bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Common and Rare Variants with Alzheimer’s Disease in 16,905 individuals with Whole‐Genome Sequence Data from the Alzheimer’s Disease Sequencing Project
Authors: Lee Wan‐Ping , Choi Seung Hoan , Schellenberg Gerald D. , DeStefano Anita L. , Haines Jonathan L. , Peloso Gina M. ,   Collaboration on Alzheimer’s Disease Research (CADRE)and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)
Published: December 2023

Background

Whole genome sequencing (WGS) data enables assessment of common and rare variants for association with human diseases. Here we report our analysis using ADSP R3 WGS data to discover genetic variants associated with AD.

Method

We performed association testing of common variants (minor allele frequency [MAF] > 0.5%) as well as aggregates of rare (MAF < 1%) coding and non‐coding variants. Given that ADSP is composed of multiple ancestry groups, we performed association testing across all participants (pooled population [PP], Ncases = 6,519 and Ncontrol = 6,852) and within the following populations: African Americans (AA, Ncases = 1,137 and Ncontrol = 1,707), Hispanics (HIS, Ncases = 1,021 and Ncontrol = 1,988), and Non‐Hispanic White (NHW, Ncases = 4,230 and Ncontrol = 3,109) defined by self‐reported race and ethnicity (Table 1).

Result

As expected, our most significant associations are at the APOE locus (chr19:44,905,796‐44,909,393) (Figure 1). In the pooled‐population analysis, we observed known AD associations for BIN1 (p = 3.2×10−09) variants with AD status. In the NHW analysis, we observed AD associations for variants in CR1 (p = 7.97×10−08), BIN1 (p = 2.16×10−08), ARHGEF33 (p = 4.85×10−8), ANK3 (p = 1.43×10−12) and MYCBP2‐AS1 (p = 4.59×10−08), and in the AA analysis, we observed a significant variant near LINC00320 (p = 1.5×10−8). In the HIS subset, a region (chr14:72,698,038‐75,846,454) has 31 significant variants (p = 3.9×10−11) crossing multiple genes. This region covers PSEN1 G206A (rs63750082), a well‐known early‐onset AD mutation. Local‐ancestry analysis shows that the mutations, including G206A, are of African ancestry. Using kinship coefficients calculated within this dataset, it was determined that the signals are not driven by a familial linkage disequilibrium.

We observed gene‐based aggregation of coding variants in PSEN1 in the pooled‐population and HIS analyses (p<5×10−8) (Figure 2). In our gene‐centric noncoding aggregates analysis, we identified noncoding variants in the promotor of TOMM40 in the pooled‐population analysis (p = 7.2×10−08). After adjusting for APOE e4 (rs429358) and e2 (rs7412) alleles, there was an attenuation, but the association remained suggestive (p = 7.1×10−06).

Conclusion

We performed common and rare association analysis of AD on ADSP WGS data. We observed associations with variants in known AD loci. We also observed population‐specific associations and an association of AD with rare noncoding variants in TOMM40, indicating WGS in diverse populations can lead to novel genetic associations with AD.
Statistical Physics of Fitness Landscapes Finds Risk Genes Specific to Different AD Genetic Backgrounds
Authors: Lagiesetty Yashwanth , Samieinasab Maryam , Al‐Ramahi Ismael , Wilhelm Kevin , Katsonis Panagiotis , Asmussen Jenn , Lee Kwanghyuk Danny , Botas Juan , Lichtarge Olivier
Published: December 2023

Background

To study how genetic backgrounds modulate neurodegenerative risk requires genotype‐phenotype association methods effective in small patient cohorts.

Method

We developed a genome sequence analysis framework rooted in Statistical Physics, which yields a reliable measure of gene functional impact in any chosen population. When comparing two populations, such as cases and controls, shifts in gene importance identify those likely to drive phenotype differences.

Results

In repeated case‐control genome sequence studies of Alzheimer’s Disease (AD) focused on a single sex, APOE allele, or ethnic ancestry, we identified gene sets that met criteria for success, including prior GWAS studies, post‐mortem of AD brain tissues expression, live Drosophila experiments, and risk modeling.

Conclusion

Statistical Physics of fitness landscape is a new tool to characterize genes and mutations that enhance or protect from AD, powerful enough to identify similarities, complementarities, and differences in risk gene in target subgroups of about 1000 subjects.
An 8‐week program of computerized cognitive training with exercise impacts cortical grey matter in older adults: Secondary findings of a randomized controlled trial
Authors: Stein Ryan G , Brinke Lisanne F , Silva Nárlon Cássio Boa Sorte , Handy Todd C , Hsiung Ging‐Yuek Robin , Liu‐Ambrose Teresa
Published: December 2023

Background

The world’s population is aging and thus, it is important that we find strategies to reduce the rate of age‐related cognitive decline. Lifestyle interventions can play an important role in delaying the onset of cognitive decline. Evidence shows both computerized cognitive training (CCT) or exercise can improve cognitive function. However, the effect of CCT on cortical structure is not well understood. This study examines the effect of 8‐weeks of CCT, with or without a preceding exercise bout, on cortical structure in community‐dwelling older adults.

Method

Structural magnetic resonance imaging (MRI) data acquired from an 8‐week, 3‐arm, proof of concept randomized controlled trial was used. Participants (N = 125) aged 65 – 85 were randomized (1:1:1) to either 8 weeks of 3x/week: 1) Balance and Toned (BAT; active control); 2) CCT; or 3) Exercise + CCT (Ex‐CCT). Measurement occurred at baseline and trial completion (i.e., 8‐weeks). Fifty‐three participants with baseline and trial completion MRI data were included in this analysis. Freesurfer was used to assess BAT vs. CCT, BAT vs. Ex‐CCT, and CCT vs. Ex‐CCT differences in cortical thickness and volume at trial completion, adjusting for age, sex, and Montreal Cognitive Assessment (MoCA) score.

Result

At trial completion, CCT vs. BAT decreased left rostral middle frontal gyrus volume (cluster size = 553.51 mm2, cluster‐wise p = .027) and left superior temporal gyrus thickness (cluster size = 525.58 mm2, cluster‐wise p = .039). Ex‐CCT vs. BAT increased cortical thickness in the left (cluster size = 900.23 mm2, cluster‐wise p = .001) and right (cluster size = 681.95 mm2, cluster‐wise p = .020) superior parietal gyri. Finally, Ex‐CCT vs. CCT increased left cuneus thickness (cluster size = 1062.12 mm2, cluster‐wise p < .001) as well as right post central gyrus thickness (cluster size = 714.85 mm2, cluster‐wise p = .005) and volume (cluster size = 1030.08 mm2, cluster‐wise p < .001).

Conclusion

Eight weeks of CCT with exercise is of sufficient duration to induce structural change in the brain. Moreover, exercise may enhance the effect of CCT on cortical grey matter structure vs. CCT alone.
MB‐204: A Novel Adenosine A2a Antagonist for AD, ADHD and Depression
Authors: Williams Mark Stephen
Published: December 2023

Background

MB‐204 is a novel Adenosine A2a antagonist that immediately reduces depression and anxiety in animal models

Method

MB‐204 was dosed one hour prior to its assessment for depression using the forced swim test (FST) and the elevated plus maze (EPM) for anxiety. General locomotive activity was measured as was the effect on rotarod balance as a surrogate for behavioural scores. Receptor occupancy studies were measured using radio‐labelled ligand and ex vivo brain tissue analysis.

Result

MB‐204 dose dependently reduced depressive symptoms in the FST (>85%, p<0.001) with no effect on non‐specific locomotive activity or rotarod balance. MB‐204 was found to time and dose dependently occupy the A2a receptor in vivo (p<0.01) which mimicked blood PK levels. In head‐to‐head studies, MB‐204 outperformed Istradefylline (the only approved A2a antagonist for the treatment of Parkinson’s disease) in almost all measurements in the EPM model, and appeared to improve social interactions as measured by sub‐vocalization analyses.

Conclusion

MB‐204 appears to be an excellent pre‐clinical candidate for the treatment of A2a associated conditions
Aβ oligomers reduce neuronal plasticity in an aged animal model of Alzheimer’s disease
Authors: Waly Bilal El , Henriques Alexandre , Poindron Philippe , Callizot Noelle
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by the extracellular accumulation of senile plaques composed of beta‐amyloid (Aβ). Aβ oligomers (AβO) induce damage beginning with loss of synapses, followed by neurite network disorganization and neuronal death. The hippocampus is a cerebral structure and a major place of neuroplasticity and a key structure for memory processing and consolidation. Hippocampal atrophy is well documented in AD. Neuronal plasticity persists during ageing and could adaptative response to cognitive decline during ageing or dementia.

Alterations in adult neuronal plasticity and synaptic dysfunctions are detected in rodent models of Alzheimer’s disease. Thus, early dysfunction in neural stem cell production and neuronal differentiation could be linked to reduced neuronal plasticity in AD.

Method

In this study, to investigate the effect of age on neurogenesis, in young (12 weeks), aged and healthy (16 months) mice and in an in vivo model of AD, based on intra‐hippocampal injection of a AβO/protofibril preparation in aged (16 months) mice.

Proliferation of cells (BrdU, Ki67), differentiation (DCX) and maturation (NeuN) into neurons were studied in the dendate gyrus of mice. Activation of glial cells was also assessed by immunohistochemistry. In addition, cognitive performance of mice were assessed using the Y‐maze test (short‐term spatial memory) in the same animal.

Result

Our results show a decrease in neurogenesis in aged mice compared to young mice. Injection of AβO in the CA1 area was also associated with decreased neurogenesis in the dentate gyrus, neuroinflammation and to reduce performance in the Y‐maze test.

This reduction in neuroblast generation was revealed by a decrease in the number of BrdU(+), Ki67(+) and DCX(+) cells in the dentate gyrus.

Conclusion

We evidenced a decreased in neuronal plasticity in aging which is exacerbated in our in vivo model of AD and connected to cognitive decline.
Minority Health and Health Disparities Research in Neuroscience: an analysis of funded research in the Division of Neuroscience at the National Institute on Aging
Authors: Pottinger Camille , Martin Damali N , Pearson Tayona , Kwok Richard , Ghaleh Maryam , Anderson Dallas
Published: December 2023

Background

In the upcoming decades, the US is poised to experience a population growth among its minority populations (e.g., African Americans, Asians, Latinx) who will represent approximately 45% of the US population ≥65 years old by 2060. Alzheimer’s disease and related dementias (AD/ADRD) studies report significant health disparities by race and ethnicity, as well as other health disparate communities (e.g., sexual and gender minorities, socioeconomically disadvantaged populations, underserved rural populations). These demographic shifts underscore the importance of addressing these disparities. The Division of Neuroscience (DN) at the U.S. National Institute on Aging (NIA) works to strengthen knowledge and understanding of AD/ADRD in minority and health disparate populations, to achieve health equity. This analysis sought to characterize the existing portfolio of research grants focusing on minority health and health disparities supported by DN to understand opportunities for scientific advancement.

Method

Using the NIH Query, View, and Report (QVR) system, combined with Research, Condition, and Disease Categorization (RCDC) codes, we identified minority health and health disparities research project grants from 2015 to 2021. These grants were manually reviewed for inclusion into the analysis. A grant was coded as minority health or health disparities or both if the specific aims of the grant specified research in this area. Further analyses were performed to understand which populations were included in these studies and identify key resources that were used to support research in this area.

Result

Research projects were distributed across the five branches in the division, with the highest number in the Populations and Genetics branch. Of the 455 grants identified, 64% were investigator‐initiated awards (R01), followed by cooperative agreements (U01). Most grants focused on racial/ethnic disparities, while a few investigated disparities by geographic location, gender, etc. African American populations were included in most research awards, followed by Latinx groups.

Conclusion

Our analysis provides an overview of the landscape and resources used for minority health and health disparities research, as well as identifies gaps and opportunities that can be used to develop comprehensive strategies to accelerate the pace of research and discoveries in this area.
Molecular biomarkers quantified using the Single Molecule Array in Brazilian patients with mild Alzheimer’s disease and mild cognitive impairment
Authors: Magalhaes Thamires Naela Cardoso , Teixeira Camila Vieira de Ligo , Moraes Adriel Santos , Cassani Ana Flavia M K C , Joaquim Helena Passarelli Giroud , Talib Leda Leme , Forlenza Orestes Vicente , Balthazar Marcio Luiz Figueredo , Teunissen Charlotte E.
Published: December 2023

Background

The clinically diagnosed late‐onset Alzheimer’s disease (AD) cases has the most heterogeneous pathology. The development of more sensitive biomarkers is essential to perform an early diagnosis, especially in the prodromal phase, mild cognitive impairment (MCI). Biomarkers such as glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) have emerged as potential markers of the pathophysiological process of AD. The objective of this study was to evaluate the concentrations of GFAP and NfL in blood serum and CSF of patients with MCI and mild AD in a Brazilian sample, never quantified using the Single Molecule Array technology (Simoa).

Method

We used samples (blood serum and cerebrospinal fluid (CSF)) from 91 participants to perform molecular analyzes. These participants were recruited in the outpatient service of the UNICAMP Clinic Hospital. All participants underwent blood collection and only the patients, lumbar puncture, to analyze GFAP and NfL levels. All patients had pathophysiological evidence of AD (low Aβ1‐42 concentrations < 540pg/mL) and was considered Tau alteration: p‐Tau > 36.7 pg/mL and t‐Tau > 76.7 pg/mL.

Result

Statistical analyzes were performed using SPSS software (version 25). We performed a multivariate analysis of covariance (MANCOVA) to compare the biomarkers levels between the groups. To compare CSF levels (Aβ42, t‐Tau, p‐Tau, GFAP and NfL) we used T‐test analyses and to correlate GFAP and NfL with CSF proteins we use partial correlations. We did not find statistical differences between the groups regarding GFAP and NfL levels, but we did find differences between Aβ1‐42 protein between MCI and mild AD (p = 0.003). We also found moderate correlations between t‐Tau, GFAP and NfL CSF levels (r = .625, p = 0.0; r = .508, p = 0.005, respectively), and p‐Tau with GFAP CSF levels (r = .373, p = 0.046).

Conclusion

GFAP and NfL reflect neuro‐axonal damage and recent studies have demonstrated its effectiveness in tracking disease progression (5). Although we did not find differences between individuals in relation to GFAP and NfL markers, we were able to observe correlations between these markers at the CSF level and the proteins classically related to the pathological process of the disease.
Relationship between depressive symptoms and cognitive function in the U.S. POINTER study
Authors: Krueger Kristin R , Farias Sarah Tomaszewski , Garcia Katelyn R , Thro Amber Adkins , Caudle Brad A , Snyder Heather M , Baker Laura D , Papp Kathryn V. ,   The U.S. POINTER Neuropsychology Groupthe U.S. POINTER Study Group
Published: December 2023

Background

Depressive symptoms play an important role in cognitive health of older adults, yet the exact nature of their influence has not been well established. There is strong evidence that depressive symptoms are independently associated with cognitive decline and dementia in older adults. Depressive symptoms have also been associated with cognitive dysfunction in the absence of dementia.

Methods

We examined the association of depressive symptoms and cognitive functioning in U.S. POINTER participants at baseline. U.S. POINTER is a large multi‐site, 2‐year study testing the impact of interventions on cognition in 2000 older adults at risk for cognitive decline. This analysis included 1,814 study participants (aged 60‐79). Exclusion criteria included major depressive disorder and bipolar disorder. We measured cognition with the Neuropsychological Test Battery modified for U.S. POINTER, or PmNTB. The battery provides a global composite score and three domain‐specific composite scores for episodic memory, executive function, and processing speed. Depression was measured with the 15‐item Geriatric Depression Scale (GDS). Simple linear regression models were run to evaluate the relationship between cognitive function and GDS after controlling for age, sex, education, race, ethnicity, and site. In secondary analyses, simple linear regression models were used to evaluate the relationship between cognitive functioning and GDS, using a median split (0‐1, 2+) and the conventional/clinical GDS cut‐off of 4 (0‐4 vs 5+).

Results

We found greater endorsement of depressive symptoms was not associated with the global composite score, episodic memory, or executive function. However, higher GDS scores were associated with slower processing speed (estimate = ‐0.023; 95% CI: ‐0.05, 0.00, p‐value = 0.05). In secondary analyses using the GDS median split, the association between GDS and processing speed was mildly attenuated (p‐value = 0.06) and the association between GDS and executive function became marginally associated (p‐value = 0.06). When using conventional GDS clinical cut‐offs, no associations between cognitive function and GDS were found.

Conclusion

At baseline, subclinical depressive symptoms may be associated with decreased processing speed and executive function in U.S. POINTER participants.
Asian Cohort for Alzheimer’s Disease Pilot Study on Genetic and Non‐Genetic Risk Factors for Alzheimer’s Disease among Asian Americans and Canadians
Authors: Wang Li‐San , Ho Pei‐Chuan , Tee Boon Lead , Li Clara , Gu Yian , Yokoyama Jennifer S. , Reyes‐Dumeyer Dolly , Faber Kelley M. , Lee Wan‐Ping , Song Yeunjoo E. , Tzuang Marian , Vardarajan Badri N , Yang Hyun‐Sik , Choi Yun‐Beom , Feldman Howard H. , Henderson Victor , Hsiung Ging‐Yuek Robin , Mayeux Richard , Rosen Howard J. , Varma Rohit , Foroud Tatiana M. , Kukull Walter A. , Peavy Guerry M. , Lee Haeok , Yu W. Haung , Chui Helena C , Jun Gyungah R , Park Van Ta , Chow Tiffany W ,   The Asian Cohort for Alzheimer’s Disease Study
Published: December 2023

Background

Asian Americans and Canadians (ASACs) are the fastest growing minority group in the U.S. and Canada. However, ASACs are under‐sampled in Alzheimer’s disease (AD) research. To address the need of culturally appropriate clinical protocols and community‐based recruitment approaches for ASACs, the Asian Cohort for Alzheimer’s Disease (ACAD), the first large dementia genetics cohort currently focuses on Chinese, Korean, and Vietnamese, launched in 2021 to examine genetic and non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history and diverse cultural and scientific training backgrounds: both are critical in leading AD and CBPR research.

Method

The ACAD pilot study has 7 recruiting sites (5 US and 2 Canadian), a coordinating site, and an analysis site. ACAD piloted a comprehensive study protocol including community outreach and recruitment strategies, the data collection packet (DCP), pre‐screening and sample collection procedures, and a centralized data management system in English, Chinese (Mandarin and Cantonese), Korean, and Vietnamese. To ensure the protocol consistency, ACAD implemented a training curriculum for the administration of the DCP and for culturally appropriate approaches to recruitment in collaboration with community partners, clinics, and nursing homes that serve Asian communities.

Result

As of December 2022, ACAD’s pilot study has consented 606 participants, 527 participants have complete DCP data submitted to REDCap (448 Chinese, 54 Korean, and 25 Vietnamese), and more than 1,500 people have expressed interests in ACAD. The majority 66.2%)women. The age range of the sample is 60‐93 years. 47.3% have college or graduate level education. 451 participants provided a saliva (274) or a blood (177) sample. Feedback in pilot indicates a need to adapt the Early Life Enrichment inventory further to apply to wartime deprivation conditions for this population, as well as more cultural tailored neuropsychological tests.

Conclusion

ACAD has learned valuable experience in interactions with ASACs and shown the feasibility of recruiting ASACs in clinical research. With an expansion plan and in collaboration with other AD research focuses on minority, insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD.
Risk Prediction of Dementia in Middle‐aged and Older Adults: The Dementia Risk Prediction Pooling (DRPP) Consortium
Authors: Allen Norrina , Krefman Amy , Stephan John , Yu Jingzhi , Carolan Padraig , Sedaghat Sanaz , Mansolf Maxwell , Soumare Aicha , Gross Alden L. , Aiello Allison , Singh‐Manoux Archana , Ikram M. Arfan , Helmer Catherine , Tzourio Christophe , Satizabal Claudia L. , Levine Deborah A , Lloyd‐Jones Donald , Briceno Emily M , Sorond Farzaneh , Wolters Frank J. , Himali Jayandra Jung , Launer Lenore J J. , Zhao Lihui , Lopez Oscar L. , Debette Stéphanie , Seshadri Sudha , Judd Suzanne E , Hughes Tim M. , Gudnason Vilmundur , Scholtens Denise
Published: December 2023

Background

Several risk prediction equations exist for the incidence of Alzheimer’s Disease and related dementias (ADRD); however, current equations are based on studies of older individuals, with limited follow‐up time and covariates, and have generally not performed well in external validation. The aim of this study is to develop a novel dementia risk prediction equation based on a pooled analysis of population‐based studies that include both middle‐aged and older adults.

Methods

We analyzed data from 13 cohorts within the Dementia Risk Prediction Pooling (DRPP) Consortium, which pooled individual participant data from cohorts in the US, France, Iceland, England, and the Netherlands, with baseline exams ranging from 1948 to 2006. Participating cohorts conducted longitudinal in‐person assessments of clinical, genetic, and behavioral risk factors over at least 10 years, and assessed dementia status. We rigorously harmonized demographic, education, lifestyle, and clinical factors as well as dementia status. From these 25 harmonized variables, we used LASSO competing risks regression to identify a parsimonious set of covariates with the best predictive performance for incident dementia based on C statistics obtained from competing risks.

Results

Among the 55,614 participants included in this analysis (mean age 62.5y, 48.8% female; see Table 1), 2,523 developed incident dementia within 10 years and 4,072 within 20 years of the index exam. The resulting clinical risk prediction equation included age, gender, education, BMI, presence of depression, physical activity, smoking, and total cholesterol. The top performing equations had C statistics of 0.86‐0.89 at 10 years and 0.88‐0.92 at 20 years. Calibration plots are shown in the Figure 1.

Conclusions

Using pooled individual‐level data from a large harmonized consortium of cohorts with detailed clinical and behavioral data, we developed a novel dementia risk prediction equation with excellent discrimination and acceptable calibration across a broad range of predicted risk; these equations have better performance than published risk scores. The ability to accurately identify high‐risk individuals, even as early as middle‐age, will allow healthcare providers to target preventive efforts (e.g., statins) to those at the greatest risk to reduce the future burden of dementia.
Towards a standardized pipeline for tau PET analysis under a GAAIN/LONI and CPAD collaborative framework
Authors: Toga Arthur W. , Pappas Ioannis , Leuzy Antoine , Karten Yashmin , Weber Christopher J. , Romero Klaus , Sivakumaran Sudhir
Published: December 2023

Background

Imaging tau burden in vivo using Positron Emission Tomography (PET) has tremendous potential for advancing our biological understanding of Alzheimer’s disease. Towards this direction, there is a need for post‐acquisition imaging data ‘harmonization’ tools and analysis methods that reduce variance across studies, sites, and scanners, while retaining the power to study complex disease related effects. The Global Alzheimer’s Association Interactive Network (GAAIN), the Laboratory of Neuro Imaging (LONI), and the Critical Path for Alzheimer’s Disease (CPAD) Consortium have undertaken a collaborative effort to provide a harmonized approach to the analysis of tau PET images.

Method

The GAAIN/LONI Pipeline is a software suite that allows the design and execution of neuroimaging workflows through flexible integration of different image preprocessing software and parallel processing via a computer grid. Each workflow has a distinct fingerprint that can be executed locally on different platforms or remotely via GAAIN, thus increasing interoperability and allowing the use of “harmonized” workflows across different datasets. Tau PET workflows were designed and deployed on the GAAIN/LONI Pipeline based on existing literature. In turn, these tau PET workflows were executed on CPAD tau PET to derive tau PET burden. Clinical validation was performed by quantifying tau PET burden on different clinical groups. Analytical validation was performed by correlating the LONI Pipeline results with independently developed pipelines.

Result

We first show feasibility results as the tau PET workflows are deployed and executed on CPAD data. For clinical validation, we tested whether derived metrics can distinguish between clinical groups. For analytical validation we tested correlations of results with existing methods that have been independently developed. These results provide a unified analysis model that can be utilized from GAAIN/LONI and CPAD to conduct harmonized analyses on multiple datasets. The full capabilities of this model will be explored in subsequent work.

Conclusion

The proposed pipeline, which is going to be part of the publicly available GAAIN/LONI platform, should provide researchers with an optimized roadmap that describes how tau PET imaging data should be processed and analyzed for reliability and reproducibility in the context of drug development and regulatory decision making.
The Aging Brain Clinic (ABC): An innovative model for managing patients with mild cognitive impairment
Authors: Roth Heidi L , Abramowitz Amy
Published: December 2023

Prevalence of dementia and mild cognitive impairment (MCI) in the US are rising due to the aging of the population. An estimated 15‐20% of people over 65 in the US have MCI. Advances in public health have effectively reduced dementia risk factors and have prevented some cases of dementia. Comprehensive dementia care has also helped to improve quality and reduce costs of managing patients living with dementia. However, there has been less focus on treatment of patients while in the mild cognitive impairment stage. These patients can benefit from interventions to manage factors that worsen cognition and from a comprehensive care model to address psychosocial needs. Evaluating patients at this stage will be of increasing importance as new therapeutics become available for patients with early cognitive impairment.

The Aging Brain Clinic (ABC) aims to address this gap. Our clinic was inspired by comprehensive care models, but our focus is on optimizing cognition in older adults with mild cognitive impairment by 1) providing interdisciplinary evaluation and treatment of cognitive disorders, 2) implementing interventions longitudinally within the clinical setting to focus on factors that worsen cognitive impairment particularly medication side effects, sleep disturbance, and anxiety/depression and 3) focusing on helping patients understand their diagnosis and adapt to cognitive changes in their everyday life. The clinic is multidisciplinary and is comprised of neurologists, a geriatric psychiatrist, a geriatrician, a neuropsychologist, and a nurse practitioner. We developed a registry for patients with MCI to track cognition using a neuropsychological battery including MOCA, HVLT‐R, craft story, trail making test, digit span, letter and semantic fluency, CERAD naming, pentagon copy, Benson figure copy, and the RCFT. Neuropsychiatric symptoms and function are assessed using the FAQ, NPI‐Q, PHQ‐9, and GAD‐7. Sleep is assessed with the Epworth Sleep Scale, the STOP‐BANG, and the PSQI. We are also creating an educational program focusing on these areas as well as psychosocial adaptation and anticipatory guidance. While new treatments targeting amyloid are becoming available for early cognitive impairment, it remains important to have a comprehensive intervention and treatment program to address all factors impacting cognition in the early stage.
Factors associated with emotional and social loneliness among Latin American family care partners of people with dementia and other long‐term conditions during Covid‐19
Authors: Tapia‐Muñoz Thamara , Leon Tomas , Slachevsky Andrea , Beber Bárbara Costa , Nubia Carla , Vilar‐Compte Mireya , Gaitan Pablo , Olavarria Loreto , Castro Loreto , Pinto Alejandra , Chen Yaohua Sophie , Grycuk Emilia , Leroi Iracema , Lawlor Brian , Duran‐Aniotz Claudia , O'Sullivan Roger , Miranda‐Castillo Claudia
Published: December 2023

Background

COVID‐19‐related restrictions led to an increase in loneliness and social isolation Historically, dementia care partners present worse mental health and higher burden than non‐dementia care partners. We aimed to analyse the during‐COVID‐19 loneliness levels of Latin American care partners and explore differences between care partners of people with dementia compared to those of people with other enduring health conditions.

Method

This was a sub‐study of the ‘Coping with Loneliness and Isolation during COVID‐19’ (CLIC) Study, an international self‐report survey of 5236 care partners during the COVID‐19 pandemic. People living at home in one of three Latin American countries: Mexico, Chile, Brazil and others. We analysed data from 241 care partners living in Latin American countries who responded to the CLIC Study survey. We used linear regression models to identify factors associated with loneliness and compared care partners of people living with dementia with care partners with other chronic deseases.

Result

Compared to pre‐pandemic, there was a significant increase in the prevalence of self‐reported total loneliness reported by the care partners. The levels of social and emotional loneliness between care partners of people with dementia vs other conditions did not differ. Low education and low perception of mental health was associated with emotional and social loneliness during the COVID‐19 pandemic.

Conclusion

loneliness during the pandemic was similar across care partners. Some groups are at special risk for higher levels of loneliness and should be considered when planning public health interventions for major societal disruptions, such as a pandemic, in the future.
Spatial navigation, physical activity, and Alzheimer disease biomarkers
Authors: Stojanovic Marta , Allison Samantha L. , Schindler Suzanne E. , Head Denise M
Published: December 2023

Background

Elevated levels of amyloid are associated with worse performance on cognitive mapping (CM), a spatial navigation task reliant on the hippocampus. Prior animal work found that exercise is associated with better learning in CM tasks. Hence, the first goal of the study was to examine whether physical activity moderates the relationship between amyloid deposition and CM. In addition, spatial navigation ability predicts Alzheimer disease (AD) clinical progression but there is a need to examine whether it also predicts subsequent levels of amyloid and tau. Hence, the second goal was to examine whether CM predicts later levels of PET‐Tau and longitudinal trajectories of PET‐Amyloid.

Method

Cognitively normal individuals (n = 65; age range 50‐84 years) were administered a CM task in a virtual environment and a self‐report measure of physical activity. For cross‐sectional analyses, amyloid deposition was estimated via cerebrospinal fluid levels of Aβ42. One assessment of PET‐Tau (n = 49) and repeated assessments of PET‐Amyloid (n = 59) were obtained following the CM session.

Result

Concurrent amyloid deposition was associated with reduced learning (p = 0.002) and retention of the environment (p = 0.002) while greater physical activity was associated with better learning (p = 0.004). There was no moderation by physical activity (all p’s > 0.156). CM performance was not associated with longitudinal trajectories of PET‐Amyloid (all p’s > 0.330) or the subsequent levels of PET‐Tau (all p’s > 0.572).

Conclusion

These results suggest that both current physical activity and levels of amyloid can be important predictors of spatial navigation skills. However, CM might be a limited predictor of AD biomarker accumulation. Future studies should use a larger sample size and greater number of assessments to examine these questions.
The association between Aβ aggregation and age depends on APOE genotype: Findings from the AMYPAD cohort
Authors: Régy Mélina , Quenon Lisa , Collij Lyduine E. , García David Vállez , Gérard Thomas , Frisoni Giovanni , Scheltens Philip , Schöll Michael , Vandenberghe Rik , Boada Mercè , Marquié Marta , Payoux Pierre , Nordberg Agneta K , Kivipelto Miia , Walker Zuzana , Dubois Bruno , Boutoleau‐Bretonnière Claire , Pasquier Florence , Dugravot Aline , Gabelle Audrey , Visser Pieter Jelle , Grau‐Rivera Oriol , Martinez‐Lage Pablo , Ritchie Craig W , Wolz Robin , Farrar Gill , Lhommel Renaud , Barkhof Frederik , Dumurgier Julien , Hanseeuw Bernard J
Published: December 2023

Background

The present study aimed to explore the association between Apolipoprotein E (APOE) genotype, the main genetic risk factor for sporadic Alzheimer’s Disease (AD), age, and cerebral β‐amyloid (Aβ) aggregation, the earliest pathological event in AD in a large, multicenter, European cohort, the AMYPAD study.

Method

We included 876 participants from the AMYPAD cohort who had known APOE genotype and went through at least one Aβ PET imaging. We first looked at the association between Aβ deposition and age according to sex, APOE genotype, and cognitive status. We then used linear regression models to look at the association between Aβ aggregation and APOE genotype in different cerebral regions with age, sex, history of dementia, MMSE score, CDR score, depression, hypercholesterolemia, diabetes and center as covariates.

Result

Our participants had a mean age of 67 years old with a mean MMSE score of 28.9/30 and counted 60% of women. We found a positive association between Aβ deposition and age with a gradually stronger association in heterozygous ԑ4 carriers (β (SD) = 1.94 (0.27)) and homozygous ԑ4 carriers (3.18 (0.52)) compared to non‐carriers (0.99 (0.12), p<0.001; Figure). We found similar results when restricting the analyses to cognitively unimpaired participants (heterozygous ԑ4: 1.65 (0.27), p<0.001; homozygous ԑ4: 3.01 (0.52), p<0.001), however Aβ aggregation was less associated to age in participants with mild cognitive impairment (heterozygous ԑ4: 1.33 (1.4), p = 0.33; homozygous ԑ4: 2.34 (1.9), p = 0.29). Moreover, we found an effect of sex on the association between Aβ aggregation and age in ԑ4 non‐carriers characterized by a stronger association in men (1.61 (0.22)) compared to women (0.63 (0.13)). Finally, we observed that the effect of APOE genotype on Aβ aggregation remained similar in the different cerebral regions, with less discernable differences between genotypes in the medial temporal and occipital regions.

Conclusion

The number of APOE4 alleles has an impact on the association between age and Aβ aggregation, such that high amyloid was observed at younger ages in homozygous APOE4 carriers than in heterozygous APOE4 carriers and in non‐carriers. The effect of APOE4 on Aβ deposition was global rather than regional in our analysis.
Dementia caregiver burden and its toll on caregiver health
Authors: Mehdipanah Roshanak , Malvitz Madelyn , Briceno Emily M , Chang Wen , Lewandowski‐Romps Lisa , Heeringa Steven G , Zahuranec Darin B , Levine Deborah A , Langa Kenneth M , Gonzales Xavier , Garcia Nelda M , Morgenstern Lewis B
Published: December 2023

Background

In 2019, more than 16 million U.S. family members and friends provided 18.6 billion hours of unpaid care to people with cognitive impairment. Mexican Americans (MAs) make up two thirds of the Latinx population and research shows that MA caregivers report more caregiver burden compared to non‐Hispanic Whites (NHW). The purpose of this study is to examine the underlying mechanisms influencing caregiver burden on the physical and mental health of caregivers by ethnicity and familism.

Method

We recruited adults 65 and older with cognitive impairment (Montreal Cognitive Assessment score>25), and their caregivers living in Nueces County, Texas. Caregiver burden was measured using the Zarit Burden Interview. Familism was measured using a 18‐item scale. Caregiver’s mental and physical health were derived from the 36‐Item Short Form Survey. Covariates included caregiver’s age, sex, ethnicity, education and care recipient’s cognitive function and physical impairment, including the ability to eat, dress or go to the toilet without assistance. We used weighted path analysis to test effects of ethnicity, familism and caregiver burden on caregiver’s mental and physical health. Covariates with p‐values>0.15 were excluded to attain a parsimonious reduced model.

Result

We included data from 516 caregivers and those they cared for. MA caregivers were younger, female, had less education and scored higher on the familism scale compared to NHW (Table 1). Figure 1 includes results from our reduced weighted path model which presented a good model fit. Increased caregiver burden was associated with worse mental (B = ‐0.53;p<0.001) and physical health (B = ‐0.14;p = 0.003). Familism had indirect positive effects on mental and physical health outcomes mediated by lowering caregiver burden (B = ‐0.15;p = 0.001). Being a MA caregiver was associated with a stronger level of familism (B = 0.49;p<0.001). Findings indicate that MA caregivers have better physical and mental health due to reduced caregiver burden because of stronger family relations.

Conclusion

Results show that increased caregiver burden is associated with worse caregiver’s mental and physical health. However, among MA, familism can be a protective factor against caregiver burden. Findings can contribute to early identification, intervention and coordination of services to help reduce caregiver burden, particularly in the growing MA informal caregiver population.
Early morning naps are correlated with incident Alzheimer’s Dementia in older adults
Authors: Gao Chenlu , Zheng Xi , Yu Lei , Buchman Aron S , Bennett David A. A , Leng Yue , Gao Lei , Hu Kun , Li Peng
Published: December 2023

Background

Previous findings suggest that frequent and longer naps during daytime are associated with elevated risks of Alzheimer’s dementia among older adults. This study aims to further examine whether naps during a particular time of a day are differentially linked to risk of Alzheimer’s dementia.

Method

A total of 1,203 participants from the Rush Memory and Aging Project (mean age at actigraphy = 80.85±7.30 years; 77% female) wore accelerometers (Actical) for up to 14 (mean = 9.57±1.17) days and completed annual neurocognitive assessment for up to 17 (mean = 6.92±4.12) years. A validated algorithm was used to identify daytime naps between 9am and 7pm. We categorized participants into those who napped versus those who did not nap during each time period, i.e., morning (9‐11am), noon (11am‐1pm), early afternoon (1‐3pm), late afternoon (3‐5pm), and early evening (5‐7pm). We conducted Cox proportional hazards models to test whether napping at a specific time of day is correlated with incident Alzheimer’s dementia, adjusting for age, sex, education years, length of actigraphy recording, body mass index, intradaily variability of rest‐activity rhythms, and nighttime sleep duration.

Result

Among all participants, 357 developed Alzheimer’s dementia during follow‐up (mean time to incidents = 6.34±3.98 years). Compared to those who did not nap in the morning (9‐11am), participants who napped in the morning had 1.4‐fold (HR[95%CI] = 1.43 [1.07‐1.93], p = 0.01) risk for developing Alzheimer’s dementia. This association was attenuated after further adjusting for total nap duration and frequency (HR[95%CI] = 1.32[0.97‐1.79], p = 0.07). However, napping during other time periods was not associated with risk for Alzheimer’s dementia, after adjusting for the covariates (noon: HR[95%CI] = 1.26[0.94‐1.68], p = 0.12; early afternoon: HR[95%CI] = 1.22[0.81‐1.84], p = 0.33; late afternoon: HR[95%CI] = 1.22[0.81‐1.84], p = 0.34; early evening: HR[95%CI] = 0.84[0.62‐1.13], p = 0.24).

Conclusion

Napping in the morning may link to an increased risk of Alzheimer’s dementia in older adults. A potential explanation is that individuals who nap more in the morning are more likely to experience disturbances in sleep‐wake regulation. Future studies should investigate this underlying mechanism and test whether interventions to reduce morning naps or consolidate naps can benefit neurocognitive outcomes.
Social cognition and emotion inference abilities in healthy aging and Mild Cognitive Impairment
Authors: Gasparre Daphne , Pepe Ilaria , Abbatantuono Chiara , Introna Alessandro , Biasi Madia Marika , Paparella Giulia , De Caro Maria Fara , Defazio Giovanni , Taurisano Paolo
Published: December 2023

Background

Social cognition (SC) is a neurocognitive domain that can be affected by the pathophysiological changes of aging, and deteriorate in individuals diagnosed with Mild Cognitive Impairment (MCI) and Alzheimer’s Disease. This social‐cognitive function involves the attribution of one’s mental states, including intentions (IA) and emotions (EA). As mentalization abilities may impact on daily functioning, research is focusing on SC processes in individuals at risk for age‐related neurocognitive decline. The present study aimed to 1) investigate SC abilities in MCI, compared to healthy individuals; 2) explore whether specific SC sub‐domains could be associated with MCI diagnosis.

Method

N = 468 outpatients referred to Bari University Hospital for neuropsychological assessment were classified into two groups: i) a cognitively spared (n = 166; Mage = 61); ii) MCI (n = 302; Mage = 67), characterized by objective deficits one or more neurocognitive domains (other than SC) not interfering with daily functioning. Sample classification resulted from multidomain, cognitive‐functional assessment procedures consistent with Petersen’s criteria (Petersen et al., 2014). A total of 185 subjects also completed the Story‐Based Empathy Task (SET), yielding four social cognition scores (i.e., global score [GS]; IA; EA; causal inference [CI]). After testing the distribution of the SET variable through the Shapiro‐Wilk test, the Mann‐Whitney U test was used to analyze mean differences between the two groups. Additionally, a binary logistic regression was conducted to assess whether impaired SC could be associated with MCI diagnosis.

Result

Patients with MCI showed significantly lower SC performances in all SET sub‐tests, compared to controls (SET‐GS: Z = ‐5.25; p<.001; SET‐IA: Z = ‐3.98; p<.001; SET‐EA: Z = ‐4.02; p<.001; SET‐CI: Z = ‐3.22; p<.001). Binary logistic regression with backward elimination revealed that among all SC sub‐domains, the inability to infer emotional states resulted being associated with MCI diagnosis (B = ‐.678; exp(B) = .507; p<.001). Regression analysis was overall significant (χ2 = 16.68; p<.001), and correctly classified 66% of cases.

Conclusion

Our findings highlighted significantly poorer SC performances in MCI, notably in the emotional inference sub‐domain. This preliminary evidence may contribute to the clinical understanding of social‐cognitive functioning in elderly individuals with mild/initial cognitive deficits, emphasizing the importance of accounting for SC in neuropsychological assessment to improve early diagnosis and strategies for dementia prevention.
Multimodal investigation of the early associations between sleep‐wake regulation, cognition and Alzheimer’s disease neuropathology and risk
Authors: Gilles Vandewalle
Published: December 2023

Background

Alterations in sleep‐wake regulation are hallmarks of the ageing process and emerge as risk factors for Alzheimer’s disease (AD). While the fine‐tuned coalescence of sleep microstructure elements may influence age‐related cognitive trajectories, its association with AD‐related processes is not fully known. Likewise, whether markers of sleep‐wake regulation assessed during wakefulness are associated with the risk of developing AD is not established.

Method

Here, we sought associations between key elements of the electrophysiology of sleep microstructure and of sleep‐wake regulation and hallmarks of AD neuropathology (early Aβ/Tau/neuroinflammation brain burden) or the polygenetic risk in 360 young adults (18‐31y) and 100 late‐midlife healthy individuals (50‐70y). We further investigated relationships with cognitive performance.

Result

We first found that spontaneous arousal during sleep are heterogenous and differently associated with Aβ and cognition. We further found the young‐like co‐occurrence of sleep spindles and slow‐depolarisation slow waves was associated to lower early burden of Aβ and was predictive of memory decline at 2‐year follow‐up. We also find that the dynamics of the daily change in cortical excitability and EEG markers of sleepiness are respectively not associated with early Ab burden and associated with the polygenic risk of developing AD. Cortical excitability dynamics is, however, association with cognitive performance.

Conclusion

These findings unravel early links between sleep‐wake regulation, AD‐related processes or genetic risks and their association with cognitive performance. Spontaneous arousals and the altered coupling of sleep microstructure elements that are key to its mnesic functions may contributes to poorer brain and cognitive trajectories in ageing. In addition, associations between markers of sleep‐wake regulation and AD can be detected during quiet wakefulness.

Support: ULiège, Wallonia‐Brussels Federation, Fonds de la Recherche Scientifique (FNRS Belgium), Fondation Recherche Alzheimer (SOA‐FRA Belgium), Fondation Léon Fredericq, EU FEDER programme