bluuebunny/crossref_metadata_2025 huggingface dataset:
From glia to cytokine signatures across the Alzheimer’s spectrum
Authors: Malpetti Maura , Swann Peter , Chouliaras Leonidas , Jones P Simon , Mak Elijah , Bevan‐Jones W Richard , Su Li , Fryer Tim D , Hong Young T , Aigbirhio Franklin I , O'Brien John T , Rowe James B
Published: January 2025

Background

Early neuroinflammation is involved in pathophysiology of Alzheimer’s Disease (AD) and contributes to faster clinical decline. Thus, neuroinflammation has emerged as a promising therapeutic target for dementia. However, a better understanding of the interaction between central and peripheral inflammation in human disease and in vivo biomarkers are required for successful clinical trials. Here we assess inflammatory patterns of serum cytokines and their relationship with central inflammation as quantified by TSPO PET (PK11195) in participants on the aging‐AD spectrum.

Method

Blood samples were obtained from 56 participants, including30 controls, 22 patients with MCI and 14 with AD) Serum cytokines were quantified using the MesoScale Discovery V‐Plex‐Human Cytokine panel. We applied a Principal Component Analysis (PCA) across all participants to identify inflammatory profiles, which were compared across groups with ANOVA and post hoc tests. Individual scores of the resulting components were correlated with regional TSPO PET binding potentials, as index of microglial activation, and cognitive impairment (MMSE scores).

Result

Analyses on 30 identified 2 components (explaining 19.4 % and 10.8% of the variance, respectively). Both components were strongly represented by pro‐inflammatory cytokines (Figure 1A). One‐way analyses of variance on the first component could not detected statistically significant differences across the groups (χ2(2)=1.69, p=0.193), while individual scores of Component 2 (χ2(2)=8.46, p<0.001) were statistically higher in patients with AD as compared to patients with MCI and to controls (Figure 1B). Correlation analyses with regional TSPO PET values identified positive widespread associations with individual Component 2 scores in frontal, temporal and parietal regions (r > 0.250, p < 0.05; while associations with Component 1 where limited to the anterior frontal/temporal regions (Figure 1C). Individual scores of Component 2 but not Component 1 were significantly associated with worse cognitive performance (lower MMSE; r = ‐0.315, p = 0.01).

Conclusion

Our approach identified proinflammatory blood signatures that relate to central inflammation and cognitive impairment across the aging‐AD spectrum. These findings encourage the combination of TSPO imaging and blood‐based markers to clarify the interaction between peripheral and central inflammation in AD, and to identify promising therapeutic targets.
A study and training of careers on effective cognitive therapy for elderly to prevent dementia in Lagos, Nigeria. (Proposed Project)
Authors: Akinyelure Feyikemi Mary , Adeyoola Tolulope , Adeife Adetayo Adetutu , Jet Lucky
Published: January 2025

Background

The immediate family members, trusted caregivers or the society often subject the elderly in Nigeria to abuse. The most vulnerable amongst the elderly are poor and disadvantaged ones who often times are on the receiving end. Effective cognitive training is a non‐pharmacology treatment that focuses on guided practice on cognitive tasks.

AIMS

To train careers in effective cognitive therapy (graded table top activities, memory exercises activities, problem solving games) and activities of daily routine.

To determine the effectiveness of cognitive therapy game impact on older adult in preventing Dementia, Alzheimer e.t, c.

To evaluate the feasibility of the training intervention implementation.

Methods

We'll train 120 health care assistant annually in Lagos Nigeria.

Training: Theoretical (Dementia knowledge), Practical (Dementia assessment and screening)

Evaluation: Standardized Mini Mental‐State Examination and the clock drawing test (CDT)

Expected outcomes.

The primary outcome is to train careers in caring for the elderly effectively which would lead to prolong life.

The secondary outcome is to reduce the impact of dementia through knowledge and skills the careers must have gained.
Large‐scale validation of an improved and resource‐saving immunoprecipitation‐mass spectrometry assay for plasma amyloid‐β biomarkers in Alzheimer's disease
Authors: Chen Yijun , Zeng Xuemei , Olvera‐Rojas Marcos , Sehrawat Anuradha , Lafferty Tara K , Klunk William E , Ikonomovic Milos D , Pascoal Tharick Ali , Erickson Kirk I. , Villemagne Victor L , Cohen Ann D , Yates Nathan , Esteban‐Cornejo Irene , Lopez Oscar L. , Snitz Beth E. , Berman Sarah , Sweet Robert , Karikari Thomas K
Published: January 2025

Background

Amyloid β (Aβ) deposition in the brain is a pathological hallmark of Alzheimer's disease (AD). While immunoprecipitation‐mass spectrometry (IP‐MS) stands out as an accurate method for quantifying blood‐based Aβ peptides, its major limitations such as prolonged sample preparation, extensive analysis time, large specimen volume, and high costs, present opportunities for improvement. Consequently, we aimed to develop a novel plasma IP‐MS Aβ assay that employs simplified and significantly shorter analytical procedures, along with much‐reduced sample volumes.

Method

We evaluated effects of reducing the sample volume, changing the buffers, implementing heavy labeled internal standards, and switching to a more cost‐effective MALDI‐Tof mass spectrometer versus the original Shimadzu IP‐MS Aβ assay (Nakamura et al., 2018 Nature). This led to an improved assay, referred to as the Pittsburgh IP‐MS Aβ assay. Analytical validation covered linearity, accuracy, precision, and recovery. In clinical validation, we compared the new and original Aβ assays for identifying Aβ‐PET positivity and cognitive impairment in two independent cohorts.

Result

The Pittsburgh assay streamlined the immuno‐enrichment step with a novel binding buffer, cutting background noise and reducing processing time by 50%. Additionally, it allowed for potential sample volumes as low as 50 µl and decreased antibody and paramagnetic bead usage by 75% each. The assay utilized the cost‐friendly MALDI‐Tof instrument from Bruker, a departure from the AXIMA Performance platform used in the original assay.

The analytical validation showed consistent signal linearity, improved spike recovery with heavy labeled Aβ1‐40 or Aβ1‐42, but equivalent precision between the two IP‐MS methods. In the AGUEDA cohort (n=148), the Pittsburgh assay demonstrated better AUCs than the older method for identifying Aβ‐PET‐positive individuals. This trend persisted in the University of Pittsburgh ADRC cohort (n=30) when comparing accuracy to identify patients with clinical assessed AD positive.

Conclusion

We have developed a more efficient and cost‐effective IP‐MS plasma Aβ assay, outperforming the original Shimadzu assay in clinical utility, while upholding consistently high analytical performance. The cost, time, and reagent savings along with the utilization of a more affordable and widely available instrument will empower more research laboratories to conduct IP‐MS analysis of Aβ in blood more effectively.
The correlation between inflammatory marker and cognitive performance in TATA Longitudinal Study of Aging cohort
Authors: Arvind Prathima , M L Abhishek , Stezin Albert , Diwakar Latha , C M Amitha , Partha Ajith , Narayanasamy Rajitha , N M Divya , R Meghana , Menon Meenakshi , HS Sunitha , Velavarajan Goutham , Malo Palash K , Singh Sadhana , Vishwanath Vindhya , HS Dev Kumar , Hameed Shafeeq K Shahul , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: January 2025

Background

In the scientific literatures, C‐reactive protein (CRP), a well‐known inflammatory biomarker1, has been closely examined in connection to cognitive function2. However, less knowledge on correlation study between the serum CRP level and different cognitive domain. Therefore, we aimed to study the relation between CRP level and cognition performance in TLSA cohort.

Method

The study involved 1164 participants from the TLSA cohort, an ongoing longitudinal study on aging in Indian urban populations. Cognitive performance was tested using ACE‐III and evaluated CRP levels. Spearman's correlation analysis was performed to see the relation between the CRP level and cognitive performance in whole cohort as well as to identify gender and age‐specific associations between inflammation and cognitive function.

Result

The mean age of the entire cohort was 61.72 ± 9.39 (N=1164), with a gender distribution of 50.5% male and 49.5% female. The median education level stood at 14.5, with a standard deviation (SD) of ± 4.26. Notably, ACE‐total, attention, and visuospatial domains exhibited significant inverse associations with CRP levels across the entire cohort (Table 1). In the subgroup analysis, individuals below 65 years of age showed significant inverse associations between CRP levels and ACE‐total, attention, memory, fluency, and visuospatial domains. However, in the above 65 years age group, only ACE‐Visuospatial demonstrated an inverse association with CRP levels (Table 2a). Further stratification by gender revealed ACE‐attention to be inversely associated in male participants, while ACE‐total and visuospatial domains exhibited associations in the female group (Table 2b).

Conclusion

This study reveals significant inverse connections between CRP levels and cognitive domains, particularly in the younger population, suggesting potential hormonal influences. The findings underscore the need for tailored approaches to understand the complex interplay between inflammation and cognitive function across diverse demographic contexts.
Multi‐Parametric MRI assessment of biomarkers in a non‐human primate model exhibiting sporadic cerebral amyloid angiopathy
Authors: Khan Suleiman , Murray Sean , Szabo Jakub , Soliman Muhammad T , Goldman Hannah , Llanos Michael , Cho Olivia , Schissler Emily , Kingsley Charles , Swain Jody , Gray Stanton B , Hopkins William D , Veraart Jelle , Wisniewski Thomas , Zaim‐Wadghiri Youssef , Scholtzova Henrieta
Published: January 2025

Background

Cerebral amyloid angiopathy (CAA) has been recognized as one of the morphologic hallmarks of Alzheimer disease (AD). The development of new AD drugs has brought unforeseen challenges that manifest as amyloid‐related imaging abnormalities (ARIA) appearing as vasogenic edema/effusion (ARIA‐E) and cerebral microhemorrhage/hemosiderosis (ARIA‐H). The prominence of CAA pathology in aged squirrel monkeys (SQMs), a New World non‐human primate model, underlines the importance of advancing this unique species for use in AD and dementia research. Previously, we demonstrated the effectiveness of atlas‐based R2* mapping, a measure of transverse tissue relaxation rate sensitive to the presence of iron, to discern age‐associated changes in SQM neuropathology along with validation of multiparametric in‐vivo MRIs to identify spontaneous ARIA in geriatric SQMs. The present study examined SQMs at distinct stages of aging by combining quantitative R2* mapping, T2‐weighted (T2‐w) sequences, and multi‐shell diffusion weighted imaging (DWI) to evaluate microstructural tissue integrity, in addition to histological assessment of the brain pathology correlates.

Method

SQMs underwent 2D T2‐w Turbo Spin Echo (TSE) RARE/FLAIR MRI scans, in addition to multi‐shell DWI acquisitions. In vivo multi‐gradient echo (MGE) scans across three age cohorts were utilized to generate R2* maps for atlas‐based quantitative assessments of neuropathology. Coronal brain sections were examined to characterize histopathological features of MRI lesions.

Result

Multiple instances of ARIA‐E‐like signal hyperintensities have been identified in brains of geriatric SQMs using T2‐w TSE RARE/FLAIR and DWI MRI. Furthermore, DWI revealed white matter (WM) abnormalities undetectable by conventional MRI. Absolute R2* values significantly increased with age in several brain regions, both in GM and WM. However, some regions experienced a reversal of this trend, suggesting a multi‐factorial model. Histological assessment of brain tissue corresponding to MRI abnormalities/hyperintensities revealed extravascular fibrinogen, diffuse IgG deposits, reactive gliosis, and disruptions of axons and myelin. In ARIA‐H regions, Perls’ stain confirmed hemosiderin depositions surrounding CAA‐positive blood vessels. Ferritin staining revealed microglial cells with characteristic morphology alongside colocalization of iron within microglia cell bodies.

Conclusion

Overall, this study demonstrates the complex interplay between ARIA, CAA, and age‐related brain changes in SQMs, highlighting the utility of this model for translational research on CAA/AD and innovative therapeutic interventions.
Assessing the feasibility of dried blood spot (DBS) collection for blood‐based biomarkers of Alzheimer’s Disease in rural South Africa
Authors: Gao Sarah , Bassil Darina T. , Wagner Ryan G. , du Toit Jacques , Huber Hanna , Ashton Nicholas J. , Cotton‐Samuel Dejania , Farrell Meagan T. , Mngomezulu Victor , Manly Jennifer J. , Tollman Stephen , Berkman Lisa F. , Zetterberg Henrik , Brickman Adam M.
Published: January 2025

Background

The characterization of Alzheimer’s disease (AD) and AD related dementias (ADRD) pathophysiology has been revolutionized by the development of highly sensitive blood‐based biomarkers. Although blood‐based biomarkers allow for greater access, cost effectiveness, and scalability, there are limitations for their implementation in resource‐constrained low‐ and middle‐income countries (LMICs) and rural settings, where access to equipment, freezers, and assays is often limited. Dried blood spot (DBS) collection emerges as a promising, convenient, and cost‐effective method for acquiring blood samples in these contexts, but it is unclear whether highly sensitive assays typically applied to cerebrospinal fluid (CSF), plasma, or serum can detect biomarker concentrations accurately. This pilot study assessed the feasibility of using DBS to measure blood‐based AD biomarkers by examining the agreement between ADRD biomarker concentrations derived from DBS and from plasma in older adults in rural South Africa.

Method

Data were collected from the Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI), an ongoing population cohort of 5,059 adults aged ≥40 years living in Agincourt, South Africa. This study focuses on a sub‐sample of 95 participants, whose venous blood and DBS were collected during the HAALSI visit and later tested for blood‐based ADRD biomarkers, including neurofilament light chain (NfL), phosphorylated‐tau181 (p‐tau181), and glial fibrillary acidic protein (GFAP). Plasma and DBS markers were analyzed using commercially available Single molecule array assays (Quanterix) at the University of Gothenburg. We ran pairwise correlations that examined the association between the plasma and DBS measures of p‐tau181, NfL, and GFAP.

Result

The sample consisted of 70.5% women, with an average age of 67.53 years (SD=9.69). We observed a positive correlation between plasma and DBS GFAP concentrations (r=0.78, p‐value<0.001). However, DBS and plasma concentrations were not correlated for p‐tau181 (r=0.05, p‐value=0.62) or for NfL (r=‐0.04, p‐value=0.68).

Conclusion

These preliminary analyses suggest that GFAP concentration, a marker of astrogliosis, can be measured consistently in DBS. These findings have important implications for the selection and analysis of AD blood‐based biomarkers in low‐resource and LMIC settings, where venous blood draws may not be feasible.
Genome‐wide association of Tau imaging and plasma biomarkers in adults with Down Syndrome
Authors: Fan Kang‐Hsien , Aslam Muhammad Muaaz , Dang Lam‐Ha T , Gorijala Priyanka , Shi Ruyu , Feingold Eleanor , Kamboh M. Ilyas , Lee Joseph H. , Xicota Laura , Cohen Ann D , Handen Benjamin L , Christian Bradley T. , Head Elizabeth , Mapstone Mark , Cruchaga Carlos ,   Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS)
Published: January 2025

Background

Adults with Down Syndrome (DS) clearly show a higher risk of developing Alzheimer's disease (AD) when compared with the general population. Thus, it is important to investigate the role AD‐related biomarkers in adults with DS. Here we have performed genome‐wide association analyses on Tau‐PET and plasma Tau levels in the participants of the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS).

Method

Genome‐wide analyses were performed on 320 individuals of European descent DS (ranging in age from 25 to 81, Male 54.1%) having biomarker data from Tau‐PET as well as plasma p‐tau 181, p‐tau 217, and total tau. The association of these biomarkers with two APOE SNPs, rs429358 (E4) and rs7412 (E2) was also examined. We used a joint model of multiple phenotypes to investigate the genetic factors contributing to all Tau biomarkers simultaneously in those participants having complete phenotypic and genotypic data.

Result

In the APOE association analysis, APOE4 was not significantly associated with any biomarker. However, individuals carrying APOE2 had lower plasma p‐tau‐181 levels (p= 0.0017) than non‐carriers. In a genome‐wide analysis, we identified three novel genome‐wide significant (GWS) associations. The first association was with plasma total Tau on chromosome 11 near JHY (top SNP= rs77264104; MAF=0.017; p=1.75E‐08; β=‐1.52). The second association was with Tau‐PET on trisomy chromosome 21 near a long coding RNA LOC105372747 (top SNP= rs76523946; MAF=0.034; p=2.04E‐08; β=0.61). Lastly, the multiple phenotype analysis revealed association with all Tau AD biomarkers on chromosome 7 in the intronic region of SEM1 (Top SNP= rs78223947; MAF= 0.039; p=1.44E‐08).

Conclusion

We have identified three novel associations with Tau biomarkers in adults with DS associated with either lower tau or higher tau biomarkers. Two of these associations (JHY and SEM1) have also been implicated potentially with Tau pathology and AD risk, respectively, in non‐DS participants. This investigation underscores the potential of leveraging the DS population as a valuable resource for discerning genetic elements that contribute to AD or AD‐related biomarkers.
Examination of Sex‐dependent sleep disruptions and OSA severity on Limbic System Integrity in Community‐Dwelling Cognitively Unimpaired Older Adults
Authors: Gills Joshua L , Cesar Oliver , Kovbasyuk Zanetta , Dharmapuri Anhiti , McBride Julian , Mbah Alfred , Valkanova Elena , Figueredo Luisa F , Parekh Ankit , Jean‐Louis Girardin A , Varga Andrew , Osorio Ricardo S. , Bubu Omonigho M
Published: January 2025

Background

Microstructure impairments of the limbic tracts are seen in early stages of the Alzheimer’s disease (AD) continuum. Sleep disruptions differ between sexes and have been linked with AD. We examined sex differences between measures of limbic white matter tracts and objective sleep parameters in cognitively unimpaired older adults.

Method

This cross‐sectional study included 170 community‐dwelling cognitively unimpaired older adults (mean±SD: age=67.2±5.2y) participating in NYU studies of sleep, aging, and memory. Subjects completed polysomnography (NPSG) and brain MRI. Sleep measures of interest included total sleep time (TST), NREM stages 2, 3 and REM sleep duration, sleep efficiency and fragmentation, and AHI4% and REM AHI4%. Microstructural properties of the cingulum, uncinate fasciculus (UF), and fornix were estimated using diffusional tensor imaging (DTI) metrics including radial kurtosis (RK), radial diffusivity (RD), and fractional anisotropy (FA). Linear mixed‐effects regression models examined associations between sex*sleep variables and DTI metrics. Models were adjusted for age, race, education, BMI, time between NPSG and MRI.

Result

Participants were 71.2% female, 44.1% Black/African‐American, and had 16.8±2.5y of education. In the cingulum, females showed increased fragmentation associated with decreased FA(β[IV]= β[SE}; β[fragmentation Left] =‐0.0023[0.00097], p=0.021), higher RD (β[fragmentation Right] =0.0021[0.00087], p=0.016; β [fragmentation Left] =0.0032[0.00096], p=0.001), and lower RK (β[fragmentation Right] =‐0.0055[0.00253], p=0.039). Additionally in the cingulum, females demonstrated higher AHI4% being associated with lower FA (β[AHI4% left]=‐0.0005[0.00026], p=0.054), higher RD (β [AHI4% left] =0.0006[0.00036], p=0.029), and lower RK (β [AHI4% Right] =‐0.0014[0.00069], p=0.052); and, less time spent in REM was associated with higher RD (β [REM left] =‐0.0016[0.00077], p=0.042). In the UF, females showed greater sleep fragmentation being related to higher RD (β[Fragmentation Left]=0.0045[0.00173], p=0.010) and lower RK (β[Fragmentation]=‐0.00077[0.00034], p=0.027), higher AHI4% was related to higher RD (β[AHI4% Right]=0.00072[0.00030], p=0.015). In the cingulum, men showed more NREM stage 3 sleep being associated with greater RK β[NREM 3 Left]=0.0065[0.00279], p=0.021). In the UF, men with higher AHI4% demonstrated associations with lower RK β[AHI4% Right]=‐0.0016[0.00080], p=0.046).

Conclusion

In this sample of community‐dwelling cognitively unimpaired older adults. Sex‐specific sleep disruption associations were observed with limbic white matter tract alterations. Thus, highlighting possible sleep related underpinnings of sex differences in Alzheimer disease risk.
Relationship of retinal vasculature with measures of amyloid, tau, and neurodegeneration across the AD continuum
Authors: Mathew Sunu , Mackay Devin , Tallman Eileen F. , Deardorff Rachael , Hottle Savannah , Vosmeier Aaron , Clark David G. , Farlow Martin R. , Brosch Jared R. , Gao Sujuan , Apostolova Liana G. , Saykin Andrew J. , Risacher Shannon L.
Published: January 2025

Background

The eye often reflects changes seen in the brain in neurodegenerative diseases. This study sought to examine the relationship of retinal vasculature measured using optical coherence tomography angiography (OCTA) with temporal lobe neurodegeneration, and cerebral amyloid and tau deposition, in older adults along the Alzheimer’s disease (AD) continuum.

Method

Participants included 13 cognitively normal subjects, 5 with subjective cognitive decline (SCD), 7 with cognitive impairment (mild cognitive impairment [MCI] and AD) from the Indiana Memory and Aging Study at the Indiana ADRC. Participants were excluded from the study if they had significant eye disease determined to interfere with OCTA, non‐AD dementia, or exclusion for MRI or PET. OCTA scans were obtained from each eye to measure retinal vessel density and perfusion density. MRI scans were processed using Freesurfer v6 to measure medial (MTL) and lateral temporal lobe (LTL) volumes. LTL SUVR values were extracted from [18F]flortaucipir PET scans. Finally, the association between retinal perfusion and vessel density with hippocampal volume, MTL tau, and lateral parietal amyloid was assessed using a partial Pearson correlation, covaried for age, sex, and diagnosis. p<0.05 was considered significant.

Result

Retinal vessel and perfusion density were decreased in patients with AD. The right and left hippocampal volume were significantly correlated with retinal vessel density and perfusion density in the right eye and left hippocampal volume was correlated with vessel density in the left eye, but it did not reach significance. The retinal vessel density and perfusion density in the right eye correlated significantly with lateral parietal lobe amyloid and medial temporal lobe tau. Finally, the total gray matter volume correlated significantly with the retinal vessel density and perfusion density in the right eye and inversely with the foveal avascular zone in the right eye.

Conclusion

Retinal perfusion and vessel density correlates with hippocampal atrophy, and general atrophy of the gray matter. It is also significantly correlated with the deposition of amyloid and tau in the brain. Imaging the retinal vasculature may represent a useful biomarker to screen patients at risk for AD prior to more invasive and prolonged testing.
Neuroimaging features of CSF α‐synuclein seed amplification assay positivity in elderly individuals in AD continuum
Authors: Tosun Duygu , Landau Susan M. , Weiner Michael S. W. , Blauwendraat Cornelis ,   Alzheimer's Disease Neuroimaging Initiative
Published: January 2025

Background

While Aβ and tau pathologies are central to AD, emerging evidence suggests the coexistence of Lewy body pathology (α‐synuclein aggregates), further contributing to neurodegenerative processes. Our objective was to investigate the association between CSF α‐synuclein seed amplification assay (SAA) positivity and in vivo neuroimaging metrics of florbetapir‐PET and flortaucipir‐PET retention, as well as atrophy measured by structural‐MRI, with a focus on Aβ+ cognitively impaired (MCI and Dementia due to AD) individuals.

Method

Participants from ADNI who were Aβ+ (CSF Aβ42<980 pg/mL) and had undergone SAA analysis, along with based on florbetapir‐PET, flortaucipir‐PET, or structural‐MRI scans within one year of CSF sample collection, were included in the analysis (Table 1). Utilizing generalized ridge regression with connectivity‐informed adaptive regularization, SAA‐associated patterns of cross‐sectional neuroimaging features, as well as SAA‐associated patterns of the longitudinal rate of change in neuroimaging features were modeled, adjusting for age, sex, APOE ε4 status, and clinical diagnosis with additional adjustments for CSF Aβ42 levels in flortaucipir models and CSF Aβ42 and p‐tau181 levels in atrophy models. Significant associations (95% CI) were determined through 50,000 bootstrap‐based sampling.

Result

In cross‐sectional analysis (Figure 1; top row), compared to SAA‐ individuals, SAA+ was associated with: (1) greater florbetapir‐SUVR, observed in the bilateral middle and superior temporal, banks of superior temporal, left middle frontal and postcentral cortices; (2) elevated flortaucipir‐SUVR in bilateral insula, left superior temporal and postcentral cortices; and (3) greater atrophy in left middle frontal and lateral orbitofrontal, right anterior cingulate and banks of superior temporal cortices, as well as greater GM tissue volume in right inferior temporal cortex. Although the longitudinal sample size was limited, SAA+ was associated with: (1) lower rates of change in florbetapir in bilateral middle/lateral orbitofrontal and anterior cingulate cortices; and (2) higher rates of atrophy in bilateral middle frontal, right inferior parietal, left pre/postcentral and inferior frontal cortices, and lower rates of atrophy in right anterior and posterior cingulate cortices (Figure 1; bottom row).

Conclusion

Our results reveal that SAA‐positivity in individuals on the AD continuum is associated with distinctive patterns of neuroimaging features, highlighting the multifaceted nature of neurodegeneration in AD.
Low Incidence of Amyloid Related Imaging Abnormalities over 104 Weeks in a Phase 2 Study of Amyloid Anti‐Oligomer Agent ALZ‐801: Phase 2 Study Results in Biomarker Positive APOE4 Carriers with Early Alzheimer’s Disease (AD)
Authors: Kesslak Patrick , Abushakra Susan , Bracoud Luc , Hey John A. , Barakos Jerome , Hort Jakub , Prins Niels D. , Suhy Joyce , Power Aidan , Tolar Martin
Published: January 2025

Background

Oral ALZ‐801 (valiltramiprosate), a brain‐penetrant agent that inhibits amyloid‐oligomer formation is being evaluated in a fully enrolled APOLLOE4 Phase 3 trial in APOE4/4 homozygotes with Early Alzheimer’s disease (AD). ALZ‐801 effects on plasma AD biomarkers were evaluated in a 104‐week Phase 2 study in APOE4‐carriers with CSF+ AD biomarkers. APOE4 is a major risk factor for amyloid‐related imaging abnormalities (ARIA) in AD patients. Incidence of ARIA‐H (microhemorrhages, MH; superficial siderosis, SS) and of ARIA‐E (edema/effusion) was analyzed.

Method

This study enrolled 84 subjects (31 APOE4/4, 53 APOE3/4) MMSE ≥22 and CDR‐G 0.5 or 1.0, with positive amyloid and CSF p‐tau181 ≥60 pg/ml. Subjects received ALZ‐801 at 265 mg BID over 104 weeks, with MRI at baseline, 52 and 104 weeks following a standardized protocol including 2D FLAIR and T2* Gradient Echo. Study allowed subjects with any number of MH, but ARIA‐E and SS lesions >1cm were exclusionary. Data were evaluated centrally by Clario neuroradiologists for eligibility assessment and ARIA safety monitoring. The study’s primary outcome was plasma p‐tau181 reduction at 104 weeks.

Result

At baseline, mean age and MMSE were 69 years and 26 respectively, with 52% female and 70% MCI subjects. Of 84 enrolled, 83, 75 and 69 subjects had baseline, 52‐week and 104‐week MRI. Baseline MRIs showed >1 MH in 7/83 (8%), and 6/75 subjects (8%) with post‐treatment MRI developed new MH, all asymptomatic. At baseline, 5 subjects had 1‐4 MH, of whom 2 developed new MH (3‐4); 1 subject had >10 MH and developed 29 new MH. 3 subjects developed de novo MH (1‐3). There was no SS or ARIA‐E. Study primary outcome was achieved with significant p‐tau181 reduction (31%, p = 0.045) and 4% Aβ42 reduction (p = 0.042), with memory stabilization over 2 years (Hey, ADPD 2024).

Conclusion

The Phase 2 APOE4‐carrier population with positive CSF biomarkers showed low incidence of microhemorrhage (8%) over 2 years, all asymptomatic, with no siderosis or ARIA‐E. This 265 mg BID ALZ‐801 dose showed significant target engagement and promising cognitive effects in this study. These data suggest a low risk of ARIA with ALZ‐801 in APOE4 carriers with Early AD.
Clinical Impact of Amyloid PET in Diverse Medicare Beneficiaries with Cognitive Impairment: Preliminary Results from New IDEAS
Authors: Rabinovici Gil D. , Gatsonis Constantine , Dilworth‐Anderson Peggye , Gareen Ilana F , Glavin Emily , Hanna Lucy , Hillner Bruce E , March Andrew , Romanoff Justin , Siegel Barry A , Smith Karen , Weber Christopher J. , Windon Charles , Whitmer Rachel A. , Wilkins Consuelo H. , Carrillo Maria C.
Published: January 2025

Background

The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study demonstrated that amyloid PET changes patient management in >60% of Medicare beneficiaries with MCI/atypical dementia. IDEAS had limited racial/ethnic diversity and excluded patients with “typical” amnestic clinical presentations. Here we present preliminary results from the New IDEAS study, which evaluates the clinical impact of amyloid PET in a more racially, ethnically and clinically diverse cohort.

Method

Launched in December 2020, the New IDEAS study (NCT04426539) is recruiting Medicare beneficiaries with typical (amnestic) and atypical (non‐amnestic) MCI/dementia at 142 dementia specialty clinics across the U.S. Multifaceted, community‐engaged and culturally‐tailored strategies are implemented to enhance the diversity of the cohort. Based on self‐identified race/ethnicity, patients are enrolled into 1 of 3 cohorts: Black/African‐American (BAA), Latino/Hispanic (LAT), or not BAA or LAT (NBL, all other racial/ethnic identities). Patients undergo amyloid PET using an FDA‐approved tracer with local visual read at 127 imaging facilities. Changes in management are measured between the pre‐PET visit (intended management, assuming no access to amyloid PET) and 90‐day post‐PET visit (implemented management, incorporating amyloid PET results). A composite management endpoint captures changes in one or more of the following: AD drug therapy, non‐AD drug therapy, counseling about safety and future planning.

Result

Out of 5,209 registered participants, 3,328 (63.9%) participants completed amyloid PET, pre‐ and post‐PET visits at time of analysis (median age 74; 55.2% female; 22.6% BAA/17.5% LAT). Demographic and clinical features by cohort are shown in Table 1. Compared to NBL, BAA and LAT cohorts presented with greater clinical impairment, more frequent atypical clinical presentations and lower rates of amyloid PET positivity. Changes in the composite management endpoint occurred in 57.5% of all participants (57.2% MCI, 58.1% dementia), with similar rates across cohorts (Table 2). Following PET, anti‐amyloid antibodies were newly recommended in 7.0% of BAA, 7.4% of LAT and 9.0% of NBL. Changes in management were more frequent in typical than atypical clinical presentations (Table 3).

Conclusion

These preliminary findings highlight the clinical utility of amyloid PET in a diverse and representative sample of cognitively impaired patients recruited in real‐world practice.
MTL networks are differentially affected by tau pathology
Authors: Hrybouski Stanislau , Das Sandhitsu R. , Xie Long , Wisse Laura E.M. , Kelley Melissa , Lane Jacqueline , Sherin Monica , DiCalogero Michael , Nasrallah Ilya M. , Detre John A. , Yushkevich Paul A. , Wolk David A
Published: January 2025

Background

The extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional alterations in the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. Here, we examined the relationship between tau accumulation in the (trans)entorhinal cortex and functional connectivity (FC) in two MTL‐affiliated brain networks — the Anterior‐Temporal (AT) and Posterior‐Medial (PM) — in normal agers, individuals with preclinical AD, and patients with symptomatic AD.

Method

In this cross‐sectional study, we analyzed data from 125 individuals from the Penn ADRC (Table 1). All participants underwent structural and functional MRI on a Siemens 3 T Prisma system, as well as 18F‐Florbetaben and 18F‐Flortaucipir (FTP) PET imaging. We used the AT/PM network architecture from our previous work (Figure 1; PMID37767219) and analyzed the effects of (trans)entorhinal tau accumulation on the AT/PM FC as a function of distance to the MTL (Figure 1). Guided by our previous findings of an inverted U‐shaped FC pattern in the AT network over the course of the disease, we performed separate analyses of the AT FC in cognitively normal and symptomatic individuals.

Results

FC between the anterior MTL and its direct neighbors in the AT network was positively correlated with tau accumulation in the MTL (r = 0.201, p = 0.031; Figure 2a). Associations with tau were not present in other MTL‐AT connections (Figures 2b‐c) or in individuals with symptomatic AD. In contrast, the PM FC was broadly affected by tau pathology with both direct MTL‐PM and more distant connections showing a negative relationship to (trans)entorhinal tau (Figure 2d‐e). Excluding amyloid‐negative controls, the relationship between MTL tau and AT/PM FC remained statistically significant in the PM [one‐hop connections: r = ‐0.323, p = 0.0479; distant connections: r = ‐0.324, p = 0.047] but not the AT network.

Conclusions

Together, the current results implicate functional abnormalities in the AT network during the preclinical stage, while those in the PM network are closely related to disease severity. This dissociation likely represents distinct pathophysiology in AD and has potential implications for FC‐based metrics as a surrogate measure for assessing functional response to disease‐modifying immunotherapies.
Differential whole‐brain patterns of cardiometabolic risk and blood biomarker using multi‐modal neuroimaging and explainable deep learning
Authors: Ma Da , Lockhart Samuel N. , Hughes Timothy M. , Bateman James R. , Register Thomas C. , Mielke Michelle M. , Gurcan Metin Nafi , Craft Suzanne
Published: January 2025

Background

Cardiometabolic disorders are emerging risk factors for Alzheimer's disease (AD) and AD‐related dementia (ADRD). There is currently insufficient understanding of how different cardiometabolic profiles and blood biomarkers impact different AD‐related brain pathology regionally. This project uses data‐driven approaches and explainable artificial intelligence methods to determine the cardiometabolic and fluid contributions toward AD‐related pathophysiologic patterns in the brain.

Method

A total of 504 participants from the Wake Forest Alzheimer's Disease Research Center (Mean age=70.1, female/male=327/177, cognitive‐comal/mild‐cognitive‐impairment/dementia/other=217/172/45/7, White/Black/Asian/Native=416/81/4/3) had 3T MRI and cardiovascular risk factors (pulse pressure = systolic ‐ diastolic blood pressure), fasting metabolic risk factors (hemoglobin A1c, fasting glucose, insulin, and lipid levels), obesity measures (hip‐to‐waist ratio, and body mass index [BMI]) and plasma biomarker (pTau181, Glial‐fibrillary‐acidic‐protein [GFAP], A Multi‐modal neuroimaging‐based regional brain phenotypes were extracted from T1, T2FLAIR, and ASL imaging sequences to derive structural volume and thickness (FreeSurfer parcellated regions), white matter hyperintensity (WMH) volume, and blood flow information. Regional cerebral blood flow phenotypes were derived from parcellated ASL images registered to the MNI template space using the AAL atlas. Whole‐brain linear association analysis was conducted, followed by a multi‐layer‐perceptron (MLP) deep‐learning‐based non‐linear regression model along with feature importance analysis (Shapley‐Additive‐exPlainations [SHAP]).

Result

Figure 1 shows the heatmap of multi‐modal whole‐brain linear association patterns. Blood biomarkers (pTau181, GFAP) showed an overall strong association with structural data (T1, T2FLAIR), while metabolic factors (esp. fasting insulin and BMI) showed a strong association with ASL (esp. in white matter). The deep‐learning‐based neuroimaging feature importance (SHAP value, Figure 2) further revealed a relatively higher impact of ASL data on various cardiometabolic risk and blood biomarkers than the linear association pattern, indicating potential whole‐brain non‐linear association of cerebral blood flow.

Conclusion

The current study demonstrated differential whole‐brain association patterns across multi‐domain cardiometabolic risk factors. Furthermore, the explainable deep learning approach revealed additional localized brain regions compared to whole‐brain association analysis, especially in gray matter regions from the regional AAL signal. Future studies will incorporate additional neuroimage modalities and derive individual domain‐specific CMR‐associated whole‐brain patterns.
Age‐Related Declines in Cerebral Blood Flow are Moderated by Sex, but not APOE ε4, in Mild Cognitive Impairment
Authors: Sanchez Danielle L , Sabbah Maria G , Bennett Ilana J
Published: January 2025

Background

Age‐related disruptions in cerebral blood flow have been linked to increased Alzheimer’s disease risk. At least one study in cognitively unimpaired (CU) older adults found that cerebral blood flow varies with interactive effects of age, sex, and Apolipoprotein (APOE) ε4 status. However, it remains unknown whether these effects are stronger in older adults diagnosed with mild cognitive impairment (MCI). Therefore, the current study examined the moderating effects of sex and APOE ε4 status on age‐related differences in cerebral blood flow separately in CU and MCI groups.

Method

Perfusion‐ and T1‐weighted magnetic resonance imaging data and APOE ε4 status (ε4+, ε4‐) were obtained from 111 CU and 49 MCI Alzheimer’s Disease Neuroimaging Initiative (ADNI3) participants at their baseline visit. Cerebral blood flow was measured as the average perfusion within anatomical masks of bilateral cortical lobes (frontal, temporal, parietal, occipital) and the hippocampus. Multiple linear regressions tested the effect of each moderator (sex, APOE ε4 status) on the relationship between age and cerebral blood flow separately in each region of interest and each cognitive status group.

Result

For the MCI group, results revealed both independent and interactive effects of Age and Sex on cerebral blood flow in the frontal, parietal, and occipital lobes, with the age‐related decline in cerebral blood flow being stronger in males than females. There were no significant effects of Age, Sex, or their interaction on cerebral blood flow in the hippocampus. Moreover, there were no significant effects of APOE ε4 status on cerebral blood flow nor moderation of Age on cerebral blood flow in any region. For the CU group, there were no significant effects of Age, Sex, APOE ε4 status, or their interactions on cerebral blood flow.

Conclusion

The age‐related decline in cortical lobe cerebral blood flow was stronger in males with clinically diagnosed MCI. This finding indicates that sex and cognitive status, but not APOE ε4 status, are important moderators of cerebrovascular health.
Association of APOE genotype and ELOVL2 methylation with brain function in non‐demented adults during aging
Authors: Ponomareva Natalya V , Andreeva Tatiana V , Kuznetsova Irina L , Protasova Maria , Kunizheva Svetlana , Kupryanova Daria , Konovalov Rodion , Krotenkova Marina V. , Kolesnikova Ekaterina P , Malina Daria , Kanavets Elena V. , Fokin Vitaly , Illarioshkin Sergey N , Rogaev Evgeny I
Published: January 2025

Background

The ε4 allele of the apolipoprotein E (APOE4+) genotype and aging synergistically contribute to the risk of Alzheimer's disease (AD), but the mechanisms underlying their influence are not completely understood. The methylation of ELOVL2 DNA accounts for 70% of the variance in the aging epigenetic clock. The ELOVL2 gene is essential for synthesizing long polyunsaturated fatty acids, crucial for cell membrane integrity, inflammation modulation, and energy maintenance. This study investigated the impact of APOE genotype and ELOVL2 methylation on EEG alpha rhythm and functional MRI (fMRI) resting‐state functional connectivity (rsFC) of brain networks in non‐demented adults during aging.

Method

We examined EEG alpha sub‐bands power and individual alpha peak frequency (IAPF) and the fMRI rsFC in 151 non‐demented volunteers, age range 20‐84 years, stratified by APOE genotype. APOE ε3/ε3 subgroup (APOE4‐) included 104 subjects, APOE ε4/ε3 (APOE4+) subgroup – 47 subjects. ELOVL2 cg16867657 methylation was examined in the blood in subgroup of 56 individuals (35 APOE4‐ and 21 APOE4+). The individuals underwent fMRI tsFC of the brain using the CONN Matlab/SPM‐based toolbox (Whitfield‐Gabrieli and Nieto‐Castanon, 2012). Informed written consent was obtained from all participants. All subjects underwent a neurological examination and cognitive screening.

Result

The presence of the APOE4+ genotype was associated with more pronounced alpha rhythm slowing and more pronounced decrease of fMRI rsFC during aging. Age‐related increase of ELOVL2 methylation was observed. The partial correlation analysis, with age as a covariate, revealed a significant correlation between ELOVL2 methylation and IAPF.

Conclusion

More pronounced alpha rhythm slowing and fMRI rsFC reduction in APOE4+ carriers during aging can be linked to synaptic dysfunction and deterioration of white matter integrity. Impaired lipid metabolism, driven by age‐dependent ELOVL2 methylation, may accelerate the impact of the APOE4+ genotype on neurophysiological alterations during aging. These changes increase the risk of AD developed.

Funding:

This study was supported by Russian Science Foundation (Project No. 19‐75‐30039 to TA genotyping; Project No. 22‐15‐00448 to NP, RK, VF, EK EEG and fMRI analysis and MP for genotyping) and by Ministry of Science and Higher Education of the Russian Federation (Agreement 075‐10‐2021‐093 project GEN‐RND‐2017).
Repeat Testing Reliability of Plasma pTau217 in Preclinical AD
Authors: Rissman Robert A. , Langford Oliver , Raman Rema , Donohue Michael C. , Molina‐Henry Doris P. , Abdel‐Latif Sara , Sims John R. , Yaari Roy , Holdridge Karen Chilcott , Johnson Keith A , Aisen Paul S. S. , Sperling Reisa A
Published: January 2025

Background

Data from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial (NCT02008357), including cognitively unimpaired participants with brain amyloid pathology on florbetapir F 18, demonstrates that levels of plasma P‐tau217, as detected by an electrochemiluminescence (ECL) immunoassay, is strong predictor of elevated cerebral amyloid on florbetapir PET in cognitively unimpaired individuals. Here we compare plasma P‐tau217 measures over 12 weeks using a P‐tau217 ECL immunoassay.

Method

A4 trial placebo‐group participants who had their first baseline and first post‐baseline plasma P‐tau217 samples collected within 175 days of each other were included in these analyses. This time was chosen to maximize the number of available samples while minimizing the likelihood of significant change. The coefficient of variation (CV) was used to measure relative variability between samples computed as the difference in plasma P‐tau217 values, and the “test‐retest” performance of the plasma P‐tau217 assay was evaluated using an intraclass correlation coefficient (ICC) from a two‐way mixed‐effects model. A Box‐Cox data transform was performed due to significant observed heteroscedasticity in the P‐tau217 values.

Result

Analysis sample included 573 A4 study participants (mean age: 71.9 +/‐ 5 years, mean florbetapir SUVr: 1.33 +/‐ 0.18; days between assays: 86.5 +/‐ 6.5 days; 59.9% female sex). Low levels of variability were observed between the samples with a coefficient of variation of 7% and the test‐retest reliability was ICC=0.90 (ICC: 0.90; 95% CI: 0.89, 0.92).

Conclusion

A P‐tau217 ECL immunoassay showed low levels of variability between samples and excellent test‐retest reliability over 12 weeks in cognitively unimpaired individuals with elevated cerebral amyloid.
Exploring the effects of using multiple different cerebellar reference regions to improve tau‐PET harmonization ‐ The HEAD Study
Authors: Bauer‐Negrini Guilherme , Povala Guilherme , Bellaver Bruna , Lussier Firoza Z , Tissot Cécile , Tsai Hsin‐Yeh , Amaral Livia , Ferreira Pamela C.L. , Tudorascu Dana , Jagust William J. , Klunk William E , Lowe Val J. , soleimani‐meigooni David N. , Oh Hwamee , Pascual Belen , Gordon Brian A. , Rosa‐Neto Pedro , Baker Suzanne L. , Pascoal Tharick A.
Published: January 2025

Background

Tau‐PET tracers have been used to diagnose and stage Alzheimer’s disease. However, different tau tracers present distinct patterns of binding throughout the brain, challenging the harmonization of their results. We hypothesize that the choice of a reference region can impact the harmonization of the tau‐PET standardized uptake value ratio (SUVR). In this context, we aimed to explore how different cerebellar reference regions impact the association between [18F]Flortaucipir and [18F]MK‐6240 SUVR values.

Method

We studied 185 individuals across the aging and AD spectrum with head‐to‐head Flortaucipir and MK‐6240 tau PET (HEAD Study). SUVRs were processed to a common 8mm FWHM using 15 different reference regions defined in the spatially unbiased atlas template of the cerebellum (SUIT) (Diedrichsen, 2009). Regression models investigated the association between Flortaucipir and MK‐6240 using multiple combinations of reference regions. R2 statistic was used to estimate goodness‐of‐fitting.

Result

225 combinations of associations Flortaucipir and MK‐6240 SUVR were tested, where the SUVRs are not necessarily quantified using the same reference region. Figure 1 presents the top 25 strongest and 25 weakest associations, ordered based on the coefficient of determination (R²). Flortaucipir and MK‐6240 exhibited the most robust associations when the inferior cerebellar gray matter or Crus I were employed for SUVR determination (R2=0.89, Figure 1‐2). Conversely, combinations incorporating the fastigial region consistently yielded weaker associations between the two tracers (R2<0.70, Figure 1‐2).

Conclusion

Interestingly, we showed that the inferior cerebellum, when used for both tracers, serves as a robust reference region for determining the most similar SUVRs for Flortaucipir and MK‐6240. Notably, these two regions have been commonly utilized in previous studies involving these tau tracers. Our results imply that the inferior cerebellum could be the optimal reference region for research aimed at harmonizing tau PET tracers using statistical scales.