bluuebunny/crossref_metadata_2025 huggingface dataset:
A cross‐sectional analysis of Alzheimer’s disease plasma biomarkers and gait variables in cognitively normal older adults
Authors: Ahmed Wajiha , Boutajangout Allal , Shao Yuekun (Hillary) , Madjarova Sophia , Ma Ziyan , Debure Ludovic , Links Jon , Karimi Sohail , Vedvyas Alok , Marsh Karyn , Betensky Rebecca A , Wisniewski Thomas , Masurkar Arjun V.
Published: January 2025

Background

A decline in gait has been associated with an escalated risk of cognitive decline and changes in Alzheimer’s disease (AD) biomarkers, thus offering prognostic insight. However, the utility of gait analysis in preclinical stages of AD is unclear, and prior studies have primarily used qualitative or gross measures of gait. Furthermore, gait analysis has predominantly been performed in cohorts of non‐Hispanic Whites. We analyzed the correlations between plasma biomarkers and quantitative gait variables in a diverse cohort of cognitively normal older adults.

Method

A cohort of 129 consecutive participants (age 56‐93, 30% Black/ African American, 10% Hispanic/Latino) from the NYU Alzheimer’s Disease Research Center were confirmed cognitively normal via the Uniform Data Set Version 3 psychometric battery. Participants underwent quantitative gait analysis via the GAITRite walkway. Means and intra‐individual variability (expressed as standard deviation across the laps) of gait variables were assessed over the eight passes of the walk. Plasma levels of Aβ42, Aβ40, NfL, pTau181, and total tau were determined using Quanterix SIMOA. The associations between the gait measures and plasma biomarkers were analyzed using multivariable linear regression models, adjusting for age, sex, and ApoE status.

Result

The mean velocity showed a statistically significant negative association with NfL and total tau, after adjusting for age, sex, and ApoE genotype. A 1pg/ml increase in NfL was associated with a 0.33 unit decrease in mean velocity (p=0.028). A 1pg/ml increase in total tau was associated with a 3.53 decrease in mean velocity (p=0.013). Intra‐individual variability in gait velocity also showed a statistically significant positive association with pTau181. A 1pg/ml increase in ptau181 level showed a 0.385 unit increase in velocity variability (p=0.018).

Conclusion

AD plasma biomarkers show correlations to quantitative gait measures even in a cognitively normal population, apart from age and ApoE genotype. Our findings also promote the utility of both means and variability of gait measures in stratifying preclinical risk of AD.
The Association and Mediating Role of Choroid Plexus Enlargement Between Cerebrospinal Fluid Inflammatory Markers, Amyloid Burden, and Cognitive Decline Across the Clinical Spectrum of Alzheimer's Disease
Authors: Choi Yoon Seong , Khong Pek‐Lan , En Calvin Tjio Kai
Published: January 2025

Background

The choroid plexus plays an important role in the pathophysiology of Alzheimer's disease (AD) and in immune surveillance. Neuroinflammation is known to occur in the early stages of AD, where amyloid accumulation leads to cognitive decline in later stages. However, the relationship between choroid plexus volume (ChPV) and cerebrospinal fluid (CSF) inflammatory markers, amyloid burden and cognitive decline in vivo remains underexplored. This study aims to investigate the association and mediating role of ChPV with 1) CSF inflammatory markers and amyloid beta 42 (Ab42); 2) Centiloids from amyloid PET and cognitive decline across the AD clinical spectrum.

Method

For Aim 1), 345 participants from ADNI 1 with baseline MRI and CSF inflammatory markers (n=345 with complement 3 [C3] and factor H [FH] and n=295 with tumour necrosis factor receptor 1 [TNFR1]) were enrolled. For Aim 2), 1,202 participants from ADNI GO/2/3 with baseline MRI and amyloid PET were enrolled. The association and mediating role of ChPV with CSF inflammatory markers and CSF Ab42, and with centiloids and the Preclinical Alzheimer Cognitive Composite (PACC) were assessed using linear regression and causal mediation analysis. The association between ChPV and centiloids was also evaluated in an independent cohort (n=1,772).

Result

ChPV showed a significant association with CSF inflammatory markers (P<0.001 for C3, P=0.001 for FH and TNFR1). ChPV mediated the relationship from CSF inflammatory markers to CSF Ab42 with significance or borderline significance (proportion mediated, 28.1%, 19.3% and 11.3%; P=0.014, 0.009 and 0.077 for C3, FH and TNFR1, respectively). ChPV showed a significant association with centiloids in the amyloid‐positive subgroup (P=0.008), with an interaction with amyloid‐positive status (P=0.009) in the overall study population. ChPV significantly mediated the association between centioids and PACC (proportion mediated, 3.2%, P=0.018). The association between ChPV and centiloids was replicated in an independent dataset (P=0.014).

Conclusion

ChPV was associated with CSF inflammatory markers, and amyloid burden from CSF and PET. ChPV also mediated the effect from CSF inflammatory markers to amyloid burden and from amyloid burden to cognition.
Hospital Based‐Exercise Interventions for persons living with Alzheimer’s Disease and Related Dementias
Authors: Houston Elizabeth Reaves , Lynch David H
Published: January 2025

Introduction

Among persons living with Alzheimer’s Disease and Related Dementias (PwD), ∼25% are hospitalized yearly, during which >95% of their time is spent in bed, leading to functional decline for 50% of hospitalized PwD. Hospital‐based exercise interventions are a proposed strategy to mitigate this risk of hospital‐associated functional decline. However, the applicability of hospital‐based exercise intervention trials for PwD is poorly understood. Our narrative review explores the inclusion of PwD within such trials and the effectiveness of hospital‐based exercise interventions in mitigating functional decline among PwD.

Methods

This review follows PRISMA‐Scr guidelines. The CENTRAL and MEDLINE databases and ClinicalTrials.gov were searched to identify randomized, controlled trials of hospital‐based exercise interventions for older adults (≥65). Eligibility criteria were defined a priori. Studies were screened at the abstract and full‐text level by one reviewer. A pre‐defined abstraction form was used to identify study characteristics, including details of the exercise intervention, functional outcomes, and adverse events. When reported, we abstracted eligibility criteria relevant to cognitive status and proportion of PwD among the study population.

Results

Of 882 articles screened, 27 met the eligibility criteria. Seventeen trials included PwD: 9 with a hospital‐based exercise intervention and 8 with a multi‐component or unit‐based intervention. Four studies of hospital‐based exercise interventions and 3 studies of multi‐component interventions reported a proportion of PwD. Of the 9 trials studying an exercise intervention, 5 found a non‐significant change in functional capacity between admission and discharge within the intervention group, and 4 found a significant difference in functional capacity. No studies stratified outcomes by the presence of dementia or cognitive impairment.

Conclusion

PwD are eligible for most trials of hospital‐based exercise interventions for older adults included in this review. However, we cannot determine the applicability of hospital‐based exercise interventions for PwD due to the inconsistency in reporting the prevalence of dementia within each study population. Further research must facilitate our ability to apply the results of hospital‐based exercise interventions to PwD, most directly by designing and testing hospital‐based exercise interventions specifically for PwD.
Virtual support for family caregivers to reduce hospitalization and fall risk in people with Alzheimer’s disease
Authors: Laird Rosemary D. , Abrevaya Jason
Published: January 2025

Background

The Florida Department of Elder Affairs and Navigating Aging Needs, LLC (NAN) recently formed a public‐private partnership providing virtual support to family caregivers of people with Alzheimer’s disease (AD) living at home. The program targets a diverse population with high‐level daily care needs and at increased risk for continuing decline and costly Medicaid‐supported care.

Objectives

To reduce the risk of hospitalizations and falls for people living with Alzheimer’s disease.

Methods

Family caregivers were offered a virtual support program that included regular meetings (Zoom or phone) with a personal licensed social worker. Of the 50 family caregiver participants, 45% were Black and 12% were Hispanic. The initial assessment included 80 questions on the AD patient’s medical, emotional, social, and legal/financial well‐being and the validated battery of 12 questions comprising the Zarit Burden Scale. Following the assessment, the social worker provided the family caregiver with a personal plan that identified areas of risk that “need attention,” along with resources to address identified needs. The social worker and family caregiver then met monthly to resolve areas identified as high risk and discuss other relevant issues as they arose. Every 3 months the social worker re‐assessed patient status with the family caregiver.

Results

After 9 months of virtual support, family caregivers reported 75% fewer falls and 68% fewer hospitalizations. Average number of falls fell from 2.2 at baseline to 0.54 (p = 0.004), and average number of hospitalizations fell from 0.90 at baseline to 0.28 (p = 0.006). Caregiver assessments also demonstrated a positive impact on AD patients’ depression, anxiety, advanced directives, and financial planning over the course of the program. Zarit Burden Scale scores for family caregivers remained stable despite AD progression.

Conclusion

Providing virtual support to family caregivers of people with AD was correlated with reduced hospitalizations and falls for people living at home with AD in this pilot program. The next step for the Florida Department of Elder Affairs and NAN is to assess the cost implications of expanding this approach on a larger scale.
A Seamless Phase 2A‐Phase 2B Multi‐Center Trial to Test the Benefits of Benfotiamine on the Progression of Alzheimer’s Disease‐Benfoteam: Design and Methods
Authors: Luchsinger Jose A. , Feldman Howard H. , Messer Karen , Edland Steven D. , Leger Gabriel C , Jacobs Diane M. , Salmon David P. , Revta Carolyn , Lupo Jody‐Lynn , Durant January , Gibson Gary E.
Published: January 2025

Background

Benfotiamine, a prodrug of thiamine, raises blood levels by 50‐100 times to achieve pharmacologic effects. It provides a novel therapeutic direction addressing a well‐characterized brain tissue thiamine deficiency and related changes in glucose metabolism in AD. BenfoTeam is a seamless phase 2A‐2B “proof of concept” (POC), double‐blind, placebo‐controlled RCT investigating tolerability, safety, and efficacy of benfotiamine, as a first‐in‐class small molecule treatment for early AD.

Method

Participants (n = 406) with MCI or mild dementia due to AD with a positive plasma biomarker test result (C2N PrecivityAD2) will be enrolled at ∼50 sites in the U.S. Phase 2A will evaluate safety and tolerability to determine which dose (600 mg or 1200 mg) to carry forward into phase 2B. This dose decision will be determined at the first of either 21 total adverse tolerability events (TEs) or alternatively when 160 person‐months of exposure have accumulated (see Figure 1). If 1200 mg/day does not have a significantly higher TE rate than placebo, then this dose will be taken forward to phase 2B and tested against placebo without stopping the trial, otherwise 600 mg/day will be carried forward. Phase 2B will assess efficacy and longer‐term safety of benfotiamine in the full study sample through 72 weeks of treatment, at the selected dose.

Result

Our trial modeling is presented in Figure 2. We project that to achieve our total sample size of 406 (203/arm), ∼ 1290 participants will need to be screened. With a 20% dropout rate, and a 5% drop‐in rate from the placebo arm to active treatment, the trial will be powered at 80% overall (90% on each endpoint separately) to detect a difference between arms on co‐primary endpoints (CDR‐SB and ADAS‐Cog 13) at 72 weeks, corresponding to a Cohen’s D effect size of 0.38 (small to moderate effect size).

Conclusion

BenfoTeam deploys an innovative seamless phase 2A‐2B design to achieve its overall aim of clinical POC. With its early adaptive dose decision, exposure will be optimized to the highest tolerated dose. A positive phase 2 POC trial that is powered to achieve a clinically significant benefit will further validate our approach.
Brain Glucose Metabolism Changes in Long‐COVID: A Brazilian Cohort Study
Authors: Silveira Maiele Dornelles , Machado Luiza Santos , Ferrari‐Souza João Pedro , de Bastiani Marco Antônio , Povala Guilherme , Borelli Wyllians Vendramini , Senger Joana Emilia , da Silva Ana Paula Bornes , de Mello Guilherme Bastos , da Ros João Pedro Uglione , Jotz Arthur Viana , Kadan Matheus Fakhri , Pascoal Tharick A. , Rosa‐Neto Pedro , Schumacher‐Schuh Artur Francisco , Matushita Cristina Sebastião , Radaelli Graciane , Lourenco Mychael V , Soder Ricardo Benardi , Coutinho Artur Martins , de Paula Faria Daniele de Paula , da Costa Jaderson Costa , Souza Diogo O. , de Souza Débora Guerini , Zimmer Eduardo Rigon
Published: January 2025

Background

The COVID‐19 pandemic is a public health crisis, and its lasting consequences are not yet fully understood. Epidemiological data suggest that low‐ and middle‐income countries, such as Brazil, will bear a considerable burden of COVID‐19‐related comorbidities. Individuals who have survived COVID‐19 often report persistent symptoms, including neurological manifestations such as brain fog. However, the underlying brain biological changes behind the neurological symptoms remain undefined. Here, our goal was to assess the influence of long‐COVID on brain metabolism in adults from a Brazilian cohort.

Method

Brazilian individuals (n=49) were recruited, examined through clinical and neuropsychological assessments, and divided into Control and Long‐COVID groups. Then, they underwent a brain [18F]FDG‐PET scan. Images were normalized by the global mean. Differences between groups were assessed through a [18F]FDG‐PET voxel‐wise linear regression accounting for age, sex and years of education (Table 1). The analysis was corrected for multiple comparisons using the cluster‐wise random field theory method (significant t < ‐3.28 and t > 3.28).

Result

Long‐COVID group exhibited recurring symptoms such as fatigue, memory complaints and lack of concentration (Table 1). They also exhibited hypometabolic clusters in the left superior parietal lobe (tmax=‐4.03; p < 0.001) and right insular cortex (tmax=‐3.31; p < 0.001) (Figure 1). Hypermetabolic clusters were found in the left whole cerebellum (tmax=4.92; p < 0.0001), right dorsolateral prefrontal cortex (tmax=3.83; p < 0.001), and right postcentral gyrus (tmax=4.24; p < 0.001) (Figure 2).

Conclusion

Our preliminary results demonstrate region‐dependent dual response on brain metabolism due to Long‐Covid. More specifically, glucose hypometabolism was found in regions associated with cognitive domains and affective modulation. By contrast, glucose hypermetabolism was observed in brain areas associated with motor coordination and sensory processing. Metabolic changes in these regions should be further evaluated to advance in the understanding of the pathophysiological mechanisms associated with persistent neurological manifestations seen in individuals presenting with Long COVID.
Residential Neighborhood Disadvantage and Amyloid Positivity: Findings from IDEAS
Authors: Windon Charles , Tsoy Elena , Livaudais‐Toman Jennifer , Hanna Lucy , Gatsonis Constantine , Carrillo Maria C. , Apgar Charles , Dilworth‐Anderson Peggye , Karliner Leah , Hillner Bruce E , Neilands Torsten B , Palmer Nynikka , Possin Katherine L , Stewart Anita L. , Whitmer Rachel A. , Wilkins Consuelo H. , Rabinovici Gil D.
Published: January 2025

Background

Residence in a disadvantaged neighborhood (e.g., high poverty rate, poor housing, etc.) is associated with greater dementia risk and possibly greater postmortem Alzheimer’s pathology. It remains unknown if neighborhood disadvantage is associated with in vivo beta‐amyloid positron emission tomography (PET) for Alzheimer’s. We examined this using data from the Imaging Dementia Evidence for Amyloid Scanning (IDEAS) study.

Methods

IDEAS captured >18,000 PET scans among cognitively impaired Medicare beneficiaries from 595 US dementia clinics between 2016‐2018. We defined neighborhood disadvantage using Area Deprivation Index (ADI), a validated composite of 17 social determinants measures captured in American Community Survey and US Census data. IDEAS participant zip code data was linked to census block group for ADI value calculation through geocoding.

Association between visual interpretation of PET in IDEAS (positive/negative) and state‐level ADI (1‐10; 10 being greatest disadvantage) was examined via logistic regression controlling for covariates (age, sex, education, level of impairment (MCI vs dementia), race/ethnicity, comorbid conditions) with cluster adjusted standard errors by practice location.

Results

Among 13,961 cognitively impaired participants, 61.6% were amyloid positive, 56.5% had MCI, and 50.4% were female (Table 1). The majority (90.2%) were non‐Latino White with 4.7% Latino, 3.2% Black, and 1.9% Asian representation (Table 1). Participants were highly educated (68.1% beyond high school) and 31.0% (4,333/13,961) resided in neighborhoods of greater disadvantage (ADI ≥ 6) (Figure 1).

Greater ADI was associated with lower odds of amyloid positivity (aOR 0.61, 95% CI 0.51‐0.73, p<.001 for ADI 10 vs ADI 2 and aOR 0.87, 0.76‐1.00, p .051 for ADI 2 vs. ADI 1(ref)). Latino (aOR 0.62, 0.48‐0.80, p<.001), Black (aOR 0.58, 0.48‐0.72, p<.001), and Asian (aOR 0.42, 0.31‐0.58, p<.001) identity was associated with lower odds of amyloid positivity along with multiple comorbidities (Table 2).

Conclusion

We observed a relationship between residence in a more disadvantaged neighborhood (higher ADI) and lower rates of amyloid positivity. Given this finding and known association between neighborhood disadvantage and postmortem AD pathology, it is possible non‐amyloid pathology also contributes towards cognitive impairment among individuals from disadvantaged neighborhoods and among diverse groups. This has implications for clinical use of novel amyloid lowering therapies.
Longitudinal plasma and CSF analyses in Down syndrome. Results from the DABNI cohort
Authors: Alcolea Daniel , Montoliu‐Gaya Laia , Carmona‐Iragui Maria , Barroeta Isabel , Videla Laura , Benejam Bessy , Arranz Javier , Lleo Alberto , Blennow Kaj , Ashton Nicholas J. , Zetterberg Henrik , Fortea Juan
Published: January 2025

Background

Alzheimer´s disease (AD) is the main cause of death in adults with Down syndrome (DS). We describe the unique contributions of the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort by studying longitudinal changes in plasma and cerebrospinal fluid (CSF) markers.

Method

We included DABNI participants with DS that contributed at least two plasma and/or CSF samples and were asymptomatic (aDS, n=155), had prodromal AD (pDS, n=46) or had AD dementia (dDS; n=53) at baseline, together with 172 euploid cognitively normal controls (CN). All participants underwent longitudinal assessments, including repeated cognitive and neuropsychological assessments, plasma and CSF analyses. We applied linear‐mixed models to study changes over time in measures of GFAP, NfL and pTau217 in plasma and in AB42/AB40, NfL and pTau217 in CSF and their association with the symptomatic stages of AD.

Result

Plasma GFAP and NfL showed higher increases in dDS compared to pDS, and in pDS and dDS compared to aDS and CN (Figure 1A and 1B). Plasma pTau217 showed higher increases in pDS and dDS compared to aDS and CN, but there were no differences between pDS and dDS (Figure 1C). In CSF, no significant longitudinal changes were detected in AB42/AB40 (Figure 1D), whereas both NfL and pTau217 showed higher slopes in advanced symptomatic stages (Figure 1E and 1F).

Conclusion

Our results indicate that longitudinal changes in plasma markers are associated to different stages in the continuum of AD in DS. These changes could be useful to track the progression of the disease.
Selection of Biomarkers and Clinical Endpoints for Clinical Trials Targeting Down syndrome‐related Alzheimer’s disease (DSAD)
Authors: Rafii Michael
Published: January 2025

Background

Major advances have been made over the past decade in understanding Down syndrome‐related AD by utilizing the latest AD biomarkers such as brain imaging and biofluid assays. Cognitive measures that can discern decline related to AD have been developed and validated in people with DS. We are now able to incorporate these data to help design clinical trials against AD in people with DS.

Method

The NIH‐funded Alzheimer’s Clinical Trial Consortium ‐ Down Syndrome (ACTC‐DS) was launched in 2018 to serve as a platform for conducting clinical trials to treat and prevent AD dementia in people with DS. We have enrolled over 200 adults with DS who will be offered the opportunity to enroll in interventional clinical trials for AD specifically designed for people with DS.

Result

We have launched a phase 1b/2, multicenter, double‐blind, randomized, placebo‐controlled study to assess the safety, tolerability, immunogenicity, and pharmacodynamic effects of ACI‐24.060 in in adults with Down syndrome and plan to launch two additional trials this year.

Conclusion

Data from longitudinal biomarker studies are informing the design and conduct of clinical trials targeting AD in people with DS.
Does socioeconomic status modify the association between glycemic level and MRI markers of ADRD risk in middle‐aged adults?
Authors: Kraal A. Zarina , McFarlane Hugh V. , Pyne Jeffrey D. , Turney Indira C. , Lao Patrick J. , Mazen Jessica , Brickman Adam M. , Manly Jennifer J.
Published: January 2025

Background

High glycemic levels, indexed by hemoglobin A1c (HbA1c), heighten risk for Alzheimer’s Disease and Related Dementias (ADRD). Previous studies suggest that high HbA1c and low socioeconomic status (SES) may be associated with MRI markers of ADRD risk, including lower cortical thickness and greater white matter hyperintensities (WMH). The weathering hypothesis suggests that the stress of low SES accelerates and exacerbates physiological deterioration, leading to worsening health outcomes. However, the role of SES as a potential moderator of the associations between HbA1c and MRI markers of ADRD is underdeveloped. We hypothesized that higher HbA1c and lower SES are associated with MRI markers of ADRD risk, and the association between HbA1c and MRI markers is stronger among individuals with low SES.

Method

Participants were middle‐aged adults in the Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease (N=616; age=54.5±10.6; 68.6% Latinx, 21.2% Non‐Latinx Black, 7.2% Non‐Latinx White; 65.6% women). HbA1c level was determined from blood assays. MRI markers included cortical thickness of AD signature regions and log‐transformed WMH. Confirmatory factor analysis estimated SES from self‐reported income and education. Structural equation models quantified main and interaction effects of HbA1c and SES on MRI markers, adjusting for age, sex, and prediabetes/type 2 diabetes.

Result

There were no main or interaction effects of HbA1c and SES on either MRI marker, independent of covariates. However, examination of moderation by each SES indicator showed that higher HbA1c was associated with lower cortical thickness among participants with high income (unstandardized estimate= ‐0.0214, SE=0.0107, 95%CI[‐0.0424, ‐0.0003]). Effect estimates were similar in analyses restricted to individuals with prediabetes and type 2 diabetes (n=250; age=58.1±9.0; 72.8% Latinx, 23.6% Non‐Latinx Black, 3.7% Non‐Latinx White; 68.8% women).

Conclusion

HbA1c‐related effects on markers of ADRD risk in middle‐age may occur via neurodegenerative processes. Associations involving cerebrovascular pathways warrant further investigation. Examination of other indicators of SES (e.g., occupation, wealth, debts) and region‐specific WMH may help clarify the role of SES in modifying the link between glycemic level and brain health.
In‐Vivo Characterization of Blood‐Brain Barrier Permeability in Cognitively Normal APOE e4 Carriers and Non‐Carriers
Authors: Solders Seraphina K. , Shen Qian , Rivera Charlotte S. , Banks Sarah , Reas Emilie T.
Published: January 2025

Background

An intact blood‐brain barrier (BBB) is critical for optimal brain health, and even transient or highly localized disruption of the BBB can have devastating consequences for neural functioning. BBB breakdown has been implicated in Alzheimer’s Disease (AD) pathogenesis, and elevated BBB permeability has been observed in APOE e4 carriers compared to non‐carriers. As prior studies have focused on a priori, AD‐vulnerable regions rather than whole‐brain analyses, little is understood about broader patterns of BBB breakdown that may relate to AD risk. This study aims to identify preclinical cerebrovascular differences in cognitively normal individuals who are genetically at high‐risk for AD.

Method

Dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) was performed on 34 cognitively normal older adults (average age = 76.6 years; 18 women) from the UC San Diego Alzheimer’s Disease Research Center, evenly split by APOE e4 status. Data were processed using ROCKETSHIP and average BBB permeability values were extracted from the Desikan‐Killiany atlas cortical gray matter regions. Permeability values were averaged across hemispheres, resulting in 34 measurements. ANCOVAs predicted BBB permeability within each region from e4 status, age, sex, and the interaction between sex and e4 status.

Result

APOE e4 carriers showed elevated BBB permeability throughout the superolateral frontal and parietal cortices and some occipital cortex compared to non‐carriers. The strongest effects were found in the caudal‐middle and superior frontal, pre‐ and paracentral, and superior parietal gyri. Further, there was a pattern of sex by e4 carrier status interaction whereby the e4 effect was stronger in men than women.

Conclusion

Older adults who carry at least one APOE e4 allele show increased BBB permeability compared to e4 non‐carriers primarily in superior frontal and parietal regions, a spatial pattern that is notably distinct from the typical topography of AD pathology. This effect may be moderated by sex, such that men may be more vulnerable to the detrimental effects of APOE e4 on certain regions of the BBB compared to women. These findings raise implications for important questions regarding APOE4 dose effects, the mechanisms by which APOE regulates BBB functioning, and the evolution of BBB permeability through the disease course.
Effects of APOE genotype on cortical atrophy in early onset Alzheimer’s disease
Authors: Chan Diane , Brickhouse Michael , Zaitsev Alexander , Wong Bonnie , Hammers Dustin B. , Dage Jeffrey L. , Foroud Tatiana M. , Eloyan Ani , Nudelman Kelly N. , Nemes Sára , Carrillo Maria C. , Rabinovici Gil D. , Apostolova Liana G. , Dickerson Bradford C. , Touroutoglou Alexandra ,   the LEADS Consortium
Published: January 2025

Background

APOE‐ɛ4 is a major risk factor for Alzheimer’s disease (AD); its effects have been examined in late‐onset AD (LOAD) but less so in early‐onset AD (EOAD). In LOAD, APOE genotype has strong effects on episodic memory and medial temporal lobe (MTL) atrophy (Wolk & Dickerson, 2010). However, EOAD often presents with more cognitive impairments in executive function, language, and visuospatial abilities than memory. These differences reflect more prominent atrophy in posterior lateral temporal and inferior parietal cortex that mainly constitute the EOAD‐signature of atrophy. Based on the cognitive and neuroanatomical profile of EOAD, we hypothesized that EOAD ɛ4 carriers will have relatively more atrophy in MTL regions subserving episodic memory, whereas non carriers would express more atrophy in cortical regions of the EOAD‐signature involved in executive function, language, and visuospatial abilities including inferior parietal and posterior temporal regions. We also expected worse performance on episodic memory tests in ɛ4 carriers with EOAD.

Methods

We examined the effects of APOE genotype on cortical atrophy and episodic memory of 144 ɛ4 carriers and 117 ɛ4 non‐carriers with EOAD from the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS). Between‐group comparisons using independent T‐tests were made for morphometric measures of cortical atrophy in MTL and hippocampus localized in LOAD as well as in cortical regions within our newly developed EOAD‐Signature tool (Touroutoglou et al., 2023). ANCOVA with Bonferonni’s correction was used to evaluate for effects of age on significant differences between groups.

Results

As predicted, ɛ4 carriers with EOAD had more atrophy in the MTL and bilateral hippocampi, whereas non‐carriers had more atrophy in regions of the EOAD‐signature including bilateral caudal temporal, parietal lobule, middle frontal gyrus, mid temporal, posterior cingulate cortex, precuneus, superior frontal gyrus, superior parietal lobule. Post hoc vertex wise cortical maps further confirmed the specificity of the results. In addition, ɛ4 carriers had worse performance on episodic memory testing (AVLT delayed recall). These results were not explained by a difference in age between the groups.

Conclusions

These results are consistent with prior work (Nemes et al. 2023) and support the hypothesis that the ɛ4 genotype modulates distinct neuroanatomic phenotypes of AD in EOAD patients.
Vulnerability of locus coeruleus projections during aging
Authors: Zufiria‐Gerboles Blanca , Veréb Daniel , Pereira Joana B
Published: January 2025

Background

The locus coeruleus (LC) is an important noradrenergic nucleus that supplies noradrenaline to the brain through extensive cortical and subcortical projections. Recent studies established that the LC is vulnerable to aging and common neurodegenerative disorders, including Alzheimer’s disease. However it is currently unclear how these projections differ between age groups and how they are affected by common age‐related comorbidities.

Method

Here, we employ probabilistic tractography to characterize structural connectivity of the LC over aging using 3T diffusion‐weighted MRI in a population‐based cohort aged from 18 to 88 years of age (n=618). We assessed the relationship between age and connectivity, as well as common age‐related comorbidities, such as subjective memory problems, hypertension, diabetes, depression and sleep disturbances. Age‐related differences were assessed using Spearman’s rank correlation, whereas comorbidity‐related changes were investigated using partial least square analyses, corrected for age, sex and education.

Result

The tractogram of the LC contained connections consistent with previous tractography and tracer studies. LC connectivity exhibited a marked decrease to a variety of brain areas including frontal and temporal regions, as well as the bilateral thalami and the left caudate (Spearman’s R < ‐0.2, pFDR<0.001). Participants with subjective memory problems exhibited increased LC connectivity to the ventral anterior cingulate cortex (p=0.0032). Participants with hypertension and diabetes exhibited decreased LC connectivity to the left middle frontal gyrus, the right amygdala and bilateral thalami (0.0001<p<0.014). Higher depression was associated with lower LC connectivity to the middle frontal, superior and inferior temporal gyri, whereas sleep problems were related to reduced temporal LC connectivity (p<0.05).

Conclusion

These results provide an in vivo account of how the structural connectivity of the LC changes through aging and imply that LC connections are further affected by common age‐related disorders.
Is there Evidence for a Continued Benefit for Long‐Term Lecanemab Treatment? A Benefit/Risk Update from Long‐Term Efficacy, Safety and Biomarker Data
Authors: van Dyck Christopher H. , Sperling Reisa A , Dhadda Shobha , Li David , Hersch Steven , Irizarry Michael C. , Kramer Lynn D
Published: January 2025

Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to amyloid‐beta (Aβ) protofibrils, was formally evaluated as a treatment for early Alzheimer’s disease in a phase 2 study (Study 201) and the phase 3 Clarity AD study. These trials both included an 18‐month, randomized study (core) and an open‐label extension (OLE) phase where eligible participants received open‐label lecanemab for up to 30 months to date. Clinical (CDR‐SB, ADAS‐Cog14, and ADCS‐MCI‐ADL), biomarker (PET, Aβ42/40 ratio, and ptau181) and safety outcomes were evaluated. Results demonstrated that lecanemab substantially reduced markers of amyloid and significantly slowed clinical decline on multiple measures of cognition, function, and quality of life in early AD at 18 months and continued for 30 months to date. Lecanemab was associated with amyloid‐related imaging abnormalities (ARIA) and infusion reactions, tending to occur early in treatment. Although lecanemab has established a clear benefit/risk benefit for 18 months of treatment, the evidence for continued treatment beyond 18 months has yet to be firmly established. In an effort to evaluate the current evidence base for longer‐term dosing, this presentation will summarize the latest clinical and biomarker results from the lecanemab Clarity AD study, including the latest efficacy and safety data out to at least 30 months. We will share details on how lecanemab has demonstrated the ability to slow tau spread in different brain regions of individuals with early Alzheimer’s disease and discuss the relevance of these data on continued treatment. Evaluations of clinical and biomarker outcomes by participants considered as having a ‘delayed start’ (core:placebo followed by OLE:lecanemab) versus those with an ‘early start’ (core:lecanemab followed by OLE:lecanemab) cohorts will be presented and discussed. Finally, the overall case for the need and benefit of early initiation and continued dosing, considering mechanistic, pharmacology, biomarker and clinical results, will be discussed.
Characterizing the effects of calcineurin/NFAT inhibitor treatment on gray and white matter microstructure in the beagle model of Alzheimer's disease
Authors: Noche Jessica A. , Radhakrishnan Hamsanandini , Ubele Margo F. , Boaz Kathy , Mefford Jennifer L. , Jones Erin D. , Perpich Jessica A. , Meacham Beverly , Smiley Jeffrey , Bailey Stasia A. Bembenek , Puskas Laszlo G. , Powell David K , Sordo Lorena , Phelan Michael J. , Norris Christopher M. , Head Elizabeth , Stark Craig EL
Published: January 2025

Background

In the context of pathological aging and Alzheimer's disease (AD), the overexpression of calcineurin has been identified as a factor linked to astrocyte reactivity, neuronal death, and inflammation. This suggests that inhibiting calcineurin or downstream nuclear factor of activated T cells (NFAT) signaling could be a promising strategy for preventing or slowing down AD pathophysiology.

Method

Baseline and annual MRI sessions including higher‐order diffusion‐weighted imaging was performed over four years on 43 dogs ranging from 5 to 8.7 years old (placebo n=14; tacrolimus n=15; Q134R n=14). Estimates from diffusion tensor and neurite orientation dispersion and density imaging (NODDI) models were assessed: orientation dispersion index (ODI), intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (MD), axial diffusivity (AxD). We examined the percent changes from select gray matter regions of interest, including the posterior cingulate gyrus (PCG), orbital gyrus, caudate nucleus, and hippocampus, as well as voxel‐wise white matter microstructure across the brain.

Result

Across all groups, the PCG showed a 1% decrease in ODI, whereas the orbital gyrus had 1% increases in ODI and in ICVF. The orbital gyrus also had a 2% increase in MD and RD and a 26% increase in ISOVF. The hippocampus had a 0.8% increase in ODI. The caudate nucleus showed numerous changes, including a substantial 36% increase in ISOVF and 1.5% decrease in FA. Only Q134R‐treated dogs showed a 0.6% increase in AxD, and tacrolimus‐treated dogs showed 0.7% and 0.9% increases to MD and RD, respectively. Whole brain white matter demonstrated an anterior‐posterior gradient to diffusion changes similar to that of human aging across all groups: decreasing FA, increasing MD, increasing RD, and decreasing AxD.

Conclusion

Microstructural alterations within gray and white matter of canines parallel human aging. The study suggests that Q134R and tacrolimus differentially impact gray matter microstructural changes within the caudate nucleus. Future investigations involving cognitive outcomes and histological evaluations will be crucial to understanding the neurobiological underpinnings of these diffusion changes and the effects of chronic tacrolimus and Q134R treatment on AD pathology and cognition.
Asymmetrical Neuroimaging Insights in CSF‐Validated Early‐Onset Alzheimer's: Integrating PET, MRI, and Cognitive Assessment
Authors: Özçelik Sinem , Yiğit Pınar , Bozdemir Tolga Can , Kaya Gamze Çapa , Yildirim Zerrin , Tee Boon Lead , Gurvit Hakan , Yener Görsev , Tempini Maria Luisa Gorno , Öz Didem
Published: January 2025

Background

Early‐onset Alzheimer's disease (EOAD), manifesting before age 65, demands nuanced diagnostic approaches. FDG18‐PET unveils metabolic insights, the MRI scale captures structural changes, and ACE‐R assesses cognitive impairment details. A holistic evaluation enhances diagnostic precision and enriches our understanding of cognitive decline in early‐onset presentations.

Method

Early‐onset Alzheimer's disease (EOAD), manifesting before age 65, demands nuanced diagnostic approaches. FDG18‐PET unveils metabolic insights, the MRI scale captures structural changes, and ACE‐R assesses cognitive impairment details. A holistic evaluation enhances diagnostic precision and enriches our understanding of cognitive decline in early‐onset presentations.

Result

Twenty‐two patients (59.1% women) with a mean age at diagnosis of 55.3 (±6.52 StD) years participated. The mean disease duration was 5.06 (±2.95 StD) years. All of the patients were right‐handed. The mean Aβ42 and phos‐tau were 392.49 (±200.13 StD) and 130.93 (±142.56 StD) pg/ml, respectively. No significant difference was found between the right and left insular cortex in PET, and no statistically significant asymmetry was found between VAS scores in MRI (p > 0.05). There was no correlation between PET index with CSF Aβ42 and and phos‐tau values.

Conclusion

This study underscores notable asymmetries in PET atrophy scores between the corresponding right and left brain regions in Alzheimer's patients. Given that EOAD manifests with atypical clinical symptoms, and all participants in this study exhibited left‐hemispheric dominance, the observed metabolic asymmetry, in the absence of a corresponding structural asymmetry, holds clinical significance.
Proteomic Dementia Risk Assessment in Chronic Kidney Disease
Authors: Zhao Bote , Wang Zhibo , Ning Yuye , Jia Jianping
Published: January 2025

Background

Chronic kidney disease (CKD) has relatively high prevalence and independently increases dementia risk. Currently, there is a lack of high‐performance dementia prediction tools designed for the CKD population in clinical practice. Through proteomics discovery, this study aimed to discover more efficient dementia risk models in CKD patients.

Method

This prospective cohort study utilized data from the UK Biobank, encompassing baseline assessments conducted between 2006 and 2010, with follow‐up extended until September 1, 2023. We included 1355 CKD patients, who were free of dementia at baseline and had available Olink blood proteomics data (approximately 3000 proteins). Feature selection was executed using a least absolute shrinkage and selection operator (LASSO) regression. Generalized Linear Models were employed to derive a proteomic risk model for dementia risk in CKD patients. The model was trained in a tested set of 949 CKD patients and validated in a set of 406 individuals. Mendelian randomization was employed to investigate the causal link between potential proteins and dementia.

Result

The proteomic risk model, comprised of 17 proteins, demonstrated superior performance compared to conventional clinical tools for dementia risk assessment, including demographic factors (age, sex, education year, APOE ε4 status) and cognitive assessments. During validation, the proteomic model achieved a receiver operating characteristic (ROC) area under the curve (AUC) value of 0.845, significantly surpassing the 0.543 to 0.627 range observed for conventional clinical models. The proteomic plus conventional assessment models did not obtain higher AUC values (ranging from 0.811 to 0.845) (Figure 1). After stratifying participants into two proteomic risk groups based on the median proteomic predicted risk value, the high‐proteomic risk group exhibited 15.14 times increase in the risk of dementia compared to the low‐ proteomic risk group (HR= 15.14, 95%CI: 6.62 ‐ 34.66) (Figure 2). Mendelian randomization analyses indicated a causal link between several proteins and dementia.

Conclusion

Based on the UK Biobank database, a proteomic risk model for dementia outperformed conventional clinical risk models in CKD patients. This plasma‐derived proteomic model is supposed to have great generalization potential, attributed to the accessibility of blood samples, thereby offering valuable guidance for dementia prevention in the CKD population.
Volumetric Characterization of Medial Temporal Lobe in Down Syndrome Along the Alzheimer's Disease Continuum
Authors: Zsadanyi Sara E , Buehner Bejamin J. , Morcillo‐Nieto Alejandra O. , Aranha Mateus Rozalem , Arriola‐Infante José Enrique , Vaqué‐Alcázar Lídia , Arranz Javier , Rodríguez‐Baz Íñigo , Maure‐Blesa Lucía , Videla Laura , Barroeta Isabel , Hoyo Laura Del , Benejam Bessy , Fernandez Susana , Hernandez Aida Sanjuan , Bargalló Núria , González‐Ortiz Sofía , Giménez Sandra , de Flores Robin , Alcolea Daniel , Belbin Olivia , Lleo Alberto , Carmona‐Iragui Maria , Fortea Juan , Bejanin Alexandre
Published: January 2025

Background

Individuals with Down Syndrome (DS) almost invariably develop Alzheimer's Disease (AD), but detecting early clinical changes is challenging due to comorbid intellectual disability, highlighting the importance of non‐invasive biomarkers. Neuroimaging of the medial temporal lobe (MTL), a key site of tau pathology, shows promise as an early AD biomarker. Here, we aimed to characterise volumetric patterns of the MTL in DS across the AD clinical continuum, and define associations with AD cerebrospinal fluid (CSF) biomarkers.

Method

253 adults with DS and 190 euploid controls from the Down Alzheimer Barcelona Neuroimaging Initiative underwent a 3T‐MRI protocol, and a comprehensive clinical assessment. T1‐weighted images were used to parse the medial temporal lobe using the Automated Segmentation of Hippocampal Subfields (ASHS) pipeline. Segmentation quality was visually inspected and W‐scores were computed for MTL subregions (anterior and posterior hippocampus, entorhinal cortex (ERC), parahippocampal cortex (PHC), and Brodmann areas Br35 and Br36) to adjust volumes for total intracranial volume, age and MRI scanner. Non‐parametric statistical tests were employed to assess volumes by AD clinical stage, age, and CSF biomarkers of AD.

Result

Hippocampal and Br36 volumes gradually decreased with AD clinical stage, and all subregions were decreased at the dementia stage (dDS) compared to asymptomatic (aDS) and prodromal (pDS) stages (Figure 1). Surprisingly, significantly larger ERC, PHC and Br35 volumes were found at the asymptomatic DS stage compared to controls. All subregions had decreased volumes with age, with inflexion points around 40y for the hippocampus, ERC and Br36, 45y for Br35 and 50y for PHC (Figure 2). Most subregions exhibited significant correlations with CSF Aβ42/40 ratio, p‐tau‐181 and neurofilament light chain, and the strongest associations were found with anterior and posterior hippocampus (Figure 3).

Conclusion

AD clinical stage and age are associated with progressive decreasing MTL volumes. Among all subregions, the hippocampus correlated best with CSF measures and appears particularly sensitive to detect early disease processes. These results indicate effectiveness of MTL volumes as a biomarker of early AD pathological changes in DS. Further studies are required to determine the pathological substrate of MTL atrophy and understand the increased volumes in some subregions.
Retinal Examination in Neurodegenerative Diseases of the Brain
Authors: Kayabasi Umur A.
Published: January 2025

Background

Alzheimer's Disease (AD) is a chronic neurodegenerative disease characterized by loss of memory and cognitive decline associated with an increase in ß‐amyloid (Aß) plaque deposition, neurofibrillary tangle formation (NFT) and inflammation. Fundus Autofluorescein (FAF) can detect lipofuscin secreted by misfolded plaques during the neurodegeneration process. And Optical Scanning Tomography ( OCT ) is able to find out the retinal layers of the accumulation ( inner retinal layers in AD ). lt is also possible to measure macular thickness by OCT ( macular thinning being the earliest sign of AD).

Method

30 patients with PET proven AD were examined by FAF and OCT. Mean age was 71. Also 10 age matched healthy controls underwent retinal exam. 15 AD patients were given Curcumin tablets for 3 days to detect changes after the supplement.

Result

All the patients with AD revealed detectable accumulations by FAF and their location was the inner retinal layers as picked up bt OCT. ln the control group, typical accumulation styles were not seen.

Conclusion

Retinal examination is one of the best methods to detect AD. lt is safe, non‐invasive and reproducable.