bluuebunny/crossref_metadata_2025 huggingface dataset:
Amelioration of tau related pathology with a novel anti‐prion protein monoclonal antibody in an AD mouse model
Authors: Boutajangout Allal , Zhang Wei , Abdali Wed , Kim Justin Sung Tae , Prelli Frances , Wisniewski Thomas
Published: December 2021

Background

A number of studies have shown that amyloid β oligomers (Aβo) mediate their toxicity, in part, via the cellular prion protein (PrPC) on the surface of neurons. We hypothesized that tau oligomers may also mediate toxicity and spread of pathology via PrPC. We have generated a novel monoclonal anti‐PrP antibody (TW1) and assessed the efficacy of passive immunization with this antibody in a mouse model of AD with only tau related pathology.

Method

HTau/PS1 transgenic AD model mice were injected at 5 months of age intraperitoneally once a week with TW1 from the age of 5 months. Control mice received only saline. Their behavior was assessed at 8 months of age and brain tissue subsequently harvested for analysis at 9 months

Result

The treated and control mice did not show any significant differences in sensorimotor testing. Significant statistical differences were observed with the novel object recognition test in the immunized mice on percentage time spent in zones (two tailed, t‐test p = 0.0019). On the closed field symmetrical maze immunized mice performed significantly better (Day1: two tailed t‐test p=0.0001; Day2: two tailed t‐test p=0.0015; Day3: two tailed t‐test p=0.0002). Fifty percent less tau pathology was observed in the dentate gyrus with PHF‐1 immunolabeling (two tailed t‐test p= 0.02) and a 60% reduction was seen in the piriform cortex (two‐tailed, t‐test p=0.01) in treated vs control animals. CP13 immunolabeling showed a significant difference in the piriform cortex (p=0.02, two‐tailed t‐test) in treated mice versus controls. There was no significant difference in astrogliosis or microgliosis in treated versus control mice. Western blots using PHF‐1 showed that TW1 therapy reduced phosphorylated tau pathology (two‐tailed t‐test p=0.03) and improved the ratio of pathological soluble tau to tubulin (two‐tailed t‐test p=0.0006). The same effect were observed with the CP13 antibody (two‐tailed t‐test p=0.0007) and improved the ratio CP13/tubulin (two tailed, t‐test p=0.0014).

Conclusion

These results indicate that passive immunization with the TW1 antibody can significantly decrease tau pathology and improve cognition in a transgenic mouse model of AD.
Neuropathologic underpinnings of PET and fluid biomarker measures
Authors: Murray Melissa E.
Published: December 2021

Background

Alzheimer’s disease (AD) biomarkers can be broadly considered to inform upon regional or global changes occurring in‐vivo. Investigation of neuropathologic underpinnings of regional and global biomarker measures may require differing strategies to validate in the postmortem brain. The goal of this presentation will be to discuss potential neuropathologic strategies to validate AD biomarkers and consider how we may leverage our understanding of the biology to inform upon disease stages.

Method

A neuropathologic overview of amyloid‐β composition, neurofibrillary tangle maturity, and glial activation will be provided in a didactic format with an emphasis on disease spectrum. The relevant AD biomarker literature with neuropathologic validation will be highlighted.

Result

Regional AD biomarker measures can be visualized and quantified using positron emission tomography (PET). Neuropathologic validation is performed using PET‐to‐autopsy studies or via autoradiographic studies in the postmortem brain tissue. Global AD biomarker measures can be assessed using PET, or fluid biomarkers that include cerebrospinal fluid and blood. Interpretation of these global AD biomarker measures can be further examined in individuals followed to autopsy, which enables a direct comparison with global neuropathologic staging scales (e.g. Braak stage, Thal phase). Neuropathologic validation of global measures and disease stage may be especially useful in identifying contributors to biomarker variability owing to the presence of multiple comorbidities that are a common finding in the AD brain.

Conclusion

The direct target of AD biomarkers (e.g. N‐terminal tau phosphorylation) may impact the sensitivity to early or advanced disease stages, both of which may be critical for disease monitoring depending upon the setting or study question. Quantitative digital pathology studies investigating regional, global, or disease stages measured by PET and fluid biomarkers provide an invaluable opportunity to inform upon the neuropathologic underpinnings of longitudinal biomarker changes.
Frequent leisure activity participation and cognitive change in the Study of Healthy Aging in African Americans (STAR)
Authors: Peterson Rachel L , George Kristen M , Gilsanz Paola , Mayeda Elizabeth Rose , Meyer Oanh L , Barnes Lisa L , Glymour M Maria , Mungas Dan M , Whitmer Rachel A
Published: December 2021

Background

Participation in leisure activities improves quality of life and is associated with lower dementia risk but has not been well studied in diverse populations. We examine type of leisure activities and cognitive change in older Black‐Americans.

Method

In the STAR cohort, an ongoing study that characterizes predictors of cognitive aging in Black‐Americans, 631 participants ages 50‐102 reported engagement in 13 leisure activities that require cognitive, social, or physical skills on a 5‐point Likert‐type scale (almost daily, weekly, monthly, yearly, or <yearly). Linear regression models examined the association of ≥weekly versus <weekly (reference) participation in individual activities measured at wave 1 with cognition assessed at wave 2 and cognitive change between waves 1‐2. Executive function, semantic memory, and verbal episodic memory were assessed using the Spanish and English Neuropsychological Assessment Scales (SENAS) and z‐standardized to wave 1 cohort distribution. Linear regression models adjusted for wave 1 age, gender, education, retirement status, time between waves, Southern state birth, and interview mode (phone/in person).

Result

Mean age was 68.3 (SD 8.6) years, 70% female, 36% 90% (reading, socializing) to 6% (attending cultural events; Table 2). Participants had better executive function scores in wave 2 if they reported they played games ≥weekly (β=0.18; 95% CI=0.05, 0.32) or read ≥weekly (β=0.30; 95% CI=0.03, 0.58) in wave 1 (Table 3). Playing games ≥weekly in wave 1 was also associated with higher wave 2 verbal episodic memory (β=0.15; 95% CI=0.004, 0.29), while ≥weekly arts and crafts participation was associated with lower Wave 2 verbal episodic memory (β=‐0.21; 95% CI=‐0.41, ‐0.01). Among participants who read ≥weekly in wave 1, executive function scores improved from wave 1 to wave 2 (β=0.20; 95% CI=0.02, 0.39; Table 4).

Conclusion

In this cohort of Black‐Americans, those who read or play games weekly or more had better executive function; those who read weekly or more also had improved executive function from waves 1‐2. Participation in leisure activities can be a way to maintain brain health and potentially reduce risk of cognitive decline.
Neural somatosensory dysfunction is masked by variable executive declines across the Alzheimer’s disease spectrum
Authors: Wiesman Alex I , Mundorf Victoria M , Wolfson Sara L , Johnson Craig M , May Pamela E , Murman Daniel L , Wilson Tony W
Published: December 2021

Background

Despite decades of research suggesting that primary somatosensory cortical function is spared until relatively late in the progression of Alzheimer’s disease (AD), very few of these studies have considered the role of domain‐specific cognitive function. This is essential, as recent literature has established a robust neurocognitive relationship between attention and executive functions and somatosensory neurophysiology, and patients with AD exhibit highly variable inter‐individual declines in these cognitive domains.

Method

In this study, we combine the high spatio‐temporal resolution of source imaged magnetoencephalography (MEG) with an extensive battery of neuropsychological tests to examine the potential mediating role of domain‐specific cognitive declines on somatosensory neural dysfunction in AD. In a sample of 38 biomarker‐confirmed patients on the AD spectrum and a group of 18 biomarker‐negative older adults, we model mediation/suppression effects of five distinct cognitive composite domains on group differences in two neurophysiological metrics of somatosensory function using a nonparametric bootstrapping approach.

Result

Initial models that did not consider cognitive abilities provided weak or null support for somatosensory dysfunction in patients on the AD spectrum. However, the addition of domain‐specific cognitive scores to these models significantly increased their predictive capacity, and revealed robust differences in somatosensory function between these patients and their cognitively‐normal counterparts. The indirect effects of these cognitive variables on somatosensory group differences were significant as well, indicating a suppression effect. Specifically, across‐participant variability in processing speed declines was found to mask groupwise differences in mean somatosensory response amplitude, and similar variability in both processing speed and attention function was found to mask differences in the functional gating of redundant somatosensory information.

Conclusion

By considering an important potential confounder in our models of somatosensory dysfunction in patients on the AD spectrum, we show that both general somatosensory responses and the functional gating of incoming somatosensory information exhibit profound alterations in these patients. These findings hold important implications for both our understanding of functional somatosensory pathology in AD, as well as for the importance of considering the role of domain‐specific cognitive variability in future AD‐neuroimaging research.
Augmenting Alzheimer’s Research: Schol‐AR
Authors: Ard Tyler , Toga Arthur W.
Published: December 2021

Background

The multi‐disciplinary field of Alzheimer’s disease research relies on many modern forms of data, from neuroimaging volumes and cellular image‐stacks to population and genetic information. Unfortunately, much of this information is difficult to communicate through the standard communication of scientific articles and static images, often resulting in incomplete data reporting and suboptimal comprehension for many readers.

Method

We introduce an augmented reality technique to layer modern digital information ontop of printable scientific figures, enabling full datasets to be attached to scientific articles. This system is additionally paired with an uploading framework that allows authors to create and disseminate augmentations from their own data.

Result

The capabilities provided through both the augmented viewing and augmentation creating systems facilitate communication and comprehension of the complex information underlying Alzheimer’s research.

Conclusion

Augmented reality technologies can improve and modernize the state of scientific communication in Alzheimer’s research, bridging the gap between modern digital data and journal article communications.
The prevalence of vascular risk factors in different AD biomarker profiles
Authors: Kučikienė Domantė , Costa Ana Sofia , Banning Leonie C.P. , van Gils Veerle , Schulz Jörg B. , Ramakers Inez H.G.B. , Verhey Frans R.J. , Vos Stephanie J.B. , Reetz Kathrin
Published: December 2021

Background

The relation between vascular risk factors and Alzheimer’s disease (AD) pathophysiology has been gaining an increasing research interest. Our aim was to investigate the prevalence of vascular factors in regard to different AD biomarker profiles in a memory clinic setting.

Method

We performed a retrospective analysis of patients of two memory clinics (University Hospital Aachen (Germany) and Maastricht University Medical Centre (The Netherlands)) in between 2008 and 2019. We included patients, who were older than 45 years and had data on demographics, vascular risk factors, cerebrospinal fluid (CSF) and brain magnetic resonance imaging (MRI). The individuals were assigned an ATN profile according to Jack et al. (2018), with “A” referring to amyloid‐pathology (CSF Aβ 1‐42/ Aβ 1‐40 ratio or CSF Aβ 1‐42), “T” to tauopathy (CSF phosphorylated Tau) and “N” ‐ neurodegeneration (CSF total Tau and/or medial temporal atrophy (MTA) score). All patients were categorised into normal ATN profile (A‐T‐N‐), non‐AD change (A‐T+N‐, A‐T‐N+, A‐T+N+) and AD‐continuum (A+T‐N‐, A+T+N‐, A+T‐N+, A+T+N+) groups.

Result

Of the 838 subjects included into the analysis, 53.2% were men; mean age was 68.7 ± 9.7 years. The most common vascular risk factors in the cohort were smoking (60.9%), hypertension (54.6%) and dyslipidemia (37.8%). A higher prevalence in the AD‐continuum group than in the normal ATN and non‐AD‐change groups was found for coronary heart disease (11,9% vs. 4,8% and 9.6% respectively, Pearson χ2 = 9.788, p=.007) and carotid artery stenosis (30.6% vs. 15.8 % and 17.1 % respectively, Pearson χ2 = 22.326, p<.001). Alcohol abuse and smoking were the most prevalent in non‐AD‐change group (alcohol abuse: 23.9% vs. 15.0% and 9.1%, Pearson χ2 = 7.501, p=.024; smoking: 69.4% vs. 60.3% and 52.1%, Pearson χ2 = 7.871, p=.020). Depression was more prevalent in the normal ATN group than in other groups (19.3% vs. 10.8% and 10.1%, Pearson χ2 = 12.930, p=.002).

Conclusion

Vascular risk factors are very common in memory clinic patients, showing distinct differences between different AD biomarker profiles. This implies the need for controlling vascular factors in memory clinics and urges to further investigate this field to improve the prevention and treatment of dementia.
The prospective association between physical activity and memory in the Canadian Longitudinal Study on Aging (CLSA)
Authors: Hammond Nicole G , Stinchcombe Arne
Published: December 2021

Background

Physical activity is a recommended health behaviour and there exists a literature base linking physical activity and cognition in mid‐life and older adulthood. Yet, longitudinal study of physical activity and cognition is needed in order to account for determinants of health which may affect participation in physical activity and attenuate previously observed relationships. The aim of this study was to examine the longitudinal relationship between different intensities of physical activity and memory at first three‐year follow‐up in a large prospective survey of Canadian adults.

Method

Data were drawn from the Canadian Longitudinal Study of Aging (CLSA), an ongoing prospective cohort study. Participants self‐reported a number of health behaviours, health‐professional diagnosed conditions, and social and demographic factors. Physical activity was measured using the Physical Activity Scale for the Elderly (PASE). Past‐week activity was classified according to type of intensity (e.g., strenuous) and duration (e.g., minutes [mins] and hours [hrs]). Memory was assessed using the Rey Auditory Verbal Learning Test, with higher scores reflective of better memory performance. We used linear regression modelling to examine associations between physical activity at baseline and memory three‐years later, after adjustment for an array of potential confounders.

Result

In fully adjusted models, the pattern of findings across type of activity and duration was mixed. We observed a protective relationship of physical activity at some levels of walking (30mins to <1 hr: b= 0.14, p=0.021, 1hr to <2 hrs: b= 0.14, p=0.029), light activity (1hr to <2 hrs: b= 0.17, p=0.035, 2 hours or more: b= 0.15, p=0.050), moderate activity (1hr to <2 hrs: b= 0.38, p<0.001, 2 hours or more: b= 0.35, p<0.001), and strenuous activity (1hr to <2 hrs: b= 0.18, p=0.004). No prospective relationships were observed for strength‐based activities.

Conclusion

Certain types of physical activity were associated with better memory at follow‐up. On average, activities within the 1 to 2 hour range were most beneficial. Potential benefits of physical activity on memory may only be realized after other health considerations are first considered.
Self‐reported OSA risk, but not daytime sleepiness, is related to memory decline in autosomal dominant Alzheimer’s disease: Preliminary findings from the COLBOS biomarker study
Authors: Pardilla‐Delgado Enmanuelle , Baena Ana Y. , Ramirez‐Gomez Liliana A. , Martínez Jairo E. , Lopera Francisco , Quiroz Yakeel T.
Published: December 2021

Background

Sleep disturbances may increase the risk of developing Alzheimer’s Disease (AD). Research suggests that excessive daytime sleepiness and obstructive sleep apnea (OSA) may be linked to increased AD pathology and cognitive dysfunction. This study aimed to investigate the relation between subjective sleepiness and OSA risk, memory, and amyloid and tau, as measured by PET in preclinical AD.

Method

Our ongoing sleep study includes members of a Colombian kindred with a Presenilin1 (PSEN1) E280A mutation for autosomal dominant AD. PSEN1 mutation carriers develop dementia in their late forties. 19 carriers (mean age 38+‐6,12 females) and 15 non‐carrier family members (mean age 36+‐5,10 females) completed the Epworth Sleepiness Scale and the STOP‐BANG for OSA risk, and underwent cognitive testing and PET examinations. A subset (n=15, 8 carriers, 7 non‐carriers) also completed these tests after 18mo. Mann‐Whitney tests were used to test between‐group differences in sleepiness and OSA risk. Spearman correlations were used to examine associations among outcome measures and cortical amyloid, entorhinal tau, and verbal memory (delayed word list recall). Change scores between baseline and follow‐up were calculated (timepoint2‐timepoint1) to assess longitudinal relations.

Result

Cross‐sectional results showed no differences between carriers and non‐carriers in daytime sleepiness or OSA risk (p’s<0.34). Sleep metrics were not related to cortical amyloid, entorhinal tau, or verbal memory (r’s>0.14, p’s<0.62). Longitudinal results revealed an increase in OSA risk score from baseline to 1.5‐year follow‐up was correlated to lower verbal memory performance for all subjects who had two time points (r=‐0.73,p=0.002). A change in sleepiness score was not associated with any of the variables of interest (r’s>0.44,p’s<0.10).

Conclusion

Preliminary baseline results showed that carriers and non‐carriers from a kindred with autosomal dominant AD did not differ in sleep‐related risk factors, such as self‐reported daytime sleepiness and OSA risk. These results suggest that baseline daytime sleepiness and OSA risk may not be related to pathology burden in early AD. In contrast, preliminary longitudinal results suggest that an increase in self‐reported OSA risk within a 1.5‐year timeframe may be related to memory decline. Future research with a larger sample is required to further assess sleep metrics in this population.
Baseline characteristics for CLARITY AD: A phase 3 placebo‐controlled, double‐blind, parallel‐group, 18‐month study evaluating lecanemab (ban2401) in early Alzheimer's disease
Authors: Lynch Shau Yu , Irizarry Michael C , Dhadda Shobha , Li David JianJun , Kanekiyo Michio , Bogoslovsky Tanya , Gee Michelle , Reyderman Larisa , Kaplow June , Rabe Martin , Hodgkinson Mark , Kramer Lynn D , Hampel Harald , Swanson Chad J
Published: December 2021

Background

Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ. In a recent multinational, phase 2, double‐blind, placebo‐controlled, study utilizing a Bayesian design with response adaptive randomization, 10‐mg/kg bi‐weekly lecanemab reduced brain Ab levels and slowed decline in cognition and function on Alzheimer’s Disease Composite Score (ADCOMS), Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐cog), and Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) at 18 months in participants with early Alzheimer’s disease (AD). Following these results, the CLARITY AD phase 3 study was designed to confirm the efficacy and safety of lecanemab in participants with early Alzheimer’s disease. Herein, we describe the baseline characteristics for participants in the ongoing CLARITY AD study.

Methods

CLARITY AD is an 18‐month treatment, multicenter, double‐blind, placebo‐controlled, parallel‐group study with open‐label extension in participants with early AD. Baseline clinical and demographic data were summarized descriptively and compared to the lecanemab phase 2 study population.

Results

As of a data cutoff of January 6, 2021, 1540 participants were randomized in CLARITY AD. The median age of participants was 72 years (range: 50‐90 years), with 81% of participants 65 years of age or older. Overall, 52% of participants were female and 75% were Caucasian. Mean (SD) baseline values for clinical endpoints were 3.2 (1.3) for CDR‐SB, 0.4 (0.1) for ADCOMS, 25.4 (7.3) for ADAS‐Cog, 25.6 (2.2) for MMSE, and 0.6 (0.2) for Global CDR. Aggregate baseline characteristics are similar to the lecanemab phase 2 study (median age 72 years [range: 50‐90 years]; 80% 65 years of age or older; 50% female; 90% Caucasian; clinical endpoints: 3.0 [1.4] for CDR‐SB, 0.4 [0.2] for ADCOMS, 22.2 [7.4] for ADAS‐Cog, 25.6 [2.4] for MMSE, and 0.6 [0.2] for Global CDR). Comparisons of the study populations will be presented.

Conclusion

Building on the encouraging findings from the lecanemab phase 2 study, the phase 3 CLARITY AD study is designed to confirm clinical efficacy and safety of lecanemab versus placebo in participants with early AD. Baseline characteristics after enrollment of 1540 participants are consistent with the phase 2 study and representative of an early AD population. Enrollment is ongoing.
Integrative analysis of eQTL and GWAS summary statistics reveals novel genes related to Alzheimer's disease
Authors: Varathan Pradeep , Gorijala Priyanka , Jacobson Tanner Y. , Nho Kwangsik , Risacher Shannon L. , Saykin Andrew J. , Yan Jingwen
Published: December 2021

Background

Large‐scale genome wide association studies (GWASs) have identified many genetic variants associated with Alzheimer’s disease (AD) and related traits. While many GWAS findings were found to co‐localize with expression quantitative trait loci (eQTL), it is of great interest to investigate the functional effect of GWAS hits on the downstream transcriptomic level. Considering the lack of gene expression data from the brain tissue, we propose to integrate the summary statistics from AD GWAS and brain eQTL analysis to investigate potential transcriptomic alterations inside AD brains. We further validate our findings using the brain gene expression data from the ROS/MAP cohort.

Method

We used the GWAS summary statistics from IGAP[1] and brain eQTL results from BRAINEAC[2]. Summary Mendelian Randomization (SMR) and Heterogeneity in Dependent Instruments (HEIDI) tests were applied to identify highly significant genes related to AD in temporal cortex, frontal cortex and hippocampal regions. For significant genes identified from each region, we further performed differential gene expression analysis using the RNA‐Seq data from the corresponding brain tissue in the Mayo Clinic cohort. SNPs from these genes were tested for association with FDG intensity and thickness of corresponding brain regions using the data from ADNI. Finally, we performed pathway analysis using ClueGO.

Result

SMR and HEIDI test identified 32 genes significantly associated with AD in the transcriptomic level, but only in temporal cortex. 10 of them were further validated with altered expression in AD temporal cortex region in the Mayo cohort (Fig.1). 19 SNPs from these genes were significantly related to the FDG intensity and thickness of temporal cortex regions, predominantly present in TOMM40 and NECTIN genes. Top pathways enriched by these genes are Neutrophil degranulation and cell surface interactions at vascular wall (Fig.2).

Conclusion

We identified several SNPs with potential regulatory role in mediating the expression level of genes, which are found altered in AD brains and associated with multiple neuroimaging phenotypes. With evidence from multiple sources, these SNPs, their downstream genes and related pathways could serve as potential targets for further therapeutic intervention of AD.
Longitudinal cascades of Alzheimer disease biomarkers across the entire adult lifespan among cognitively normal adults
Authors: Xiong Chengjie , Luo Jingqin , Agboola Folasade , Grant Elizabeth A. , Masters Colin L. , Albert Marilyn S. , Johnson Sterling C. , McDade Eric , Fagan Anne M. , Benzinger Tammie L.S. , Hassenstab Jason , Bateman Randall J. , Moulder Krista L. , Perrin Richard J. , Cruchaga Carlos , Morris John C.
Published: December 2021

Background

The temporal cascade of Alzheimer disease (AD) biomarkers among cognitively normal individuals, including cerebral spinal fluid (CSF) Aβ42, Aβ40, total tau (Tau) and phosphorylated tau (pTau), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar β‐amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound‐B (PiB), magnetic resonance imaging (MRI)‐based hippocampal volume and cortical thickness, and cognition has been hypothesized, but not yet fully tested with longitudinal data.

Method

Leveraging a large harmonized database of 2703 cognitively normal individuals 18 to 103 years of age from 8 longitudinal studies with a median follow up of 5∼6 years, we estimated the longitudinal trajectories of all major AD biomarkers as functions of baseline age, located the age window at which the longitudinal change accelerated by comparing it across adjacent age bins, and examined possible modifying effects of apolipoprotein E (APOE) genotypes.

Result

Participants 18 to 45 years of age at baseline exhibited ‘learning effects’ on both cognition and all but the MRI‐based biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio at the baseline age of 45 to 50 years, followed by hippocampal volume at the baseline age of 55 to 60 years, further by CSF Tau, PET PiB mean cortical SUVR, cortical thickness, and cognition at the baseline age of 65 to 70 years. The accelerated longitudinal changes remained in the covariate‐adjusted analyses. APOE ε4 modified the observed ‘learning effects’ from 18 to 45 years. Further, there was preliminary evidence that APOE ε4 carriers may have experienced the first significant acceleration of the longitudinal change in almost all major AD markers within the baseline age window of 45 to 55 years, whereas among APOE ε4 non‐carriers, only PiB PET SUVRs and cortical thickness and the cognitive composite showed the earliest longitudinal acceleration of change at the same baseline age interval.

Conclusion

Our results characterize the temporal cascades of longitudinal changes for all major AD biomarkers across entire adult lifespan, and address the modifying effect of APOE ε4. These findings may better inform the design of prevention trials on AD.
Encouraging interim results at 9 months from an open‐label study of simufilam in patients with Alzheimer’s disease
Authors: Burns Lindsay H , Doehner Tamara , Puente John , Beck Brian , Gonzalez‐Rojas Yaneicy , Lopez‐Brignoni Evelyn , Nikolov Boris , Wang Hoau‐Yan , Pei Zhe , Hernandez Antonio , Crowley Carrie A , Friedmann Nadav
Published: December 2021

Background

Simufilam is a novel drug candidate for Alzheimer’s disease (AD). This small molecule reverses an altered conformation of filamin A in the AD brain, reducing tau hyperphosphorylation and neuroinflammation initiated by Aβ42. In a prior randomized, controlled trial in 64 patients with mild‐to‐moderate AD, simufilam significantly improved eleven CSF biomarkers of AD pathology, neurodegeneration, neuroinflammation and blood‐brain barrier integrity over 28 days, with no safety issues. A one‐year, open‐label, multi‐center study is now evaluating simufilam’s long‐term safety and tolerability and following cognition and neuropsychiatric symptoms of dementia. The study has pre‐planned interim analyses at 6 and 9 months.

Method

Approximately 150 patients with mild‐to‐moderate AD, MMSE 16 to 26, will be enrolled across 16 sites in the US and Canada. Study participants receive 100 mg twice‐daily oral simufilam for one year. In addition to safety, patients are assessed on the 11‐item Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog11) and the 10‐item Neuropsychiatric Inventory (NPI10).

Result

Interim results summarize data from the first 50 patients to complete at least 9 months of treatment. Simufilam was safe and well‐tolerated, consistent with prior safety results. Six months of treatment improved patients’ cognition scores by ‐1.6 points on ADAS‐Cog11, a 10% mean improvement from baseline (negative score indicates improvement). At 9 months, ADAS‐Cog11 scores improved by ‐3.0 points, a 19% mean improvement from baseline. At 9 months, 69% of patients showed improved or stable ADAS‐Cog11 scores from baseline. Mean baseline ADAS‐Cog11 score for these 50 patients was 16. Mean baseline MMSE was 22. Six months of treatment also improved NPI scores by ‐1.3 points, a 29% mean improvement from baseline (negative score indicates improvement). At 9 months, NPI scores improved by ‐0.7 points, a 16% mean improvement from baseline. At 9 months, 76% of patients showed improved or stable NPI scores from baseline. Mean baseline NPI10 score was 4.5.

Conclusion

Interim analyses at 6 and 9 months indicate open‐label treatment with simufilam 100 mg improved scores of cognition and neuropsychiatric symptoms in patients with Alzheimer’s disease, with no safety issues. This work was funded by NIA grant AG065152.
Investigating white matter connectomes in amnestic and non‐amnestic Alzheimer's disease clinical variants
Authors: Bharne Pandurang R. , Kinney Nikolas G. , Da Re Fulvio , Spotorno Nicola , Olm Christopher A. , Cook Philip , Irwin David J. , McMillan Corey T. , Grossman Murray , Phillips Jeffrey S.
Published: December 2021

Background

Recent models propose that spread of Alzheimer's disease (AD) pathology may be mediated by white matter connectivity. AD clinical variants exhibit partially distinct patterns of gray matter atrophy. However, it is less clear whether phenotypic differences extend to patients' white matter connectomes. We hypothesized that white matter connectivity would differ between healthy controls, amnestic AD (aAD), and non‐amnestic AD (naAD), including behavioral variant Alzheimer's disease (bvAD), logopenic‐variant primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA).

Method

We examined white matter connectomes in 194 participants (controls=60, aAD=42, bvAD=25, lvPPA=39, PCA=28). All participants with dementia had evidence of AD pathologic change based on autopsy, Aβ1–42 from cerebrospinal fluid, or [18]F‐florbetaben positron emission tomography. T1‐weighted and diffusion tensor images were collected using a 3 Tesla scanner. We calculated gray matter volume for cortical regions of interest and median fractional anisotropy (FA) for the tract connecting every pair of regions. Tracts with the most variable FA values across participants were excluded to yield graphs with 30% density. Linear regressions adjusted for sex and age were used to investigate group differences in degree and betweenness centrality as well as the relationship between gray matter volume and FA measures. Phenotypic differences in tractwise FA were evaluated using t‐tests.

Result

Both node and edge metrics indicated significant (p<.05, corrected) widespread differences between patient groups and controls. In contrasts between disease groups, aAD patients had reduced degree in multiple occipital and inferior temporal regions; and higher betweenness centrality in bilateral frontal and parietal regions relative to naAD phenotypes. Tractwise FA values did not differ between patient groups. Across groups, endpoint gray matter volume was correlated with tractwise FA measures.

Conclusion

Both node‐ and edge‐based metrics suggested patients’ white matter connectomes exhibited degeneration relative to controls. Phenotypic differences between patient populations were few, suggesting that AD clinical variants with distinct patterns of gray matter disease nevertheless had broadly similar patterns of white matter degeneration. Gray matter atrophy was closely associated with lower values of FA of white matter tracts connecting atrophied regions, consistent with Wallerian degeneration of white matter.
Neighborhood environment and cognition in older adults: Exploring the mediating effect of physical activity
Authors: Fausto Bernadette A , Yu Kexin
Published: December 2021

Background

Emerging evidence suggests neighborhood environment may shape both health behaviors and outcomes. Neighborhood environment could be particularly influential for community‐dwelling older adults who prefer to age in place. Recent studies report that neighborhood social and built environment characteristics significantly influence older adults’ cognition. However, the underlying mechanisms by which neighborhood environment affects cognition are not well understood. Regular physical activity in late life is associated with a lower risk for cognitive decline and may be affected by neighborhood amenities and resources. This study examined how the neighborhood social and built environment affects cognition in older adulthood and explored whether physical activity levels mediated these relationships.

Method

The cross‐sectional analyses included older adults from Wave 2 of the National Social Life, Health, and Aging Project (N = 3,196; mean age = 73.17, SD = 7.34; 52.6% female; median education = high school diploma; 77.3% Caucasian). We tested a structural equation model to examine associations among neighborhood social and built environment and cognition as measured by the Montreal Cognitive Assessment. Built environment was operationalized as a latent variable of living density, litter, noise, traffic, pollution, and conditions of respondents’ building and other buildings nearby. The social environment latent variable was constructed with social cohesion, social ties, and perceived neighborhood danger. We tested whether self‐reported frequency of rigorous physical activity mediated these environment‐cognition relationships.

Result

The results indicated (1) greater disadvantages in the neighborhood built environment were associated with worse cognition (est = ‐0.05, p < .001) and with lower levels of physical activity (est = ‐0.03, p = .001); (2) greater advantages in the neighborhood social environment were associated with better cognition (est = 0.03, p < .001) and higher levels of physical activity (est = 0.02, p < .001); however, (3) physical activity levels were not significantly associated with cognition (est = ‐0.02, p = .17).

Conclusion

These results highlight the influence of neighborhood environment on both physical activity and cognition in older adulthood. While physical activity was not an underlying mechanism by which environment influences cognition, future studies should test for mediation using objectively‐measured physical activity.
Analysis of exclusion criteria in NIA‐funded Alzheimer’s disease and Alzheimer’s disease‐related dementias clinical trials
Authors: Mitchell Alexandra K , Massett Holly A , Shakur Mujaahida , Lockett Jaron , Han Sae H
Published: December 2021

Background

Eligibility criteria are an integral component of clinical trials, ensuring participant safety and reducing factors that may confound results. Research suggests that unnecessarily restrictive exclusion criteria may disphroportionately exclude African Americans (AA) and Hispanics/Latinos (H/L), reduce generalizability, and prevent timely enrollment. This may be of particular concern for Alzheimer’s and related dementias (AD/ADRD), as AA and H/L are at greater risk than non‐Hispanic Whites for AD/ADRD yet underrepresented in clinical trials (CT). This abstract analyzes exclusion criteria proposed within active National Institute on Aging (NIA)‐funded AD/ADRD CTs (N=235) to document the most widely used criteria and to analyze the potential impact on AA and H/L CT participation.

Method

CT exclusion criteria and study design were obtained from NIA grant folders and ClinicalTrials.gov. A codebook was developed using a sample of CTs to identify key exclusion categories (N=47 categories; intercoder reliability=92%) and used to code the 235 trials. A review of published literature was also conducted to identify which categories have documented ethno‐racial disparities (e.g., diabetes is more prevalent among H/L).

Result

A median of 8 exclusion criteria were listed per CT (range=1‐41). The top categories/conditions were: 1) psychiatric (64% of trials, top ranked: depression, bipolar), 2) neurological (52%, top ranked: head/spinal injury, abnormal EEG/brain MRI), and 3) dementia/cognitive impairment (49%). Literature identifies almost half (47%) of all categories as disproportionately affecting AA and H/L, including psychological disorders and cardiovascular disease. Of 47 exclusion categories, AA have the potential to be disproportionately eliminated by 19 categories (40%) and H/L by 16 (34%). Additional analyses will be presented by trial population, phase, enrollment, and intervention type.

Conclusion

Our findings demonstrate commonly used exclusion criteria in active NIA‐funded AD/ADRD CTs. We found many criteria that disproportionately affect AA and H/L, which may play a role in their reduced enrollment in AD/ADRD trials. Similar to an effort in the oncology field (Kim, 2017), AD/ADRD stakeholders should undertake a concerted effort to jointly address the use of overly restrictive criteria, advocate for the use of clear rationale when establishing criteria, and implement more equitable, scientifically justified exclusion criteria for AD/ADRD CTs.
HDL particle morphology in Alzheimer’s disease patients compared to healthy human subjects and chemically modified HDL
Authors: Zheng Jack Jingyuan , Hong Brian V. , Agus Joanne , Guo Fei , Cavicchi Richard E. , Jin Lee‐Way , Maezawa Izumi , Lebrilla Carlito B. , Harvey Danielle J. , Zivkovic Angela M.
Published: December 2021

Background

In various chronic diseases including Alzheimer’s disease, a common clinical manifestation is defective high‐density lipoprotein (HDL) status. Published evidence suggests that HDL particles from Alzheimer’s patients are functionally deficient, as measured by impaired cholesterol efflux capacity. However, the structural and compositional alterations of HDL particles that contribute to this loss of function in Alzheimer’s disease are currently not well understood.

Method

In this study, we investigated the morphological characteristics of HDL particles from 7 patients confirmed with Alzheimer’s disease and 3 age‐matched healthy subjects using transmission electron microscopy. We also analyzed how oxidation, glycation, deglycosylation, and acidification alter the morphology of HDL isolated from healthy human subjects and compared these chemically treated HDL with HDL from Alzheimer’s patients and controls.

Result

Distinct treatment‐specific variation patterns of HDL particles, including particle size change, aggregation, and disintegration, were observed. Most prominently, HDL incubated at a pH of 5.5 for 18 hours had an increased average HDL particle diameter from 10.65 ± 2.22 nm to 13.08 ± 2.77 nm (P<0.001). In addition, both glycation and oxidation treatment caused HDL to form aggregates. HDL isolated from patients with Alzheimer’s disease and age‐matched, cognitively normal subjects displayed aggregate structures that resembled those of chemically glycated and oxidized HDL. These aggregated HDL structures were found in both patients and controls.

Conclusion

Further studies with larger sample sizes are needed to better characterize the morphological, structural, and compositional alterations that cause the loss of HDL function in patients with Alzheimer’s disease.
Persistent pain is associated with lower locus coeruleus integrity in older adults
Authors: Bell Tyler Reed , Elman Jeremy A. , Puckett Olivia K. , Franz Carol E. , Kremen William S.
Published: December 2021

Background

Persistent pain has been recently linked to increased Alzheimer’s disease (AD) risk, calling for the identification of related AD biomarkers. One biomarker of interest is integrity of the locus coeruleus (LC), a brainstem region that is thought to be the earliest site of tau deposition in the brain. The LC is also the main projection site for norepinephrine (NE), a major neurotransmitter inhibiting pain via rostral and caudal LC projections. A recently proposed mechanism suggests that persistent pain alters LC‐NE function and advances AD pathology in this region, explaining increased AD risk. Here we examined the association between persistent pain and LC integrity in older adults.

Method

Data were derived from the Vietnam Era Twin Study of Aging (VETSA) in which community‐dwelling men were assessed across up to 12 years in 3 waves. At the third wave, 426 community‐dwelling men (mean age = 67.55) underwent MRI‐assessment sensitive to neuromelanin, a byproduct of LC NE production. Using neuromelanin signal intensities, we calculated contrast‐to‐noise ratios between LC regions (i.e., rostral and caudal) and a pontine tegmentum reference region. Higher contrast‐to‐noise ratios indicate better LC integrity. Persistent pain was defined as reporting 2 or more waves of moderate‐to‐severe pain on the SF‐36 Bodily Pain Scale (n = 80, 16.5%). Generalized linear models examined associations between persistent pain and LC integrity after weighting for survival effects and adjusting for demographic (i.e., age, race, young adult general cognitive ability, income) and health confounders (i.e., comorbidities, depressive symptoms, opioid use), and nested twin observations.

Result

Persistent pain was associated with .21 standard deviation lower rostral LC integrity (95% CI: ‐.40 to ‐.03) and .23 standard deviation lower caudal LC integrity at the third wave (95% CI: ‐.44 to ‐.04).

Conclusion

Persistent pain was associated with worse LC integrity in older adults. Persistent pain related to worse integrity in both the rostral and caudal LC regions. These associations are consistent with the recent proposed mechanism emphasizing the role of pain on LC‐NE dysfunction, but this relationship may also be bidirectional. Longitudinal designs would be informative, as would studies looking at later dementia trajectories.
APOE ε4 allele status similarly predicts a latent dementia index as clinical diagnosis of dementia
Authors: Beam Christopher R , Saenz Joseph , Kim Alice J
Published: December 2021

Background

Latent dementia index (LDI) variables are increasingly popular, mainly because they make it possible to quantify a continuous measure of dementia risk using cognitive and functional ability variables when no clinical gold standard is available. Validation studies of LDI variables tend to include clinical gold standard outcomes and demographic variables (e.g., age and gender). No studies to date, however, have validated LDI variables using APOE ε4 allele status. To the extent that effects are similar, we can claim greater convergent validity of the LDI. The purpose of this study is evaluate whether effects of APOE ε4 allele status on LDI is similar to effects of e4 status on clinical gold standard.

Method

The study included 856 participants from the 2001‐2003 Aging, Demographics, and Memory Study (ADAMS), a subsample from the United States Health and Retirement Study. Respondents completed a comprehensive neuropsychological battery, including tests evaluating cognitive ability across multiple cognitive domains (such as memory, executive function, orientation, attention, spatial ability, and language). Informants provided data on functional ability. The LDI was modeled as a latent variable indicated by task specific cognitive scores and functional ability tasks. Lower LDI scores indicate greater risk of dementia. APOE status was an ordinal variable to indicate the absence (0 alleles) or presence (1 or 2 alleles) of ε4 allele status. Clinical gold standard was determined by neuropsychological assessment, which included medical, functioning, cognitive, and physical exams. Regression analyses were performed to test the correlation between APOE ε4 allele status and both measures of dementia.

Result

APOE ε4 allele status significantly predicted clinical gold standard (OR: 1.44 [.95CI: 1.23, 1.69]). APOE ε4 allele status also significantly predicted LDI (β = ‐0.15, SE =0.04, p < .001). APOE ε4 allele status accounted for approximately half the amount of the variance in LDI (2%) as in clinical gold standard (3.6%).

Conclusion

Based on the similarity of the effects of APOE ε4 allele status on LDI and clinical gold standard, the LDI appears to be a valid continuous proxy measure of dementia.
Acute inositol‐stabilized arginine silicate supplementation may elicit benefits on cognitive tasks
Authors: Gills Joshua L , Campitelli Anthony , Jones Megan , Paulson Sally , McWilliams Dalton L , Dale Stephanie , Madero Erica N , Myers Jennifer Rae , Glenn Jordan M , Gray Michelle
Published: December 2021

Background

Alzheimer’s disease and related dementias exhibit similar pathologies such as decreases in cerebral blood circulation and aluminum accumulation leading to decreases in cognitive ability. Acute inositol‐stabilized arginine silicate (ASI) purportedly enhances cerebral blood flow and removes aluminum from the brain. Moreover, ASI supplementation demonstrated the ability to increase processing speed in young adults. While processing speed is important, ASI’s ability to improve other domains of cognitive function remain unknown. Therefore, the purpose of this current investigation is to evaluate the acute effects of ASI supplementation in young healthy adults on various cognitive tasks.

Method

Eight young adults participated in this randomized, double‐blind, placebo‐controlled crossover study. Each participant completed the Repeatable Battery for the Assessment of Neuropsychological Status before and after the supplement (placebo 8g of dextrose or 1.5g ASI and 8g of dextrose) was consumed. Paired samples t‐test were utilized to assess the differences between language (LAN), attention (ATT), and delayed memory (DM) in each supplement group. Percent differences were used to assess differences between supplement trials.

Result

Paired samples t‐test showed a significant difference (p < 0.05) for DM index scores in both supplement groups; statistical trends were noticed in LAN (p = .05) and ATT (p = .07) domains after ASI supplementation. ATT improved by 8% after ASI supplementation compared to 0% in the control group; additionally, LAN scores increased by ∼8% for both supplement groups. DM scores decreased in both trials pre to post examination; but the percent decrease was less in the ASI trial (8%) compared to the placebo trial (12%).

Conclusion

Our preliminary results demonstrated no significant differences between placebo and ASI trials. However, a larger sample size could illustrate significant findings during language and attention tasks while supplementing with ASI. Further research is needed to determine ASIs effect on brain health and ability to improve cognition in healthy younger adults.