fluid biomarker profiles using the NULISAseq platform. Moreover, ACTS Transfer Index Task revealed that geriatric SQMs perform significantly worse than young SQMs in the learning phase, while there were no differences in the reversal trials. In the Conceptual Set Shifting Task, we found a difference in learning latency between young and geriatric SQMs. Ongoing efforts are focused on integrating fluid biomarkers with cognitive and neuroimaging measures.

CONCLUSION: We believe that successful incorporation of this NHP model will improve diagnostic capability and mechanistic understanding of AD pathology development, particularly CAA, as well as help quicken the progress towards new therapeutics with an assessment of their associated ARIA risk.},
}

*Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/cerebrospinal fluid/blood
Male
Humans
Female
Chitinase-3-Like Protein 1/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Aged
Animals
Aged, 80 and over
Glial Fibrillary Acidic Protein/cerebrospinal fluid
Cross-Sectional Studies
S100 Calcium Binding Protein beta Subunit/cerebrospinal fluid

@article {pmid41500220,
year = {2025},
author = {Ferreira, LC and Paes, RS and Limberger, C and Baldasso, GM and De Bastiani, MA and Zimmer, ER},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105616},
doi = {10.1002/alz70856_105616},
pmid = {41500220},
issn = {1552-5279},
mesh = {Humans ; Polymorphism, Single Nucleotide/genetics ; Male ; Female ; *Alzheimer Disease/genetics/metabolism/diagnostic imaging ; Aged ; Biomarkers/metabolism ; *Glucose/metabolism ; *Brain/metabolism/diagnostic imaging ; Positron-Emission Tomography ; *Pyruvate Kinase/genetics ; Fluorodeoxyglucose F18 ; *Cognitive Dysfunction/genetics/metabolism/diagnostic imaging ; Aged, 80 and over ; },
abstract = {BACKGROUND: Brain glucose hypometabolism is associated with neurodegeneration in Alzheimer's disease (AD). Individuals at risk for AD can exhibit reduced glucose metabolism in brain regions typically affected by AD pathology, even years before the diagnosis. However, the impact of glycolytic metabolism dysfunction on AD progression remains to be fully elucidated. Herein, we investigated the impact of single nucleotide polymorphisms (SNPs) in the pyruvate kinase M (PKM) gene - a key glycolytic enzyme - on brain glucose metabolism across AD stages.

METHOD: We analyzed 203 cognitively unimpaired (CU) and 416 cognitively impaired (CI) individuals from ADNI. Seven SNPs (rs62026270, rs2856929, rs8192431, rs8192386, rs2607090, rs1037680, and rs4506844) related to the PKM gene were identified. We examined the association between SNP carriership and brain glucose metabolism in FDG metaROI using linear mixed-effect models, adjusted for age, sex, APOE4, amyloid, and tau status (p < 0.05). We also performed ROI-wise correlation analysis to investigate the effect of SNP carriership on FDG regional SUVr levels.

RESULT: We found that six SNPs are significantly associated with reduced brain glucose metabolism in CI individuals (β = -0.21 to -0.23, p < 0.05), with no effect presented in CU individuals (Figure 1). Glucose hypometabolism was particularly evident in typical AD hypometabolic regions, including the entorhinal, temporal, cingulate, and inferior parietal cortex (Figure 2).

CONCLUSION: Our findings indicate that SNPs in the PKM gene may influence glucose metabolism in CI individuals. The reduced FDG-PET signal, especially in regions linked to AD vulnerability, suggests these genetic variants may contribute to the hypometabolism associated with AD progression. This reinforces the idea that glucose hypometabolism is not just a consequence of neurodegeneration but may play a critical role in disease progression. Future research should investigate how these SNPs affect metabolic efficiency to identify new intervention targets for AD-risk populations.},
}

Humans
Polymorphism, Single Nucleotide/genetics
Male
Female
*Alzheimer Disease/genetics/metabolism/diagnostic imaging
Aged
Biomarkers/metabolism
*Glucose/metabolism
*Brain/metabolism/diagnostic imaging
Positron-Emission Tomography
*Pyruvate Kinase/genetics
Fluorodeoxyglucose F18
*Cognitive Dysfunction/genetics/metabolism/diagnostic imaging
Aged, 80 and over

@article {pmid41500206,
year = {2025},
author = {Kucharska-Newton, AM and Chen, J and Pike, JR and Pleasants, H and Lutsey, PL and Bey, G and Abner, EL and Whitsel, EA and Stewart, JD and Palta, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106661},
doi = {10.1002/alz70856_106661},
pmid = {41500206},
issn = {1552-5279},
mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; Middle Aged ; Neurofilament Proteins/blood ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/blood ; tau Proteins/blood ; Glial Fibrillary Acidic Protein/blood ; Aged ; Cohort Studies ; Peptide Fragments/blood ; Socioeconomic Factors ; Neighborhood Characteristics ; },
abstract = {BACKGROUND: Early life exposure to adverse experiences correlates with poor health outcomes in adulthood. We therefore examined the association of childhood neighborhood socioeconomic position (nSEP) with midlife and late life levels of plasma-based biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration.

METHODS: The study population included 1362 Atherosclerosis Risk in Communities (ARIC) cohort participants (mean [SD] midlife age: 58.1 [4.8] years; 60.2% female; 26.4% Black) with amyloid-β 42/40 (Aβ42/40), pTau-181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) ascertained at midlife (Visit 3; 1996-1982) and older adulthood (Visit 5; 2011-2013) using Quanterix Simoa assays. We used residential addresses at age 10 years to create a childhood composite of six, z-scored U.S. Census-based measures of nSEP: median household income; median value of owner-occupied housing units; percent households receiving interest, dividend, or net rental income; percent adults with a high school degree; percent adults with a college degree; and percent adults in professional, managerial, or executive occupations. We used weighted, mixed-effects models to estimate standardized log 2 transformed biomarker concentrations across tertiles of childhood nSEP adjusted for midlife age, race-study center, sex, education, and presence of the APOE ε4 allele.

RESULTS: At midlife, participants who were in the lowest versus highest tertile of childhood nSEP had higher mean (SD) concentrations of pTau181(1.58 [0.94] vs. 1.53 [1.0], pg/ml), NfL (13.1 [7.4] vs. 12.1 [6.4], pg/ml), and GFAP (108.5 [64.9] vs. 103.9 [50.8], pg/ml.) Differences in biomarker concentrations between low and high childhood nSEP were attenuated in late life. The AB42/40 ratio at midlife and late life was comparable across the childhood nSEP tertiles. After covariate adjustment, midlife pTau181, NfL and GFAP concentrations were inversely associated with childhood nSEP (Figure 1). The association was marginally statistically significant for NfL (p-trend=0.05). No associations were observed between childhood nSEP and levels of selected biomarkers ascertained in late life (Figure 2).

CONCLUSION: Observed trend in the association of low childhood socioeconomic position with an adverse midlife, but not late life, profile of plasma-based biomarkers of AD pathology and neurodegeneration warrants further study.},
}

Humans
Female
*Biomarkers/blood
Male
Middle Aged
Neurofilament Proteins/blood
*Amyloid beta-Peptides/blood
*Alzheimer Disease/blood
tau Proteins/blood
Glial Fibrillary Acidic Protein/blood
Aged
Cohort Studies
Peptide Fragments/blood
Socioeconomic Factors
Neighborhood Characteristics

@article {pmid41500205,
year = {2025},
author = {Egerton, RJ and Sweeney, A and McGuinness, B and Ross, OA and Beverland, D and Passmore, AP and Heslegrave, AJ and Zetterberg, H and Bowman, E and Cunningham, EL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105455},
doi = {10.1002/alz70856_105455},
pmid = {41500205},
issn = {1552-5279},
mesh = {Humans ; Female ; Biomarkers/blood ; Male ; Aged ; *tau Proteins/blood ; Cohort Studies ; Mental Status and Dementia Tests/statistics & numerical data ; Aged, 80 and over ; Arthroplasty, Replacement, Hip ; Arthroplasty, Replacement, Knee ; *Alzheimer Disease/blood ; *Delirium/blood ; },
abstract = {BACKGROUND: Plasma phosphorylated-tau217 (pTau217) is a blood-based biomarker of Alzheimer's Disease (AD) pathology. Cognitive resilience describes the presence of neurodegenerative pathology and preserved cognition. Cognitive resistance describes avoidance of neurodegeneration. This post hoc analysis of the Post-Operative Delirium Belfast (PODB) cohort aimed to define cognitive resilience using plasma pTau217 and Mini Mental State Examination (MMSE) measures.

METHODS: PODB was an observational cohort study, investigating people aged 65 and over, without a diagnosis of dementia, undergoing elective hip and knee replacement between 2012-2014 with subsequent long-term follow-up. In this analysis, pre-operative plasma pTau217 was used as a marker of neuropathology. A cutoff of 0.42 pg/mL was used (Ashton NJ et al. 2024). Pre-operative and 8-year follow-up MMSE scores were used as a marker of cognition. A score of ≥24 was considered preserved. Definitions used were: Cognitive resilience = pTau217 ≥0.42 pg/mL plus MMSE ≥24. Cognitive resistance = pTau217 <0.42pg/mL plus MMSE ≥24. Affected = pTau217 ≥0.42 pg/mL plus MMSE <24. Those with normal markers plus poor cognition were defined as pTau217 <0.42pg/mL plus MMSE <24. These four groups were identified at baseline and follow-up, respectively. In this analysis, 231 participants were included at baseline, 104 at follow-up.

RESULTS: Of the n = 231 participants included at baseline, n = 147/231 (64%) were cognitively resilient, n = 65/231 (28%) resistant, n = 17/231 (7%) affected, and n = 2/231 (<1%) had normal markers and MMSE <24. Of the n = 104 participants with follow-up information included in this analysis, n =  61/104 (59%) were cognitively resilient, n = 33/104 (32%) were resistant, n = 8/104 (8%) affected, and n = 2/104 (<1%) had normal markers and MMSE <24. Cognitively resilient participants at baseline were younger (p = 0.011) and tended to be female (p = 0.977) compared to affected participants. At follow-up, those who were cognitively resilient tended to be younger (p = 0.196) and female (p = 0.212) compared to affected participants (Table 1). Of those cognitively resilient at follow up, n = 59/61 (97%) of these participants were also cognitively resilient at baseline.

CONCLUSIONS: Using pTAu217, at the cut-off quoted, we found a high incidence of cognitive resilience in an older elective surgical cohort.},
}

Humans
Female
Biomarkers/blood
Male
Aged
*tau Proteins/blood
Cohort Studies
Mental Status and Dementia Tests/statistics & numerical data
Aged, 80 and over
Arthroplasty, Replacement, Hip
Arthroplasty, Replacement, Knee
*Alzheimer Disease/blood
*Delirium/blood

@article {pmid41500203,
year = {2025},
author = {Ding, H and Lyu, C and Searls, E and Ho, K and Li, Z and Burk, A and Low, M and Anderson, K and Tan, O and Serrano, X and Steinberg, EG and Mez, J and Gifford, KA and Alosco, ML and Kolachalama, VB and Lin, H and Au, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105199},
doi = {10.1002/alz70856_105199},
pmid = {41500203},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis ; Aged ; *Neuropsychological Tests ; Biomarkers ; Middle Aged ; Aged, 80 and over ; Smartphone ; Reaction Time ; },
abstract = {BACKGROUND: Self-administered mobile cognitive assessment tools such as the Defense Automated Neurobehavioral Assessment (DANA) have recently emerged as promising solutions for the efficient monitoring of cognitive health. This study investigated the association of DANA with the risk of mild cognitive impairment (MCI).

METHOD: The study sample included participants enrolled in the Boston University Alzheimer's Disease Research Center (BU ADRC) who completed six DANA tasks on their smartphone, yielding five digital cognitive measures per task (four response time metrics and cognitive efficiency). Participants were categorized as either cognitively intact or diagnosed with MCI based on consensus diagnostic meetings at the BU ADRC, adhering to the criteria set by the National Alzheimer's Coordinating Center Uniform Data Set. Digital measures were standardized to have a mean of zero and a standard deviation of one. Logistic regression analyses, adjusted for age, sex, and education, related digital cognitive measures to cognitive status.

RESULT: A total of 132 participants were included in the study (mean age 71.9 ± 10.2 years, 57.6% female), among which, 17 were diagnosed as MCI. All five digital measurements from the code substitution task were associated with MCI. Each standard deviation increase in cognitive efficiency in the code substitution task was associated with a 76% reduction in the odds of MCI (OR = 0.24, 95% CI = 0.09-0.51, P < 0.001). All except standard deviation of response time for all test trials from the procedural response time task were associated with MCI. However, none of the digital measurements from the go/no-go task, match-to-sample, spatial processing, and simple response time were associated with MCI.

CONCLUSION: Digital measures associated with executive function appear to be most sensitive to the identification of MCI in this pilot study. These findings suggest that self-administered smartphone applications provide an alternative tool for cognition monitoring and early detection of cognitive impairment.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis
Aged
*Neuropsychological Tests
Biomarkers
Middle Aged
Aged, 80 and over
Smartphone
Reaction Time

@article {pmid41500202,
year = {2025},
author = {Rodríguez-Baz, Í and Bernhardt, AM and Aldecoa, I and Arranz, J and Arriola-Infante, JE and Maure-Blesa, L and Carmona-Iragui, M and Longen, S and Trossbach, SV and Giese, A and Matthias, T and Benejam, B and Videla, L and Hoyo, LD and Barroeta, I and Hernandez, AS and Fernandez, S and Vaqué-Alcázar, L and Aranha, MR and Morcillo-Nieto, AO and Nübling, G and Wagemann, O and Stockbauer, A and Tondo, M and Bejanin, A and Lleó, A and Alcolea, D and Molina, L and Fortea, J and Levin, J},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106390},
doi = {10.1002/alz70856_106390},
pmid = {41500202},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; *Alzheimer Disease/cerebrospinal fluid/pathology ; *alpha-Synuclein/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; *Down Syndrome/cerebrospinal fluid/pathology ; Middle Aged ; tau Proteins/cerebrospinal fluid ; Aged ; Adult ; Neurofilament Proteins/cerebrospinal fluid ; Cohort Studies ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND: Down syndrome (DS) is a genetic cause of Alzheimer's disease (AD), with virtually all individuals developing AD pathology by their fourth decade due to Amyloid Precursor Protein (APP) gene overexpression. In addition to amyloid beta (Aβ) plaques and hyperphosphorylated tau (p-Tau) aggregates, DS-associated AD (DSAD) often includes α-synuclein (αSyn) aggregates, contributing to Lewy body pathology (LBP). The αSyn Seed Amplification Assay (SAA) in cerebrospinal fluid (CSF) enables the in vivo detection of misfolded αSyn. While αSyn-SAA has revealed αSyn pathology in autosomal dominant (6%-11%) and sporadic (21%-45%) AD, its role in DSAD remains unexplored. This study investigates αSyn-SAA positivity in DSAD, linking in vivo findings to fluid biomarkers and neuropathology.

METHOD: We analyzed CSF of 270 adults with DS from the DABNI and AD21 cohorts by αSyn-SAA, encompassing asymptomatic and symptomatic AD stages (prodromal/dementia). Additional biomarkers included CSF Aβ1-42/1-40, CSF and plasma p-Tau181 and neurofilament light chain (NfL) levels. Neuropathological evaluations in 19 brain donors, including 5 with antemortem CSF, assessed AD neuropathology and LBP.

RESULT: As shown in Table 1, αSyn-SAA positivity was observed in 9.2% of participants, consistent across age groups (Figure 1) and cognitive stages. Symptomatic αSyn-SAA-positive individuals exhibited significantly higher plasma NfL levels compared to αSyn-SAA-negative individuals (31.0 vs. 21.1 pg/mL, p =  0.027). Neuropathological analysis revealed LBP in 47% of cases, with the amygdala and olfactory bulb being the most frequently affected regions (Table 2). Among the five donors with antemortem CSF, the only αSyn-SAA-positive case corresponded to an individual with severe neocortical LBP.

CONCLUSION: This study examines the relationship between LBP and DSAD, identifying a prevalence of αSyn-SAA positivity comparable to autosomal dominant AD but lower than sporadic AD. A potential association was noted between severe neocortical LBP and αSyn seeding activity, while age and cognitive status did not significantly influence positivity rates. Misfolded αSyn was detectable from early ages in individuals with DS. Further research is required to elucidate the mechanisms underlying LBP in DSAD, assess its clinical impact on cognitive and motor symptoms, and explore relationships with other biomarkers.},
}

Humans
*Biomarkers/cerebrospinal fluid
Male
Female
*Alzheimer Disease/cerebrospinal fluid/pathology
*alpha-Synuclein/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
*Down Syndrome/cerebrospinal fluid/pathology
Middle Aged
tau Proteins/cerebrospinal fluid
Aged
Adult
Neurofilament Proteins/cerebrospinal fluid
Cohort Studies
Peptide Fragments/cerebrospinal fluid

@article {pmid41499956,
year = {2025},
author = {Lageman, SB},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104945},
doi = {10.1002/alz70856_104945},
pmid = {41499956},
issn = {1552-5279},
mesh = {Humans ; Male ; Biomarkers/cerebrospinal fluid ; Female ; Aged ; *Amyloid beta-Peptides/cerebrospinal fluid ; Positron-Emission Tomography ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/diagnosis/physiopathology ; Magnetoencephalography ; tau Proteins/cerebrospinal fluid ; *Brain/diagnostic imaging/physiopathology/metabolism ; Amyloid Precursor Protein Secretases/cerebrospinal fluid ; Aspartic Acid Endopeptidases/cerebrospinal fluid ; Benzothiazoles ; Aged, 80 and over ; Aniline Compounds ; Middle Aged ; Neuropsychological Tests ; },
abstract = {BACKGROUND: In Alzheimer's disease (AD), amyloid-beta (Aß) pathology induces neuronal hyperactivity when cognition is still normal. Although this effect on a macroscale is difficult to detect non-invasively and accurately in patients, alterations in brain activity can be detected using magnetoencephalography (MEG) in preclinical AD. Here, we tested the hypothesis that proteins involved in amyloid metabolism and synaptic integrity contribute to changes in brain activity in preclinical AD.

METHOD: This study included 120 cognitively normal (CN) older individuals who underwent cognitive testing, resting-state MEG, a lumbar puncture to obtain cerebrospinal fluid (CSF) and a [[18]F]flutemetamol PET scan to determine Aß (+/-) status. MEG spectral relative power was calculated globally and regionally (hippocampus, precuneus and orbital gyrus) in the canonical frequency bands, as was peak frequency. AD-related proteins involved in amyloid metabolism and synaptic integrity were measured in CSF, including Aß38, BACE1, neurogranin and total tau. Linear regression models were employed to investigate associations between spectral power and protein concentrations. Interaction effects were calculated to test the dependance of these associations on Aß status.

RESULT: Overall, we observed that higher protein levels were linked to acceleration of oscillatory activity (Figure 1). Higher BACE1 concentrations were associated with lower global and regional theta power and higher regional alpha2 power, higher t-tau levels were associated with lower hippocampal delta power and higher Aß38 levels were related to higher peak frequency in the precuneus. Finally, we observed that the relationship between protein levels and delta power in the hippocampus depended on Aß status, as was the case for the delta, theta and beta power in the orbital gyrus, suggesting that in Aß+ individuals higher protein levels were associated with oscillatory slowing (Figure 2).

CONCLUSION: Our findings indicate that proteins involved in amyloid metabolism and synaptic integrity are associated with acceleration in global and regional oscillatory power in CN adults. This profile might already shift from acceleration in oscillatory activity in Aß- individuals to slowing of activity, well-established in later-stage AD, in Aß+ individuals. Our results offer novel insights into the relationship between pathology and brain activity and provide new support for brain activity as an early biomarker.},
}

Humans
Male
Biomarkers/cerebrospinal fluid
Female
Aged
*Amyloid beta-Peptides/cerebrospinal fluid
Positron-Emission Tomography
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/diagnosis/physiopathology
Magnetoencephalography
tau Proteins/cerebrospinal fluid
*Brain/diagnostic imaging/physiopathology/metabolism
Amyloid Precursor Protein Secretases/cerebrospinal fluid
Aspartic Acid Endopeptidases/cerebrospinal fluid
Benzothiazoles
Aged, 80 and over
Aniline Compounds
Middle Aged
Neuropsychological Tests

@article {pmid41499950,
year = {2025},
author = {Aftab, K and Montagnese, M and Rittman, T},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105988},
doi = {10.1002/alz70856_105988},
pmid = {41499950},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/diagnostic imaging/pathology ; Biomarkers ; Magnetic Resonance Imaging ; *Lewy Body Disease/diagnostic imaging/pathology ; Aged ; *Gray Matter/diagnostic imaging/pathology ; White Matter/diagnostic imaging/pathology ; *Brain/diagnostic imaging/pathology ; Neuroimaging ; Fractals ; Aged, 80 and over ; },
abstract = {BACKGROUND: Fractal dimension (FD) is a measure of cortical complexity which is altered in ageing and other neurodegenerative disorders. It can serve as a useful structural marker to detect neurodegenerative changes in Dementia with Lewy bodies (DLB). We assessed the regional and whole brain fractal dimension indices in DLB in comparison to healthy controls and Alzheimer's disease (AD).

METHOD: We included T1 weighted MRI scans of 87 DLB, 88 AD and 100 age- and gender-matched healthy controls from the National Alzheimer's Coordinating Center (NACC), Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD), Multimodal Imaging in Lewy Body Disorders (MILOS) and AMyloid imaging for Phenotyping LEwy body dementia (AMPLE) datasets. We segmented the cortical gray matter and white matter using Freesurfer version 7.3.4 and computed FD from the freesurfer outputs using the fractalbrain toolkit. Statistical analysis was performed using the R statistical package to explore group-wise differences using MANOVA and Kruskal-Wallis tests. The significance level was set at false-discovery rate (FDR) corrected p < 0.05.

RESULT: Cortical gray matter FD was significantly reduced globally as well as in bilateral frontal, temporal, parietal and occipital lobes in DLB compared to healthy controls. Moreover, FD was significantly lower in the cerebral white matter. Cortical gray matter FD was also reduced in AD compared to DLB globally and in bilateral parietal and left temporal lobes regionally. Cortical gray matter FD correlated with Addenbrooke's Cognitive Examination - Revised (ACE-R) total scores and mean cortical thickness.

CONCLUSION: Cortical complexity is reduced in the gray and white matter in DLB and can also be used to differentiate DLB from AD patients. Correlation with cognition and other structural markers may help in understanding disease-specific structural changes.},
}

Humans
Female
Male
*Alzheimer Disease/diagnostic imaging/pathology
Biomarkers
Magnetic Resonance Imaging
*Lewy Body Disease/diagnostic imaging/pathology
Aged
*Gray Matter/diagnostic imaging/pathology
White Matter/diagnostic imaging/pathology
*Brain/diagnostic imaging/pathology
Neuroimaging
Fractals
Aged, 80 and over

@article {pmid41499949,
year = {2025},
author = {Blujdea, ER and Hok-A-Hin, YS and Trares, K and Del Campo, M and Teunissen, CE and Vermunt, L},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105820},
doi = {10.1002/alz70856_105820},
pmid = {41499949},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/blood/diagnosis ; Proteomics/methods ; *Lewy Body Disease/cerebrospinal fluid/blood ; Dementia/cerebrospinal fluid ; },
abstract = {BACKGROUND: A comprehensive analysis of proximity-extension assay (PEA) proteomic studies have led to the development and validation of novel cerebrospinal fluid (CSF) biomarker panels for Alzheimer's disease (AD; Del Campo et al., 2022 Nat Aging) and dementia with Lewy bodies (DLB; Del Campo et al., 2023 Nat Comm.). However, to what extent the markers are dementia- and matrix- (CSF or plasma) specific is largely unknown. To establish the clinical context for these novel markers, data from PEA proteomic studies in CSF and plasma will be collected and meta-analyzed across neurological disorders.

METHODS: A systematic review following PRISMA-guidelines is being conducted to collect relevant CSF and plasma PEA studies. For six CSF and plasma studies with readily available data in dementia and movement disorders, Cohen's d effect sizes were calculated for seven proteins identified as AD-specific (ABL1, ITGB2, ENO2, SMOC2, and THOP1) or DLB-specific (DDC and CRH) - measuring the mean difference between disease and control groups. A random-effects meta-analysis model was applied within the same disorders and plotted, Figure 1.

RESULTS: Analysis showed that for all seven proteins, when comparing effect sizes between CSF and plasma, the direction of change is opposite. This suggests that these markers may only be useful in CSF, and in plasma may even associate with other disorders; as THOP1 seems to be most increased in prodromal PD, Figure 1. Within-disease analysis revealed variability mainly in preclinical AD, for ABL1, ITGB2, and THOP1, and prodromal PD for DDC, supporting the biological heterogeneity of these groups. Additionally, DDC and CRH in CSF are distinctly dysregulated for Parkinson's-plus syndromes (PD, DLB, PSP, CBS) highlighting the overlapping biological mechanisms.

CONCLUSIONS: Our meta-analysis across multiple cohorts is expanding to include around 150 studies in dementias, movement disorders and in psychiatric conditions. The framework of analysis established in this study provides a foundation for future expansion of the database in various neurological disorders, such as psychiatric disorders, and to other proteomic platforms. These findings may contribute to the development of more accurate diagnostic tools and offer insights into the complex interplay of protein markers in neurodegenerative diseases.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/cerebrospinal fluid/blood/diagnosis
Proteomics/methods
*Lewy Body Disease/cerebrospinal fluid/blood
Dementia/cerebrospinal fluid

@article {pmid41499862,
year = {2025},
author = {Nadais, A and Castro, C and Martins, I and Trigo, D and Nunes, C and Henriques, AG and de Lourdes Pereira, M and da Cruz E Silva, OAB},
title = {Nanoparticle-mediated Zn delivery impacts neural protein phosphatase activity.},
journal = {Biomaterials advances},
volume = {182},
number = {},
pages = {214675},
doi = {10.1016/j.bioadv.2025.214675},
pmid = {41499862},
issn = {2772-9508},
abstract = {In recent years, the use of nanoparticles (NPs) in diagnosis and treatment of different disorders has been a matter of intensive research. Due to their physical and chemical properties, zinc oxide nanoparticles (ZnO NP) have been explored in a range of biological applications, including cancer and neurological diseases. Regarding the latter, while some studies report protective effects of ZnO NP in cultured cells and animal models, others indicate that these NPs have a harmful impact on the brain, such as promoting oxidative stress and cell death. Previous results from our group have suggested beneficial effects for zinc (Zn) cations in both modulating protein aggregation and on Alzheimer's disease (AD) pathology. In this context, the effect of encapsulated Zn as a nanoparticle on protein aggregation and its influence on protein phosphorylation events associated with AD were explored. The results herein presented show that ZnO NP contributed to a decrease in protein aggregation in neuronal cells. However, these NPs were also found to decrease PP1 and PP2A activity, potentially contributing to increased phosphorylation of tau and APP, which are AD pathology hallmarks. In conclusion, while the use of NPs as a Zn delivery system may offer benefits by reducing aggregate formation, they also appear to induce undesired molecular changes, like those observed in AD. Therefore, a holistic approach should be incorporated as we move forward in this research line, as their effects on distinct cellular processes may be dual edged.},
}

@article {pmid41499812,
year = {2025},
author = {Lewandowski, D and Konieczny, M and Poszwa, J and Florczak-Wyspianska, J and Owecki, W and Szymanowicz, O and Drużdż, A and Kozubski, W and Dorszewska, J},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104825},
doi = {10.1002/alz70856_104825},
pmid = {41499812},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/genetics/blood ; *Growth Differentiation Factor 15/blood/genetics ; *Adaptor Proteins, Signal Transducing/genetics ; *Tumor Suppressor Proteins/genetics ; Aged ; Biomarkers/blood ; *Apolipoproteins E/genetics ; *Nuclear Proteins/genetics ; Genotype ; Aged, 80 and over ; Middle Aged ; Polymorphism, Single Nucleotide ; },
abstract = {BACKGROUND: Currently, Alzheimer's disease (AD) risk genetic variants include among others APOE and BIN1. APOE possesses 3 alleles: protective (ε2), neutral (ε3), and pathogenic (ε4). APOE gene is present in amyloid plaques and binds to Aβ peptides. BIN1 gene is involved in the regulation of apoptosis and immune response. Growth and differentiation factor 15 (GDF15) is an inflammation-associated hormone and, with diseases with inflammatory etiologies. GDF15 was shown to be associated with incident dementia including AD. Moreover, GDF15 is thought to be important in predicting dementia in both the long and short term. Individuals with higher levels of GDF15 are more likely to develop dementia. The role of GDF15 is poorly defined METHOD: The aim of the study was to analyze the APOE and BIN1 genetic variants and GDF15 protein concentration in AD patients and related (CR), and unrelated (CU) controls with AD. The studies were conducted on 29 patients with AD. The control group included 25 CR and 27 CU. The APOE genotype was determined by real-time PCR. The BIN1 genotypes were determined by HRM and sequencing. GDF15 levels were analyzed by the ELISA method.

RESULT: The study showed statistically significantly higher levels of GDF15 in CU compared to CR (p = 0.048) and similar levels in CR and AD. In CU carriers of APOE ε3ε3 and ε3ε4 (p = 0.0946) alleles trend towards higher GDF15 levels were demonstrated as compared with CR and AD. At the same time, CU with the BIN1 CC genotype showed statistically significantly lower GDF15 levels compared to AD with BIN1 CC (p = 0.050). The highest GDF15 levels were shown in individuals with the BIN1 TT genotype, both CR and AD. In contrast to CU in CR and AD, only in APOE ε3ε3 individuals, the GDF15 protein level was 2-3 times higher than the average score in the analyzed group.

CONCLUSION: GDF15 appears to be more strongly involved in the development of dementia with immune regulatory factors (BIN1 TT genotype).},
}

Humans
Male
Female
*Alzheimer Disease/genetics/blood
*Growth Differentiation Factor 15/blood/genetics
*Adaptor Proteins, Signal Transducing/genetics
*Tumor Suppressor Proteins/genetics
Aged
Biomarkers/blood
*Apolipoproteins E/genetics
*Nuclear Proteins/genetics
Genotype
Aged, 80 and over
Middle Aged
Polymorphism, Single Nucleotide

@article {pmid41499811,
year = {2025},
author = {Chiotis, K and Blazhenets, G and Schonhaut, DR and Lagarde, J and Soleimani-Meigooni, DN and Maiti, P and Zhang, J and Shankar, R and Amuiri, A and Rocha, S and Hammers, DB and Eloyan, A and Koeppe, RA and Carrillo, MC and Dickerson, B and Apostolova, LG and Joie, R and Rabinovici, GD and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104867},
doi = {10.1002/alz70856_104867},
pmid = {41499811},
issn = {1552-5279},
mesh = {Humans ; Positron-Emission Tomography ; Female ; Male ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aged ; *tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Longitudinal Studies ; Carbolines ; Middle Aged ; *Brain/diagnostic imaging/metabolism ; Aged, 80 and over ; Cognitive Dysfunction/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: We aimed to assess differences in baseline and longitudinal tau PET tracer binding between early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) in the LEADS and ADNI cohorts, respectively.

METHOD: We analyzed amyloid-beta PET-positive, cognitively impaired participants from the LEADS (EOAD; n = 383) and ADNI (LOAD; n = 196) cohorts with available [18]F-Flortaucipir tau PET data (Table 1). A subset had longitudinal [18]F-Flortaucipir PET data from LEADS (n = 232) and ADNI (n = 94) with average follow-up intervals of 1.95 and 2.44 years, respectively. All [18]F-Flortaucipir PET scans were processed using the CenTauR pipeline. Cognitively normal participants from LEADS (n = 94) and ADNI (n = 421) with baseline [18]F-Flortaucipir and amyloid-beta PET scans were also analyzed for comparison. We performed EOAD vs. LOAD comparisons using multivariate linear and linear mixed-effects models for cross-sectional and longitudinal analyses, respectively.

RESULT: Baseline comparisons revealed large effect-size, significant differences in [18]F-Flortaucipir binding between EOAD and LOAD (Figure 1). EOAD participants had higher [18]F-Flortaucipir levels in widespread neocortical regions compared to LOAD, after adjusting for covariates. In both groups, tau load was negatively associated with age. In EOAD, a significantly steeper slope was found in the association between amyloid-beta and [18]F-Flortaucipir load, as well as between cognitive scores and [18]F-Flortaucipir load. Longitudinally, EOAD participants exhibited a faster increase in [18]F-Flortaucipir binding than LOAD, predominantly in frontal and occipital areas (Figure 2), with both groups showing an inverse linear relationship between [18]F-Flortaucipir accumulation rates and age.

CONCLUSION: EOAD patients demonstrate significantly higher tau loads, broader neuroanatomical involvement and faster tau accumulation over time compared to LOAD, independent of disease stage. These findings suggest that earlier age-of-onset in AD is linked to a more aggressive tauopathy. The early, extensive tau spread in symptomatic EOAD, even at an early clinical stage, may also limit the efficacy of anti-amyloid-beta therapies in this population.},
}

Humans
Positron-Emission Tomography
Female
Male
*Alzheimer Disease/diagnostic imaging/metabolism
Aged
*tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Biomarkers/metabolism
Longitudinal Studies
Carbolines
Middle Aged
*Brain/diagnostic imaging/metabolism
Aged, 80 and over
Cognitive Dysfunction/diagnostic imaging/metabolism

@article {pmid41499810,
year = {2025},
author = {Cai, Y and Yang, J and Liang, L and Fang, L and Zhou, X and Li, A and Liu, L and Sun, P and He, Z and Zhu, Y and Wang, Y and Li, M and Ma, T and Han, Y and Guo, T},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104870},
doi = {10.1002/alz70856_104870},
pmid = {41499810},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; Male ; Female ; Magnetic Resonance Imaging ; *tau Proteins/metabolism ; Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; Aged ; *White Matter/diagnostic imaging/pathology/metabolism ; Positron-Emission Tomography ; *Brain/diagnostic imaging/pathology/metabolism ; },
abstract = {BACKGROUND: White matter hyperintensities (WMH) often co-exist with β-amyloid (Aβ) and tau tangles in Alzheimer's disease (AD). However, the association of WMH, Aβ plaques, and tau tangles in AD remains elusive. Using two large datasets, this study comprehensively examined the relationship between regional WMH and longitudinal tau accumulation in AD.

METHOD: A total of 951 participants from the ADNI and A4 cohorts with Aβ-PET, fluid-attenuated inversion recovery images (FLAIR), and tau-PET data were included, with Resting-state functional MRI (RS-fMRI) available for a subset of participants. FLAIR images were segmented using a U-Net deep learning model to obtain regional WMH volumes. Tau propagation along connectivity patterns was assessed using connectivity-associated tau spread metrics derived for the whole cortex and specific cortical regions (βGlobal, βFrontal, βParietal, βTemporal, and βOccipital). We examined the associations between regional WMH, tau accumulation, and connectivity-associated tau spread. Additionally, two cortical tau subtypes were identified: "Occipital > Parietal" and "Parietal > Occipital", characterized by higher or lower occipital tau relative to parietal tau, and the impact of regional WMH on tau accumulation was assessed within these subtypes.

RESULT: Aβ+ individuals showed higher baseline levels and faster increases in total WMH compared to Aβ- individuals, but no differences were observed between T+ and T- individuals. Among Aβ+ individuals, temporal meta-ROI tau was not associated with faster WMH increases. However, greater total WMH was linked to accelerated temporal meta-ROI tau accumulation (Figure 1), although this relationship did not persist after controlling for Aβ. Greater occipital WMH was associated with faster tau accumulation in occipital regions, particularly the cuneus, and with increasing βOccipital, independent of Aβ (Figure 2). The "Parietal > Occipital" subtype exhibited more rapid tau progression than the "Occipital > Parietal" subtype. In contrast, higher WMH was linked to faster tau increases in the cuneus exclusively within the latter subtype (Figure 3).

CONCLUSION: Greater WMH burden, particularly in the occipital lobe, is associated with faster tau accumulation and spread in posterior cortical regions, independent of Aβ. These findings provide novel insights into understanding how vascular damages reflected by WMH contribute to cortical tau aggregation in the posterior cortical region of AD.},
}

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

@article {pmid41499807,
year = {2025},
author = {Hazelton, JL and Migeot, J and Gonzalez-Gomez, R and Altschuler, F and Duran-Aniotz, C and Wen, O and Rial, DSG and Barttfeld, P and Medel, V and Campo, CG and Laguardia, AMC and Hernandez, H and Gonzalez-Silva, C and Castaner, O and Hu, K and Li, P and Behrens, MI and Bruno, MA and Cardona, J and Custodio, N and Santamaria-Garcia, H and Garcia, AM and Godoy, ME and Funes, JAÁ and Maito, MA and Matallana, DL and Miller, BL and Lopera, F and de Oliveira, MO and Pina-Escudero, S and Possin, KL and de Paula França Resende, E and Reyes, PA and Slachevsky, A and Sosa, AL and Takada, LT and Yokoyama, JS and Ibanez, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104821},
doi = {10.1002/alz70856_104821},
pmid = {41499807},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/physiopathology/diagnostic imaging/pathology ; Aged ; Biomarkers ; *Frontotemporal Lobar Degeneration/physiopathology/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Middle Aged ; *Brain/pathology/physiopathology/diagnostic imaging ; Risk Factors ; *Cardiovascular Diseases ; Gray Matter/diagnostic imaging/pathology ; Heart Disease Risk Factors ; },
abstract = {BACKGROUND: Cardiovascular risk factors, such diabetes, hypertension, blood pressure, obesity, and smoking, are linked with allostatic-interoception - the continuous monitoring of internal bodily states in anticipation of environmental demands. These risk factors are associated with dementia risk. How these factors affect brain networks vulnerable to neurodegeneration and involved in allostatic-interoception, such as the Allostatic-Interoceptive Network (AIN), is unknown. We investigated the relationship between cardiovascular risk and AIN structure and function in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).

METHOD: We recruited 1501 participants (304 with FTLD, 512 with AD, and 685 healthy controls) from the Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat)(Figure 1). A cardiovascular risk score was calculated based on: age, sex, diabetes, hypertension, systolic blood pressure, body mass index, and smoking status. Cardiovascular risk was associated with gray matter integrity and functional connectivity in age- and sex-matched patient-control groups focusing on predefined regions of interest within the AIN.

RESULT: Higher cardiovascular risk was associated with reduced structural integrity and functional connectivity within the AIN in both FTLD and AD. In FTLD patients, extensive structural (Figure 2) and functional connectivity disruptions (Figure 3) were observed throughout the AIN. In AD patients, structural reductions in the AIN were prominent (Figure 2), with functional connectivity restricted to the hippocampus, parahippocampal gyrus, and orbitofrontal regions (Figure 3).

CONCLUSION: Cardiovascular risk factors appear to adversely impact the AIN structure and function, with disease-specific patterns of vulnerability. Our results underscore the importance of integrating cardiovascular health into models of neurodegenerative disease and managing cardiovascular health to support brain integrity in dementia. Future work is needed to uncover longitudinal effects of cardiovascular risk in dementia and to determine if cardiovascular risk factors exacerbate neurodegenerative processes.},
}

Humans
Male
Female
*Alzheimer Disease/physiopathology/diagnostic imaging/pathology
Aged
Biomarkers
*Frontotemporal Lobar Degeneration/physiopathology/diagnostic imaging/pathology
Magnetic Resonance Imaging
Middle Aged
*Brain/pathology/physiopathology/diagnostic imaging
Risk Factors
*Cardiovascular Diseases
Gray Matter/diagnostic imaging/pathology
Heart Disease Risk Factors

@article {pmid41499797,
year = {2025},
author = {Grigoli, MM and Pachane, BC and Fuzer, AM and de Oliveira, SD and Targas, ABA and Alexandre-Silva, V and Selistre-de-Araujo, HS and Manzine, PR and Cominetti, MR},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105542},
doi = {10.1002/alz70856_105542},
pmid = {41499797},
issn = {1552-5279},
mesh = {Humans ; Tretinoin/pharmacology ; Cell Line, Tumor ; *Cell Differentiation/drug effects/physiology ; Laminin/pharmacology ; Biomarkers/metabolism ; *Neurons/drug effects/metabolism ; Acetylcholinesterase/metabolism ; Neuroblastoma/pathology ; Tubulin/metabolism ; Neurites ; Extracellular Matrix/metabolism ; },
abstract = {BACKGROUND: The SH-SY5Y neuroblastoma cell line is a valuable in vitro model for studying neuronal differentiation and neurodegenerative diseases like Alzheimer's disease (AD). Traditional differentiation protocols mainly use retinoic acid (RA); however, they lack extracellular matrix (ECM) components that are critical for mechanotransduction and cellular adhesion, which limits their physiological relevance. Laminins, a key ECM glycoprotein, play an essential role in neurite outgrowth and synaptic formation, indicating their potential to enhance neuronal differentiation.

METHOD: SH-SY5Y cells were cultured in DMEM/F12 supplemented with fetal bovine serum (FBS) and essential additives. Differentiation was induced using RA (10 µM and 25 µM) and a laminin-rich ECM (LrECM). Plates were pre-coated with Matrigel® (a laminin-rich ECM) before seeding the cells. Differentiation efficiency was monitored over 10 days through light microscopy, immunofluorescence for neuronal markers (NeuN and β3-tubulin), and acetylcholinesterase (AChE) activity assays. Western blotting assessed β3-tubulin expression, and neurite lengths were quantified using FIJI software.

RESULT: The combined RA and LrECM treatment significantly enhanced SH-SY5Y differentiation when compared to RA alone. Neuronal morphology, marked by extensive neurite outgrowth, became evident as early as day 4 and was sustained for up to 10 days. Immunofluorescence confirmed increased NeuN expression, showing a shift from cytoplasmic to perinuclear localization over time. β3-tubulin levels remained consistently high in LrECM-treated cells, unlike those treated with RA alone, which demonstrated a decline after day 7. Enhanced cholinergic differentiation was indicated by elevated AChE activity, particularly at 25 µM RA, although higher RA concentrations were unable to sustain neuronal characteristics and raised concerns about cytotoxicity.

CONCLUSION: The incorporation of LrECM into SH-SY5Y differentiation protocols significantly enhances neuronal differentiation and maintains neuron-like characteristics, providing a more physiologically relevant in vitro model for studying AD and other neurodegenerative diseases. This approach enables cost-effective, rapid differentiation and more accurately mimics the brain microenvironment, establishing a strong platform for neurobiological research and therapeutic screening.},
}

Humans
Tretinoin/pharmacology
Cell Line, Tumor
*Cell Differentiation/drug effects/physiology
Laminin/pharmacology
Biomarkers/metabolism
*Neurons/drug effects/metabolism
Acetylcholinesterase/metabolism
Neuroblastoma/pathology
Tubulin/metabolism
Neurites
Extracellular Matrix/metabolism

@article {pmid41499788,
year = {2025},
author = {Zhou, J and Wearn, A and Huck, J and Hughes, CS and Baracchini, G and Sylvain, E and Tremblay-Mercier, J and Poirier, J and Breitner, JCSCS and Villeneuve, S and Chakravarty, MM and Tardif, CL and Gauthier, CJ and Daugherty, AM and Turner, GR and Spreng, RN and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105845},
doi = {10.1002/alz70856_105845},
pmid = {41499788},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Biomarkers/blood/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology ; *Hippocampus/metabolism/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; *Iron/metabolism ; *tau Proteins/blood ; Apolipoprotein E4/genetics ; Longitudinal Studies ; *Memory, Episodic ; Brain/metabolism ; Middle Aged ; },
abstract = {BACKGROUND: Elevated brain iron deposition is recognized as a characteristic of normal aging and neurodegenerative diseases, particularly Alzheimer's disease (AD), where it correlated with amyloid-β plaques and neurofibrillary tangles. Our study aimed to investigate the relationship between longitudinal changes in hippocampal iron deposition and episodic memory, and how this relationship is impacted by AD pathology and APOE4 allele carriership.

METHOD: We measured longitudinal changes in brain iron levels using quantitative susceptibility mapping (QSM)-MRI (see Figure 1), in a cohort of old adults at risk of AD (N =143, 102 females, 41 males; mean age = 67.7 ± 5.0 years; longitudinal duration = 2.7 ± 0.4 years). Cognition was assessed using the RBANS. Plasma was collected from all participants at a single time point (Time 2, T2) and p-tau181 measured using in-house single-molecule arrays. We examined the relationship between iron accumulation and memory, the mediating effect of plasma p-tau181. We also investigated how APOE4 status moderates the relationship between iron deposition and plasma p-tau181.

RESULT: Hippocampal iron levels demonstrated a significant increase over time (t(142)=2.45, Cohen's d=0.21, p = 0.016). Changes in iron levels were significantly negatively correlated with memory performance (β=-0.223, p = 0.009, Figure 2A), and positively associated with plasma p-tau181 (β=0.217, p = 0.011, Figure 2B). Plasma p-tau181 were also negatively associated memory (β=-0.207, p = 0.015, Figure 2C). Furthermore, p-tau181 mediated the relationship between hippocampal iron increases and memory performance, accounted for 16.2% of the total association (β = -0.034, p = 0.045, CI: -0.09 to -0.004, Figure 2D). APOE4 status moderated the impact of increased hippocampal iron on plasma p-tau181 levels (β =0.431, p = 0.021, CI: 0.06 to 0.8, Figure 3).

CONCLUSION: These findings underscore the unique effect of hippocampal iron accumulation on cognition, which is additionally impacted by AD pathology. Further, we find a novel association in APOE4 carriers, wherein increases in iron interact with AD pathology, which highlights the need for early detection and intervention strategies tailored to APOE4 carriers. This work deepens our understanding of the interplay among iron dysregulation, tau pathology, and APOE4, offering a promising avenue for precision-based approaches to AD risk assessment and therapeutic development.},
}

Humans
Male
Female
Aged
Biomarkers/blood/metabolism
*Alzheimer Disease/genetics/metabolism/pathology
*Hippocampus/metabolism/diagnostic imaging/pathology
Magnetic Resonance Imaging
*Iron/metabolism
*tau Proteins/blood
Apolipoprotein E4/genetics
Longitudinal Studies
*Memory, Episodic
Brain/metabolism
Middle Aged

@article {pmid41499783,
year = {2025},
author = {Ding, H and Serrano, X and Karjadi, C and Young, CB and Mormino, EC and Sunderaraman, P and Gurnani, AS and Au, R and Gifford, KA},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104922},
doi = {10.1002/alz70856_104922},
pmid = {41499783},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers ; Middle Aged ; Positron-Emission Tomography ; *Alzheimer Disease/diagnosis/diagnostic imaging/metabolism ; Amyloid beta-Peptides/metabolism ; Neuropsychological Tests ; Aged ; *Voice/physiology ; },
abstract = {BACKGROUND: Interest in acoustic voice features as digital biomarkers of underlying Alzheimer's disease (AD) has been increasing. However, lacking confirmation of AD specificity and reference values or normative information, particularly in relation to AD-specific biomarkers, greatly limits the ability to determine measurement thresholds that are clinically meaningful. We present preliminary normative values of acoustic voice features for those who are positron emission tomography (PET) beta amyloid positive (Aß+) and negative (Aß-).

METHOD: This study included 268 cognitively unimpaired participants (mean age 57.2 ± 9.9 years; 50.4% female) from the Framingham Heart Study Brain Aging Program who had voice recordings of neuropsychological assessment obtained within one year before amyloid PET imaging. Sixty-five acoustic features (i.e., prosodic, spectral, and sound quality voice features) were extracted from recordings during the Wechsler Memory Scale Logical Memory Delayed recall tests using open-source Speech and Music Interpretation by Large-space Extraction (OpenSMILE). Reference values were established at the 2.5th, 25th, 50th, 75th, and 97.5th percentiles for each acoustic feature within the entire sample, amyloid-positive (Aß+) and amyloid-negative (Aß-) groups. Differences between the Aß+ and Aß- groups were evaluated using Mann-Whitney U tests.

RESULT: Of the 268 participants, 30 (11%) were Aß+. Reference values for all 65 acoustic features were established across all percentile thresholds within the whole sample, the Aß+ and Aß- groups (see Table). Four acoustic features differed between the Aß+ and Aß- groups: voicingFinalUnclipped (P = 0.03), pcm_fftMag_spectralKurtosis (P = 0.04), MFCC[5] (P = 0.02), and MFCC[10] (P = 0.03). Three of them have higher median values in Aß+ group. As a sound quality measure, VoicingFinalUnclipped indicates the voicing probability of the final fundamental frequency candidate without zero-clipping. The pcm_fftMag_spectralKurtosis represents magnitude of spectral kurtosis. MFCCs reflect the power spectrum of a sound and are mathematical representations of essential human speech characteristics.

CONCLUSION: These results suggest acoustic features may be an effective marker for preclinical AD screening of older adults who are Aß+. Future studies should stratify based on biomarker status to refine reference values and expand doing so with more diverse populations.},
}

Humans
Female
Male
*Biomarkers
Middle Aged
Positron-Emission Tomography
*Alzheimer Disease/diagnosis/diagnostic imaging/metabolism
Amyloid beta-Peptides/metabolism
Neuropsychological Tests
Aged
*Voice/physiology

@article {pmid41499782,
year = {2025},
author = {Paranhos, T and Katsumi, Y and Brickhouse, M and Eckbo, R and Zaitsev, A and Du, A and Eloyan, A and Joie, R and Nudelman, KN and Foroud, TM and Dage, JL and Carrillo, MC and Rabinovici, GD and Apostolova, LG and Dickerson, BC and Touroutoglou, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105039},
doi = {10.1002/alz70856_105039},
pmid = {41499782},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/pathology/diagnostic imaging ; Disease Progression ; *Alzheimer Disease/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Aged ; Atrophy/pathology ; Biomarkers ; Prognosis ; *Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Prognostic risk stratification for patients at the mild cognitive impairment (MCI) stage of early-onset Alzheimer's disease (EOAD) would allow professionals and loved ones to make better-informed medical and life planning decisions. While research including our own (Bakkour, Morris, Dickerson, 2009) has demonstrated the prognostic value of MRI-based measures of brain structure in late-onset amnestic AD, its utility for predicting progression to dementia in EOAD remains unclear. Here, we measured the magnitude of cortical atrophy within our recently described EOAD signature regions (Touroutoglou et al. 2023) in patients with EOAD at the MCI stage (N = 130) recruited in LEADS. The main goal of the study was to evaluate the utility of this measure as a predictor of time to subsequent progression to dementia. Our second goal was to examine the independent or synergistic contributions of EOAD signature of atrophy and standard clinical severity measures used in clinical trials.

METHOD: For each patient, we measured the time between baseline visit and subsequent visit at which progression to mild dementia was documented or last observation. Baseline cortical atrophy was measured as W-scores (i.e., Z-scores adjusted for age and sex relative to a sample of healthy controls) in the EOAD signature. Baseline clinical severity was quantified with the Clinical Dementia Rating Sum-of-Boxes scores (CDR-SB). Simple and multivariable Cox regression models examined the relationship between atrophy in EOAD signature, baseline CDR-SB, and the likelihood of progression to dementia.

RESULT: Greater baseline atrophy in the EOAD signature predicted higher risk of progression to dementia (hazard ratio = 1.2, 95% CI 1.1-1.3) and provided additive value to the CDR-SB (hazard ratio: 2.1, 95% CI:1.7-2.8) in predicting progression.

CONCLUSION: These findings point to the role of EOAD MRI signature as an imaging biomarker to guide prognostication for patients with EOAD and their families and to inform the design of clinical trials.},
}

Humans
Male
Female
*Cognitive Dysfunction/pathology/diagnostic imaging
Disease Progression
*Alzheimer Disease/pathology/diagnostic imaging
Magnetic Resonance Imaging
Aged
Atrophy/pathology
Biomarkers
Prognosis
*Brain/pathology/diagnostic imaging
Neuropsychological Tests
Aged, 80 and over
Middle Aged

@article {pmid41499762,
year = {2025},
author = {de Bruin, H and Groot, C and , and Barthel, H and Bischof, GN and Blazhenets, G and Boellaard, R and Boon, BDC and Brendel, M and Cash, DM and Coath, W and Day, GS and Dickerson, BC and Doering, E and Drzezga, A and van Dyck, CH and van Eimeren, T and van der Flier, WM and Fredericks, CA and Fryer, TD and van de Giessen, E and Gordon, BA and Radford, JG and Grinberg, LT and Hansson, O and Hobbs, DA and Höglinger, GU and Hönig, MC and Irwin, DJ and Jones, PS and Josephs, KA and Katsumi, Y and Joie, R and Lee, EB and Levin, J and Malpetti, M and McGinnis, SM and Mecca, AP and Mohanty, R and Nasrallah, IM and O'Brien, JT and O'Dell, RS and Palleis, C and Perneczky, R and Phillips, JS and Putcha, D and Rabinovici, GD and Rahmouni, N and Rosa-Neto, P and Rowe, JB and Rullmann, M and Sabri, O and Saur, D and Schildan, A and Schott, JM and Schroeter, ML and Seeley, WW and Servaes, S and Sintini, I and Smith, R and Spina, S and Stevenson, J and Stomrud, E and Strandberg, O and Therriault, J and Tideman, P and Touroutoglou, A and Trainer, AE and Visser, D and Wekselman, F and Weston, PS and Whitwell, JL and Wolk, DA and Yong, KXX and Pijnenburg, YAL and Franzmeier, N and Ossenkoppele, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104871},
doi = {10.1002/alz70856_104871},
pmid = {41499762},
issn = {1552-5279},
mesh = {Humans ; Positron-Emission Tomography ; *tau Proteins/metabolism ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; Aged ; Biomarkers/metabolism ; *Brain/diagnostic imaging/pathology/metabolism ; Middle Aged ; Disease Progression ; Aged, 80 and over ; Longitudinal Studies ; Atrophy/pathology ; },
abstract = {BACKGROUND: The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non-amnestic-predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression.

METHOD: We included tau-PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD) from 14 sites, with a subset of patients (n = 78) having longitudinal tau-PET data. As an independent sample, we further included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modeling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology, and 2) functional connectivity of tau-PET epicenters and tau-PET accumulation epicenters was associated with cross-sectional and longitudinal tau patterns.

RESULT: Tau-PET epicenters-defined as the 5% brain regions with the highest tau load-aligned with clinical variants, e.g. a posterior pattern in PCA-AD ("visual AD") and left-hemispheric temporal predominance in lvPPA-AD ("language AD") (Figure 1). More strongly functionally connected regions showed correlated concurrent tau-PET levels, which was confirmed with post-mortem data (Figure 2). Moreover, the connectivity profile of tau-PET epicenters and accumulation epicenters corresponded to tau-PET progression patterns (Figure 3).

CONCLUSION: Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific endpoints in clinical trials.},
}

Humans
Positron-Emission Tomography
*tau Proteins/metabolism
Male
Female
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
Aged
Biomarkers/metabolism
*Brain/diagnostic imaging/pathology/metabolism
Middle Aged
Disease Progression
Aged, 80 and over
Longitudinal Studies
Atrophy/pathology

@article {pmid41499730,
year = {2025},
author = {Molfetta, GD and Brum, WS and Benedet, A and Rahmouni, N and Stevenson, J and Pola, I and Montoliu-Gaya, L and Blennow, K and Zetterberg, H and Rosa-Neto, P and Ashton, NJ},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106338},
doi = {10.1002/alz70856_106338},
pmid = {41499730},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *tau Proteins/blood ; *Biomarkers/blood ; Aged ; *Alzheimer Disease/blood/diagnosis/diagnostic imaging/pathology ; Amyloid beta-Peptides/blood ; Positron-Emission Tomography ; Middle Aged ; Phosphorylation ; Cohort Studies ; Aged, 80 and over ; },
abstract = {BACKGROUND: Recent anti-amyloid trial designs for Alzheimer's disease (AD) have aimed to identify amyloid-β (Aβ)-positive patients without an advanced tau pathology, as they are most likely to benefit from these therapies. Blood-based biomarkers might reduce the need to use cerebrospinal fluid (CSF) or positron emission tomography (PET) but it is unclear whether phosphorylated tau-217 (pTau217) alone would be effective to exclude this high-tau group at screening. We investigated whether a blood-based protein panel, including pTau217, could better distinguish early from late-stage tau pathology in Aβ-positive patients compared to pTau217 alone.

METHOD: Aβ-positive participants from the TRIAD cohort (n = 129; mean [SD] age, 70.4 [8.3] years; females [58.9%]) were classified as BraakLate (Braak V-VI: n = 51) or BraakEarly (Braak I-IV: n = 78) by tau PET imaging([18F]MK6240). We employed the NULISAseq CNS Panel to quantify 120 CNS-related proteins. A bootstrapped (1000x) LASSO regression was used to identify the most recurringly selected proteins for distinguishing BraakLate from BraakEarly. Generalized linear models (GLM) for the multi-analyte panel and pTau217, adjusted for age and sex, were used and their performance evaluated by ROC analyses and Akaike Information Criterion (AIC) scores. GLMs were also used to estimate probability scores for each patient for belonging to BraakLate.

RESULT: The bootstrapped LASSO regression retained pTau217, neuropentraxin receptor (NPTXR), vascular growth factor (VGF) and growth-derived neurotrophic factor (GDNF) in >75% of the iterations. ROC analysis demonstrated that the multi-analyte panel (AUC=0.93: 95% CI 0.89-0.98) had a significantly better prediction of BraakLate than pTau217 alone (AUC= 0.88; 95% CI 0.88-0.94; P[DeLong]= 0.004). The fit of the model was also assessed by comparing AIC, where the multi-analyte panel showed a reduction in the score to detect the Braak category, suggesting a better model fit. This was further supported by an ANOVA comparison between the two models, where the multi-analyte model was significantly better than pTau217 alone (P[ANOVA] < 0.001).

CONCLUSION: We identified three complementary proteins (NPTXR, GDNF, VGF) to pTau217 that can improve its ability in detect later Braak stages in Aβ-positive patients. This suggests an immunoassay-based panel might be a cost-effective tool to exclude participants with high tau pathology in anti-amyloid trials designs.},
}

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

@article {pmid41499714,
year = {2025},
author = {Jacob, C and Tollenaere, M and Fransen, E and De Deyn, PP and Van Dam, D and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104824},
doi = {10.1002/alz70856_104824},
pmid = {41499714},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/diagnosis/blood ; Male ; Female ; *Down Syndrome/blood/complications ; Middle Aged ; tau Proteins/blood ; Cohort Studies ; Adult ; },
abstract = {BACKGROUND: By age 40, virtually all individuals with Down Syndrome (DS) will have developed the pathological symptoms of Alzheimer's Disease (AD) (McCarron, McCallion et al. 2017), making it the genetic leading cause of AD worldwide. Our lab developed a specialized behavior-based scale to aid in the diagnosis of AD in DS, the BPSD-DSII (Dekker, Ulgiati et al. 2021). Individuals with DS with or without (questionable) AD (total = 157) were tested with the BPSD-DSII, and subsequently, we also performed immune-based assays (Simoa) to further characterize blood biomarkers in this cohort. Three years after the original BPSD-DSII was administered in this cohort, the individuals were, again, categorized in percentiles based on the BPSD-DSII behavior frequency changes. The outcome of the different sections of the BPSD-DSII at baseline and the levels of several blood-based biomarkers at baseline were put in a statistical prediction model based on linear regression.

METHOD: Linear regression prediction model coded in R with R studio RESULT: The outcome of several sections of the BPSD-DSII questionnaire, as well as pTau181 levels and GFAP levels, were predictive of percentiles indicating AD in DS.

CONCLUSION: Specific behavioral changes at baseline such as in apathetic behavior, depressive behavior, and eating and drinking behavior, as well as pTau181 and GFAP levels were predictive for the development of AD in DS.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/diagnosis/blood
Male
Female
*Down Syndrome/blood/complications
Middle Aged
tau Proteins/blood
Cohort Studies
Adult

@article {pmid41499710,
year = {2025},
author = {He, B and Ospina, P and Espinosa, A and Becerra-Mateus, JC and Osorio, L and Alzate, D and Alvarez, S and Grazia, A and Teipel, S and Malotaux, V and Tristão-Pereira, C and Rowe, M and Giudicessi, A and Carmo, SD and Niño, DFA and Cuello, AC and Quiroz, YT},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105027},
doi = {10.1002/alz70856_105027},
pmid = {41499710},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/genetics/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Biomarkers ; Adult ; *Cognitive Dysfunction/genetics/pathology ; Middle Aged ; Presenilin-1/genetics ; Neuropsychological Tests ; *Basal Forebrain/pathology/diagnostic imaging ; Disease Progression ; Mutation/genetics ; Colombia ; },
abstract = {BACKGROUND: The basal forebrain (BF), home to cholinergic neurons essential for attention and memory undergoes structural changes in sporadic Alzheimer's Disease and in at-risk individuals, contributing to cognitive decline. To investigate whether BF volume is reduced in preclinical autosomal-dominant Alzheimer's disease (ADAD), we studied cognitively-unimpaired carriers of the PSEN1 E280A mutation from the Colombian kindred, the largest ADAD cohort with a single mutation, known for early cognitive decline (mild cognitive impairment at age 44, dementia at 49). Age was used as a proxy for disease progression to analyze BF volume and its relationship with age and cognitive performance.

METHOD: This study included 127 cognitively-unimpaired individuals from the PSEN1 Colombian kindred (60 carriers, 67 non-carriers; mean-age: 30.67 ± 6.65 years; mean-education: 12.24 ± 3.06 years). Unimpaired status was defined by Functional Assessment Staging (FAST) scores <2. Participants underwent structural MRI and cognitive testing, with BF volumes measured using a cholinergic nuclei map. Cognition was assessed with the Mini-Mental State Examination (MMSE) and the CERAD Word List Learning (WLL) task. BF volume differences between groups were assessed using a t-test, and partial Pearson correlations (adjusted for sex, education, and intracranial volume) were used to evaluate relationships between BF volume, age, and cognition.

RESULT: BF volumes did not differ significantly between carriers (693.83 ± 68.3 mm3) and non-carriers (694.00 ± 65.24 mm3) (p =  0.82). Age was negatively correlated with BF volume in the overall sample (r = -0.41, p =  2.7e-06), carriers (r = -0.41, p =  0.001), and non-carriers (r = -0.44, p =  2.6e-04). However, BF volume showed no significant correlation with MMSE or WLL in the overall sample, carriers, or non-carriers.

CONCLUSION: These findings suggest that Alzheimer's-related volumetric changes in the basal forebrain may not manifest during the early preclinical stages of ADAD. This highlights the importance of future studies incorporating longitudinal measures to track BF changes over time, spanning the continuum from preclinical to clinical stages. Such research could provide critical insights into the temporal dynamics of BF involvement and its potential as a marker for early detection or therapeutic target in ADAD.},
}

Humans
Male
Female
*Alzheimer Disease/genetics/pathology/diagnostic imaging
Magnetic Resonance Imaging
Biomarkers
Adult
*Cognitive Dysfunction/genetics/pathology
Middle Aged
Presenilin-1/genetics
Neuropsychological Tests
*Basal Forebrain/pathology/diagnostic imaging
Disease Progression
Mutation/genetics
Colombia

@article {pmid41499694,
year = {2025},
author = {Barboure, MC and Verberk, IMW and Vigneswaran, S and Barkhof, F and van de Giessen, E and Biessels, GJ and Teunissen, CE and van der Flier, WM and van Harten, AC},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104832},
doi = {10.1002/alz70856_104832},
pmid = {41499694},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; Cross-Sectional Studies ; *Cognitive Dysfunction/blood/diagnosis ; *Alzheimer Disease/blood/diagnosis ; Aged ; *Neurofilament Proteins/blood ; *Dementia, Vascular/blood/diagnosis ; Middle Aged ; Cohort Studies ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {BACKGROUND: Plasma neurofilament light (NfL) is increasingly used as a general marker for neurodegeneration in memory clinics to aid differential diagnosis. However, interpreting its levels in the presence of vascular pathology remains unclear. We investigated the individual and combined effects of Alzheimer's and vascular pathologies on plasma NfL in individuals across the cognitive spectrum.

METHOD: Cross-sectional data from 1099 individuals in the Amsterdam Dementia Cohort were analyzed, including participants with a clinical diagnosis of subjective cognitive decline (SCD, n = 371), mild cognitive impairment (MCI, n = 326), Alzheimer's disease (AD, n = 347), and vascular dementia (VaD, n = 55). NfL was measured using SIMOA (Quanterix) and log-transformed. Amyloid pathology was defined by positive CSF/PET biomarkers. Vascular pathology was defined as having a small vessel disease (SVD) score ≥1 (range 0-3), with one point given for each feature present: white matter hyperintensities (Fazekas score ≥2), microbleeds (≥1), and/or lacunes (≥1). Participants were classified by vascular (V) and amyloid (A) status: A-V- (n = 293), A-V+ (n = 173), A+V- (n = 325), A+V+ (n = 308). Group differences were calculated using Kruskal-Wallis with Bonferroni correction. Multivariate regression analyses investigated the effects of amyloid and vascular pathology on NfL levels, adjusting for age, sex, and syndrome diagnosis.

RESULT: NfL levels increased stepwise from A-V- to A+V+ groups, suggesting an additive effect of amyloid and vascular pathologies (Figure 1). Subsequent regression analysis revealed SVD score as a significant predictor of NfL levels, while amyloid status was not (Model 1 and 2, Table 1). An interaction term revealed that amyloid status moderated the effect of SVD score on NfL levels (Model 3). Stratified analysis showed higher baseline NfL levels in amyloid-positive individuals, with SVD score remaining a significant predictor in both groups. While included as a covariate, dementia diagnosis emerged as a strong determinant of NfL levels, particularly in amyloid-negative individuals (Figure 2). SVD score explained more variance in amyloid-negative (40%) than amyloid-positive (21%) individuals.

CONCLUSION: Vascular burden influences NfL levels, particularly in amyloid-negative individuals. These results underscore the importance of considering multiple pathologies when interpreting NfL as a neurodegeneration biomarker in memory clinic settings.},
}

Humans
*Biomarkers/blood
Male
Female
Cross-Sectional Studies
*Cognitive Dysfunction/blood/diagnosis
*Alzheimer Disease/blood/diagnosis
Aged
*Neurofilament Proteins/blood
*Dementia, Vascular/blood/diagnosis
Middle Aged
Cohort Studies
Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over

@article {pmid41499690,
year = {2025},
author = {Adrien, TV and Sivaramakrishnan, K and Morancy, L and Perez-Lao, A and Arias, F and Asken, BM and Velez-Uribe, I and Rosselli, M and Armstrong, MJ and Curiel, RE and Loewenstein, DA and Duara, R and Smith, GE and Levy, SA},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105329},
doi = {10.1002/alz70856_105329},
pmid = {41499690},
issn = {1552-5279},
mesh = {Humans ; Male ; *Biomarkers/blood ; Female ; Aged ; tau Proteins/blood ; *Alzheimer Disease/blood ; *Diabetes Mellitus, Type 2/blood ; Glial Fibrillary Acidic Protein/blood ; *Blood Pressure/physiology ; Aged, 80 and over ; Neurofilament Proteins/blood ; *Cognitive Dysfunction/blood ; },
abstract = {BACKGROUND: Vascular risk factors contribute to Alzheimer's disease (AD) dementia, but their interaction with AD pathology remains unclear. This study examined systolic blood pressure (SYSBP) and Type 2 Diabetes (T2D) as moderators of the relationship between plasma biomarkers and cognitive and functional impairment in older adults.

METHOD: Data from 479 participants (Table 1.) in the 1Florida Alzheimer's Disease Research Center were analyzed. SYSBP and T2D were assessed, and plasma biomarkers included GFAP, NFL, Ptau181, and Ptau217. Linear regressions and post-hoc simple slopes analyses examined whether SYSBP and T2D moderated biomarker associations with impairment, measured by the Clinical Dementia Rating Scale-Sum of Boxes, controlling for age, sex, education, and APOE status.

RESULT: See table 2. In brief, a significant positive interaction was found between GFAP and SYSBP on impairment (b = 0.074, p = .046), with GFAP significantly predicting impairment at all SYSBP levels (low b = 0.109, average b = 0.180, high b =0.250, p <.001) and a stronger association as SYSBP increased. In contrast, a significant negative interaction was observed between PTau217 and SYSBP (b = -0.091, p = .007), where PTau217 was significantly associated with impairment at all SYSBP levels but with a weakening effect as SYSBP increased (low b = 0.391, average b = 0.302, high b = 0.213, p <.001). For T2D, a significant positive interaction was found between GFAP and T2D (b = 0.308, p = .033), with GFAP predicting impairment in both groups but showing a stronger effect in T2D. A significant negative interaction was observed between NFL and T2D (b = -0.410, p = .044), where NFL predicted impairment in both groups, though the association was weaker in T2D.

CONCLUSION: These findings highlight vascular health as a key modifier of neurodegeneration and inflammation related impairment. The stronger GFAP-impairment relationship at higher SYSBP and in T2D suggests astrocyte activation may drive decline more in individuals with vascular or metabolic comorbidities. In contrast, the weaker effects of PTau217 at high SYSBP and NFL in T2D suggest alternative mechanisms such as hyperperfusion and glycemic dysregulation. Future research should incorporate longitudinal designs, neuroimaging, and refined vascular risk assessments to clarify these relationships.},
}

Humans
Male
*Biomarkers/blood
Female
Aged
tau Proteins/blood
*Alzheimer Disease/blood
*Diabetes Mellitus, Type 2/blood
Glial Fibrillary Acidic Protein/blood
*Blood Pressure/physiology
Aged, 80 and over
Neurofilament Proteins/blood
*Cognitive Dysfunction/blood

@article {pmid41499680,
year = {2025},
author = {Li, Y and Khandelwal, P and Xie, L and Wisse, LEM and Mundada, NS and Brown, CA and McGrew, E and Denning, AE and Das, SR and Wolk, DA and Yushkevich, PA},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105240},
doi = {10.1002/alz70856_105240},
pmid = {41499680},
issn = {1552-5279},
mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Alzheimer Disease/diagnostic imaging/pathology ; Biomarkers ; Male ; Female ; Aged ; *Hippocampus/diagnostic imaging/pathology ; *Temporal Lobe/diagnostic imaging/pathology ; Image Processing, Computer-Assisted/methods ; Cognitive Dysfunction/diagnostic imaging ; Middle Aged ; Anisotropy ; },
abstract = {BACKGROUND: Morphometry of medial temporal lobe (MTL) subregions in brain MRI is sensitive biomarker to Alzheimer's Disease and other related conditions. While T2-weighted (T2w) MRI with high in-plane resolution is widely used to segment hippocampal subfields due to its higher contrast in hippocampus, its lower out-of-plane resolution reduces the accuracy of subregion thickness measurements. To address this issue, we developed a nearly isotropic segmentation pipeline that incorporates image and label upsampling and high-resolution segmentation in T2w MRI.

METHOD: First, a high-resolution atlas was created based on an existing anisotropic atlas derived from 29 individuals. Both T1-weighted and T2w images in the atlas were upsampled from their original resolution to a nearly isotropic resolution using a non-local means approach. Manual segmentations within the atlas were also upsampled to match this resolution using a UNet-based neural network, which was trained on a cohort consisting of both high-resolution ex vivo and low-resolution anisotropic in vivo MRI with manual segmentations (Figure 1a). Second, a multi-modality deep learning-based segmentation model was trained within this nearly isotropic atlas (Figure 1b). This method was evaluated on independent sets, including cross-sectional (N = 196) and longitudinal (N = 31) MRI scans, which were used for the group difference analysis (Amyloid+ mild cognitive impairment (A+MCI) vs. Amyloid- cognitively normal (A-CN)) and longitudinal consistency analysis, respectively (Figure 1c).

RESULT: Table 1(a) displays the group differences of cross-sectional median thickness between A+MCI and A-CN with age as covariate. The T2w segmentation in isotropic space achieved larger effect sizes in the predicted direction (A+MCI < A-CN) and outperformed T2w anisotropic segmentation over most subregions. Table 1(b) shows the consistency analysis of longitudinal median thickness. When measured as the sum of absolute median thickness differences, the consistency of isotropic T2w segmentation outperformed that of anisotropic T2w segmentation over most subregions. Figure 2 shows the visualization of the segmentation and point-wise group difference analysis at different resolutions, with isotropic T2w segmentation demonstrating a smoother surface and larger effect sizes than anisotropic T2w segmentation.

CONCLUSION: Nearly isotropic subregion segmentation improved the accuracy of cortical thickness as an imaging biomarker for neurodegeneration in T2w MRI.},
}

Humans
*Magnetic Resonance Imaging/methods
*Alzheimer Disease/diagnostic imaging/pathology
Biomarkers
Male
Female
Aged
*Hippocampus/diagnostic imaging/pathology
*Temporal Lobe/diagnostic imaging/pathology
Image Processing, Computer-Assisted/methods
Cognitive Dysfunction/diagnostic imaging
Middle Aged
Anisotropy

@article {pmid41499670,
year = {2025},
author = {Cai, H and Wang, R and Li, L and Huang, K and Gao, H and Yang, F and Feng, S and Qin, L and Yang, X and Wang, S and Liao, Q and Liu, Y and Zhou, D and He, J and Zhou, L and Tian, R and Hu, N and Chen, Q},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105376},
doi = {10.1002/alz70856_105376},
pmid = {41499670},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Positron-Emission Tomography ; Aged ; *Hydrocephalus, Normal Pressure/diagnostic imaging/metabolism/pathology ; Biomarkers/metabolism ; *Amyloid beta-Peptides/metabolism ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Middle Aged ; *Brain/diagnostic imaging/metabolism/pathology ; Prospective Studies ; *Glymphatic System/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) often co-occurs with beta-amyloid deposition, both of which share a common pathophysiology involving glymphatic dysfunction. This study aimed to investigate the clinical impact of beta-amyloid co-pathology and the effects of glymphatic dysfunction on beta-amyloid deposition in patients with iNPH.

METHODS: Patients diagnosed with probable iNPH (n = 60; 28 with A+, positive amyloid PET; 32 with A-, negative amyloid PET) and Alzheimer's disease (AD) (n = 30, A+T+N+) were enrolled from prospective cohorts at the West China Hospital of Sichuan University. All participants underwent neuropsychological tests, magnetic resonance imaging and [18]F-AV45 PET. The choroid plexus volume/estimated total intracranial volume (CPV/eTIV) and [18]F-AV45 PET standard uptake value ratio (SUVR) were calculated based on automatic segmentation to evaluate the glymphatic function and amyloid burden. ANOVA and Kruskal-Wallis test were used for group comparison between iNPH with positive amyloid PET and other groups, and Bonferroni correction was used for post-hoc analysis. Multivariate generalized linear models were constructed to analyze the association between CPV/eTIV and [18]F-AV45 PET SUVR in patients with iNPH and AD.

RESULT: Patients with iNPH A+ exhibited the highest CPV/eTIV compared to the patients with iNPH A- (p = 0.006). Patients with iNPH A+ showed lower MMSE score compared to iNPH A- (PBon=0.013) and AD (PBon=0.039), while no significant difference was found between iNPH A- and AD. In iNPH patients, higher CPV/eTIV were associated with higher [18]F-AV45 PET SUVR in temporal (p = 0.007), parietal (p = 0.002), and occipital lobes (p = 0.004); however, no association was observed in patients with AD in these regions.

CONCLUSION: Our study demonstrated that beta-amyloid co-pathology may exacerbate the cognitive symptoms of iNPH. Moreover, glymphatic dysfunction might play a distinct role in promoting beta-amyloid deposition in iNPH compared to Alzheimer's disease.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Positron-Emission Tomography
Aged
*Hydrocephalus, Normal Pressure/diagnostic imaging/metabolism/pathology
Biomarkers/metabolism
*Amyloid beta-Peptides/metabolism
Magnetic Resonance Imaging
Neuropsychological Tests
Middle Aged
*Brain/diagnostic imaging/metabolism/pathology
Prospective Studies
*Glymphatic System/diagnostic imaging/metabolism

@article {pmid41499669,
year = {2025},
author = {Soldan, A and Na, CH and Zhu, Y and Pettigrew, C and Moghekar, A and Erus, G and Davatzikos, C and Albert, MSS and Worley, PF and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105326},
doi = {10.1002/alz70856_105326},
pmid = {41499669},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Biomarkers/cerebrospinal fluid ; Middle Aged ; *Cognitive Dysfunction/cerebrospinal fluid/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Aged ; *Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging ; Disease Progression ; Brain/pathology/diagnostic imaging ; Atrophy/pathology ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND: More abnormal cerebrospinal fluid (CSF) levels of amyloid and tau among cognitively unimpaired individuals are associated with higher risk of mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD). However, the predictive accuracy of these markers alone is limited. This study examined whether novel synaptic markers and neural signaling proteins are associated with time to onset of MCI symptoms and with long-term neurodegeneration, based on MRI, after accounting for traditional CSF AD biomarker levels.

METHOD: CSF was collected from 268 cognitively unimpaired BIOCARD Study participants (mean baseline age = 57.7 years; mean follow-up = 16.3 years; n = 77 progressed to MCI/dementia; see Table 1). Levels of eight peptides involved in neuronal signaling were measured, using quantitative parallel reaction monitoring mass spectrometry: CNTFR, GFRA3, VGF, ACHE, NCAM1, DPP6, GPC1, and CARTPT. Levels of Aβ42/Aβ40 and p-tau181 were measured from the same CSF specimens using Lumipulse assays. Atrophy on volumetric MRI scans was quantified from 213 participants as two composites: (1) AD signature regions (SPARE-AD) and (2) regions indexing brain aging (SPARE-BA). All analyses covaried age, sex, years of education, and APOE-e4 status.

RESULTS: In Cox regression models, after accounting for covariates and baseline AD biomarker levels, higher baseline levels of both neurosecretory protein VGF and dipeptidyl peptidase-like protein 6 (DPP6) were associated with a lower risk of MCI symptom onset (both p <0.04, see Table 2. In mixed effect models, higher levels of VGF and DPP6 were also associated with less atrophy over time in AD-signature regions (see Table 3), and higher VGF was associated with less age-related atrophy. Interestingly, when AD biomarker levels were not accounted for, none of the signaling proteins were associated with MCI symptom onset or MRI atrophy.

CONCLUSION: These findings suggest that among cognitively unimpaired individuals, higher levels of the synaptic proteins VGF and DPP6 may slow the onset of the symptomatic phase of AD as well as longitudinal atrophy in AD-vulnerable regions, independently of AD pathology levels. These findings support the view that VGF and DPP6 may be resilience factors against neurodegeneration and cognitive decline and represent fruitful targets for novel therapeutics.},
}

Humans
Male
Female
*Biomarkers/cerebrospinal fluid
Middle Aged
*Cognitive Dysfunction/cerebrospinal fluid/pathology/diagnostic imaging
Magnetic Resonance Imaging
Amyloid beta-Peptides/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Aged
*Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging
Disease Progression
Brain/pathology/diagnostic imaging
Atrophy/pathology
Peptide Fragments/cerebrospinal fluid

@article {pmid41499663,
year = {2025},
author = {Shekari, M and Escalante, AG and López-Martos, D and Milà-Alomà, M and Sánchez-Benavides, G and Brugulat-Serrat, A and Niñerola-Baizán, A and Falcon, C and Ashton, NJ and Karikari, T and Rodriguez, JL and Snellman, A and Day, TA and Dage, JL and Ortiz-Romero, P and Tonietto, M and Klein, G and Kollmorgen, G and Quijano-Rubio, C and Vanmechelen, E and Minguillón, C and Fauria, K and Perissinotti, A and Molinuevo, JL and Zetterberg, H and Blennow, K and Salvadó, G and Grau-Rivera, O and Vállez-Garcia, D and Suárez-Calvet, M and Gispert, JD and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106562},
doi = {10.1002/alz70856_106562},
pmid = {41499663},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/cerebrospinal fluid/blood ; Male ; *Biomarkers/cerebrospinal fluid/blood ; Female ; Positron-Emission Tomography ; Aged ; *Alzheimer Disease/diagnostic imaging/cerebrospinal fluid ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/cerebrospinal fluid ; Plaque, Amyloid/diagnostic imaging ; Middle Aged ; Longitudinal Studies ; Disease Progression ; Brain/diagnostic imaging/metabolism ; Aniline Compounds ; Cohort Studies ; },
abstract = {BACKGROUND: The relationship between longitudinal tau-PET trajectories and fluid tau biomarkers in early Braak stages is crucial for understanding Alzheimer's disease (AD) progression and identifying predictive biomarkers for early diagnosis and intervention. This study examines how baseline plasma and cerebrospinal fluid (CSF) tau biomarkers, amyloid plaques, and cognitive performance interact with longitudinal tau-PET trajectories in cognitively unimpaired (CU) individuals.

METHOD: Forty-six CU individuals from ALFA+ cohort were included, each with two [18F]RO-948 tau-PET scans (∆t=2.31±0.34 years), two T1-weighted MRIs, and baseline [18F]flutemetamol amyloid-PET (Figure 1). Baseline fluid tau biomarkers, measured using RocheNTK, RocheElecsys, Simoa, and Lilly assays, as well as memory, were also available. [18F]RO-948 uptake was measured in entorhinal (BraakI/II), limbic (BraakIII/IV), and neocortical (BraakV/VI) regions and normalized to the inferior cerebellum to render SUVR. Amyloid-PET was quantified using Centiloid. Tau-PET stage transitions from baseline to follow-up assessed using predefined positivity thresholds. Linear mixed-effects models evaluated associations between baseline biomarkers, Centiloid, memory, and tau-PET SUVR over time, adjusting for age, sex, APOE-ε4, and time intervals.

RESULT: Three participants (6.52%) were positive for BraakI/II at both baseline and follow-up (Stable-Positive), two (4.34%) transitioned to positive (Progressors), while the majority (41, 89.13%) remained negative (Stable-Negative) (Figure 1). Interaction between baseline predictors and time was not statistically significant for any predictive variables (Table 2). However, higher plasma ptau181 and ptau217 levels were significantly associated with higher baseline BraakI/II SUVR, while only plasma ptau181 showed a significant association with baseline BraakIII/IV. For CSF, higher ptau217 and ptau181/Aβ42 ratio were significantly associated with higher baseline tau-PET SUVR in both BraakI/II and BraakIII/IV (Table 1 & Figure 2). Additionally, Centiloid was positively associated with tau-PET SUVR in BraakI/II but not in other regions. Lower baseline memory scores were significantly associated with higher tau-PET SUVR in BraakI/II and BraakIII/IV in baseline.

CONCLUSION: Our findings support the potential of plasma and CSF tau biomarkers as early indicators of Alzheimer's pathology in cognitively unimpaired individuals. The negative association between memory and tau-PET SUVR suggests subtle cognitive differences may reflect underlying tau accumulation. However, no significant longitudinal effects were observed, likely due to the limited sample size or short follow-up.},
}

Humans
*tau Proteins/cerebrospinal fluid/blood
Male
*Biomarkers/cerebrospinal fluid/blood
Female
Positron-Emission Tomography
Aged
*Alzheimer Disease/diagnostic imaging/cerebrospinal fluid
Magnetic Resonance Imaging
Amyloid beta-Peptides/cerebrospinal fluid
Plaque, Amyloid/diagnostic imaging
Middle Aged
Longitudinal Studies
Disease Progression
Brain/diagnostic imaging/metabolism
Aniline Compounds
Cohort Studies

@article {pmid41499563,
year = {2025},
author = {González-Mayoral, A and Gonzalez-Ortiz, F and Victorino, DB and Potier, MC and Blennow, K and Villain, N},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104853},
doi = {10.1002/alz70856_104853},
pmid = {41499563},
issn = {1552-5279},
mesh = {*tau Proteins/metabolism/blood/genetics ; Animals ; Humans ; *Alzheimer Disease/diagnosis/blood/metabolism ; *Biomarkers/blood ; Mice, Transgenic ; Mice ; Enzyme-Linked Immunosorbent Assay ; Disease Models, Animal ; Brain/metabolism ; Phosphorylation ; Reproducibility of Results ; Immunoassay/methods ; },
abstract = {BACKGROUND: The measurement of phosphorylated tau (pTau) in biofluids, particularly at position 217 (pTau217), has proven to be a valuable diagnostic and prognostic marker in Alzheimer's disease (AD). However, due to tau variability across species existing immunoassays optimized for human lack compatibility with mouse models, posing a challenge for studying these markers in preclinical research. Single Molecule Array (Simoa) technology offers unparalleled sensitivity and precision, making it an ideal platform for developing novel assays to address these challenges.

METHODS: Human and mouse tau isoforms were analyzed via sequence alignment to identify conserved regions suitable for cross-species antibody targeting. Western blot (WB) and Enzyme-Linked Immuno Sorbent Assay (ELISA) experiments evaluated cross-reactivity of human tau antibodies with mouse tau on brain extracts. A novel pTau217 immunoassay was developed and validated on the Simoa platform with plasma samples from three distinct mouse models containing either endogenous or transgenic human tau (APP23, P301S and WT) and human plasma samples for cross-species validation. Optimization for sensitivity, specificity, and reproducibility included different antibodies concentration tests, limit of quantification, and buffer adjustments to diminish plasma matrix interference.

RESULTS: The sequence alignment, WB and ELISA analyses guided the selection of antibodies targeting conserved epitopes, ensuring cross-species applicability. The novel pTau217 immunoassay, based on Simoa technology, demonstrated good performance in detecting pTau in brain extracts and plasma across all three mouse models containing endogenous mouse tau and transgenic human tau. It also proved to detect human plasma pTau217. The assay exhibited high sensitivity, achieving reliable detection of pTau even in plasma samples with low abundant protein concentrations and matrix interference effect, and showed robust specificity to pTau217.

CONCLUSIONS: We present the validation of the first Simoa-based pTau217 immunoassay designed to measure p-tau across species (mouse and human), whether in plasma samples with genuine mouse tau sequence or transgenic human tau sequence. Further development will focus on linearity tests and correlation with neuropathologic changes. Our findings have broad implications for biomarkers research and help bridge the gap between human and animal studies in AD research.},
}

*tau Proteins/metabolism/blood/genetics
Animals
Humans
*Alzheimer Disease/diagnosis/blood/metabolism
*Biomarkers/blood
Mice, Transgenic
Mice
Enzyme-Linked Immunosorbent Assay
Disease Models, Animal
Brain/metabolism
Phosphorylation
Reproducibility of Results
Immunoassay/methods

@article {pmid41499558,
year = {2025},
author = {Ioannou, K and Perrin, RJ and Abdullaieva, K and Bluma, M and Poulakis, K and Leuzy, A and Religa, D and Rodriguez-Vieitez, E and Chiotis, K},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104812},
doi = {10.1002/alz70856_104812},
pmid = {41499558},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; *Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging ; *tau Proteins/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; alpha-Synuclein/cerebrospinal fluid ; Positron-Emission Tomography ; *Cognitive Dysfunction/cerebrospinal fluid/pathology ; Aged, 80 and over ; Autopsy ; Brain/pathology ; },
abstract = {BACKGROUND: This study leverages biomarker and autopsy data with the aim to evaluate the impact of mixed pathologies on interpreting cognitive impairment within the Αβ and tau (AT) biomarker system.

METHOD: Individuals with at least one instance of antemortem CSF AD biomarkers measurement (Roche, Elecsys ®) and a full postmortem assessment were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Previously validated cut-offs were used to define A+ (Aβ42 ≤ 981 pg/mL) and T+ (p-tau181 ≥ 24.3 pg/mL). Aβ PET burden was quantified in-house using the Centiloid pipeline. AT groups were compared with respect to cognitive performance, CSF α-synuclein positivity (Amprion, SYNTap ®), Aβ PET burden, clinical comorbidities, and neuropathological evidence of proteinopathies associated with cognitive impairment or vascular brain injury (VBI). Mixed AD was defined as the copresence of Alzheimer's disease neuropathologic change (ADNC) and at least another non-AD proteinopathy at autopsy.

RESULT: We identified and grouped 77 individuals by AT status (median [IQR] interval from CSF sampling to death = 3.13 [1.45, 5.69] years). Both A+T- and A+T+ groups were more severely cognitively impaired than the A-T- group at CSF sampling (Table 1). The A+T- and A+T+ groups had similar demographics, frequency of CSF α-synuclein positivity, Aβ PET burden and frequency of clinical comorbidities. The two A+ groups showed differences in APOE ε4 frequency (79% in A+T+ vs. 22% in A+T-, p-value < 0.001) (Table 1). The A+T+ group showed a higher frequency of ADNC (100% vs. 78%, p-value = 0.008) than the A+T- group. When ADNC was present, the A+T- group exhibited a higher frequency of mixed AD (79% vs. 28%, p-value = 0.002) than the A+T+ group, even when taking VBI into consideration (Figure 1).

CONCLUSION: Cognitive impairment associated with Aβ positivity and low tau (A+T-) is linked to mixed AD. These cases deviate from the expected disease path, as proposed by the most recent criteria (Jack CR Jr, et al. Alzheimers Dement. 2024) (Figure 2), and highlight the need for specific biomarkers for non-AD proteinopathies.},
}

Humans
*Biomarkers/cerebrospinal fluid
Male
Female
*Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging
*tau Proteins/cerebrospinal fluid
*Amyloid beta-Peptides/cerebrospinal fluid
Aged
alpha-Synuclein/cerebrospinal fluid
Positron-Emission Tomography
*Cognitive Dysfunction/cerebrospinal fluid/pathology
Aged, 80 and over
Autopsy
Brain/pathology

@article {pmid41499557,
year = {2025},
author = {Svaldi, DO and Iaccarino, L and Higgins, IA and Kotari, V and Franzmeier, N and Ewers, M and Shcherbinin, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104873},
doi = {10.1002/alz70856_104873},
pmid = {41499557},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism ; *tau Proteins/metabolism ; *Biomarkers/metabolism ; Male ; Positron-Emission Tomography ; Female ; Aged ; *Brain/diagnostic imaging/metabolism ; Disease Progression ; Carbolines ; },
abstract = {BACKGROUND: This study compares approaches for defining target regions in their ability to consistently capture tau progression relative to anatomical composites used in Alzheimer's disease trials.

METHOD: Paired, baseline and 18-month regional flortaucipir data were included from TRAILBLAZER-ALZ2 (NCT04437511, Low/Medium/High Tau) and TRAILBLAZER-ALZ (NCT03367403, Low/Medium Tau) placebo participants. Regional SUVRs were combined into four composite regions according to individual- versus group-level and anatomical- versus data-driven approaches. Composites were defined and ranked according to hypothetical longitudinal spatial gradients based on descending mean regional SUVR (Q1→Q4). Anatomical composites were defined by lobes, whereas data-driven composites (quartiles) were defined by either baseline SUVR or functional connectivity (FC) to the highest baseline SUVR quartile. Group-level methodologies used mean regional SUVRs across participants, whereas individual-level used single participant regional SUVRs. Finally, the minimum positive composite (lowest SUVR>2 standard deviations (SD) above amyloid-negative cohort mean) was considered a target region. Longitudinal signal-to-noise (SNR) for each composite (mean/SD of change) and mean SNR across composites were compared to group lobar composites (reference method, Figure 1A). Homogeneity between individual-level spatial gradients and across trial-level spatial gradients were evaluated for methods showing similar/superior SNR to reference.

RESULT: Group-level, data driven approaches exhibited lower mean SNR across composites relative to the reference (Figure 1). Individualized methods exhibited similar/higher mean SNR (Figure 1). Data-driven individualized methods also exhibited significantly increased spatial homogeneity (p < 0.05 Mann Kendall test) between participants (Figure 2) and visually across trials (Figure 2) versus the reference. Minimum positive composites exhibited superior SNR relative to Q1-Q4 across individualized and anatomical methodologies (Figure 1C). Spatial gradients were similar between SUVR-based and FC-based methodologies (Figures 1-2).

CONCLUSION: Participant specific target regions may improve consistency in longitudinal tau PET analyses. For each participant, focusing on regions that have recently reached positivity may improve SNR. The similarity between SUVR-based and FC-based methods continues to suggest connectivity between regions is a significant mechanism contributing to tau spread. Additional analyses to support results summarized here as well as analyses testing these methodologies on asymptomatic individuals from A4 may also be presented.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism
*tau Proteins/metabolism
*Biomarkers/metabolism
Male
Positron-Emission Tomography
Female
Aged
*Brain/diagnostic imaging/metabolism
Disease Progression
Carbolines

@article {pmid41499518,
year = {2025},
author = {Bertazzoli, G and Passera, B and Ozdemir, R and Buss, SS and Shafi, M and Fried, PJ},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105060},
doi = {10.1002/alz70856_105060},
pmid = {41499518},
issn = {1552-5279},
mesh = {Humans ; *Amyloid beta-Peptides/blood ; Female ; Male ; Biomarkers/blood ; Aged ; Transcranial Magnetic Stimulation ; Middle Aged ; *Alzheimer Disease/blood/diagnosis/physiopathology ; Aged, 80 and over ; *Peptide Fragments/blood ; Magnetic Resonance Imaging ; Long-Term Potentiation/physiology ; *Motor Cortex/physiopathology ; Neuronal Plasticity/physiology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by early amyloid-beta (Aβ) accumulation, which can precede clinical symptoms by years. Plasma Aβ42/Aβ40 oligomers have emerged as a surrogate biomarker for brain amyloid, providing a non-invasive method to identify individuals at high risk. Cortical excitability and long-term potentiation (LTP)-like plasticity, assessed via transcranial magnetic stimulation (TMS), are impaired in early symptomatic stages of AD. Aβ disrupts normal glutamatergic activity, increasing cortical excitability and reducing LTP-like plasticity. This study tests the hypothesis that cortical excitability and plasticity are associated with plasma Aβ42/Aβ40 levels in cognitively unimpaired individuals to develop neurophysiological markers for early Aβ-related dysfunction.

METHODS: Plasma Aβ42/Aβ40 levels were obtained in 58 cognitively normal adults (32 women, aged 58-89). MRI-guided TMS assessments from the left motor cortex were performed in a subset. We used the Aβ42/Aβ40 cutoff of <0.1, based on Rissman et al. (2024; doi: 10.1002/alz.13542), to classify participants at high risk for brain amyloid. Cortical excitability was measured by resting motor threshold (RMT) and corticomotor recruitment slope (change in MEP amplitude between 120% and 135% RMT). LTP-like plasticity was assessed by changes in excitability post-intermittent theta-burst stimulation (iTBS). Group differences were tested using non-parametric Wilcoxon tests (α=0.05).

RESULTS: Data are reported in mean ± standard deviation. Of the 58 participants, 50% were classified as high Aβ risk (Figure 1A). The high-risk group showed a lower RMT (70.0 ±12.5) than the low-risk group (78.5 ±14.4), p = 0.039 (Figure 1B). The corticomotor recruitment slope was also greater in the high-risk group (85.8 ±55.6) vs. low-risk (50.0 ±52.3), p = 0.014 (Figure 1C). Both groups exhibited decreased MEP amplitude following iTBS, but the decrease was smaller in the high-risk group (-2.3 ±39.8%) vs. low-risk (-28.9 ±23.8%), p = 0.017 (Figure 1D).

CONCLUSIONS: In cognitively unimpaired elderly, a higher risk of brain Aβ is associated with altered cortical excitability and plasticity, similar to changes in symptomatic AD. TMS may provide early markers of amyloid-associated neurophysiological dysfunction.},
}

Humans
*Amyloid beta-Peptides/blood
Female
Male
Biomarkers/blood
Aged
Transcranial Magnetic Stimulation
Middle Aged
*Alzheimer Disease/blood/diagnosis/physiopathology
Aged, 80 and over
*Peptide Fragments/blood
Magnetic Resonance Imaging
Long-Term Potentiation/physiology
*Motor Cortex/physiopathology
Neuronal Plasticity/physiology

@article {pmid41499485,
year = {2025},
author = {Hoffmeister, GL and Limberger, C and Martins, GC and Schmaedek, MR and de Souza, RB and De Bastiani, MA and Zimmer, ER},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106392},
doi = {10.1002/alz70856_106392},
pmid = {41499485},
issn = {1552-5279},
mesh = {Humans ; *Polymorphism, Single Nucleotide/genetics ; *Alzheimer Disease/genetics/diagnostic imaging/metabolism ; Positron-Emission Tomography ; Male ; Female ; Aged ; *Brain/metabolism/diagnostic imaging ; Fluorodeoxyglucose F18 ; Biomarkers/metabolism ; Aged, 80 and over ; Glucose/metabolism ; Astrocytes/metabolism ; },
abstract = {BACKGROUND: FDG-PET studies have demonstrated that glucose metabolism abnormalities can be detected up to a decade prior to the clinical onset of Alzheimer's disease (AD). This finding underscores that early metabolic alterations are fundamental to AD pathogenesis, rather than merely secondary to neurodegeneration. While neurons are central to this process, astrocytes also play a pivotal role in maintaining metabolic brain homeostasis. However, the specific contributions of neuron-astrocyte metabolic interactions to AD pathology remain poorly understood. In this study, we examined the influence of single nucleotide polymorphisms (SNPs) in genes associated with astrocyte-neuron metabolic cooperation across the AD continuum.

METHOD: We analyzed genetic variants, FDG-PET imaging, and cognitive data from 619 cognitively unimpaired (CU) and cognitively impaired (CI) individuals from the ADNI database. An initial screening investigated 3,506 SNPs in genes related to brain energy metabolism. Linear models were used to assess associations between SNP carriership and regional FDG-PET measures. Voxel-wise analyses were then conducted for the most significant SNPs, examining their relationship with brain glucose metabolism changes and their potential impact on cognitive decline.

RESULTS: The SNP rs17867763 in the glutamate metabotropic receptor 8 (GRM8) gene showed the strongest association with FDG hypometabolism in cognitively impaired (CI) individuals (Figure 1A). This SNP was also significantly correlated with greater cognitive impairment across six cognitive/clinical assessments, including MMSE and CDR-SB. Voxel-wise analysis identified cortical clusters where FDG hypometabolism was linked to cognitive decline (Figure 1B). Additionally, voxel-wise analysis of five other GRM8 SNPs in both cognitively unimpaired (CU) and CI individuals revealed patterns of FDG hypo- and hypermetabolism in brain regions associated with Alzheimer's disease pathology (Figure 2).

CONCLUSION: The association of GRM8 SNPs with hypo- and hypermetabolism supports the hypothesis that synaptic dysfunction and metabolic imbalance contribute to early AD pathology. As mGluR8 modulates synaptic transmission, learning, and memory, its disruption likely affects glucose metabolism and cognitive decline. This highlights the relevance of glutamatergic neurotransmission in supporting optimal brain function in AD.},
}

Humans
*Polymorphism, Single Nucleotide/genetics
*Alzheimer Disease/genetics/diagnostic imaging/metabolism
Positron-Emission Tomography
Male
Female
Aged
*Brain/metabolism/diagnostic imaging
Fluorodeoxyglucose F18
Biomarkers/metabolism
Aged, 80 and over
Glucose/metabolism
Astrocytes/metabolism

@article {pmid41499468,
year = {2025},
author = {Meysami, S and Raji, CA and Lee, S and Garg, S and Akbari, N and Pompa, RS and Gouda, A and Nguyen, TD and Basar, S and Chodakiewitz, YG and Merrill, DA and Patel, A and Durand, DJ and Hashemi, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106425},
doi = {10.1002/alz70856_106425},
pmid = {41499468},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Middle Aged ; Magnetic Resonance Imaging ; Aged ; *Brain/diagnostic imaging/pathology ; Adult ; *White Matter/diagnostic imaging/pathology ; *Aging/pathology ; Biomarkers ; Neuroimaging/methods ; Deep Learning ; },
abstract = {BACKGROUND: Brain age - an estimate of chronological age- derived from structural brain MR neuroimaging may reveal underlying factors driving brain aging. White matter hyperintensities (WMH) are areas of abnormally high signal on FLAIR that frequently reflect chronic small vessel ischemic changes and potentially increased aging.

METHOD: Overall, 1,164 healthy participants from four sites (mean chronological age 55.17 ± 12.37 years, 52% women; 48% men; 39% non-white) were scanned on 1.5T MR machines with a whole-body protocol. For each participant, a 2D multi-slice FLAIR image was obtained. A 2D convolutional neural network, trained on data from 120 individuals across three public datasets (MICCAI 2017, ISLES2015, and ISLES2022), was employed to automatically segment WMH from the FLAIR scans. Deep learning with FastSurfer on MPRAGE trained on 134 participants aged 27-66 and segmented 96 brain regions. Brain age was computed using a regression-based 3D Simple Fully Convolutional Network trained on in-house T1-weighted MRI scans collected from 5,500 healthy individuals (, aged 18 to 89 years). Brain age gap (BAG) was computed by subtracting chronological age from brain age. Partial correlation and regression models evaluated the relationship between WMH normalized to total brain volume (gray matter and white matter), brain age, brain volumes controlling for age, sex, and total intracranial volume. Chronological age was not adjusted for in the brain age models to avoid collinearity.

RESULT: Mean brain age was similar to chronological age (mean brain age = 56.04 ± 12.65, mean BAG = 0.69). The median of WMH were 1.4 mL (0.75-2.51 mL). Increased WMH were related to lower brain volumes in the i) hippocampus (rp= -0.13, p =  1.174e-05) ii) cerebral white matter (rp= -0.08, p = .004) iii) thalamus (rp= -0.16, p = 1.634e-07). Additionally, increased WMH was related to larger cerebral ventricle size (rp= 0.28, p =  6.604e-21). The regression model showed that increased WMH was related to increased brain age (t= 5.92, rp= .42, p <.001) and increased brain age gap (t= 4.07, rp= .12, p <.001).

CONCLUSION: Increased WMH are related to brain atrophy - in both Alzheimer's and non-Alzheimer's affected regions - and are also related to increased brain age and accelerated brain aging.},
}

Humans
Male
Female
Middle Aged
Magnetic Resonance Imaging
Aged
*Brain/diagnostic imaging/pathology
Adult
*White Matter/diagnostic imaging/pathology
*Aging/pathology
Biomarkers
Neuroimaging/methods
Deep Learning

@article {pmid41499417,
year = {2025},
author = {Young, AL and Wijeratne, PA and Aksman, LM and Binette, AP and Strandberg, O and Oxtoby, NP and Altmann, A and Alexander, DC and Stomrud, E and Palmqvist, S and Mattsson-Carlgren, N and Vogel, JW and Hansson, O},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104804},
doi = {10.1002/alz70856_104804},
pmid = {41499417},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/metabolism/cerebrospinal fluid ; Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/pathology ; Male ; Female ; *Biomarkers/cerebrospinal fluid/metabolism ; Aged ; Disease Progression ; *Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Sweden ; *Brain/diagnostic imaging/metabolism ; Middle Aged ; *Amyloid/metabolism ; },
abstract = {BACKGROUND: Amyloid and tau accumulation in Alzheimer's disease is known to be dynamic, with expected rates of accumulation varying depending on disease stage. Establishing the precise timeline of amyloid and tau accumulation and quantifying their dynamic progression is important for identifying an optimal intervention window and predicting treatment response.

METHOD: 960 individuals were selected from the Swedish BioFINDER-2 study with at least two tau-PET scans (Table 1; follow-ups were at 1 year (N = 66), 2 years (N = 924), 4 years (N = 335); 6 years (N = 60)). Two intersecting data subsets were selected: 773 individuals having at least two amyloid-PET scans for estimating amyloid duration, and 434 CSF-amyloid-positive individuals for comparison with timelines across the whole population. Regional tau-PET SUVR abnormality was computed in five established data-driven regions using mixture modelling. A novel explicit-duration version of the temporal event-based model (T-EBM) was used to determine the order and timeline of global amyloid-PET and regional tau-PET abnormality. The explicit duration approach accounts for censoring of an individual's first and last visit and handles arbitrary time intervals.

RESULT: The T-EBM inferred that tau accumulates in a Braak-like pattern (Figure 1a), estimating an average timeline of global amyloid and regional tau accumulation (Figure 1b) of around 20 years. Progression from stage 1 (amyloid) to stage 2 (entorhinal tau) was estimated to take 8 years on average, from stage 2 to stage 3 (temporal lobe tau) 5.5 years, and 2-3 years between each subsequent stage. The timeline was consistent in amyloid-positive individuals (most amyloid-negative individuals were stage 0 and did not influence the timeline). Figure 1c shows the number of individuals progressing between stages at follow-up. Individuals who progressed in stage (progressors) were older, had more advanced symptoms (diagnosis), more APOE4 alleles, worse MMSE scores, and were more frequently amyloid-positive compared to non-progressors (Table 2).

CONCLUSION: Amyloid accumulates slowly, after which tau spreads from the entorhinal cortex to the temporal lobe, initially at a slower pace before accelerating to a faster rate across the cortex. This data indicates that slower rates of accumulation would be expected at earlier stages. Work is ongoing validating these timelines in additional datasets.},
}

Humans
*tau Proteins/metabolism/cerebrospinal fluid
Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/pathology
Male
Female
*Biomarkers/cerebrospinal fluid/metabolism
Aged
Disease Progression
*Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Sweden
*Brain/diagnostic imaging/metabolism
Middle Aged
*Amyloid/metabolism

@article {pmid41499380,
year = {2025},
author = {Guo, W and Shao, H and Zhang, Y and Zheng, H and Liang, D and Liu, J and Liu, L and Zhang, L and Guo, T and Hu, Z},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104805},
doi = {10.1002/alz70856_104805},
pmid = {41499380},
issn = {1552-5279},
mesh = {Humans ; Female ; Positron-Emission Tomography ; Aged ; *Alzheimer Disease/diagnostic imaging/metabolism ; Male ; Magnetic Resonance Imaging ; Biomarkers/metabolism ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/metabolism ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; Middle Aged ; },
abstract = {BACKGROUND: Amyloid-β (Aβ) and neurofibrillary tau deposition are two hallmark pathological proteins of Alzheimer's disease (AD) that accumulate through brain networks and drive cognitive decline. This study investigates whether the functional network abnormalities influence the Aβ-tau interactions and cognitive impairment in AD, which may provide more insightful perspectives in understanding the neural mechanisms and pathogenesis of AD.

METHOD: We divided the 190 participants from Shanghai Renji Hospital (68.6 ± 8.4 years, 62% female) into three groups, A-/T- (control group, N = 48), A+/T- (N = 121), and A+/T+ (N = 21), based on established global [18]F-AV-45 amyloid PET thresholds and [18]F-PI-2620 PET (tau PET) thresholds. All subjects underwent [18]F-AV-45 PET, [18]F-PI-2620 PET, resting state functional magnetic resonance imaging (fMRI) and T1-weighted MRI scans. Functional activity and functional network connectivity were determined using regional homogeneity (ReHo) and functional connectivity (FC) respectively.

RESULT: Participant demographics and summary descriptive statistics of the cognitive assessments and the PET data analyses are provide Table 1. The health control group (A-/T-, n = 48): The average age is 69.9 ± 8.3 years, with 62.5% being female. The mean education level is 10.1 ± 4.0 years. A+/T- Group (n = 121): The average age is 68.2 ± 8.9 years, with 60.0% being female. The mean education level is 10.4 ± 3.9 years. A+/T+ group(n = 21): The average age is 68.3 ± 5.0 years, with 71.4% being female. No significant difference was found for age and years of education across health control group and AD groups. We compared the brain's functional activity among A-/T- group, A+/T- group, and A+/T+ group, and we found that functional activity in some brain regions, such as bilateral cerebellum, right insula cortex, right precentral gyrus, right middle frontal gyrus, differed significantly among these forementioned three groups CONCLUSION: This study found significant differences in functional activity in brain regions such as the cerebellum, insula cortex, precentral gyrus, and middle frontal gyrus among control, A+/T-, and A+/T+ AD groups. These results suggest functional network abnormalities may influence Aβ-tau interactions and contribute to cognitive impairment in AD, shedding light on the neural mechanisms of the disease.},
}

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

@article {pmid41499277,
year = {2025},
author = {Eitan, E and Ayupova, D and Volpert, O and Gekas, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106641},
doi = {10.1002/alz70856_106641},
pmid = {41499277},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; *alpha-Synuclein/blood/cerebrospinal fluid ; Male ; Female ; *Alzheimer Disease/blood/diagnosis ; Aged ; Parkinson Disease/blood ; Middle Aged ; Cohort Studies ; Lewy Body Disease/blood ; Aged, 80 and over ; },
abstract = {BACKGROUND: Lewy body pathology, a hallmark of synucleinopathies, is present in most Parkinson's disease patients and approximately 30% of dementia cases, affecting over 24 million people worldwide. While cerebrospinal fluid (CSF) alpha-synuclein (aSyn) seeding assays have emerged as promising diagnostic tools, they remain invasive and insufficient for widespread clinical implementation. The development of reliable blood-based biomarkers is crucial for advancing early diagnosis and disease monitoring.

METHOD: Plasma NDEs were isolated using ExoSORT, and aSyn was quantified using the Mesoscale kit and a custom-developed Luminex assay.

RESULT: Assay validation included specificity, precision, and compatibility testing. Key performance metrics included within-batch variability (7%; 10 individuals, 3 repeats), between-batch variability (13%; two pooled plasma samples, 17 batches), and assay linearity (R = 0.73, p < 0.01). The clinical potential of the assay was demonstrated across four independent cohorts: COHORT I: Healthy (N = 77, 19±21 pg/ml), synucleinopathy (N = 113, 217±401 pg/ml), and Alzheimer's Disease (N = 37, 235±598 pg/ml); AUC between synucleinopathy and healthy: 0.86 (p <0.001). Cohort II: Healthy (N = 9, 8±9 pg/ml) vs. Lewy Body Dementia (N = 37, 80±109 pg/ml); AUC: 0.91 (p <0.001). GBA mutation status did not affect aSyn levels. Cohort III (postmortem-confirmed): Healthy (N = 15, 62±110 pg/ml), Alzheimer's without Lewy bodies (N = 15, 109±76 pg/ml), Lewy Body Dementia (N = 15, 178±92 pg/ml); AUC between LBD and healthy: 0.92 (p <0.001), and between AD and LBD: 0.76 (p <0.02). Cohort IV: Healthy (N = 15, 29±32 pg/ml) vs. Dementia (N = 45, 142±307 pg/ml). Tau pathology did not influence aSyn levels among dementia patients. We are now in the process of analyzing additional cohorts with over 900 subjects.

CONCLUSION: NDE-associated aSyn is significantly elevated in synucleinopathy patients across multiple cohorts, supporting its potential as a blood-based biomarker. Further work is needed to standardize preanalytical conditions, establish a unified diagnostic threshold, and evaluate assay sensitivity at the individual level for clinical application.},
}

Humans
*Biomarkers/blood/cerebrospinal fluid
*alpha-Synuclein/blood/cerebrospinal fluid
Male
Female
*Alzheimer Disease/blood/diagnosis
Aged
Parkinson Disease/blood
Middle Aged
Cohort Studies
Lewy Body Disease/blood
Aged, 80 and over

@article {pmid41499206,
year = {2025},
author = {Mis, RE and Lester-Smith, RA and Rousseau, J and Cui, J and Biswas, E and Shen, Y and Ghosh, N and Thomaz, E and Benge, JF},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107144},
doi = {10.1002/alz70856_107144},
pmid = {41499206},
issn = {1552-5279},
mesh = {Humans ; Aged ; Female ; Male ; Biomarkers ; Aged, 80 and over ; *Cognitive Dysfunction/diagnosis/psychology ; Alzheimer Disease/diagnosis/psychology ; *Privacy ; },
abstract = {BACKGROUND: Passive digital monitoring of real-world behaviors holds potential for identifying cognitive decline in Alzheimer's disease and related dementias (ADRD). However, little is known about how privacy concerns may affect older adults' participation in these studies, or how to educate older adults on mitigating privacy risks. This study aimed to characterize digital privacy concerns in older adults enrolling in a passive digital monitoring study and evaluate the efficacy of an educational intervention.

METHOD: Fifty-one older adults (mean age: 74.94±5.29 years) enrolled in this study, with 32 classified as cognitively-normal and 19 cognitively-impaired (MoCA-blind cut-off=18). At baseline, participants answered questions addressing level of general and study-specific digital data privacy concerns and self-perceived knowledge on maintaining data privacy. Following a brief educational presentation reviewing data protection measures in this study (e.g., specifying data collected/not collected, instruction on deactivating collection of specific data elements), privacy concerns were re-assessed. A 2 (Time; pre/post) x 2 (Condition; general/study-specific) x 2 (Cognitive Status; cognitively-normal/impaired) mixed model ANOVA analyzed the effect of the educational intervention on privacy concerns, and a 2 (Time) x 2 (Cognitive Status) mixed model ANOVA analyzed its effect on self-perceived knowledge.

RESULT: In the privacy concern model, there was a significant within-subjects effect of Condition, F(1,49)=13.69, p <.001, ηp [2]=.22, with greater concern about general versus study-specific data privacy. A significant Condition x Cognitive Status interaction, F(1,49)=4.16, p = .05, ηp [2]=.08, indicated cognitively-impaired participants endorsed lower concern about general privacy than cognitively-normal participants. A significant main effect of Time, F(1,49)=23.62, p <.001, ηp [2]= .33, indicated privacy concerns were reduced following the intervention. The remaining two- and three-way interactions were not significant, p's >.21. No significant main effects or interactions were found in the knowledge model, p's >.09.

CONCLUSION: Older adults with and without cognitive impairment expressed greater confidence in their study-related digital data privacy despite having general privacy concerns. A brief educational intervention effectively reduced participants' privacy concerns. Results suggest educational efforts by research teams can attenuate digital data privacy concerns in older adults participating in ADRD digital monitoring studies. As digital tools are increasingly incorporated in ADRD studies, it is crucial researchers prioritize participants' digital data privacy.},
}

Humans
Aged
Female
Male
Biomarkers
Aged, 80 and over
*Cognitive Dysfunction/diagnosis/psychology
Alzheimer Disease/diagnosis/psychology
*Privacy

@article {pmid41499194,
year = {2025},
author = {Singh, M and Shafighi, K and Detcheverry, FE and Dagasso, G and Dabo, F and Housni, I and Narayanan, S and Forkert, ND and Taliun, SAG and Bzdok, D and Badhwar, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106648},
doi = {10.1002/alz70856_106648},
pmid = {41499194},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/pathology ; Polymorphism, Single Nucleotide ; *White Matter/diagnostic imaging/pathology ; Genome-Wide Association Study ; *Biomarkers ; Magnetic Resonance Imaging ; *Brain/pathology/diagnostic imaging ; Male ; Female ; Aged ; },
abstract = {BACKGROUND: White matter hyperintensities (WMHs), visible as bright regions on T2-weighted FLAIR MRI, are frequent with age and elevated in Alzheimer's disease (AD). Representing axonal damage, demyelination, and edema, WMHs are driven by vascular mechanisms, including endothelial dysfunction and impaired cerebrovascular autoregulation. WMHs also exhibit strong heritability (55-73%), with overlapping genetic pathways shared with AD. Emerging evidence suggests systemic factors across the brain-body axis influence WMHs, yet these contributions and their genetic overlap with AD remain underexplored. Our study investigated genetic underpinnings specific to WMHs and those shared with AD by assessing partitioned heritability of WMHs and AD across the brain-body axis with SNP level tissue- and cell-specific annotations; identifying genes associated with WMHs and AD through integration of gene expression data, establishing causal links between SNP-level findings and imaging-derived phenotypes (IDPs), particularly structural variations in regional brain volumes.

METHOD: Partitioned heritability was assessed using stratified-linkage disequilibrium score regression (sLDSC) on GWAS summary statistics (N = 3 WMH studies; N = 6 AD studies) using human A1) tissue level annotations (N = 10) and A2) continuous cell-specific annotations (N = 64). MAGMA and FUSION analyses highlighted genes associated with WMH and AD for further bioinformatics analysis (using human protein atlas (HPA) and STRING database). MACAW (Vigneshwaran et al, 2024) modeled causal relationships between WMH-associated SNPs (from FUMA analysis) and IDPs (N = 172), leveraging directed acyclic graphs to evaluate genetic effects while controlling for confounders (Figure 2).

RESULT: Tissue-specific analysis revealed significant enrichment of WMH-associated SNPs in the CNS, liver, cardiovascular system, and kidneys, while AD-associated SNPs were enriched in the CNS, connective bone, liver, and immune tissues. (Figure 1). Cell-specific analysis identified vascular endothelial cells as enriched across WMH-enriched tissues. MAGMA analysis, combined with HPA analysis, corroborated sLDSC tissue-level findings. MAGMA and FUSION analyses highlighted genes associated with WMHs (N = 39 and 69) and AD (N = 291 and 193). MACAW linked WMH-associated SNP to 172 IDPs, consistently impacting WM hypointensities and regional brain volumes (e.g., left inferior temporal volume).

CONCLUSION: Our findings highlight systemic multi-tissue contributions (CNS, liver, cardiovascular system, and kidneys) to WMHs, driven by vascular endothelial dysfunction and shared AD genetics, with SNPs across the body also affecting brain imaging derived phenotypes.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging/pathology
Polymorphism, Single Nucleotide
*White Matter/diagnostic imaging/pathology
Genome-Wide Association Study
*Biomarkers
Magnetic Resonance Imaging
*Brain/pathology/diagnostic imaging
Male
Female
Aged

@article {pmid41499177,
year = {2025},
author = {Alam, MH},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106399},
doi = {10.1002/alz70856_106399},
pmid = {41499177},
issn = {1552-5279},
mesh = {Humans ; Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/therapy/diagnosis/psychology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Female ; Male ; Middle Aged ; Aged ; Neuropsychological Tests ; Aged, 80 and over ; },
abstract = {BACKGROUND: Identifying biomarkers in Alzheimer's disease (AD) is essential for early diagnosis and intervention. This study explores the impact of cognitive training combined with physical exercise on cognitive performance and neurodegeneration markers in adults diagnosed with AD.

METHOD: Utilizing a convenience sampling approach, we will recruit eighteen participants aged 60 and above from a local community of 150 individuals. Participants will be non-randomly assigned to either a control group (n = 9) or an experimental group (n = 9). A quasi-experimental design and structured interview will be conducted pre- and post-intervention to assess cognitive performance (using ADAS-Cog and MoCA) and health factors. Further more the experimental group will engage in a tailored regimen designed to enhance cognitive function and target biomarkers. Additionally statistical analyses will include t-tests to compare cognitive scores and regression analyses to investigate the relationship between biomarker levels (amyloid-beta >300 pg/mL and tau proteins >400 pg/mL) and cognitive performance, with significance set at p < .05.

RESULT: We anticipate significant improvements in cognitive performance, with higher levels of amyloid-beta and tau proteins correlating with lower cognitive scores.

CONCLUSION: This study aims to provide critical insights into the effectiveness of integrated cognitive and physical interventions in addressing cognitive decline in AD, emphasizing the importance of community-based research in developing future therapeutic strategies.},
}

Humans
Biomarkers/cerebrospinal fluid
*Alzheimer Disease/therapy/diagnosis/psychology
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
Female
Male
Middle Aged
Aged
Neuropsychological Tests
Aged, 80 and over

@article {pmid41499098,
year = {2025},
author = {Evans, TE and Chudleigh, E and Genius, P and Rodríguez-Fernández, B and Anastasi, F and Minguillón, C and Esteller, M and Navarro, A and Adams, HHH and Vilor-Tejedor, N},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105451},
doi = {10.1002/alz70856_105451},
pmid = {41499098},
issn = {1552-5279},
mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid ; Male ; *Alzheimer Disease/genetics/cerebrospinal fluid/pathology ; Female ; Genome-Wide Association Study ; Biomarkers/cerebrospinal fluid ; Aged ; *Hippocampus/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Peptide Fragments/cerebrospinal fluid ; Polymorphism, Single Nucleotide ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: Understanding the influence of genetic ancestry on Alzheimer's disease (AD) is essential to addressing health disparities and improving the generalizability of genetic discoveries. While most Genome-Wide Association Studies (GWAS) rely on global ancestry, local ancestry inference (LAI) provides a refined methodology to detect ancestry-specific genetic effects. We aimed to integrate local ancestry inference at chromosome 19 into regional genetic association analysis to identify local ancestry specific variants associated with hippocampal volume (HV) and cerebrospinal fluid (CSF) Amyloid beta 42 (Aβ42) levels.

METHODS: The framework integrated Gnomix tool for chromosome 19 local ancestry deconvolution and Tractor for regional ancestry-informed GWAS adjusted by chronological age, sex, years of education, APOE-ε4 status and eight components derived from LAI analysis, capturing the ancestry-specific genetic structure. The analyses were performed using genetically well characterized participants from the ALFA cohort, focusing on two key AD-related endophenotypes: HV (N = 1,325) and CSF-Aβ42 levels (N = 282). Scans were obtained using a 3T Philips Ingenia CX MRI scanner using a uniform high-resolution 3D protocol. CSF-Aβ42 concentration was measured using the Elecsys® electrochemiluminescence immunoassay on the fully automated cobas e601 analyzer (Roche Diagnostics International Ltd.) at the Clinical Neurochemistry Laboratory, University of Gothenburg, Sweden. Genotyping was performed using the Illumina Infinium Neuro Consortium Array (build GRCh37/hg19), with imputation via the TOPMed Imputation Server using the r3 reference panel and Eagle v2.4 phasing.

RESULTS: LAI analysis revealed unique single nucleotide polymorphisms (SNPs) associated with HV and CSF-Aβ42 that were undetected by traditional GWAS, highlighting the role of ancestry-specific variants. Notably, significant SNPs in the EIF3K and ZNF675 regions were linked to African (HV) and West Asian (Aβ42) ancestries [Figure 1], respectively, while classic GWAS and global ancestry models failed to identify these loci [Figure 2]. The LAI approach also provided enhanced resolution in identifying SNPs within the APOE region, emphasizing its relevance in understanding cross-ancestry genetic risk.

CONCLUSION: This study advances the understanding of genetic variation in AD. The findings support the inclusion of local ancestry analysis as a critical component of future AD genetic research, promoting equity in genetic discovery and personalized medicine.},
}

Humans
*Amyloid beta-Peptides/cerebrospinal fluid
Male
*Alzheimer Disease/genetics/cerebrospinal fluid/pathology
Female
Genome-Wide Association Study
Biomarkers/cerebrospinal fluid
Aged
*Hippocampus/pathology/diagnostic imaging
Magnetic Resonance Imaging
*Peptide Fragments/cerebrospinal fluid
Polymorphism, Single Nucleotide
Middle Aged
Cohort Studies

@article {pmid41498782,
year = {2025},
author = {Rodrigues, MS and Bellaver, B and Povala, G and Bauer-Negrini, G and Lussier, FZ and Amaral, L and Ferreira, PCL and Oliveira, MS and Rocha, A and Saha, P and Madeiros, MS and Soares, C and Ruppert, E and Mroué, R and Masdeu, JC and Tudorascu, DL and Soleimani-Meigooni, DN and Fortea, J and Lowe, VJ and Oh, H and Pascual, B and Gordon, BA and Rosa-Neto, P and Baker, SL and Pascoal, TA},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106398},
doi = {10.1002/alz70856_106398},
pmid = {41498782},
issn = {1552-5279},
mesh = {Humans ; Positron-Emission Tomography ; Male ; Female ; Biomarkers/metabolism ; *tau Proteins/metabolism ; Aged ; Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Risk Factors ; Aged, 80 and over ; Carbolines ; },
abstract = {BACKGROUND: Many risk factors can contribute to the occurrence of Alzheimer`s Disease (AD). However, little is known about the impact of dementia risk factors to the uptake of tau-PET tracers. Therefore, in this work we aim to investigate the influence of dementia risk factors and comorbidities on [18]F-Flortaucipir (FTP) and [18]F-MK6240 (MK) tau-PET tracers' uptake. Additionally, we will assess how these factors impact the association of tau-PET and cognition.

METHOD: We accessed 436 individuals across the aging and AD spectrum (251 amyloid negative and 185 amyloid positive) from the HEAD study, with available Aβ-PET, FTP, MK, and clinical assessments. Linear regression models corrected for age, sex, clinical diagnosis, and study site tested the association of factors with tau-PET tracers in the medial temporal lobe (MTL). A tau-PET × risk factor term was added to test the influence of risk factors to the association of tau with cognition.

RESULT: In amyloid-β negative individuals, high BMI were positively associated with the uptake of both FTP and MK, whereas hearing loss were positively associated only with MK in the MTL (Figure 1A). In amyloid-β positive individuals, high body mass index (BMI), hearing loss and sleep disorders were negatively associated with the uptake of both tau-PET tracers in the MTL. On the other hand, hypertension showed negative association only with MK uptake (Figure 1B). Using Mini-Mental State Examination (MMSE) scores as outcome, we observed that amyloid-β negative individuals with high BMI showed worse cognitive performance as a function of both MK and FTP in the MTL, whereas individuals with vision impairment and hearing loss showed worse cognitive performance as a function of MK only (Figure 2A). Amyloid-β positive individuals with hypercholesterolemia and hypertension presented worse cognitive performance as a function of both MK and FTP in the MTL (Figure 2B).

CONCLUSION: In this preliminary analysis, sleep disorders, hypertension, and high BMI were independently associated with tau-PET tracer uptake, with the effects varying according to amyloid-β pathology. These prevalent factors in the elderly also changed the association between tau-PET and cognition, underscoring the need for further studies to better understand their role in modulating this relationship.},
}

Humans
Positron-Emission Tomography
Male
Female
Biomarkers/metabolism
*tau Proteins/metabolism
Aged
Amyloid beta-Peptides/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Risk Factors
Aged, 80 and over
Carbolines

@article {pmid41498777,
year = {2025},
author = {Sergio, JP and Thompson, LI and Price, AN and Strenger, J and Stradtman, M and Benjamin, S 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 = {},
pages = {e104874},
doi = {10.1002/alz70856_104874},
pmid = {41498777},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Aged ; Male ; Female ; *Alzheimer Disease/pathology/blood ; Aged, 80 and over ; Middle Aged ; *Cognitive Reserve/physiology ; *Cognitive Dysfunction/pathology/blood ; Retina/pathology ; Neuropsychological Tests ; Brain/pathology ; },
abstract = {BACKGROUND: While brain imaging techniques such as amyloid PET scans are sensitive and specific biomarkers of Alzheimer's disease (AD) neuropathology, they are not scalable from a public health perspective. Other biomarkers, including blood and retinal biomarkers, are proposed as suitable alternatives which correlate with amyloid PET burden. Additionally, individual differences in resiliency to AD neuropathology may be explained by the cognitive reserve theory. Higher cognitive reserve, measured by proxies including education and occupational attainment, allows individuals to maintain optimal cognitive functioning for longer despite the presence of AD neuropathology. Indeed, education and occupational complexity reduce the risk of developing AD. Therefore, it is imperative to better understand the relationship between biomarkers of AD and brain resiliency. The current study examines associations between biomarkers of AD (blood and retinal layer thickness), cognition, and proxies of cognitive reserve.

METHOD: Participants (n = 115) were older adults aged 55-80, including 15 MCI patients (MoCA>19, <24, CDR=.5) and 100 cognitively unimpaired (CU) (MoCA>=26, CDR=0) recruited as part of the Atlas of Retinal Imaging in Alzheimer's Study. A structural equation model was run to elucidate relationships between several constructs including latent variables of cognition, which included measures of attention, processing speed, visuospatial construction, and executive function, AD pathology burden, as indicated by plasma biomarkers, and cognitive reserve (indicators including years of education and occupational complexity). Retinal layer thickness of the ganglion cell layer complex (GCC) was also measured. Regressions, accounting for age, included AD pathology burden and GCC thickness predicting cognition, cognitive reserve predicting GCC thickness, and cognitive reserve predicting AD pathology burden.

RESULT: Age was a significant predictor of AD pathology burden and average GCC thickness. AD pathology burden was a significant predictor of cognition while accounting for age. No other predictors in the SEM were significant.

CONCLUSION: A latent variable including blood biomarkers ptau217, ptau181, and neurofilament light chain to represent AD pathology burden predicted cognition. This adds to mounting evidence that blood biomarkers accurately predict cognitive changes in CU and MCI older adults. Delineating whether these effects were driven by MCI or high-risk CU may be a future direction with larger sample sizes.},
}

Humans
*Biomarkers/blood
Aged
Male
Female
*Alzheimer Disease/pathology/blood
Aged, 80 and over
Middle Aged
*Cognitive Reserve/physiology
*Cognitive Dysfunction/pathology/blood
Retina/pathology
Neuropsychological Tests
Brain/pathology

@article {pmid41498775,
year = {2025},
author = {Tan, JXM and Kang, MS and Yeh, YH and Rahmouni, N and Bezgin, G and Lussier, FZ and Hong, SJ and Isen, J and McLaurin, J and Bernhardt, B and Stefanovic, B and Soucy, JP and Gauthier, S and Black, SE and Rosa-Neto, P and Goubran, M and Ottoy, J},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106076},
doi = {10.1002/alz70856_106076},
pmid = {41498775},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Connectome ; Aged ; *tau Proteins/metabolism ; *Entorhinal Cortex/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; Biomarkers/metabolism ; *Brain/diagnostic imaging/metabolism ; Positron-Emission Tomography ; Diffusion Magnetic Resonance Imaging ; Middle Aged ; },
abstract = {BACKGROUND: Prior studies have focused on tau spread from the entorhinal cortex along first-order (short-range) connections within anatomical brain space (seed-to-target). Here, we explore tau spread along long-range connections within a novel coordinate space called connectome gradients, which is reflective of the brain's hierarchical organization. Exploring tau spread within this new framework offers insights into long-range connectivity alterations and network susceptibility in Alzheimer's disease (AD).

METHOD: We included 213 participants from TRIAD (103 A- CN, 103 A+ CN, and 75 A+ CI) with diffusion-weighted MRI, resting-state functional MRI, and 18F-MK6240 tau-PET. First, we employed graph theory-based stepwise connectivity analyses to unveil long-range connectivity patterns from the entorhinal cortex to the rest of the brain. Differences in connectivity patterns were compared between A+ vs A- groups, adjusted for age, sex, and APOE-ε4. Second, we investigated the stepwise connectivity patterns in relation to tau within a novel coordinate system spanned by the principal functional and structural connectome gradients.

RESULT: In the preclinical stage (A+ CN) compared to controls (A- CN), we observed connectivity increase through functional gradient space (Figure 1A red). In the clinical stage (A+ CI), connectivity reduced from the entorhinal cortex to the transmodal end of the functional gradient (DMN/limbic; Figure 1A blue) and to the posterior end of the structural gradient (temporo-occipital; Figure 1B blue). Long-range connections from the entorhinal cortex showed increased connectivity toward the unimodal and anterior ends of the functional and structural gradient, respectively (Figure 1A, B red), potentially initiating new paths for tau spread. Indeed, tau-connectivity correlations shifted spatially within gradient space with disease progression (Figure 2), moving from the highest-order (DMN/limbic) cognitive system of the functional gradient in A+ CN to the second-highest order (frontoparietal) system in A+ CI.

CONCLUSION: We employed a novel integration of stepwise connectivity and connectome gradients to enable a better understanding of how connectivity is related to tau spread along the major axes of brain organization. We observed widespread network reorganization in AD and notably that the tau-connectivity correlations shifted between major networks of the functional connectome gradient with disease progression.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/metabolism
*Connectome
Aged
*tau Proteins/metabolism
*Entorhinal Cortex/diagnostic imaging/metabolism
Magnetic Resonance Imaging
Biomarkers/metabolism
*Brain/diagnostic imaging/metabolism
Positron-Emission Tomography
Diffusion Magnetic Resonance Imaging
Middle Aged

@article {pmid41498754,
year = {2025},
author = {Uceda-Heras, A and Burgueño-García, I and Ruiz-Valderrey, P and Saiz, L and López-Martínez, MJ and Rabano, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105434},
doi = {10.1002/alz70856_105434},
pmid = {41498754},
issn = {1552-5279},
mesh = {Humans ; Male ; Biomarkers/blood ; Female ; *Alzheimer Disease/pathology/blood ; Aged ; *Glial Fibrillary Acidic Protein/blood ; Aged, 80 and over ; *Brain/pathology/metabolism ; tau Proteins/metabolism ; Cohort Studies ; Hippocampus/pathology ; Cerebrovascular Disorders/pathology ; },
abstract = {BACKGROUND: Astrocytes are an essential glial cell which express GFAP, a marker of astrocytic activation and structural integrity. A recent study by our group links serum GFAP levels to tau pathology in Alzheimer's disease (AD), suggesting its value as a diagnostic biomarker. Our aim is to examine the GFAP levels in serum (GFAPs) in correlation with various neuropathological variables, specifically focusing on the medial temporal lobe (MTL).

METHOD: In 156 brains from the VARS dementia cohort, we analyzed a set of neuropathological variables including macroscopic data and classification and staging criteria for AD, Lewy Body Pathology (LBP), Cerebrovascular Disease (VD), Hippocampal sclerosis (HS), and TDP-43 pathology (LATE).

RESULT: First, we observed a correlation between GFAPs and tissue GFAP immunostaining in the entorhinal cortex (r=0.211, p <0.05). Then, we found a correlation of GFAPs with brain weight (r=-0.366, p <0.001), NIA A (r=0.262, p <0.01), NIA B (r=0.416, p <0.001), NIA C (r=0.256, p <0.01), LPC classification (r=0.218; p <0.01), and with the presence of more combined pathologies with high burden (r=0.28, p <0.001). Besides, we observed a trend of increasing GFAPs values with higher stages of MTL atrophy, Braak tau, HS, and LATE. However, no significant correlation was detected between GFAPs and VD. Finally, a lineal regression model showed that NIA B (p <0.001), HS (head of the hippocampus) (p <0.05), and Braak α-syn stages (p <0.05) were the best predictors for GFAPs.

CONCLUSION: Our study shows that GFAP in serum correlates with neuropathological variables, specially with tissue tau pathology, supporting the potential of GFAP as a diagnostic biomarker for AD and related pathologies, except for cerebrovascular disease.},
}

Humans
Male
Biomarkers/blood
Female
*Alzheimer Disease/pathology/blood
Aged
*Glial Fibrillary Acidic Protein/blood
Aged, 80 and over
*Brain/pathology/metabolism
tau Proteins/metabolism
Cohort Studies
Hippocampus/pathology
Cerebrovascular Disorders/pathology

@article {pmid41498751,
year = {2025},
author = {Biel, D and Steward, A and Dewenter, A and Dehsarvi, A and Zhu, Z and Roemer-Cassiano, S and Frontzkowski, L and Hirsch, F and Brendel, M and Franzmeier, N},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104771},
doi = {10.1002/alz70856_104771},
pmid = {41498751},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *tau Proteins/blood ; Aged ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Longitudinal Studies ; *Cognitive Dysfunction/diagnostic imaging ; Amyloid beta-Peptides ; Aged, 80 and over ; Brain/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: With the approval of anti-amyloid therapies in Alzheimer's disease (AD), surrogate biomarkers are urgently needed to monitor treatment effects that translate into clinical benefits. Candidate biomarkers, including amyloid-PET, tau-PET, plasma phosphorylated tau (p-tau), and MRI-assessed atrophy, capture core pathophysiological changes in AD. While cross-sectional biomarker assessments are critical for diagnosis and staging, biomarker change rates may better reflect disease dynamics, making them more suitable for monitoring treatment efficacy. Therefore, we determined which biomarker most effectively tracks cognitive changes in AD, identifying those best suited for efficient monitoring of disease-modifying treatments.

METHOD: We leveraged ADNI (N = 108) and A4 (N = 151) participants with longitudinal AD biomarker data (global amyloid-PET, temporal meta tau-PET, plasma p-tau217, MRI-assessed cortical thickness in the AD signature region) together with cognitive assessments (ADNI: MMSE, ADAS13, CDR-SB; A4: MMSE, PACC). Linear mixed models were used to calculate change rates for biomarkers and cognition. To test whether biomarker changes track cognitive decline, linear models were applied, to test biomarker change rates as a predictor of cognitive change rates. Standardized beta values from bootstrapped linear models were extracted to compare the strengths of correlations between biomarkers and cognitive decline. For non-parametric comparisons, 95% confidence intervals (CIs) of standardized beta values were compared. Models were controlled for age, sex, education, and baseline cognition, with ADNI models additionally adjusted for clinical status.

RESULT: In both cohorts, changes in temporal tau-PET, plasma p-tau217, and MRI-assessed cortical thickness were associated with cognitive decline (ADNI: Figure 1; A4: Figure 2). Amyloid-PET changes showed no significant association with cognitive changes (ADNI: Figure 1A+F+K; A4: Figure 2A+F). Bootstrapping confirmed that tau-PET, plasma p-tau217, and cortical thickness track cognitive decline, but not amyloid-PET (ADNI: Figure 1E+J+O; A4: Figure 2E+J). Overlapping CIs for tau-PET and plasma p-tau217 indicated comparable predictive accuracy.

CONCLUSION: Our findings demonstrate that tau-PET and plasma p-tau217 are robust biomarkers for monitoring cognitive changes, with plasma p-tau217 offering a cost-effective, scalable alternative for clinical use. Changes in amyloid-PET do not reliably reflect cognitive decline, limiting its utility as a treatment monitoring tool. Although cortical thickness correlates with cognitive changes, its application is limited by pseudoatrophy and volume loss induced by anti-amyloid antibody treatments.},
}

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

@article {pmid41498704,
year = {2025},
author = {Bathe, T and Salomasova, S and Lalia, M and Kunze, LH and Palumbo, G and Oos, R and Joseph, E and Brendel, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104796},
doi = {10.1002/alz70856_104796},
pmid = {41498704},
issn = {1552-5279},
mesh = {Animals ; *Biomarkers/cerebrospinal fluid/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Alzheimer Disease/drug therapy ; Positron-Emission Tomography ; tau Proteins/metabolism ; Humans ; Brain/metabolism/pathology/diagnostic imaging/drug effects ; *Tauopathies/drug therapy ; Microglia/metabolism ; },
abstract = {BACKGROUND: The prevalence of neurodegenerative diseases (ND), including Alzheimer's disease (AD) and non-AD tauopathies, is projected to rise significantly by 2050 due to an aging global population. Chronic neuroinflammation, driven by glial activation in response to protein pathologies, is a major contributor to disease progression. Targeting glial dysfunction through immunomodulatory therapies offers a promising approach to mitigate the effects of tauopathies and other ND.

METHOD: PS19 mice receive chronic treatment with GV1001 over 5 months. Serial neuroimaging techniques, including PET scans targeting tau protein, microglial activation, and astrocytic responses, are employed to assess treatment effects in vivo (Figure 1). Postmortem validation is performed using immunohistochemistry and biochemical methods, comparing treated mice to placebo and non-transgenic controls.

RESULT: The research scope is to monitor the efficacy of GV1001 in a transgenic tau mouse model (PS19) with an early-intervention biomarker study using molecular biology and neuroimaging techniques including TSPO (microglia) PET, deprenyl (astroglia) PET, tau PET (perfusion and retention) and CSF markers of inflammation (e.g. sTREM2) and neurodegeneration (NfL). Preliminary findings, expected to be presented at the conference, will provide insights into the drug's ability to modulate glial activity, restore homeostasis, and reduce tau pathology.

CONCLUSION: This study highlights the potential of monitoring immunomodulatory strategies to address the complex interplay between chronic neuroinflammation and protein aggregation in ND. If successful, these findings could inform the development of novel therapeutic approaches for AD and related disorders, bridging the gap between preclinical research and clinical application.},
}

Animals
*Biomarkers/cerebrospinal fluid/metabolism
Mice
Mice, Transgenic
Disease Models, Animal
*Alzheimer Disease/drug therapy
Positron-Emission Tomography
tau Proteins/metabolism
Humans
Brain/metabolism/pathology/diagnostic imaging/drug effects
*Tauopathies/drug therapy
Microglia/metabolism

@article {pmid41498687,
year = {2025},
author = {Ardle, RM and Kirk, C and Din, SD and Bai, Y and Kaski, D and Rohrer, JD and Galna, B and Thomas, AJ and Rochester, L and Bancroft, MJ and Yong, KXX},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104769},
doi = {10.1002/alz70856_104769},
pmid = {41498687},
issn = {1552-5279},
mesh = {Humans ; Aged ; Female ; Male ; *Alzheimer Disease/diagnosis/physiopathology ; *Accelerometry ; *Walking/physiology ; Biomarkers ; Middle Aged ; *Lewy Body Disease/diagnosis/physiopathology ; Atrophy ; },
abstract = {BACKGROUND: Posterior cortical atrophy (PCA) is a dementia subgroup commonly misdiagnosed due to unusual presentation and limited clinical awareness. Previously, the GaitDem study provided proof-of-concept for the use of accelerometery-based walking assessment in clinical and real-world settings in supporting differentiation Lewy body disease (LBD) and Alzheimer's disease (AD). Real-world walking assessment also provides insights into the impact of disease on everyday behaviours. Here, we aimed to assess the feasibility of accelerometery-based real-world walking assessment of PCA and describe differences between PCA and more prevalent neurodegenerative dementia syndromes, AD and LBD.

METHODS: Fourteen participants with PCA (Age: 71 years(56-78); 57% female) wore an accelerometer (AX6, Axivity) affixed to their lower back for up to seven days. Using validated algorithms, real-world walking outcomes were derived including measures of walking quality (step velocity), volume (minutes spent walking, steps per day, bouts per day), pattern (mean bout duration) and variability (of bout durations). Data was compared to the GaitDem cohort, which included 36 people with AD (Age: 77 years(67-88); 58% female) and 46 with LBD (Age: 77 years(65-91); 17% female), following a similar protocol. Kruskal-Wallis Test assessed between-group differences with post-hoc Dunn tests. 26 controls (Age: 74(60-89), 58% female) were included for visual comparison (Figure 1).

RESULTS: Twelve PCA participants completed seven days of real-world walking assessment; two completed 5-6 days. The PCA group walked faster, spent more minutes walking, took more steps and walking bouts per day (p <0.01 for all) than the LBD group; no significant differences were found for pattern and variability outcomes or between PCA and AD groups (p >0.05; Figure 1).

CONCLUSION: All PCA participants completed real-world walking assessment for the recommended period of >3 days, suggesting feasibility. Preliminary results suggest that the PCA group's real-world macro walking behaviours are more similar to AD than LBD. Despite a small sample, this novel data provides proof-of-concept. Only real-world macro walking outcomes are reported. Previously, clinic-based accelerometery outcomes relating to micro gait characteristics (e.g. spatiotemporal and signal-based features) were more sensitive to differences between LBD and AD; this will be further explored for PCA.},
}

Humans
Aged
Female
Male
*Alzheimer Disease/diagnosis/physiopathology
*Accelerometry
*Walking/physiology
Biomarkers
Middle Aged
*Lewy Body Disease/diagnosis/physiopathology
Atrophy

@article {pmid41498671,
year = {2025},
author = {Wuestefeld, A and Spotorno, N and Binette, AP and Mattsson-Carlgren, N and Ossenkoppele, R and Palmqvist, S and Smith, R and Stomrud, E and Strandberg, O and van Westen, D and Hansson, O and Wisse, LEM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104826},
doi = {10.1002/alz70856_104826},
pmid = {41498671},
issn = {1552-5279},
mesh = {Humans ; Female ; Positron-Emission Tomography ; Amyloid beta-Peptides/cerebrospinal fluid ; Male ; *tau Proteins/cerebrospinal fluid/metabolism ; Biomarkers/cerebrospinal fluid ; Middle Aged ; Aged ; *Cognitive Dysfunction/diagnostic imaging/cerebrospinal fluid/pathology ; Atrophy/pathology ; *Brain/pathology/diagnostic imaging/metabolism ; Aniline Compounds ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND: Previous studies, including ours (Wuestefeld et al., Brain, 2023), showed tau positron emission tomography (PET) uptake in medial temporal and neocortical regions of amyloid-beta (Aβ)-negative cognitively unimpaired (CU) individuals, associated with neurodegeneration and worse memory performance. To further understand if tau-PET uptake is clinically relevant in this population, we characterized Aβ-negative CU individuals with higher longitudinal tau-PET accumulation and its associations with atrophy and cognitive decline.

METHOD: We included 333 CU BioFINDER-2 participants, negative for both global [18F]flutemetamol Aβ-PET and cerebrospinal fluid (CSF) Aβ42/Aβ40 (age=63.8, 55% female, 2.28±1.36 years follow-up). Using linear mixed-effects models, we calculated the rate of change (ROC) in [18F]RO948 tau-PET SUVR in composite regions of interest (ROI), recapitulating the Braak stages. Individuals were classified as "tau-accumulators" vs. "non-accumulators" based on the mean+standard deviation of Braak I-IV tau-PET ROC in young controls (20-40 years, n = 29; Figure 1A). Tau-PET ROC and thickness of the entorhinal cortex, Brodmann area (BA)35 and neocortical AD-regions (precuneus/posterior cingulate, lateral occipital, superior frontal) were extracted. Group differences and associations with CSF AD biomarkers, delayed word-list recall, and modified Preclinical Alzheimer Cognitive Composite were tested.

RESULT: 16% of individuals were identified as tau-accumulators. They were older, had lower levels of Aβ as indicated by a higher CSF Aβ42/40 ratio (no difference on Aβ-PET) and numerically higher CSF MTBR-tau243/Aβ40 (not significant, note missingness; Figure 1B+C). Tau-accumulators showed significantly greater tau-PET at baseline and accumulation in regions not included in Braak I-IV (all p <0.001). Additionally, we observed more atrophy in BA35 (Figure 2A, not after age-adjustment) and numerically worse baseline cognitive performance, but no difference in decline over time (Figure 2B). In the whole sample, Braak I-IV tau-PET accumulation was significantly associated with increased age, more BA35 atrophy and at trend-level with higher levels of CSF Aβ42/40 and CSF MTBR-tau243/Aβ40 (Figure 3).

CONCLUSION: A subgroup of Aβ- CU individuals show longitudinal tau accumulation across the neocortex. Preliminary results suggest an association with a tau-specific CSF biomarker and focal atrophy, which did not translate to changes in cognition. We will complement our analyses with a data-driven approach of classifying tau-accumulators.},
}

Humans
Female
Positron-Emission Tomography
Amyloid beta-Peptides/cerebrospinal fluid
Male
*tau Proteins/cerebrospinal fluid/metabolism
Biomarkers/cerebrospinal fluid
Middle Aged
Aged
*Cognitive Dysfunction/diagnostic imaging/cerebrospinal fluid/pathology
Atrophy/pathology
*Brain/pathology/diagnostic imaging/metabolism
Aniline Compounds
Peptide Fragments/cerebrospinal fluid

@article {pmid41498653,
year = {2025},
author = {Lehodey, A and Montagne, B and Rehel, S and Kaliman, P and Chocat, A and Mézenge, F and Landeau, B and Vivien, D and De la Sayette, V and Chételat, G and Rauchs, G and Poisnel, G and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104780},
doi = {10.1002/alz70856_104780},
pmid = {41498653},
issn = {1552-5279},
mesh = {Humans ; Aged ; Male ; Female ; Biomarkers/blood ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease ; Circadian Rhythm/physiology ; Positron-Emission Tomography ; *Sleep/physiology ; *Aging ; Middle Aged ; *Telomere Shortening/physiology ; Telomere ; Sleep Wake Disorders ; Brain/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: Sleep and circadian rhythms disturbances have been linked to cognitive decline and an increased risk of Alzheimer's disease (AD). These disruptions are also closely associated with biological aging processes. Telomere shortening, a key marker of cellular aging, has been implicated in various age-related diseases, including AD. Although sleep disturbances have been linked to shorter telomere length (TL), the effects of sleep, its variability, and circadian rhythms on telomere dynamics-particularly the percentage of critically short telomeres (%CST), which would be a more specific marker of brain aging and vulnerability to AD-remains unknown. Furthermore, the interplay between these factors and AD risk has yet to be investigated in healthy older adults.

METHOD: Data from 124 healthy older adults (mean age ± SD: 69.27 ± 3.73y) from the Age-Well interventional trial (NCT02977819) were analyzed. Amyloid (Aβ) status was assessed using AV45-PET, and blood samples were collected to determine three TL measures (50th and 20th percentile TL, and %CST) at baseline and after an 18-month follow-up. Sleep and its variability were assessed using the Somno-Art® device (5 nights), and circadian rhythms with actigraphy (1 week). Multiple linear regressions examined whether baseline sleep and circadian rhythms-related measures predicted TL changes over time. Interaction analyses were performed to examine the modulatory effects of Aβ and APOE4 status on these relationships. Age, sex, education, BMI, and intervention group were included as covariates. Only associations surviving Bonferroni correction are reported.

RESULT: Poor sleep quality (lower sleep efficiency and higher WASO) and greater variability in sleep efficiency predicted an increase in %CST (Figure 1A, 1B). Greater regularity in sleep/wake patterns was associated with a decrease in 50th and 20th percentile TL and an increase in %CST (Figure 1C). In Aβ-positive individuals, longer rapid eye movement sleep latency predicted a reduction in 20[th] percentile TL and an increase in %CST (Figure 2).

CONCLUSION: This study suggests that sleep, its variability and circadian rhythms may accelerate cellular aging through telomere shortening in older adults with and without AD risk factors. Our results highlight the potential value of interventions targeting sleep to reduce biological aging and vulnerability to age-related diseases.},
}

Humans
Aged
Male
Female
Biomarkers/blood
Amyloid beta-Peptides/metabolism
Alzheimer Disease
Circadian Rhythm/physiology
Positron-Emission Tomography
*Sleep/physiology
*Aging
Middle Aged
*Telomere Shortening/physiology
Telomere
Sleep Wake Disorders
Brain/diagnostic imaging/metabolism

@article {pmid41498640,
year = {2025},
author = {Groot, C and Calandri, IL and Bader, I and Bocancea, DI and de Bruin, H and Carrigan, M and Kamps, S and de Koning, LA and Mastenbroek, SE and Rikken, RM and van Tol, BGJ and Vermeiren, MR and Wesseling, AJ and Xia, Y and Teunissen, CE and van de Giessen, E and Barkhof, F and Jonkman, LE and van der Lee, SJ and de Boer, C and Rozemuller, AJM and Duits, F and Tijms, BM and van der Flier, WM and Pijnenburg, YAL and Coomans, EM and Ossenkoppele, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104809},
doi = {10.1002/alz70856_104809},
pmid = {41498640},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Biomarkers ; *Alzheimer Disease/diagnosis/pathology/mortality/diagnostic imaging ; Aged ; *Cognitive Dysfunction/pathology/diagnosis/diagnostic imaging ; Middle Aged ; Atrophy/pathology ; Cohort Studies ; Magnetic Resonance Imaging ; Aged, 80 and over ; Brain/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: Limbic-predominant age-related TDP-43 encephalopathy (LATE) clinically mimics and often co-occurs with Alzheimer's disease (AD). Expert consensus criteria have been proposed for the LATE clinical diagnosis, integrating clinical and radiological features, and AD biomarkers. Here, we applied the newly proposed criteria in a tertiary memory clinic population.

METHOD: We included participants from the Amsterdam Dementia Cohort aged >50 years who received a diagnosis of MCI or dementia between 1997-2024. Following the LATE consensus criteria scheme (Figure 1), we categorized participants as "Probable LATE", "Possible LATE" or "Possible LATE-AD" (i.e. LATE clinical and radiological profile with AD biomarker profile). Participants not fulfilling criteria for LATE but fulfilling NIA-AA criteria for AD were categorized as AD. We compared the LATE groups with AD on cognitive decline (N = 1046, N Mean time=2.7[1.8] years) and atrophy (N = 208, Mean time=2.1[1.6]) using linear-mixed effects models, and on mortality rates using Cox proportional hazard models.

RESULT: Of the 3367 individuals, 1920 were classified into one of the four groups. Fifty-one (1.5%) were classified as Probable LATE, 102 (3.0%) as Possible LATE, 122 (3.6%) as Possible LATE-AD, and 1645 (48.8%) as AD (Table 1). Compared to AD, Probable LATE showed an attenuated cognitive decline (b[SE] for MMSE=0.12[0.05], p = 0.02) and lower mortality rates (HR[95% CI]=0.75[0.58-0.95], p = 0.02), while individuals with Possible LATE-AD had faster cognitive decline (b for MMSE=-0.12[0.05], p = 0.01) and higher mortality rates (HR=1.55[1.25-1.92], p <0.001, Figure 2). Compared to AD, Probable LATE had, at baseline, lower hippocampal volumes (b=-0.83[0.27], p <0.01), and higher inferior-temporal to hippocampal volume ratios (b=0.81[0.27], p <0.01). Furthermore, in Probable LATE, atrophy in a whole-brain region-of-interest was slower compared to AD (b=0.14[0.08], p = 0.04). Possible LATE-AD had, at baseline, thinner whole-brain cortex (b=-0.69[0.30], p = 0.02), lower hippocampal volumes (b=-1.54[0.31], p <0.01), and higher inferior-temporal to hippocampal volume ratios (b=1.73[0.30], p <0.01) than AD, but there was no difference in atrophy rates between Possible LATE-AD and the other groups (Figure 3).

CONCLUSION: In a tertiary memory clinic population, the newly proposed clinical LATE criteria reveal clinical and atrophy trajectories that are distinct from AD, especially for Probable LATE and Possible LATE-AD. Differential clinical and biological disease trajectories highlight the relevance of the LATE classification for diagnostic and prognostic purposes.},
}

Humans
Male
Female
*Biomarkers
*Alzheimer Disease/diagnosis/pathology/mortality/diagnostic imaging
Aged
*Cognitive Dysfunction/pathology/diagnosis/diagnostic imaging
Middle Aged
Atrophy/pathology
Cohort Studies
Magnetic Resonance Imaging
Aged, 80 and over
Brain/pathology/diagnostic imaging

@article {pmid41498615,
year = {2025},
author = {Victoriano, PHM and da Silva, VA and Grigoli, MM and de Oliveira, SD and Popolin, CP and de Carvalho Pelegrini, LN and Ramos, AA and Cominetti, MR},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104801},
doi = {10.1002/alz70856_104801},
pmid = {41498615},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *ADAM10 Protein/blood ; Aged ; Biomarkers/blood ; Cross-Sectional Studies ; Middle Aged ; *Amyloid Precursor Protein Secretases/blood ; *Cardiovascular Diseases/blood ; Heart Disease Risk Factors ; Aged, 80 and over ; Alzheimer Disease/blood ; Neuropsychological Tests ; Enzyme-Linked Immunosorbent Assay ; Membrane Proteins ; },
abstract = {BACKGROUND: Cardiovascular risk factors (CVRF) have been strongly implicated in elevating the risk of developing Alzheimer's disease (AD), highlighting the intricate relationship between cardiovascular health and neurodegeneration. In this context, ADAM10 emerges as a promising blood-based biomarker for AD, given its well-established association with amyloid deposition and its potential to provide insights into the link between cardiovascular health and amyloid pathology. This study explores the potential relationship between CVRF and plasma ADAM10 levels in cognitively healthy older adults.

METHOD: In this cross-sectional analysis, the cognitive function was assessed using the Addenbrooke's Cognitive Examination-Revised (ACE-R). The Framingham Score determined the cardiovascular risk profile. ADAM10 plasma levels were measured using Enzyme-linked immunosorbent assays (ELISA). Group comparisons were conducted using the Wilcoxon signed-rank test for continuous variables and the Chi-square test for categorical variables. Linear regression models were employed to investigate associations with cognitive outcomes.

RESULT: The study included 84 adults aged 60 and older, from whom 52 participants (96.2% females) were assigned to the low cardiovascular risk group, whereas 33 participants (15.2% females) were classified as medium/high cardiovascular risk. Despite the robust strength of the association between ADAM10 plasma levels and cognitive scores in non-adjusted analyses (β = 0.162, 95% CI [0.008, 0.316], P = .040), this association did not remain statistically significant in the mutually adjusted model (β = 0.077, 95% CI [-0.048, 0.202], P = .226). As expected, multivariate analyses revealed that older age (β = -0.465, 95% CI [-0.767, -0.162], P = .003) was significantly associated with worse cognitive performance. Conversely, higher levels of formal education (β = 0.774, 95% CI [0.510, 1.038], P < .001) were associated with better cognition.

CONCLUSION: No evidence of a robust association between ADAM10 levels and CVRF was found. The lack of a significant association may be attributed to the insufficient number of participants classified as having high CVR. Larger samples are needed to enable more detailed analyses with optimal group stratification. We speculate that the inclusion of participants with higher levels of formal education may have contributed to this non-significant result, given the association between higher education and preventive health care.},
}

Humans
Female
Male
*ADAM10 Protein/blood
Aged
Biomarkers/blood
Cross-Sectional Studies
Middle Aged
*Amyloid Precursor Protein Secretases/blood
*Cardiovascular Diseases/blood
Heart Disease Risk Factors
Aged, 80 and over
Alzheimer Disease/blood
Neuropsychological Tests
Enzyme-Linked Immunosorbent Assay
Membrane Proteins

@article {pmid41498605,
year = {2025},
author = {Phuah, CL and Parihar, M and Chen, Y and Carr, DB and Lee, JM and Babulal, GM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104724},
doi = {10.1002/alz70856_104724},
pmid = {41498605},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Automobile Driving ; Aged ; Magnetic Resonance Imaging ; Biomarkers ; *White Matter/diagnostic imaging/pathology ; Longitudinal Studies ; Middle Aged ; Brain/diagnostic imaging/pathology ; Alzheimer Disease ; Cognitive Dysfunction ; },
abstract = {BACKGROUND: White matter hyperintensities (WMH) compromise cognitive reserve, potentially accelerating dementia onset in etiologies like Alzheimer's disease (AD). Extant neuroimaging studies link WMH severity to driving cessation in older adults (OA). Region-specific WMH distributions reflect distinct etiologies, offering insights into differential cognitive and functional impacts. We investigated WMH impact on complex cognitive performance through longitudinal analysis of naturalistic driving behavior in OA. Our investigation bridges gaps in understanding how subtle structural changes influence real-world cognitive functioning.

METHOD: We analyzed data from 212 cognitively intact OA (aged ≤65 years, CDR=0) in the DRIVES (Driving Real-World In-Vehicle Evaluation System) Project cohort, with 3T MRI brain scans within two years of starting longitudinal driving assessments. We examined 16 driving metrics aggregated monthly using in-vehicle data loggers, encompassing trip characteristics, speed/acceleration/braking patterns, and route complexity. We quantified WMH using a deep learning algorithm, enabling precise measurements of total WMH volume and region-specific WMH distributions. Linear mixed-effects models with random coefficients, adjusted for demographic factors (age, sex, race, education) and socioeconomic status (area deprivation index), assessed WMH influence on longitudinal changes in driving performance. Significance was set at FDR-adjusted p <0.05.

RESULT: Our study included 74,275 weeks of driving data (2015-2024, average follow-up 6.1 years). Increased WMH burden correlated with decreased trip frequency (p = 0.0005), fewer near-home trips (p = 0.0004), reduced unique destinations (p = 0.0003), and lower driving entropy (p = 0.001) over time. Decrease in driving complexity was primarily driven by posteriorly-located WMH lesions, especially in parietal and occipital regions (β=-0.09, p = 0.002 and β=-0.10, p = 0.0009, respectively) involved in visual processing, motion detection and spatial awareness. WMH impact on driving behavior intensified over time in participants developing cognitive impairment (n = 36), manifesting as increased hard breaking and impact events.

CONCLUSION: WMH in OA significantly impacts driving behavior, leading to latent self-regulation and reduced driving complexity. Cognitive impairment with WMH increases risky driving. Posterior WMH influence suggests a dominant role of AD pathology in driving performance decline. WMH shows potential as a biomarker for identifying individuals at higher risk of unsafe driving and premature driving cessation, highlighting its value in early screening and intervention strategies for road safety among aging populations, particularly those at risk for AD.},
}

Humans
Male
Female
*Automobile Driving
Aged
Magnetic Resonance Imaging
Biomarkers
*White Matter/diagnostic imaging/pathology
Longitudinal Studies
Middle Aged
Brain/diagnostic imaging/pathology
Alzheimer Disease
Cognitive Dysfunction

@article {pmid41498582,
year = {2025},
author = {Gwag, CH and Byun, MS and Yi, D and Ahn, H and Kim, Y and Yoon, Y and Kim, G and Oh, Y and Sohn, BK and Lee, S and Kim, M and Lee, JY and Kim, YK and Lee, YS and Kang, KM and Sohn, CH and Kim, K and Lee, DY},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104664},
doi = {10.1002/alz70856_104664},
pmid = {41498582},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Aged ; *Cognitive Dysfunction/diagnostic imaging/metabolism/pathology ; Positron-Emission Tomography ; Biomarkers/metabolism ; Magnetic Resonance Imaging ; Longitudinal Studies ; *Brain/diagnostic imaging/metabolism/pathology ; Neuropsychological Tests ; Republic of Korea ; Aged, 80 and over ; Disease Progression ; Amyloid beta-Peptides/metabolism ; Cluster Analysis ; Middle Aged ; Neuroimaging ; Amyloid/metabolism ; },
abstract = {BACKGROUND: It remains uncertain whether regional predominance patterns of amyloid accumulation are associated with neurodegeneration rates and the prognosis of Alzheimer's disease (AD) patients. This study aimed to examine differences in longitudinal neurodegeneration rates and clinical trajectories across AD subtypes defined through clustering analysis based on amyloid deposition pattern.

METHOD: Participants were recruited from the Korean Brain Aging Study of Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), started in 2014, Seoul, Republic of Korea. A total 149 amyloid-positive cognitively impaired (CI) older adults consisting of mild cognitive impairment (N = 72) and mild AD dementia (N = 77) were included for this study. Participants underwent clinical and neuropsychological assessments at baseline, as well as at 1-year and 2-year follow-ups. Multimodal neuroimaging, including [[11]C] PiB-PET and MRI, was conducted at baseline and at the 2-year follow-up. Consensus clustering analysis was performed to identify AD subtypes based on regional predominance patterns of amyloid accumulation. Linear mixed-effects models were used for longitudinal analyses.

RESULT: We identified three AD subtypes with distinct regional predominance patterns of amyloid deposition among amyloid-positive CI older adults using consensus clustering analysis: Cluster A (N = 62), characterized by orbitofrontal cortices and dorsal striatum predominance; Cluster B (N = 47), characterized by occipito-temporal predominance; and Cluster C (N = 40), with fronto-parietal predominance. At baseline, there were no significant differences in clinical diagnosis (i.e., MCI vs. AD dementia), clinical severity (i.e., CDR-SOB), global cognition, or neurodegeneration biomarkers such as AD-signature cortical thickness. However, in longitudinal analyses, Cluster C exhibited faster clinical decline and greater cortical atrophy in AD-signature region compared to the other subtypes, even after adjusting potential confounders, including age, sex, education, apolipoprotein E4 positivity, and global amyloid burden.

CONCLUSION: We found distinct longitudinal trajectories regarding both clinical progression and neurodegeneration rates among AD subtypes characterized by different patterns of amyloid predominance. Our findings suggests that an AD subtype with predominant frontal-parietal amyloid deposition may have worse prognosis compared to other subtypes, underscoring the need for subtype-specific therapeutic strategies. Further studies are required to elucidate the relationship between regional amyloid predominance patterns and progression rates of AD.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Aged
*Cognitive Dysfunction/diagnostic imaging/metabolism/pathology
Positron-Emission Tomography
Biomarkers/metabolism
Magnetic Resonance Imaging
Longitudinal Studies
*Brain/diagnostic imaging/metabolism/pathology
Neuropsychological Tests
Republic of Korea
Aged, 80 and over
Disease Progression
Amyloid beta-Peptides/metabolism
Cluster Analysis
Middle Aged
Neuroimaging
Amyloid/metabolism

@article {pmid41498580,
year = {2025},
author = {Prosser, L and Malone, IB and O'Connor, A and Ferguson, D and Alston, D and Rice, H and Pieperhoff, L and Barkhof, F and Fox, NC and Oliveira, TG and Weston, PS},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104802},
doi = {10.1002/alz70856_104802},
pmid = {41498580},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/genetics/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Middle Aged ; Biomarkers ; Aged ; *White Matter/pathology/diagnostic imaging ; *Gray Matter/pathology/diagnostic imaging ; Mutation/genetics ; *Brain/pathology/diagnostic imaging ; Adult ; },
abstract = {BACKGROUND: Previous work has suggested that the grey-white matter contrast (GWC) on T1-weighted MRI may be an early marker of neurodegeneration in Alzheimer's disease (AD). Here we aimed to calculate regional GWC in a familial AD (FAD) population and examine its utility in detecting early neurodegeneration in comparison to traditionally used cortical thickness measures.

METHOD: Seventy individuals from families affected by FAD were included, including presymptomatic mutation carriers, symptomatic mutation carriers and their non-carrier sibling controls (Table 1). The presymptomatic group was split at median estimated years to onset (EYO; median = -9.5 yrs), into early-presymptomatic and late-presymptomatic. Both GWC and cortical thickness were estimated using Freesurfer for six pre-defined regions of interest (ROIs), known to be particularly vulnerable to AD pathology: entorhinal cortex, superior frontal lobe, precuneus, superior parietal lobe, inferior parietal lobe, and supramarginal gyrus. All analyses were age adjusted.

RESULT: Symptomatic mutation carriers had lower GWC than non-carriers in ROIs: the precuneus and superior parietal lobe (p < 0.05), and inferior parietal lobe and supramarginal gyrus (p < 0.07), while cortical thickness was lower in symptomatic carriers across five ROIs (Figure 1). In presymptomatic mutation carriers, GWC was significantly correlated with EYO (a proxy measure of disease stage). Lower GWC was associated with closer proximity to symptom onset in both the inferior parietal and supramarginal cortices, with a negative trend (p ≤ 0.1) for all but one of the ROIs (Figure 2a). This association with EYO during the presymptomatic period was not consistently present for cortical thickness, with only one ROI showing any trend towards an association (Figure 2b).

CONCLUSION: GWC is associated with disease stage and proximity to onset during the 20 years prior to symptoms manifesting; a crucial window for AD therapeutic trials. While cortical thickness measures can detect atrophy in the symptomatic disease stage of AD, it appears less able than GWC to track changes during presymptomatic stages. While the influence of factors such as age and amyloid related inflammation require further investigation, GWC shows promise as an easily accessible clinical MRI tool for disease staging and tracking during the years preceding clinical onset.},
}

Humans
Male
Female
*Alzheimer Disease/genetics/pathology/diagnostic imaging
Magnetic Resonance Imaging
Middle Aged
Biomarkers
Aged
*White Matter/pathology/diagnostic imaging
*Gray Matter/pathology/diagnostic imaging
Mutation/genetics
*Brain/pathology/diagnostic imaging
Adult

@article {pmid41498578,
year = {2025},
author = {Luechaipanit, W and Haethaisong, T and Chongsuksantikul, A and Oangkhana, P and Booncharoen, K and Khieukhajee, J and Likitjaroen, Y and Thanapornsangsuth, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104726},
doi = {10.1002/alz70856_104726},
pmid = {41498578},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; Female ; *tau Proteins/blood ; Male ; *Alzheimer Disease/diagnosis/blood/cerebrospinal fluid ; Aged ; Retrospective Studies ; Amyloid beta-Peptides/cerebrospinal fluid ; Immunoassay/methods ; Positron-Emission Tomography ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Recently, immunoassay-based plasma phosphorylated tau 217 (p-tau217) was commercially available as research used only (RUO) test kit. Due to its exceptional performance compared to other p-tau species and designation as a core early-changing biomarker, p-tau217 may become a standalone for Alzheimer's disease biomarker, potentially gaining regulatory approval in the near future. However, not every immunoassay demonstrates high diagnostic accuracy in clinical setting. In this study, we retrospectively evaluated 146 participants, comparing the performance of single molecule assay (Simoa) on SR-X platform and electrochemiluminescence (ECL) on Meso Scale Discovery (MSD) Quickplex SQ120 platform.

METHOD: Participants with cognitive complaints were enrolled between 2022 and October 2024 during clinical visits at the Memory Clinic at King Chulalongkorn Memorial Hospital and Neurology Clinic at Neurological Institute of Thailand. A head-to-head comparison of commercially available of immunoassay-based plasma p-tau217 quantification was conducted on 146 samples. Amyloid-positron emission tomography (PET) using [[18]F]-Florbetaben or CSF amyloid-β42/p-tau were performed as reference tests to distinguish AD and non-AD patients. Optimal cut-offs were defined using the Youden's Index. Diagnostic performance of both plasma p-tau217 kits was statistically compared using Delong's test, McNemar Test.

RESULT: Among 146 participants enrolled, 100 (68%) were female. The median age was 67 years. With 79 participants (54.1%) were confirmed to have AD. Plasma p-tau217 (MSD) had an area under the curve (AUC) of 0.932 (95% confidence interval (CI) 0.89-0.97) with 90% sensitivity and 85% specificity, while plasma p-tau217 (Simoa) had AUC of 0.919 (CI 0.88-0.96) with 86% sensitivity and 87% specificity for distinguishing AD and non-AD patients. Single cut-point value was evaluated based on Youden index as < 7.45 pg/mL for MSD and < 0.42 pg/mL for Simoa SR-X. Differences are not significant.

CONCLUSION: The diagnostic performance of both immunoassay-based plasma p-tau217 was shown equivalent to benchmark tests, also accurately diagnosing AD among participants enrolled from specialized memory clinic. Utilizing plasma p-tau217 biomarker may serve as an accurate AD diagnostic tool in real-world memory clinic.},
}

Humans
*Biomarkers/blood/cerebrospinal fluid
Female
*tau Proteins/blood
Male
*Alzheimer Disease/diagnosis/blood/cerebrospinal fluid
Aged
Retrospective Studies
Amyloid beta-Peptides/cerebrospinal fluid
Immunoassay/methods
Positron-Emission Tomography
Middle Aged
Aged, 80 and over