bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduction of agitation and caregiver distress using a combination intervention of tetrahydrocannabinol and melatonin in dementia due to Alzheimer disease
Authors: Arbelaez María Juanita , Gutierrez Evelyn , Sanchez Laura Tatiana , Tangarife Maria Alejandra , Delgado‐Murillo Laura , Rodriguez‐Soacha Diego , Shahnawaz Saadia S , Ghazaryan Varduhi , Naranjo Maria Paula , Venegas Margarita , Garcia David Silva , Pujals Karen Y , De Jesus William Julio , Grimaldi Claudia , Lanctôt Krista L. , Hong L Elliot , Mukunda Ram
Published: December 2023

Background

Agitation, common in AD, often associated with higher caregiver burden, increases in intensity and duration as the disease progresses. Although about 76% of AD patients suffer from agitation, only 6.9% of ongoing trials for AD target symptoms such as agitation. Here, we present preliminary data for improvement in NPI‐agitation (NPI‐ag) scores and associated caregiver distress (NPI caregiver distress, NPI‐D) scores using IGC‐AD1, a combination of tetrahydrocannabinol (THC) and melatonin (IGC‐AD1).

Method

Twelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) participated in a three Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts 2 and 3, one ml BID and TID were administered respectively, with a minimum of 4‐days washout between Cohorts. In Cohort‐1 (QD), 9 participants (7‐active, 2‐placebo) with NPI‐ag and NPI‐D assessment at baseline were analyzed. In Cohort‐2 (BID), and Cohort‐3 (TID) six patients and five patients respectively had NPI‐ag and NPI‐D scores at baseline. Daily, solicited and non‐solicited adverse events (AEs) were monitored along with vital signs. A Wilcoxon matched pairs signed‐rank test (R‐Studio, dplyr) was used to compare separately the difference between the mean NPI‐ag and mean NPI‐D scores at baseline and EOT.

Result

In Cohort‐1 mean NPI‐ag at baseline and EOT was 4.71 and 3 respectively (mean difference = ‐1.75, 36.3%, V = 10, p = 0.047). In Cohort‐2 mean NPI‐ag at baseline and EOT was 4.33 and 1.5 respectively (mean difference = ‐2.83, 65.3%, V = 10, p = 0.049). In Cohort‐3 mean NPI‐ag at baseline and EOT was 4.2 and 1.4 respectively (mean difference = ‐2.8, 66.6%, V = 10, p = 0.04). We report similar improvements in NPI‐D. (Cohort‐1: mean difference = ‐1.57, 50%, v = 15, p = 0.028; Cohort‐2: mean difference = ‐2, 66.6%, v = 10, p = 0.049; Cohort‐3: mean difference = ‐1.45, 8.3%, v = 10, p = 0.049). No serious AEs, no deaths, and no dropouts due to AEs were reported. No major changes in concomitant medications were observed.

Conclusion

IGC‐AD1 was safe and well tolerated and is potentially efficacious in reducing agitation and associated caregiver distress in AD as measured by the NPI, warranting a larger placebo‐controlled study.
Relationship of diffusion weighted imaging of the hippocampal cingulum and cognition across the Alzheimer’s disease continuum
Authors: Hirschfeld Lauren Rose , Chumin Evgeny J. , Deardorff Rachael , Wu Yu‐Chien , Risacher Shannon L , Yi Dahyun , Byun Min Soo , Lee Jun‐Young , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Nho Kwangsik , Saykin Andrew J. , Lee Dong Young
Published: December 2023

Background

Diffusion tensor imaging (DTI) measures water diffusion within brain tissue and can provide information regarding white matter, myelin, and axonal degeneration. We analyzed the cingulum bundle of the hippocampus (CBH), chosen for relevance to Alzheimer’s Disease (AD) and memory (Wen et al, 2019; Dalboni da Rocha et al, 2020), using fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AxD), and mean diffusivity (MD), as well as their relationship to cognition, measured by DTI data from the initial phase of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE).

Methods

Participants from KBASE included cognitively normal older adults (CN, n = 276), mild cognitive impairment (MCI, n = 142), and AD dementia (AD, n = 87) studied with baseline neuroimaging and cognitive testing at Seoul National University and processed at Indiana University School of Medicine. Affine and non‐linear transformations were used to align individual FA maps to the FMRIB58FA template (FSL). Voxel values were extracted from unilateral CBH regions (determined using JHU ICBM‐DTI‐81‐white‐matter‐labels atlas) and averaged. Univariate‐GLM and Bonferroni‐corrected post‐hoc T‐tests controlling for age and sex were used to analyze diagnostic group differences, with lower FA and higher RD, AxD, and MD values expected in MCI and AD groups compared to CN. Bonferroni‐adjusted partial correlations controlling for age, sex, and education were used to test the hypothesis that DTI values would be associated with worsening cognitive scores.

Results

As hypothesized, bilateral CBH DTI values in AD and MCI were significantly worse than those in CN (p<0.001) (Fig 1) with moderate effect sizes (η2 = 0.111 – 0.307). Worsening DTI values were significantly associated with worsening Digit Span Backward, Trailmaking A and B, GDS, MMSE‐KC, CDR‐SB, Word List Recall, and Logical Memory scores at the Bonferroni‐adjusted p‐value of 0.003. Bilaterally, higher Digit Span Forward scores were significantly associated with AxD values and lower Total SMCQ scores were associated with RD, AxD, and MD values.

Conclusion

Within the KBASE cohort, MCI and AD demonstrated significantly worse DTI, memory, and cognition consistent with the pattern of white matter microstructural damage previously reported in MCI and AD (Wen et al, 2019; LoBuono et al., 2019).
Memory Performance in Mild Sporadic and Familial Behavioral Variant Frontotemporal Dementia: Findings from the ALLFTD Consortium
Authors: Boeve Brad F. , Fields Julie A. , Syrjanen Jeremy A. , Johnson Noah , Kremers Walter K. , Staffaroni Adam M. , Huey Edward D. , Rascovsky Katya , Weintraub Sandra , Ramos Eliana Marisa , Knopman David S. , Miyagawa Toji , Forsberg Leah K. , Heuer Hilary W. , Boxer Adam L , Rosen Howard J. ,   ALLFTD Consortium
Published: December 2023

Background

Memory impairment is generally considered minimal to absent in those with behavioral variant frontotemporal dementia (bvFTD). We sought to assess the frequencies of subjective and objective memory impairment in individuals with mild bvFTD according to consensus criteria.

Method

Assessments were performed in mildly symptomatic bvFTD [defined by global FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD) = 1] mutation carriers (Familial) and non‐mutation carriers (Sporadic) who are participants in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD, www.allftd.org) study. Mutation carriers had a pathogenic mutation in the MAPT, GRN or C9orf72 gene. The presence of subjective memory impairment was defined by a rating >0 on the memory domain of the CDR®+NACC FTLD. Evidence of objective memory impairment was based on performance across 7 memory measures, which include the National Alzheimer’s Coordinating Center Uniform Data Set Version 3 – Craft Story Immediate Recall (CSImm) and Delayed Recall (CSDel), Benson Figure Delayed Recall (BenDel), and the California Verbal Learning Test – Learning (CVLearn), Immediate Recall (CVImm), Delayed Recall (CVDel), and Recognition (CVRecog). Performance was considered abnormal for z‐scores ≤ ‐1.5.

Result

Data from 38 Familial (mean age 60±8 years, 61% male), and 109 Sporadic (mean age 63±7 years, 70% male) participants were analyzed. Memory ratings >0 on the CDR®+NACC FTLD were common for both Familial (84%) and Sporadic (88%). The frequencies of abnormal performance in the Familial vs Sporadic groups, respectively, per memory measure were: CSImm 43.8% vs 45.9%, p = 0.83; CSDel 46.9% vs 52.6%, p = 0.58; BenDel 29.4% vs 46.4%, p = 0.08; CVLearn 54.8% vs 39.8, p = 0.14; CVImm 64.5% vs 50%, p = 0.16, CVDel 80.6% vs 55.1%, p = 0.01, and CVRecog 51.6 vs 49%, p = 0.80. The frequencies of abnormal performance did not differ (all p>0.05) between Familial and Sporadic for ≥2 tests (79.3% vs 67.7%), ≥4 tests (55.2% vs 44.1%) and ≥6 tests (34.5% vs 31.2%).

Conclusion

These data suggest that among those with a mild global severity of bvFTD features: 1) subjective and objective memory impairment are relatively frequent, and 2) the frequency of impairment across memory measures is largely similar between familial and sporadic bvFTD. The presence of memory impairment should not preclude a diagnosis of bvFTD.
Investigating Dendritic Spine Morphology as a Mediator of Cognitive Outcomes in Aged Diversity Outbred Mice
Authors: Ouellette Andrew R , Herskowitz Jeremy H , Greathouse Kelsey M , Weber Audrey J , Hadad Niran , Kaczorowski Catherine C.
Published: December 2023

Background

The intersection of genetic diversity, memory, and synaptic function is a critical component in better understanding age‐related cognitive decline. Diversity Outbred mice offer the opportunity to investigate cognitive aging across a genetically diverse population in a controlled lab environment. DO mice exhibit an appreciable amount of variance in Contextual Fear Memory and Acquisition (CFM, CFA), which can be linked to individual differences in genetic background (Ouellette A. et al, 2022, Cell Reports). Here, we investigate the role of dendritic spines as a mediator of individual age‐related changes in memory.

Methods

524 DO mice (289 female, 235 male) were aged to either 8 or 18‐months. All mice received contextual fear conditioning (CFC) at 8mo, while another suet received an additional recall test at 17mo and renewal at 18mo. After CFC a subset of brains from each cohort were collected for spine morphology analyses (females, n = 42). One CA1 pyramidal neuron from each brain was imaged and quantified for the density of thin, stubby, mushroom and/or filipodia classified spines in addition to spine volume.

Results

While was not a decline in CFM or CFA between 8 and 18mo, we observed expectedly wide range in individual memory outcomes. Thin spine density significantly decreased between 8mo and 18mo, and stubby spine density increased. Spine volume across all spine types increased with age. Apical thin spine density explained 61% of the variance in CFM outcomes, while thin spine volume explained 79% and 43% of variance CFA in apical and basal dendrites respectively. Thin spine density, however, did not associate with CFA outcomes.

Conclusions

We have linked dendritic spine density and morphology as a potential mediator of individual outcomes across a genetically diverse population. Our results suggest that there may be an age‐related conversion of thin to stubby spine types, and that mice with fewer thin spines are more likely to have better CFM outcomes, coinciding with reports of thin spines as dynamic “learning spines” rather than “memory storage” spines (Hayashi, Y. 2005, Neuron). We also show that the size of these “learning” thin spines may be more important memory acquisition than their total density.
Discrimination between dementia with Lewy bodies and Alzheimer’s disease based on biofluid monoamines, biomarker values and cognitive parameters
Authors: Heylen Annelies , Vermeiren Yannick , Van Dam Debby , De Deyn Peter Paul
Published: December 2023

Background

Despite disease‐specific symptoms, differentiation between Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) remains challenging, especially in early, prodromal stages. This is fueled by overlapping pathology in both diseases (Slaets et al., 2013). Monoamine neurotransmitters are significantly altered between DLB and AD and are capable of distinguishing DLB from AD, when added to the panel of cerebrospinal fluid (CSF) dementia biomarkers (Aβ1‐40, Aβ1‐42, T‐tau, P‐tau) and as standalone biomarkers (Janssens et al., 2018). Additionally, cognitive and behavioral differences linked to monoaminergic changes between DLB, AD patients and non‐demented control individuals, have been previously described (Engelborghs et al., 2006, Vermeiren et al., 2015).This study aimed to further explore these dissimilarities for improving discrimination between prodromal and advanced DLB and AD stages.

Method

Monoamine neurotransmitter levels were measured in CSF and plasma of 160 prodromal AD (proAD), prodromal DLB (proDLB), AD and DLB patients and 40 non‐demented individuals, using ultra‐high‐performance liquid chromatography. CSF biomarker levels were determined through ELISA. A battery of cognitive and behavioral tests was performed. Monoaminergic, biomarker, cognitive and demographic data were integrated in stepwise regression models to discriminate between (prodromal) DLB and AD.

Result

Significant serotonergic differences in CSF between DLB and AD, as well as noradrenergic, dopaminergic and serotonergic differences in plasma between DLB and AD and with non‐demented individuals were noted. CSF dementia biomarkers levels differed significantly between proAD, proDLB, DLB and AD stages and with non‐demented individuals. There were no CSF, plasma monoamines or CSF biomarker changes between proDLB versus DLB, and proAD versus AD stages. Cognitive functioning differed significantly between prodromal and advanced DLB and AD stages and with non‐demented individuals. Stepwise regression identified that models including plasma and CSF serotonergic components, as well as cognitive tests were the most accurate at discriminating between proDLB versus DLB, proAD versus AD, proDLB versus proAD and DLB versus AD, with area under the curve (AUC), sensitivity and specificity values > 0.9.

Conclusion

These findings support differentially affected monoaminergic, pathological biomarker levels and cognitive abilities between (prodromal) AD and DLB, and with non‐demented individuals. In addition, this study provides robust models for discrimination between (prodromal) DLB and AD.
Females Derive Greater Neuroprotective Benefits from Social Connectedness than Males
Authors: Manchella Mohit K. , Logan Paige E. , Perry Brea L , Peng Siyun , Risacher Shannon L , Saykin Andrew J. , Apostolova Liana G.
Published: December 2023

Background

Social connectedness is associated with better cognitive performance among older adults. Previously, we found that bridging (access to an expansive network of diverse and loosely connected individuals) and bonding (close and supportive relationships to familiar others) associated with preserved gray matter density (GMD). We sought to examine whether sex modulates these relationships in the Social Networks and Alzheimer’s Disease study (SNAD).

Method

We analyzed baseline data of 176 SNAD participants (58 male, 118 female; 117 cognitively‐unimpaired, 59 cognitively‐impaired; average age 68.57+/‐12.26 years). Bridging and bonding metrics were collected via in‐person interviews. We ran analyses in the pooled sample split by sex. Demographics and biomarkers between sexes were compared. Correlations between MRI regions of interest and bridging and bonding in males and females were performed. Voxel‐wise covaried for age, education, and intracranial volume in SPM12 yielded statistical maps for males and females which were corrected for family‐wise errors at p<0.01.

Result

Table 1 shows demographic and biomarker comparisons between males and females. In females greater social bridging was significantly associated with (left p = 0.004, right p<0.001), as well as left frontal lobe thickness (p = 0.002), putamen (p = 0.011), and thalamus volumes (p = 0.002). No significant associations were observed for social bridging in males. Greater social bonding was significantly associated with preserved right frontal pole (p = 0.018) and caudal anterior cingulate thickness (p = 0.017) in females and greater right orbitofrontal thickness (p<0.001) in males (Figure 1).

Our 3D voxel‐wise regression maps showed that in females greater social bridging was associated with preserved GMD of the frontal, temporal and parietooccipital lobes, while males showed no significant associations (Figure 2). In females greater social bonding was associated with preserved GMD in the lateral temporal and parietal lobes, while in males the associations were localized to the medial frontal and right orbitofrontal lobe (Figure 2).

Conclusion

Women compared to men showed stronger effects of social enrichment on GMD and subcortical structures. Social bridging and bonding were associated to different brain regions in males and females. These results suggest that females may have a greater social‐based protection against neurodegeneration compared to their male counterparts.
Glia response on Amyloid plaque microenvironment protects against pathological tau conversion in Alzheimer’s disease resilience
Authors: Garfe Nur Jury , You Yanwen , Redding Javier , Martinez Pablo , Karahan Hande , Kim Jungsu , Troncoso Juan C , Reeves Cristian A Lasagna
Published: December 2023

Background

Aymptomatic Alzheimer’s disease (AsymAD) subjects have an intrinsic capacity to tolerate the presence of Aβ‐plaques and neurofibrillary tangles (NFTs) without developing cognitive impairment. In contrast to typical demented Alzheimer’s disease (AD) brains, AsymAD brains show distinct neuroinflammatory response and less accumulation of soluble pathological tau species at synaptic levels. The link between these observations and AD neuropathology is not fully understood, but increasing evidence suggests that the local plaque microenvironment plays a key role in the Aβ plaque‐associated tau pathogenesis. In this work we aim to identify the main molecular contributors of resiliency against amyloid and tau aggregation in AsymAD brains.

Method

We conducted a detailed histological and biochemical analysis using postmortem brain cortex samples from age‐matched controls (N = 21), demented AD (N = 22), and AsymAD subjects (N = 30). In fixed brain tissue, we performed the GeoMx whole spatial transcriptome atlas to compare the Aβ‐plaque microenvironment in AsymAD versus typical demented AD cases.

Result

There was no difference observed in the overall amyloid plaque burden between AsymAD and demented AD brains. However, immunofluorescence analyses indicates that AsymAD cases have the capability to form a glial barrier surrounding filamentous plaques, thereby avoiding the pathological conversion of tau. This observation is supported by biochemical analysis, which reveals that AsymAD cases have lower levels of high molecular weight tau and less seeding activity in soluble fractions. Using spatial whole transcriptomics to further characterize the plaque niche, we found an enrichment of migration signaling and autophagy in the AsymAD plaque niche, but not in AD. We are currently investigating the significance of these two molecular pathways in the Aβ plaque‐associated tau pathogenesis.

Conclusion

Our study provides new insights into the mechanism of Alzheimer’s disease resilience focus in the local Aβ plaque‐associated tau pathogenesis and potentials therapeutic approach to cognitive deterioration
Distinct pools of cholesterol regulate APP maturation and Aβ42/40 ratio
Authors: Kruijff Iris Daphne , van der Kant Rik
Published: December 2023

Background

Changes in amyloid precursor protein (APP) processing towards an increased Aβ42/40 ratio is a major hallmark of Alzheimer’s disease (AD). For sporadic AD, it is unknown what drives this increase, but cholesterol has been shown to regulate APP maturation via export from the endoplasmic reticulum (ER). Brain cholesterol metabolism is tightly regulated via the initiation or inhibition of cholesterol synthesis, storage, uptake, and export. The latter two processes are regulated by apolipoprotein E (APOE), a major cholesterol carrier. Here we test whether cholesterol can affect the Aβ42/40 ratio using cholesterol metabolism‐targeting drugs.

Method

Different isogenic human iPSC lines were used: APOE2/2 (protective), APOE3/3 (normal), APOE4/4 (AD risk) and APOE knockout (KO). iPSCs were differentiated to neurons via NGN2 overexpression and treated with cholesterol targeting interventions (statins, ACAT inhibitors, LXR agonists). Secreted levels of sAPPα, sAPPβ, Aβ40, Aβ42 and the ratio of Aβ42/40 were determined.

Result

Inhibiting cholesterol synthesis (statins) and cholesterol esterification (ACAT inhibitors) in the ER reduced levels of sAPPα, sAPPβ, Aβ42 and Aβ40, but did not affect the Aβ42/40 ratio. Induction of cholesterol export and inhibition of its synthesis (LXR agonists) caused a strong increase in Aβ42/40 ratio. At low LXR agonist concentrations, we observe increased Aβ42 levels, while Aβ40 remained unchanged. At higher concentrations, both Aβ42 and ‐40 levels decreased, while maintaining the elevated Aβ42/40 ratio. sAPPα and sAPPβ levels changed in similarly to Aβ40. APOE genotype did not affect responses to LXR agonists.

Conclusion

Our results indicate that inhibition of cholesterol synthesis or esterification in the ER influence overall APP processing. The LXR‐induced increase in Aβ42/40 ratio seems to depend on changes in a separate cholesterol pool. A previous study proposed that Aβ40 is mainly produced by PSEN1 in the plasma membrane, whereas Aβ42 is mainly produced by PSEN2 in the endo‐lysosomal system. Re‐localization of cholesterol might therefore be responsible for this ratio change, possibly in a PSEN‐dependent manner. Interestingly, the effects on Aβ processing are independent of APOE, as the APOE KO showed similar changes on all peptide levels. Our findings can help to further elucidate the interplay between cholesterol metabolism and Aβ processing.
Comparison of plasma Ab42, Ab40, and p‐tau181 assessed on two different platforms with CSF AD biomarkers and amyloid (PiB) PET
Authors: Sutphen Courtney L. , Rudolph Marc D. , Lockhart Samuel N. , Whitlow Christopher T. , Sai Kiran K. Solingapuram , Hughes Timothy M. , Bateman James R. , Dage Jeff L. , Russ Kristen A. , Mielke Michelle M. , Craft Suzanne , Register Thomas C.
Published: December 2023

Background

As blood‐based biomarkers of Alzheimer’s disease enter clinical diagnostic use, key considerations remain including the concordance with CSF or amyloid PET and the comparability of results between different assay platforms.

Method

Participants (n = 42) from the Clinical Core of the Wake Forest ADRC, were selected using CSF Aβ42/Aβ40 values which clearly indicated amyloid pathology status (‐ or +). A subset of 29 participants had amyloid (PiB) PET measures within one year of CSF. Participants were considered amyloid positive when CSF Aβ42/40 ≤0.058 and/or amyloid PET was adjudicated as “positive”. CSF and plasma Aβ42, Aβ40, and pTau181 were assessed using the Lumipulse platform at the Wake Forest ADRC; plasma Aβ42, Aβ40, and pTau181 were also assessed using the Quanterix SIMOA platform at the National Centralized Repository for Alzheimer’s disease. CSF and plasma from each participant were collected on the same day.

Result

Amyloid positive and negative groups differed significantly in age and APOE‐ε4 status (Table 1). Although raw values between plasma platforms differed significantly, biomarkers were highly correlated (Table 2). The correlation between CSF and plasma was: Lumipulse for Aβ42/Aβ40 (ρS = 0.76, p<0.0001) and pTau181 (ρS = 0.64, p<0.0001) and SIMOA Aβ42/Aβ40 (ρS = 0.63, p<0.0001) and pTau181 (ρS = 0.50, p = 0.0009). When comparing groups positive or negative for either CSF or PET, the ROC AUC for plasma Aβ42/Aβ40 was 0.94 for Lumipulse and 0.92 for SIMOA. Ptau181 AUC was 0.80 for Lumipulse and 0.82 for SIMOA. Figure 1 shows a clear relationship between decreasing Aβ42/Aβ40 and increasing pTau181 in the CSF which is present but diminished in Lumipulse plasma and largely absent in SIMOA plasma data.

Conclusion

Raw values from both platforms differed significantly which may limit generalizability and translatability of plasma data across platforms, but results were correlated. CSF values correlated marginally with both Lumipulse and SIMOA plasma. Plasma indices performed better than previously reported in other AD cohorts, likely due to our stringent CSF‐based selection criteria, and AUC did not differ between Lumipulse and SIMOA for either Aβ42/Aβ40 or pTau181. Further work is underway to expand the dataset and define population‐based cutoffs which also consider comorbidities, such as chronic kidney disease.
Amyloid ratios in plasma and CSF are biomarkers of pre‐symptomatic Alzheimer’s disease
Authors: Fonteh Alfred N. , Wu Xiaomeng , Astraea Natalie , Elenberger Tamara , Buennagel David P , Sin Caleb , Spezzaferri Mitchell , Rising Shant , Nolty Anne , Chui Helena C , Minazad Yafa , Kloner Robert A , Arakaki Xianghong
Published: December 2023

Background

The CSF amyloid to tau ratio can isolate cognitively healthy participants into normal Aβ42/tau (CH‐NAT) or a pathological Aβ42/tau (CH‐PAT) with a low or high risk of cognitive decline, respectively. We aim to determine if plasma Aβ42/tau ratios can differentiate CH‐NAT from CH‐PAT participants.

Method

Study participants (> 65 years of age) were recruited, and demographic, neurological, and neuropsychological data were obtained in an ongoing HMRI Brain Aging study. Overnight fasting plasma and CSF were collected within a month of examination, and the levels of Aβ38, Aβ40, Aβ42 (MSD 6E10 kit), and total tau were quantified using the MSD electrochemiluminescence platform. Differences in fluid biomarker levels and the plasma ratios (n = 55) and CSF ratios (Aβ42/Aβ40, n = 41, Aβ42/tau, n = 55) were determined using nonparametric student t‐test and correlations using a Spearman test.

Result

Aβ40 and Aβ42 levels were higher (15‐18‐fold, and 10‐14‐fold, respectively), while tau levels are 8‐13‐fold higher in CSF than in plasma. Plasma and CSF Aβ40 were not distinct in CH‐NAT compared with CH‐PAT. In contrast, Aβ42 levels were 30.9% lower in CH‐PAT (16.3 ± 18.3 pg/ml) compared with CH‐NAT plasma (23.6 ± 26.4 pg/mL) (p < 0.05). CSF Aβ42 levels in CH‐PAT (171.6 ± 124.6 pg/mL) were lower by 47.6% compared with CH‐NAT (327.6 ± 182.6 pg/ml) (p < 0.0001). The Aβ42/Aβ40 ratio was significantly lower in both plasma and CSF (Table 1A). Similarly, the Aβ42/tau ratio was significantly lower in plasma and CSF (Table 1B). Individually, plasma levels of Aβ42 and tau did not correlate with CSF levels. However, the ratio of Aβ42 to total tau in plasma significantly correlated with the CSF ratios (Spearman r = 0.36, p = 0.0071). Finally, CSF Aβ42/Aβ40 ratio correlated with Aβ42/tau ratio for all samples, CH (n = 100) and MCI (n = 35) (Fig. 1).

Conclusion

While not as robust as CSF ratios, plasma Aβ42/Aβ40 and Aβ42/tau ratios can isolate cognitively healthy participants with lower risk from participants with a higher risk of cognitive decline. Thus, plasma represents a less invasive medium for the biomarker classification of aging participants.
Rates of change in structural and functional brain connectivity are associated with longitudinal changes in episodic memory in non‐demented older adults
Authors: Alm Kylie H. , Zhu Yuxin , Soldan Anja , Pettigrew Corinne , Faria Andreia , Hou Xirui , Lu Hanzhang , Mori Susumu , Albert Marilyn S. , Bakker Arnold
Published: December 2023

Background

Individual differences in brain connectivity have been associated with cognitive variability in older adults, making them ideal markers of early changes that may predict subsequent cognitive decline. Using MRI measures, we previously demonstrated that cross‐sectionally, both structural and functional connectivity each uniquely contributed to variability in episodic memory performance (Alm et al., 2022). The present investigation expanded on these findings to examine whether longitudinal changes in brain connectivity were related to changes in episodic memory.

Method

Analyses included 152 non‐demented BIOCARD study participants (at first scan, 135 cognitively normal and 17 with Mild Cognitive Impairment). Structural connectivity was measured using radial diffusivity (RD) and mean diffusivity (MD) of two limbic pathways (fornix and hippocampal cingulum) derived from diffusion‐weighted MRI. Based on our previous findings, the salience network was chosen as the functional connectivity network of interest, as measured by resting‐state fMRI. Delayed episodic memory was evaluated with a composite score. Separate linear mixed effects (LME) models with multivariate outcomes tested whether longitudinal changes in episodic memory were related to longitudinal changes in each measure of brain connectivity (mean follow‐up = 3.11 (0.96) years), covarying age, sex, education, and diagnosis. LME models were fit simultaneously, allowing for the random effects in each model to be correlated. Significant correlations between the random slopes indicated a relationship between longitudinal changes in outcome variables.

Result

Longitudinal memory decline was associated with increases in fornix RD and MD (p’s < .01) and increases in salience network functional connectivity (p < .01), but not hippocampal cingulum measures (p’s > .05). When only cognitively normal participants were included, the fornix findings remained significant (p’s < .01); however, the salience network model failed to converge.

Conclusion

Extending prior cross‐sectional results, these findings show that rate of memory decline over time is associated with rate of change in both structural (fornix) and functional (salience network) connectivity markers, providing further evidence that both connectivity modalities uniquely contribute to episodic memory function. These may, therefore, be important brain markers in predicting person‐specific disease trajectories, considering structural connectivity at the earliest stages of aging and functional connectivity with disease progression.
Sex‐specific CSF proteomic profiling of amyloid/tau positivity identifies distinctive sex‐specific alternation of multiple proteins involved in Alzheimer’s disease
Authors: Do Anh , Ali Muhammad , Timsina Jigyasha , Wang Lihua , Ruiz Agustin , Pastor Pau , Cruchaga Carlos , Sung Yun Ju
Published: December 2023

Background

Sporadic Alzheimer’s disease (AD) is a highly heterogeneous multifactorial disease in which females have a higher risk. Among 5.3 million senior Americans diagnosed with AD, over 60% are female. Despite the well‐established sex differences, sex‐specific molecular findings in AD are still limited. We therefore examined the role of sex in the proteomic alterations due to AD to elucidate potential protein markers of AD heterogeneity.

Method

In the discovery cohort, 599 preclinical AD and 435 controls underwent lumbar puncture. Over 7,000 proteins in cerebrospinal fluid (CSF) were measured using SomaLogic assay. Amyloid/tau positivity (AT classification) was determined using ELISA Aβ42 and pTau181 levels in CSF. Proteins with sex‐specific effects were identified through linear models focusing on the interaction term between AT classification and sex. Results were tested in the independent cohort (N = 732) using the identical approaches. We analyzed brain proteomics and transcriptomics data to validate the replicated sex‐specific proteins. We performed pathway enrichment, interaction network using ConsensusPathDB and drug‐target prediction.

Result

We identified 594 proteins with sex‐specific effects in discovery (P<0.05 and permutation FDR <0.05). Among them, 36 were validated in replication (P<0.05 and consistent direction). These proteins were found to be involved in neurologic disorders and highly enriched in axon regeneration (fold enrichment = 9.38 and FDR = 2.8×10−4). Among the 36 proteins identified, 13 were classified as female‐specific and 23 as male‐specific. These 36 proteins strongly predicted amyloid/tau positivity (AUC = 0.926) for all individuals as well as 13 female‐specific proteins for females (AUC = 0.929). The interaction network identified CCN2 as a hub and contained 10 additional proteins including JAG1 and DLL4 of Notch signaling pathway and CTSB, an amyloid precursor protein secretase, among others. The results of 36 proteins in brain proteomics and transcriptomics confirmed the sex‐specific effect of CCN2 and others on AD in different tissues. Drug target prediction suggests minocycline and etoposide as potential treatments for females as well amitriptyline and verteporfin for males.

Conclusion

We robustly identified 36 proteins that showed significant sex‐specific alterations by preclinical AD. Several proteins involved in AD and neurodegeneration were highlighted. Our findings facilitate mechanistic understanding of sex differences for AD risk and progression.
Plasma ALZpath p‐tau217 for the identification of amyloid and tau positivity
Authors: Ashton Nicholas J. , Molfetta Guglielmo Di , Brum Wagner Scheeren , Benedet Andrea Lessa , Arslan Burak , Jonaitis Erin M. , Langhough Rebecca E , Cody Karly Alex , Betthauser Tobey J , Hogan Kirk J. , Christian Bradley T. , Rahmouni Nesrine , Stevenson Jenna , Montoliu‐Gaya Laia , Rodriguez Juan Lantero , Triana‐Baltzer Gallen , Kolb Hartmuth C. , Vanbrabant Jeroen , Stoops Erik , Jeromin Andreas , Rosa‐Neto Pedro , Johnson Sterling C , Blennow Kaj , Zetterberg Henrik
Published: December 2023

Background

In the last 5 years, immunoassays for the quantification of phosphorylated tau (p‐tau) in blood have proven to accurately identify Alzheimer’s disease (AD) pathology with important implications for primary care management and therapeutic trials. Comparisons of p‐tau epitopes (p‐tau181, p‐tau217, p‐tau231) show small differences in diagnostic accuracy, however, often p‐tau217 is preferred, citing its larger fold‐change in symptomatic patients and lower rate of false positives in amyloid‐negative individuals. This study describes the performance of a novel Single molecule array (Simoa) for p‐tau217 (p‐tau217ALZpath)

Method

We included 355 participants from Translational Biomarkers in Aging and Dementia (TRIAD) participants, which was representative of the AD continuum. Further, 425 cognitively unimpaired individuals, with longitudinal plasma measures (≤8 years), were included from Wisconsin Registry for Alzheimer’s Prevention (WRAP). All plasma samples were measured for ALZpath p‐tau217ALZpath, a validated Simoa assay at the University of Gothenburg, Sweden. In TRIAD, amyloid positivity (A+) was defined as [18F]AZD‐4694 SUVR >1.5 or CSF Aβ42/40 <0.068. In WRAP, A+ was defined by [11C]PiB >1.16. 18F‐MK‐6240 determined tau status (T+) both cohorts (TRIAD, >1.24 SUVR; WRAP, >1.3).

Result

In TRIAD, p‐tau217ALZpath determined A+ (AUC = 0.957, 0.935‐978) and T+ (AUC = 0.952, 0.929–0.976) individuals with high accuracy. A sensitivity analysis, including only participants with imaging (amyloid and tau) and CSF biomarkers (p‐tau181, p‐tau205, p‐tau217, Aβ42/40), p‐tau217ALZpath demonstrated equivalent accuracies in determining A+ (Figure 1A) and T+ (Figure 1B) than these high‐performing modalities. In addition, plasma p‐tau217AlzPATH demonstrated a good accuracy to identify T+ from all A+ participants (AUC = 0.839, 0.767‐910). Concentration cut‐points derived in WRAP to identify A+ (>0.676 pg/mL; PPV = 87.2%) and A– (<0.235 pg/mL; NPV = 98.2%) were directly tested in TRIAD with high accuracy (>0.676 pg/mL, PPV = 98.8%; <0.235 pg/mL, NPV = 95.1%. In WRAP, longitudinal analysis (Figure 2) demonstrated that over 8‐years, p‐tau217AlzPATH increased only in A+ individuals and more steeply in A+T+ participants (βestimate = 0.1 pg/mL per year; P<0.0001) compared to A+T‐ (βestimate = 0.022 pg/mL per year, P = 0.0008).

Conclusion

The novel p‐tau217ALZpath immunoassay demonstrates high accuracy to determine amyloid and tau pathology across all stages of AD continuum. Clinical cut‐points to identify A+ or A– with high PPV and NPV are directly transferable across cohorts.
Associations among plasma, MRI and amyloid PET biomarkers of dementia and the impact of health‐related comorbidities
Authors: Rudolph Marc D. , Sutphen Courtney L. , Register Thomas C. , Whitlow Christopher T. , Sai Kiran K. Solingapuram , Hughes Timothy M. , Bateman James R. , Dage Jeff L. , Russ Kristen A. , Mielke Michelle M. , Craft Suzanne , Lockhart Samuel N.
Published: December 2023

Background

Knowledge regarding associations between plasma and neuroimaging biomarkers indexing neurodegeneration and neuropathology observed in dementia is limited. Further, it is uncertain how comorbid health complications (e.g., kidney function) may alter plasma levels and impact associations with neuroimaging biomarkers.

Method

We examined associations between plasma and neuroimaging biomarkers in cognitively normal participants (NC; N = 300) and individuals with consensus diagnosis (Dx) of mild cognitive impairment (MCI; N = 192) or dementia (DEM; N = 64) enrolled in the Wake Forest ADRC (Table 1). We examined plasma biomarkers (Quanterix SIMOA HD‐X: Aβ42/40, GFAP, NfL, p‐tau181) and neuroimaging measures of amyloid deposition (global PiB PET SUVr; Aβ‐PET), total brain volume (BVOL), global white matter hyperintensity volume (WMH), diffusion‐weighted fractional anisotropy (FA) and NODDI freewater (FW; white matter). Linear models adjusted for APOE‐ε4 carrier status, demographics (age, sex, race, education), and cardiometabolic factors (estimated glomerular filtration rate (eGFR); BMI).

Results

Plasma biomarkers were moderately correlated with each other (absolute r = .22‐.64; all p<.001) and significantly elevated (Aβ42/40 lower) in DEM and MCI (Figure 1) versus NC, and Aβ‐PET‐positive (SUVr >1.21) versus negative individuals (all p<.001). Plasma and neuroimaging markers were significantly associated in both unadjusted models and models including eGFR and BMI (all p<.05; attenuation effect <10% with and without Dx; Figure 2a & 2b). In fully adjusted models (Figure 2b: Dx and all covariates), age, sex, and race differentially impacted associations of Aβ42/40, p‐tau181, and NfL with neuroimaging biomarkers (coefficients p <.05). APOE‐ε4 status exclusively impacted associations with Aβ‐PET SUVr/status. GFAP remained significantly associated with all neuroimaging biomarkers after covariate adjustment; no Aβ42/40 associations survived adjustment. P‐tau181 remained significantly associated with Aβ‐PET and BVOL, while associations with NfL were reduced in models stratified by Dx.

Conclusion

Among aging community‐dwelling participants, plasma biomarkers significantly differed between diagnostic groups (DEM>MCI>NC), were elevated in Aβ‐PET positive individuals, and associated with poorer brain health. Except for GFAP, and to an extent p‐tau181, associations between plasma and neuroimaging biomarkers were differentially impacted by inclusion of comorbidities and covariates when stratified by diagnosis. Future work will examine high‐dimensional interactions among comorbidities, demographic information, and plasma and neuroimaging biomarkers in individuals with or at‐risk of dementia.
Genetically Regulated Telomere Length Relates to Brain Amyloidosis
Authors: Libby Julia B. , Roshani Rashedeh , Seto Mabel , Wang Ting‐Chen , Nudelman Kelly N. H. , Buckley Rachel F. , Saykin Andrew J. , Mormino Elizabeth C. , Sperling Reisa A. , Mayeux Richard , Dumitrescu Logan C , Hohman Timothy J.
Published: December 2023

Background

It is well‐established that telomeres shrink over the course of aging and that this process is genetically regulated. Work from our group and others has highlighted the complex interplay between measured leukocyte telomere length and Alzheimer’s Disease (AD) biomarkers over the course of AD. We expand on this work to explore whether a polygenic score predicting telomere length relates to PET measures of brain amyloidosis in the preclinical stages of disease.

Method

A Polygenic Risk Score (PRS) of telomere length was built from a published GWAS on telomere length from UK Biobank (N = 472,174). We leveraged genetic data from non‐Hispanic White participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 1,414) and the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s study (A4; N = 3,002). The relation of the score to measured telomere length was validated using leukocyte telomere length data from ADNI. A linear regression model was used to evaluate whether the PRS relates to a PET measure of brain amyloidosis in a harmonized dataset including ADNI and A4, with a total sample size of 3,940 after restricting to individuals with both genetic data and amyloid measurements. Covariates included age, sex, and diagnostic status.

Result

As expected, telomere PRS related to measured telomeres in ADNI when covarying for age, sex, and baseline diagnosis (Figure 1, p = 0.045). Interestingly, we also observed a counter intuitive association between genetically predicted telomere length and amyloidosis whereby longer predicted telomere length was associated with higher amyloid burden (Figure 2, β = 1305, p = 0.006).

Conclusion

A PRS for telomere length modestly relates to measured telomere length in older adults and relates to higher amyloid burden. Previous work from our group has highlighted the interaction between measured telomere length and amyloid status such that the association is counter intuitive among those who are biomarker positive. The present results highlight the exciting possibility that telomere length may relate directly to AD biomarkers and open the opportunity for future work further probing the complex interplay between telomere length and AD biomarkers leveraging this powerful genetic tool.
Optimization of voice biomarkers to predict Alzheimer’s disease
Authors: Ko Hyunwoong , Kwon Sukbong
Published: December 2023

Background

Emerging evidence indicates the feasibility of utilizing a surrogate biomarker to detect Alzheimer’s disease. One of the noninvasive markers, the vocal biomarker, may be used to screen for dementia without the use of language markers. Regarding model performance based on vocal biomarker, speech activity detection algorithm (SAD) that eliminates the non‐speaking portion of demented speech may improve the outcome. The aim of the study was to determine whether the SAD algorithm can achieve superior performance.

Method

For this experiment, the ADReSSo Challenge dataset from DementiaBank was used. The participants consisted of 87 AD and 74 CN. 18 silence‐related features (e.g., silence count rate), 2 MFCCs, 2 Spectrograms, MelSpectrogram, 2 Spectral centroids, 4 pitchs, loudness, 5 jitters, 5 shimmers, and harmonics‐to‐noise ratio comprised the vocal biomarker features. SincNet was used to develop the SAD method, which is based on a deep convolution neural network. To compare the SAD’s quality, naive bayes, the most basic machine learning algorithm, was utilized.

Result

With SAD, the F1 score was 0.750 (0.083). Without the SAD, the F1 score was 0.59 (0.075).

Conclusion

The performance of the prediction of AD based only on speech may be improved by including essential SAD algorithm characteristics. In practice, even eliminating irrelevant speech parts may result in improved performance.
Elucidating APOE4‐dependent cholesterol dysregulation in endolysosomes related to Alzheimer’s disease biology
Authors: Leeuw Sherida M , Putter Julian , van der Kant Rik , Nuriel Tal
Published: December 2023

Background

Aberrant cholesterol processing may be the missing link in the biology of AD, and in our understanding of AD etiology. APOE4 is a major genetic risk factor for AD, and a key player in cholesterol metabolism in the brain. Previous research from our group has shown that APOE4 is related to increased lysosomal cholesterol accumulation in human iPSC‐astrocytes, and altered endolysosomal morphology has been observed in the entorhinal cortex (EC) of aged APOE4 mice. However, it is unclear how endolysosomal cholesterol mistrafficking changes with age.

Method

Therefore, we studied endolysosomal cholesterol accumulation in middle (15‐16month) and old age (25‐26month) old mice, enabling us to study these processes already in mid‐life. We used brain sections of humanized APOE mice, looking at different brain regions to study regional vulnerability and temporal progression. Cholesterol was labeled using the novel and highly specific D4H probe, enabling its quantification within the endolysosomal system using immunohistochemistry. Cholesterol and endolysosomal markers were quantified and colocalized using Cellprofiler.

Result

Older APOE4 mice showed an increase of total cholesterol in their brain, and specifically an increase of lysosomal cholesterol. Middle aged mice did not show a difference in total cholesterol, however, there was a specific decrease in early endosomal (EE) and late endosomal (LE) cholesterol only in the entorhinal cortex (EC) of female APOE3 mice, while lysosomal cholesterol was increased in this group (APOE4 and APOE2 showed similar levels). The EE and LE cholesterol differences were specific to neurons, but not the lysosomal cholesterol increase, indicating that non‐neuronal cells play a role. Another striking finding was the increase of neuronal EE cholesterol in the EC of middle aged APOE3 male vs female mice, whereas the reverse was seen in APOE4 brain tissue.

Conclusion

Altogether these results indicate that endolysosomal cholesterol is a dynamic process throughout aging, which may play and active role in AD biology. There is a noticeable shift from EE and EL cholesterol changes in midlife, to lysosomal cholesterol accumulation in older age, which are APOE‐genotype dependent. Notably, the EC specifically of female mice show the most variable endolysosomal cholesterol levels, and may be involved in increased vulnerability to pathology.
Role of Discrimination and Physiological Dysregulation in Racial Disparities in Cognitive Function: The Multi‐Ethnic Study of Atherosclerosis (MESA)
Authors: Forrester Sarah N , Gallo Joseph J , Leoutsakos Jeannie‐Marie S , Thorpe Roland J. , Rapp Stephen R. , Hayden Kathleen M. , Luchsinger Jose A , Seeman Teresa E.
Published: December 2023

Background

Black‐White disparities in cognitive test scores are well documented. Studies suggest that structural racism‐related factors like quality of education and cumulative stress exposure may contribute to disparities in inflammation and cardiometabolic health that undergird racial disparities in Alzheimer’s disease and cognitive health.

Method

We used MESA data from (N = 1,839) participants that self‐report being racialized as Black or White. We used path analyses to examine the association between racialized group and age‐ and education‐adjusted cognitive scores from the Cognitive Ability Screening Test (CASI) at Exam 5 (2010‐12) and Exam 6 (2016‐18). We examined the relationship between discrimination using the Everyday Discrimination Scale at Exam 1 (2000‐02) and physiological dysregulation at Exam 5 (using a cardiometabolic index = waist‐to‐hip ratio, triglycerides, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, glucose, systolic blood pressure, resting heart rate, and pulse pressure). All models were adjusted for Exam 5 age, sex, site, depression, general stress, socioeconomic stress, and APOE‐e4.

Result

Mean age was 69.6 years (SD = 9.3) at Exam 5. Participants racialized as Black had significantly lower CASI scores at Exam 5 (b = ‐0.26) and Exam 6 (b = ‐0.29) than counterparts. Physiological dysregulation was directly associated with lower CASI scores at both exams (Table 1). Discrimination and physiological dysregulation had a significant indirect association with racialized group‐cognition at both exams (Figure 1). Physiological dysfunction was associated with lower CASI scores for participants racialized as Black compared to White at Exam 5 (b = ‐0.004, 95% CI: ‐0.010, ‐0.001) and Exam 6 (b = ‐0.005, 95% CI: ‐0.011, ‐0.002). Higher discrimination was associated with higher CASI scores for participants racialized as Black compared to White at Exam 5 (b = 0.013, 95% CI: 0.001, 0.024) and Exam 6 (b = 0.012, 95% CI: 0.001, 0.024). There was no racialized difference in decline from Exam 5 to Exam 6.

Conclusion

Physiological dysregulation may be a mechanism to partially explain the Black‐White disparity in cognitive test scores among middle‐aged and older adults. Endorsing more everyday discrimination was associated with a significantly higher cognitive test scores, though further research is needed to determine if this is due to coping‐related resilience.