bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain delivery of erythropoietin results in a significant reduction of brain Aβ and spatial memory deficits in the APP knock‐in mouse model
Authors: Chang Rudy Tieu , Chandrashekar Devaraj V. , Roules Grace‐Ann Chuli , Iwasaki Emi , Jagadeesan Nataraj , Sumbria Rachita K.
Published: January 2025

Background

Although novel treatments for Alzheimer’s disease (AD) have begun to show modest therapeutic effects, agents that target hallmark AD pathology and offer neuroprotection are desired. Erythropoietin (EPO) is a glycoprotein hormone with neuroprotective effects but is faced with challenges including limited brain uptake and increased hematopoietic side effects with long‐term dosing. Therefore, EPO has been modified and bound to a chimeric transferrin receptor monoclonal antibody (cTfRMAb); the latter shuttles EPO past the blood‐brain barrier (BBB) into brain parenchyma and reduces its plasma exposure and potential for side effects. Our study sought to characterize the safety and pharmacokinetics (PK) of modified EPO following chronic dosing in healthy mice, and then utilize the optimized dose in mitigating hallmark AD pathologies in APP‐SAA knock‐in (KI) mice, a model that recapitulates Aβ pathology in the absence of APP overexpression, in vivo.

Methods

For the PK and safety study, a multidose design was employed with 10‐week‐old C57BL/6 male mice (n = 4‐5/dose) receiving doses ranging from 1‐ to 20‐mg/kg SQ for 4 weeks, aimed to evaluate the dose‐dependent plasma concentrations, and metabolic and hematologic safety of the modified EPO. The dose that resulted in the highest safety and sustained plasma exposure was dosed SQ to 5.5‐month‐old male APP‐SAA KI mice (n = 6) for 14 weeks. Control APP‐SAA KI mice (n = 5) received vehicle. The effect of modified EPO on Aβ load by immunoassays, and spatial memory via Y‐maze test, were assessed.

Results

The 1mg/kg dose resulted in no adverse effects and sustained plasma exposure which are conducive to longitudinal dosing. APP‐SAA KI mice treated with the modified EPO had a remarkable (70‐80%, p<0.001) reduction in 6E10‐positive‐Aβ plaque area and number in the brain. Aggregated Aβ measured by ELISA was also significantly lower (p<0.05) with modified EPO treatment. Modified EPO increased the discrimination index for the novel arm (p<0.05), suggesting an improvement in spatial memory recall of the reinforced arm of the maze.

Conclusions

These findings provide essential data for dose optimization for longitudinal studies using cTfRMAb‐based therapeutics, and specifically modified EPO used herein, and illustrate the therapeutic potential of the brain‐penetrating cTfRMAb‐EPO in a novel AD mouse model devoid of APP overexpression.
Solving synaptic PET‐biomarker puzzle in Alzheimer's and other tauopathies with UCB‐J
Authors: Scarpa Miriam , Vallera Elisavet , Ausellé‐Bosch Sira , Rocha Filipa Monteiro , Mercan Buse Esra , Nordberg Agneta K , Kumar Amit
Published: January 2025

Background

Synaptic loss is an eminent feature of tauopathies. The recently developed novel SV2A PET‐tracer UCB‐J has shown great promise in tracking synaptic loss in tauopathies. However, there have been discrepancies between the in vivo findings and a lack of mechanistic insight. Many of these studies indicated potential correlations between tau deposition, atrophy, cognitive‐impairment, and loss of UCB‐J binding. Hence, we found it of utmost relevance to perform extensive pre‐clinical validation of UCB‐J in tauopathic brains to gain a deeper understanding of synaptic loss for future PET‐biomarker validation.

Method

We applied an innovative multidimensional approach of postmortem brain imaging techniques (large and small frozen brain section autoradiography) and radioligand binding studies (saturation, competition, and regional distribution) alongside in‐depth biochemical analyses using a large repertoire of synaptic markers in Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and control brains.

Result

Saturation/competition studies showed one‐binding site (Kd: 3‐10 nM) for UCB‐J in the frontal cortex and globus pallidus (GP) of AD, PSP, and control brains. UCB‐J regional binding studies at the synaptosomal level clearly showed synaptic loss in different regions of AD and PSP brains as compared to control brains. In AD brains, the loss of UCB‐J binding showed the following order: Hippocampus > Frontal cortex > Temporal Cortex > Parietal Cortex > Cerebellum. Immunoblot analyses showed a positive‐correlation between UCB‐J binding and expression of synaptic proteins SV2A, synaptophysin, and synaptotagmin and demonstrated association with GABA/glutaminergic neurotransmitter machinery in GP of PSP brains. Interestingly, cortical and sub‐cortical 4R‐tau load distinctly affected synaptic marker protein levels in PSP brains. Large brain‐section autoradiography studies in AD brains indicated potential ‘off‐target’ interaction of UCB‐J with nuclear P‐tau. PSP brain's small brain‐section autoradiography also showed higher binding in cortical regions, specifically, in the parietal cortex where significantly (*p=0.034) higher 3H‐UCB‐J binding was observed compared to CN.

Conclusion

Our studies explicitly showed the high specificity of UCB‐J for SV2A and demonstrated synaptic deficits/loss in AD and PSP brain regions. Ongoing studies will shed more light on the interplay between different synaptic and pathological markers and help establish the reliability of UCB‐J as a definite marker of synaptic density/loss for tauopathies.
Exploring the role of telomere length in the efficacy of an exercise intervention for vascular cognitive impairment: a 12‐month randomised controlled trial substudy
Authors: Packer Amy , Barha Cindy K , Hsiung Ging‐Yuek Robin , Ambrose Caitlin E. , Pflueger Shannon , Tam Roger , Madden Kenneth , Field Thalia S , Davis Jennifer C , Wong Tsz Y. , Malanchini Margherita , Dima Danai , Powell Timothy R. , Liu‐Ambrose Teresa
Published: January 2025

Background

Subcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Exercise is a potentially effective intervention for SIVCI. However, the mechanisms through which exercise promotes brain health and cognitive function are not well understood. Telomere length restoration and an increased capacity for cellular proliferation may provide a putative mechanism. Therefore, in this exploratory study we aimed to 1) assess the effect of a resistance training program on leukocyte telomere length; and 2) determine whether telomere length and/or change in telomere length is related to intervention response (i.e., change in cognitive function and/or brain structure).

Method

The sample consists of a subset of participants from a 12‐month single‐blinded, randomized controlled trial (ClinicalTrials.gov Identifier: NCT02669394). Participants (N = 91) were randomized to twice‐weekly resistance training (RT) or an active control group (balance and tone exercises; BAT). Study eligibility included: 1) age 55 years and older; 2) magnetic resonance imaging (MRI) evidence of cerebral small vessel disease; 3) mild cognitive impairment; and 4) the absence of dementia. We measured participants’ leukocyte (blood) telomere length at baseline, 6 months, and 12 months, using a qPCR‐based method. The intervention outcomes include cognitive function measured by the Alzheimer’s Disease Assessment Scale‐Cognitive‐Plus (ADAS‐Cog‐13 with additional cognitive tests) and structural brain magnetic resonance imaging (MRI) markers of SIVCI (e.g., white matter hyperintensities).

Result

We have generated telomere length data, demonstrating very good reproducibility with an intraclass correlation coefficient (ICC) of 0.853 [0.772, 0.907]. We will present findings that provide novel insights into the usefulness of telomere length as a predictive biomarker for intervention response. Furthermore, our work will contribute to the mechanistic understanding of exercise‐induced benefits for cognitive and brain health in SIVCI.

Conclusion

To our knowledge, this is the first study to investigate the role of telomere length in the efficacy of an exercise intervention for vascular cognitive impairment. This could inform the development of personalised interventions and aid the discovery of novel therapeutic targets.
Cross‐cultural adaptation and validation of everyday functioning for traditional Chinese in Taiwan
Authors: Chen Poyu , Wu Chin‐Yi , Chuang I‐Ching , Huang Yu‐hua , Hsu Jung‐Lung , Sikkes Sietske A.M
Published: January 2025

Background

Detecting functional performance decline from normal aging to dementia is critical for early detection and intervention. The informant‐based A‐IADL‐Q‐SV has been demonstrated with good psychometric properties. The aims of this study were to: (1) translate, culturally adapt, and validate the Traditional Chinese version of the A‐IADL‐Q‐SV‐TC for Taiwanese; (2) evaluate the psychometric properties.

Methods

We conducted the forward and backward translations with culture adaptation, followed by the consensus meeting with the original developer. The psychometric properties were investigated in both community and memory clinic settings. The Mini‐Mental State Examination (MMSE) and ICF‐based IADL scales were evaluated to test the construct validity and concurrent validity, respectively. Furthermore, diagnoses were established in a multidisciplinary consensus meeting, independent of the A‐IADL‐Q‐SV‐TC scores. The discriminate validity was examined by investigating the difference in A‐IADL‐Q‐SV‐TC between diagnostic groups across the dementia spectrum as well as the optimal cut‐off score to differentiate MCI from cognitively intact populations.

Results

146 informants of participants with normal cognition (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia participated this study. Results showed strong correlation between A‐IADL‐Q‐SV‐TC T‐score and both MMSE (r = .850, p <.001) and ICF‐based IADL scales (CDI, r = ‐.874, p <.001; DI, r = ‐.903, p <.001). As for the discriminate validity, participants diagnosed with cognitive impairment had lower A‐IADL‐SQ T‐scores (M= 45. 68, SD = 13.92) than participants without cognitive impairment (M = 65.03, SD = 4.53), t (85.521) = 11.227, p < .001. Furthermore, the overall diagnostic accuracy based on the AUC was 0.915 (95% CI: 0.87‐ 0.96) for the A‐IADL‐Q‐SV‐TC. The optimal cut‐off score for A‐IADL‐Q‐SV‐TC to differentiate MCI from cognitively intact populations was 54.58, resulting in a sensitivity of 0.72 and specificity of 0.98.

Conclusions

We demonstrated the A‐IADL‐SQ‐TC has sound psychometric properties as a valuable diagnostic tool.
COX‐2 as a potential blood based biomarker and a possible therapeutic target in Alzheimer’s Disease
Authors: Kumari Sakshi , Dey Sharmistha
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive brain disorder which leads to gradual decline in memory, thinking, behaviour and social skills. The current scenario for drug development is based on neuro‐inflammation and oxidative stress. Amyloid‐β (Aβ) deposition, a major hallmark of the disease activates microglia leading to neuro‐inflammation and neuro‐degeneration induced by activation of COX‐2 via NFkB p50 in glioblastoma cells.

Method

The level of proteins and their mRNA in blood of study groups were measured by surface plasmon resonance(SPR) and further validated by western blot and quantitative polymerase chain reaction (qPCR), respectively. The binding of designed peptide with COX‐2 was confirmed by SPR. Also, the rescue of neurotoxicity by peptide was checked by MTT assay on SH‐SY5Y cells (neuroblastoma cell line).

Result

Proteins and mRNA were found to be highly expressed in AD and MCI compared to GC. However, level of COX‐2 decreases with disease duration. The peptide showed binding affinity with COX‐2 with low dissociation constant in SPR and rescued the neurotoxicity of SH‐SY5Y cells by decreasing the level of Aβ, Tau and pTau proteins.

Conclusion

It can be concluded that COX‐2 protein can serve as a potential blood‐based biomarker for early detection and can be a good platform for therapeutic intervention for AD.
Hypothalamic involvement and biomarker candidacy in Alzheimer’s disease in Down syndrome
Authors: Brown Stephanie S G , Zaman Shahid , O'Brien John T ,   ABC‐DS Consortium
Published: January 2025

Background

Poor sleep is emerging as an important and modifiable risk factor in the development of dementia. The hypothalamus is the only neuroanatomical site of orexin‐producing neurones in the brain and modulates sleep and wakefulness behaviour. Due its small size and lack of defined contrast in conventional neuroimaging acquisitions, relatively little evidence exists as to the role of the hypothalamus in humans in neurodegeneration and sleep quality, and whether it may have mechanistic importance and biomarker candidacy.

Methods

A total of 353 participants with DS and 37 sibling controls underwent structural brain scanning at 3T as part of the ABC‐DS international consortium research project. Hypothalami were segmented in the T1‐weighted images (Figure 1) and assessed volumetrically as proportional to intracranial volume (ICV) and grey matter volume.

Results

Whole hypothalamic volumes, when normalised to ICV, are significantly reduced in people with DS who have mild cognitive impairment (MCI) and dementia compared to those who are healthy (p < 0.05) (Figure 2). Additionally, smaller hypothalamic volumes normalised to ICV were significantly associated with poorer cognitive performance (p < 0.05). When normalised to grey matter volume, which controls for the atrophic processes of dementia on a whole brain level, we find that healthy people with DS disproportionally smaller hypothalamic nuclei developmentally. Specifically, hypothalamic volume in the anterior‐inferior sub‐nucleus is significantly smaller in people with DS with an AD diagnosis (p < 0.05) when normalised to grey matter volume, and significantly associated with age (p < 0.05), indicating an accelerated or preferential atrophy in this location. Larger hypothalamic volumes were associated with being overweight or obese.

Conclusions

These findings suggest that the whole hypothalamic structure is sensitive to AD‐related atrophic processes (Figure 3), which are not present in sibling controls, and that hypothalamus volume is closely associated with cognitive performance in DS. The finding of an anterior‐inferior nucleus‐specific atrophy in AD which is disproportionate to whole brain grey matter loss is supportive of this region having an accelerated decline which may be linked to sleep as a risk factor or sleep‐related dementia symptomatology, as it is known to contain the suprachiasmatic nucleus.
The impact of BDNF on the interplay between sleep time and cognitive function
Authors: Zeynoun Joy , Wiedner Crystal , Baril Andree‐Ann , Young Vanessa M. , Bernal Rebecca , Beiser Alexa S , Pase Matthew P. , Seshadri Sudha , Himali Jayandra J.
Published: January 2025

Background

Disrupted sleep patterns have been shown to exacerbate Alzheimer's disease (AD) risk, potentially because of sleep's role in memory consolidation and synaptic plasticity. Recent evidence highlights that high brain‐derived neurotrophic factor (BDNF) levels, a protein enabling neuroplasticity and memory functions, could play a protective role in age related cognitive impairment. We examined the association between total sleep time and cognition, and BDNF levels as a potential modifier.

Method

Third Generation, Omni 2, and New Offspring cohorts from the Framingham Heart Study Exam 2 (2008‐2011) were included (n=2,344; age 48(9.1) y; 48%F; Table 1). Self‐reported total sleep duration was categorized as: short sleep duration (≤6h), average sleep (7‐8h, reference), and long sleep duration (≥9h). A composite measure of global cognition was calculated from neuropsychological tests, including Trails B, visual reproduction (VR), logical memory (LM), and similarities. A multivariable linear regression estimated the association between sleep duration and global cognition, and individual cognitive tasks. We further tested effect modification by BDNF level (median split).

Results

Long sleep duration was associated with worse global cognition (β±SE: ‐2.19 ±0.06; p<.001), compared to average sleep (Table 2). The association between sleep duration and individual cognitive tests are shown in Table 2. BDNF levels significantly modified the association of sleep duration with global cognition (p=0.03). Long sleep duration was associated with poorer global cognition (‐0.17±0.08; p=0.04) in persons with lower BDNF, but not in those with higher BDNF levels (Table 3). Finally, short sleep duration was associated with poorer global cognition (‐0.1±0.05; p=0.04) only among those with higher BDNF (Table 3).

Conclusion

Long sleep duration was associated with poorer global cognition, an effect most notable in those with lower BDNF levels. Short sleep duration was also associated with worse global cognition, but in those with higher BDNF. An appropriate sleep duration may promote neuronal integrity and prevent age‐related cognitive disorders. Further studies shall elucidate the role of BDNF in the interplay between sleep duration and cognition.
Brain Functional Connectivity During Stroop Task and CSF Amyloid/tau in Cognitively Healthy Individuals
Authors: Al‐Ezzi Abdulhakim , Astraea Natalie , Yu J , Wu Xiaomeng , Fonteh Alfred N. , Minazad Yafa , Kloner Robert A , Arakaki Xianghong
Published: January 2025

Background

At the pre‐clinical stages of Alzheimer’s disease (AD) development, the accumulation of amyloid‐β (Aβ) and tau induces neural toxicity, synaptic dysfunction, and excitation/inhibition instability of neural network activity, leading to cognitive decline. However, the effects of Aβ/tau accumulation on electroencephalography (EEG) functional connectivity (FC) in cognitively healthy (CH) individuals during a cognitive challenge have not been elucidated. Therefore, the main objective of this work is to evaluate the association between Aβ/tau level and brain FC during a cognitive challenge in CH individuals.

Method

Established EEG data was recorded using a 21‐EEG sensor headset (Wearable Sensing, DSI‐24) during a cognitive challenge (Stroop interference test). Amyloid‐β and total‐tau proteins were measured from cerebrospinal fluid (CSF) using electrochemiluminescence. We assessed FC at sensor level using Partial Directed Coherence (PDC) from EEG data of CH participants including 22 normal CSF Aβ/tau ratio (CH‐NAT) and 24 pathological CSF Aβ/tau (CH‐PAT). For each trial type (congruent or incongruent) in the Stroop task and each of 19 sensors, linear regression was used to estimate the difference in mean FC between CH‐NAT and CH‐PAT, while controlling for age, gender, and years of education. The Benjamini–Hochberg procedure was used to control the false discovery rate below q = .1.

Result

Compared with CH‐NATs, CH‐PATs exhibit higher causal connectivity at specific sensors which each had an estimated local effect size index Cohen’s f2 >0.15, and putatively represent brain regions including medial prefrontal cortex (Fz, Fp1, and F8), central cortex (Cz and C4), and posterior cingulate cortex (Pz). For each of the same sensors, the estimated difference between CH‐NAT and CH‐PAT had an adjusted P value below .1.

Conclusion

These findings suggest a potential association between the CSF Aβ42/tau pathology and differences between individuals in brain connectivity during a cognitive challenge. These differences may involve compensatory mechanisms as the brain adapts to the amyloid/tau pathology. These results provide potential insights into the neurobiological implications of varying CSF amyloid/tau on brain networks. The areas with estimated medium‐to‐large effect sizes are favorable to doing a study with a lower significance level to confirm the findings.
Evaluating BDNF Levels in Plasma and its Relationship to Established Biomarkers of Alzheimer’s Disease
Authors: Kueck Paul J , Honea Robyn A , Kemna Riley E , Burns Jeffrey M , Morris Jill K
Published: January 2025

Background

Plasma biomarkers show a promising future to improving the quality of diagnosing Alzheimer's Disease (AD). However, blood processing procedures should be considered when measuring plasma biomarkers. Here we investigate brain‐derived neurotrophic factor (BDNF) in platelet‐rich and platelet‐poor plasma. Furthermore, we examine the relationship between BDNF and pTau181, a known biomarker of AD, in comparison to healthy older adults (CH).

Method

98 participants (21 AD) completed a clinical and cognitive examination, a fasting blood draw and MRI scan. Participants with cognitive impairment other than dementia were excluded. Cognitive scores were standardized to yield a global z‐score. EDTA platelet‐rich plasma (PRP) was centrifuged 1500xg for 10min, while platelet‐poor plasma (PPP) was generated by immediately centrifuging a second time at 1700xg for 15min. Biomarker analyses were performed on Simoa HD‐X (Quanterix). T1‐weighted images were collected on a Siemens 3.0T scanner. Gray matter volume (GMV) was calculated using CAT12 toolbox and normalized to total intracranial volume. Log transform was used to normalize biomarker data. Diagnostic differences were assessed using ANOVA controlling for age and sex, and relationships between continuous variables were analyzed via linear regression.

Result

There were no differences in age and sex between groups. As expected, AD global cognitive z‐scores (p<0.001) and GMV (p<0.001) were lower compared to CH. BDNF measured from PRP was significantly greater than PPP (p<0.001). Group differences were not observed in PRP BDNF (p=0.765), and AD were trending to have lower PPP BDNF (p=0.075) compared to CH. AD were observed to have elevated pTau181 (p=0.015) compared to CH. pTau181 showed a negative association with GMV across both groups (β=‐0.252, p=0.012). PPP BDNF showed a positive association to pTau181 in the AD (β=0.645, p=0.008) but not in the CH.

Conclusion

Platelets can release BDNF and thus it’s important to remove during processing to better reflect circulating BDNF levels. BDNF protects against tau‐related neurodegeneration in animal models. Here we see cross‐sectionally a relationship between BDNF and pTau181. The positive association may reflect a compensatory mechanism, given BDNF’s known role in neuroplasticity. Further research is needed to better understand the possible mechanism involved and the long‐term relationship between these biomarkers.
Using fixel‐based analysis to understand the role of crossing fibers in age‐related white matter decline
Authors: Sathe Aditi , Shashikumar Niranjana , Moore Elizabeth E. , Pechman Kimberly R. , Schilling Kurt , Landman Bennett A. , Gifford Katherine A. , Bender Andrew R. , Hohman Timothy J. , Jefferson Angela L. , Archer Derek B.
Published: January 2025

Background

Aging is linked to significant white matter abnormalities, which are often studied using traditional diffusion tensor imaging (DTI) metrics; however, these traditional metrics have limited sensitivity/specificity to neurobiological characteristics. Here, we use fixel‐based analysis (FBA) – an approach with more precision in areas of crossing fibers – to study age‐related white matter microstructural decline.

Method

This study uses cross‐sectional data from the Vanderbilt Memory & Aging Project cohort [n=325, age at baseline: 72.9 ± 7.3 years, 40% mild cognitive impairment (MCI)]. Diffusion MRI was preprocessed using the PreQual pipeline and MRtrix was used to calculate fiber density (FD), fiber‐bundle cross‐section (FC), their combined effect (FDC), and complexity (CX) of the multi‐fiber organization within a voxel. To account for heterogeneity in the number of crossing fibers, the TractSeg Bottleneck atlas was split into distinct low/medium/high regions‐of‐interest (ROIs) based on the number of white matter bundles converging within a single voxel. Fixel‐based metrics were then quantified in each ROI. We conducted a linear regression to determine the association between age and all FBA metrics, covarying for age, sex, education, race/ethnicity, apolipoprotein‐e4 status, and cognitive status.

Result

FD, FC, and FDC all show significant decline with age, with the primary fiber bundle displaying the greatest reductions in FDC (p<0.0001). This decrease is predominantly driven by changes in FD, while FC remains relatively consistent over time. Alterations to the primary fiber bundle are the most prominent in the high and medium bottleneck ROIs as opposed to low (p<0.0001). FBA of the cingulum bundle (a tract vulnerable to abnormal aging) also showed differential decline in FD and FC over time. Figures 1‐3 provide illustrations of notable findings. The low/medium/high bottleneck ROIs correlate exceedingly well with global CX, supporting the use of the Bottleneck atlas to interpret structural white matter differences.

Conclusion

This study provides novel insights into the micro‐ and macro‐structural differences underlying age‐related white matter alterations. The findings underscore the value of FBA in characterizing age‐related white matter degeneration, particularly in regions susceptible to bottleneck effects. This research also lays the foundation for future investigations into tract‐specific patterns of neurodegeneration in aging.
Retinal perivascular amyloid imaging in relationship to MRI neuroimaging abnormalities and cognitive impairment
Authors: Dumitrascu Oana M , Doustar Jonah , Fuchs Dieu‐Trang , Koronyo Yosef , Sherman Dale S. , Miller Michelle , Johnson Ken , Carare Roxana O. , Verdooner Steven R , Lyden Patrick , Schneider Julie A. , Black Keith L , Koronyo‐Hamaoui Maya
Published: January 2025

Background

Scanning laser ophthalmoscopy (SLO) visualizes two important markers of cognitive dysfunction in the retina: vascular changes and amyloid plaque (AP) deposition. The relationship between retinal arteriolar versus venular changes and perivascular amyloid deposition across the continuum of neurodegeneration is imperfectly understood. We investigate the retinal perivascular AP distribution in relationship to cognitive and neuroimaging measures in a cohort of cognitively normal and impaired individuals.

Method

34 subjects with normal or impaired cognition underwent retinal SLO, brain magnetic resonance imaging and standard neuropsychometric testing. Retinal peri‐arteriolar and peri‐venular curcumin positive AP were quantified in the supero‐temporal retinal quadrant, in the first, second and third‐order retinal vascular branches. The peri‐venular and peri‐arteriolar AP count were compared between patients with normal and impaired cognition, and their correlation with brain volumes, white matter hyperintensities and cognitive Z‐scores was determined.

Result

We analyzed retinal para‐venous and para‐arteriolar amyloid count in 28 subjects, mean (SD) age 65 (7.3), 50% female, 19 (52.6%) with impaired cognition. Para‐arteriolar plaque count was higher than peri‐venular plaque in the entire cohort (p<0.0001). Secondary branch peri‐venular amyloid plaque count was higher in patients with MOCA ≤26. Tertiary branch perivascular AP count significantly and negatively correlated with hippocampal volume and positively correlated white matter hyperintensity lesion count.

Conclusion

Retinal AP deposit peri‐arteriolarly overall and peri‐venularly in the secondary branches in cognitively impaired. Perivascular amyloid burden in small retinal branches correlates with hippocampal volume and white matter hyperintensities.
ApoE genotype and hippocampus have heterogenic influence on diagnosis and cognitive performance in the UCD ADRC longitudinal diversity cohort
Authors: Min Eva , Farias Sarah Tomaszewski , Johnson David K , Jin Lee‐Way , Maillard Pauline , Fletcher Evan , Whitmer Rachel A. , Decarli Charles
Published: January 2025

Background

The UCD ADRC longitudinal diversity cohort consists of individuals from diverse backgrounds including White, Black African or Hispanic/Latino Americans that vary in cognitive ability from normal to dementia. Prior studies show differences in the pathological substrate of dementia in this group1 as well as the relationship between MRI measures and cognition2. Prior work also indicates differential influence of ApoE genotype on dementia by race3. For this study, we analyzed the influence of ApoE genotype and hippocampal volume on episodic memory performance and clinical syndrome of normal (NL), mild cognitive impairment (MCI) or dementia as a group and stratified by race/ethnicity.

Method

Methods of participant recruitment and assessment for the UCD ADRC have been previously described4 Clinical syndrome was determined by a multispecialty group and coded according the UDS5. Episodic memory was measured by the SENAS6. Hippocampus was quantified using published methods7. Multivariate linear and logistic regressions were used to assess the relationships between ApoE4 genotype, diagnosis, cognition, and hippocampal volume for the entire group in addition to stratified analyses for each ethnoracial group. All analyses were adjusted for age, sex, and education (and race/ethnicity as needed).

Result

Subject characteristics are summarized in Table 1. In brief, this is a cohort diverse in race/ethnicity, cognitive ability, and educational achievement.

For the entire group, odds ratios for ApoE4 prevalence were significantly higher comparing NL to MCI (1.7, p= 0.002), NL to Dementia (3.1, p <0.001) and MCI to dementia (1.7, p=0.004). ApoE4 (Table 2) was also significantly associated with smaller hippocampus (β=‐0.14, p<0.001)) and poorer memory (β=‐0.21, p<0.001). In models where hippocampus is included, both measures are associated with episodic memory and syndrome.

Different results were found for the stratified analysis where ApoE4 was not associated with syndrome or episodic memory among Blacks (Table 3). Hippocampal volume was also not associated with ApoE among Hispanic/Latinos.

Conclusion

The relationship between ApoE genotype, hippocampus, syndrome, and memory performance is variable by ethnoracial background with only White participants showing associations of ApoE with both hippocampal volume and cognition. Further evaluation is needed to understand possible causes for these differences.
Distinct Spatial Patterns for White Matter Microstructure Changes in an Aging and Alzheimer’s Disease Cohort
Authors: Tian Jianqiao , Raghavan Sheelakumari , Cogswell Petrice M , Reid Robert I. , Przybelski Scott A. , Schwarz Christopher G. , Graff‐Radford Jonathan , Lowe Val J. , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Vemuri Prashanthi
Published: January 2025

Background

White matter (WM) damage is seen with neurodegenerative and cerebrovascular pathologies and contributes to cognitive dysfunction. We hypothesized that there are multiple disease progression patterns in WM microstructural changes related to aging and dementia, and these can be identified using SuStaIn (data‐driven clustering algorithm for disease subtype and stage discovery) on multishell diffusion MRI (NODDI) data. NODDI provides information on cellular tissue architecture – neurite density index (NDI) measures packing density of axons and dendrites, and free water fraction (FWF) measures unrestricted water, e.g., interstitial and cerebrospinal fluid.

Method

We identified 1136 participants (mean age=70 years, 51% male, 40% Aβ‐positive, 19% MCI/AD dementia) from the Mayo ADRC and Mayo Clinic Study of Aging. We analyzed NDI and FWF in 55 WM regions. We selected a subset of WM features that monotonically changed with clinical disease progression and then applied the Z‐score SuStaIn algorithm.

Result

NDI in seven regions and FWF in six regions survived selection criteria (Figure 1). Noteworthy, the NDI regions were predominantly located in the temporal lobe, while FWF regions were primarily distributed in the frontal and subcortical regions. The SuStaIn algorithm discovered two stable clusters: the NDI‐First (Temporal) and FWF‐First (Frontal) groups (Figure 2). For the NDI‐First group, temporal lobe NDI changed early followed by frontal FWF. The FWF‐First group had the reverse order. There was clear phase separation based on which measure changed first. Stages of the NDI‐First group correlated better with meta‐ROI Tau‐PET SUVR and with MMSE than the FWF‐First group (p<0.01), suggesting that NDI‐First may be indicative of a primarily AD pathway.

Conclusion

Given NDI changes are likely degenerative and FWF are suggested to be other processes such as neurodegeneration or inflammatory, the observed changes in the temporal and frontal regions may be due to distinct etiologies, i.e., neurodegenerative in the temporal lobes vs. vascular dysfunction often observed in the frontal lobes. The SuStaIn algorithm showed promise in discovering disease subtypes of WM microstructural changes. Further work is needed to understand the mechanistic basis of these observed changes and integrate WM changes for differential etiology identification and disease staging.
Understanding sex differences in neuroimaging biomarkers and clinical trials
Authors: Buckley Rachel F.
Published: January 2025

The most recent Alzheimer’s clinical trials, including those which reported successful outcomes, use neuroimaging biomarkers of both amyloid and tau for screening participants and demonstrating a treatment effect on pathology. Some of these trials, notably Lecanemab, hint at a potential sex bias in treatment outcome, alluding to major implications for clinical practice when recommending treatment options. Sex differences in treatment response are not surprising given that women are at greater risk of progression to AD dementia, particularly if they carry APOEe4. Clinical trials, however, do not tend to sex disaggregate their topline results. Over the past 5 years, many independent studies across the world have reported sex differences in neuroimaging biomarkers of tau through positron emission tomography (PET). Women, primarily those with higher levels of amyloid, show significantly higher tau signal in the medial temporal and lateral temporal regions of the brain than men, after adjusting for age. This sex difference is evident not only in clinically normal middle and older‐aged adults, but also in diverse populations, and those with clinical impairment. Sex differences in tau‐PET also translate to faster rates of cognitive decline in women than men. Most recently, our group conducted a meta‐analysis of 1,286 unimpaired adults from four longitudinal cohorts including Alzheimer’s Disease Neuroimaging Initiative, Harvard Aging Brain Study, Wisconsin Registry of Alzheimer’s Prevention and Mayo Clinic Study of Aging. Among individuals with elevated baseline amyloid, women exhibited significantly faster tau accumulation in the medial and lateral temporal gyrus. This is some of the strongest evidence to date to suggest that not only could screening for clinical trials be effected by sex differences, but that treatment response – impacted by lowering pathological burden – could be highly sex‐specific. In this talk, we will present simulated data to demonstrate the issue of sex‐biases in tau baseline and accumulation levels to influence treatment response outcomes. We sit at a junction in the field where knowledge from observational studies of sex differences in AD neuroimaging biomarkers has not yet filtered through to clinical trials. This will be critical to ensure that both sexes are well served by treatment outcomes.
Leveraging biofluid markers as a real‐time window to understand molecular drivers of sex differences in AD clinical trials
Authors: Casaletto Kaitlin B.
Published: January 2025

Women account for almost two‐thirds of Alzheimer’s disease (AD) cases, yet evidence significantly less clinical benefit from recently deployed amyloid‐lowering therapies. To close this disparity gap, there is an urgent need to identify biological drivers of sex differences in the manifestation and clinical response to AD therapeutics. A recent review of multi‐omic studies of AD reported >75% of studies showed female‐specific changes at the molecular level (vs. 20% showing male‐specific changes), including enrichment in innate and adaptive immune system changes. However, the majority of these studies rely on brain tissue, which lacks temporal resolution needed to address questions related to real‐time biological responses to treatment. We propose that deep molecular phenotyping of human biofluids [blood, cerebrospinal fluid (CSF)] may offer a key window to understand in‐vivo biological signatures driving sex differences in response to AD therapies. Technological advancements in biofluid quantification now enable early, scalable detection of AD biology and have been used to show target engagement for recent amyloid antibody therapies. Both Lecanemab and Donanemab show significant improvements in CSF and plasma phosphorylated tau (p‐tau) and GFAP, for instance. Yet, despite p‐tau and GFAP evidencing sex differences in converging observational studies, clinical trials have not historically sex disaggregated their data. Newer high‐throughput platforms now allow capture of >thousands of analytes from one human biofluid sample. These approaches are shedding light on novel pathways implicated in AD, evidence cross‐tissue utility, and may allow dynamic quantification of the molecular signatures that change with AD treatment in a person‐specific manner. Human in‐vivo proteomic studies in other diseases highlight their utility for disentangling sex‐differences biology. For instance, a recent study examining the most commonly used medications in adults identified hormonal contraceptives as having the single largest effect on the plasma proteome. In cardiovascular disease, large‐scale plasma proteomics have identified differential pathways underlying cardiac disease in men versus women and identified novel molecular targets that may explain sex differences in response to heart failure treatments. In this session, we will underscore the opportunity to leverage in‐vivo biofluid analytics to develop a sex‐aware understanding of AD therapeutics.
The association of birth in the Stroke Belt and neuroimaging brain biomarkers in a cohort of older Black Americans
Authors: Lor Yi , George Kristen M. , Peterson Rachel , Gutierrez Sirena , Posis Alexander Ivan B. , Decarli Charles , Barnes Lisa L. , Gilsanz Paola , Whitmer Rachel A.
Published: January 2025

Background

Having ever lived in the southeastern United States, a region referred to as the Stroke Belt (SB), is associated with higher dementia incidence and poorer late‐life cognition. We assessed whether birth in the SB was associated with late‐life MRI‐based regional brain volumes among racially/ethnically diverse older adults who are long‐term residents of Northern California.

Method

KHANDLE and STAR are harmonized cohort studies of long‐term members (ages ≥65 and ≥50, respectively) of an integrated healthcare delivery system. A sub‐sample of participants received MRI imaging, which included regional gray matter and ventricle volumes and total white matter hyperintensities (WMH). The analytic subsample was limited to US‐born Black participants given so few from other ethno‐racial groups were born in the SB. Self‐reported state of birth was dichotomized as birth in the SB or non‐SB. Linear regression models analyzed associations of SB birth with twelve MRI regions of interest, standardized for total cranial volume (except free water and fractional anisotropy). All models adjusted for age at MRI scan, sex, parental education, and own education. Sensitivity analyses were performed in those aged ≥65.

Result

Of 304 participants (mean age=70.8, SD=8.5), one‐third (n=117) were born in the SB (Table 1). Those born in the SB were older (mean age=75.4±7.6), less likely to be college educated (33% vs. 41.5%), and less likely to have parents with a high school diploma (21.4% vs 38.9%). Birth in the SB was associated with smaller parietal cortex volume (β=‐1.82; 95% CI=‐3.31, ‐0.33) (Table 2; Model 2), which remained significant for those who were ≥65 years old (Model 3). Birth in the SB was associated with lower log‐transformed WMH (β=‐0.41; 95% CI=‐0.78, ‐0.03) among those aged ≥65 (Model 3). The associations of other MRI‐derived brain volumes and cognition and cognitive change were null.

Conclusion

Black Americans born in the SB had lower parietal cortex volumes, but also lower WMH volumes in late life. Parietal cortical thinning has been linked with cardiovascular risk, which may warrant further investigation into mechanisms of the association of cardiovascular risk and brain health in those born in the SB.
Reduced plasma Aß42/40 in individuals with SCD predicts increasing plasma p‐Tau 181
Authors: Göschel Laura , Koertvelyessy Peter , Hoede Patty , Teunissen Charlotte , Flöel Agnes
Published: January 2025

Background

In Alzheimer’s disease (AD), the decline of plasma Aß42/40 occurs before cognitive decline, presenting a potential early screening tool. However, the factors leading to the progression of the disease, specifically the increase in plasma p‐Tau 181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), remain unclear. This study investigates whether perceived cognitive impairment is associated with downstream biomarker changes in individuals with decreasing Aß42/40.

Method

Plasma was longitudinally collected from a study population of cognitively healthy controls (HC, n=21) and individuals with subjective cognitive decline (SCD, n=32) for up to five time points over up to five years. Plasma biomarkers were measured using Simoa HD‐X (Billerica, USA) with the commercially available kits NEUROLOGY 4‐PLEX E and p‐Tau 181 advantage kit V2. A 2‐means cluster analysis classified the participants as Aß decliners/non‐decliners based on their plasma Aß42/40 change (difference between plasma Aß42/40 at the first visit and last visit). The self‐reported Everyday Cognition (ECOG) and Multifactorial Memory Questionnaire (MMQ) provided two continuous measures of subjective cognition. Using linear mixed models, we examined z‐scaled longitudinal plasma p‐Tau 181, GFAP and NfL for Aß decliners and non‐decliners with a diagnosis of SCD (model 1), elevated scores in ECOG (model 2) or decreased scores in MMQ (model 3).

Result

The cluster analysis separated the participants into Aß decliners (plasma Aß42/40 change=‐0.5sd, n=22) and non‐decliners (Aß change=0.2sd, n=31). Model 1 showed a substantial difference in longitudinal p‐Tau 181 in Aß decliners for HC vs. SCD (estimated mean difference=‐0.19sd, p<0.001). A yearly increase of plasma p‐Tau 181 in Aß decliners was found only for SCD (0.10sd [0.03; 0.18], p=0.008) but not HC (‐0.09sd [‐0.17; ‐0.01], p=0.028) participants. Neither model 2 nor model 3 showed relevant effects of ECOG or MMQ on longitudinal plasma p‐Tau 181, GFAP or NfL, in neither Aß decliners nor non‐decliners.

Conclusion

Our findings suggest a predictive value of the diagnosis SCD for pathologic progression in participants with declining plasma Aß42/40. Our study contributes to a better understanding of early pathological changes of AD and highlights the use for a multi‐modal diagnostic approach involving both objective biomarkers and professional evaluation.
A head‐to‐head comparison between plasma p‐tau217 and tau‐PET for predicting future cognitive decline among cognitively unimpaired individuals
Authors: Ossenkoppele Rik , Salvadó Gemma , Janelidze Shorena , Binette Alexa Pichet , Therriault Joseph , Jonaitis Erin M. , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Stomrud Erik , Bourgeat Pierrick , Dore Vincent , Masters Colin L , Johnson Sterling C. , Villeneuve Sylvia , Rosa‐Neto Pedro , Rowe Christopher C. , Hansson Oskar
Published: January 2025

Background

An accurate prediction of Alzheimer’s disease (AD) progression is important for patient management and optimization of participant selection for trials. Here, we compared and combined plasma p‐tau217 and tau‐PET measures for predicting longitudinal cognitive decline and clinical progression in cognitively unimpaired participants.

Method

We included 982 participants from six independent cohorts (AiBL, BioFINDER‐1, BioFINDER‐2, TRIAD, PREVENT‐AD and WRAP; Table 1) with available plasma p‐tau217 and tau‐PET measures (measured less than one‐year apart), being either amyloid‐positive or amyloid‐negative. Biomarker and cognitive data were z‐scored by cohort using cognitively unimpaired CSF/PET amyloid‐negative participants as reference for a unified analysis. We performed linear mixed models (for predicting cognitive decline on the mPACC and MMSE) and Cox‐proportional hazards models (to assess progression to MCI or dementia), testing among both amyloid‐negative and amyloid‐positive individuals. We entered baseline plasma p‐tau217, and tau‐PET uptake in the medial temporal lobe (MTL) or in the temporal neocortex individually, and also performed combined plasma/PET models. Age, sex, years of education and cohort were used as covariates.

Result

All individual tau biomarkers significantly predicted cognitive decline for both mPACC (R2p‐tau217=0.27, R2MTL‐tau=0.31, R2neotemporal‐tau=0.28, Figure 1) and MMSE (R2p‐tau217=0.12, R2MTL‐tau=0.16, R2neotemporal‐tau=0.19, Figure 2). The best model for predicting mPACC change included plasma p‐tau217 and MTL tau‐uptake (R2=0.32, pcomparison<0.001), while for MMSE change included plasma p‐tau217 and tau‐uptake in the temporal neocortex (R2=0.20, pcomparison≤0.007). Progression to MCI or dementia was also best predicted when including both plasma p‐tau217 (HR[95%CI]=1.29[1.14,1.47], p<0.001) and MTL tau‐uptake (HR[95%CI]=1.39[1.25,1.54], p<0.001, c‐index=0.83). Analyses by individual cohorts showed similar trends.

Conclusion

Our data suggest that plasma p‐tau217 is a suitable screening method for clinical trials in CU populations given its logistic advantages. In scenarios where a more refined prediction of cognitive decline is mandated, Tau‐PET (preferably in a combined algorithm with plasma p‐tau217) would be the methodology of choice.