bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood‐based biomarkers for clinical trials of Alzheimer’s disease in Down syndrome
Authors: Ashton Nicholas J. , Montoliu‐Gaya Laia , Alcolea Daniel , Huber Hanna , Blennow Kaj , Jeromin Andreas , Fortea Juan , Zetterberg Henrik
Published: December 2023

Background

A blood biomarker for a clinical diagnosis of Alzheimer’s disease (AD) is of particular importance in Down syndrome, where a change in cognitive function is often difficult to delineate. Recent advances in ultra‐sensitive detection methods have allowed for the quantification of GFAP, p‐tau and NfL, which demonstrate high specificity for diagnosis of AD pathology and neurodegeneration, which has been utilised in recent anti‐amyloid trials.

Methods

Novel data presented in this talk will compare a multi‐centre study (n>800) on plasma NfL, GFAP, and phosphorylated tau (p‐tau181, p‐tau217, p‐tau231) from sporadic AD, familial AD, adults with Down syndrome and euploid controls in a cross‐sectional and longitudinal manner.

Results

We compared plasma biomarker performance to monitor clinical progression or identify changes in 18F‐fluorodeoxyglucose, amyloid PET and cortical atrophy by MRI. Further, explorative proteomics in cerebrospinal fluid (CSF) aims to identify novel candidates of clinical decline in Down syndrome individuals. Lastly, novel pilot data demonstrate that measures of GFAP, NfL and p‐tau are possible via capillary blood, extracted from a finger prick test, which have important implications as an off‐site blood collection in the Down Syndrome community without the need for strict blood processing protocols.

Conclusion

Plasma biomarkers of sporadic AD, specifically GFAP, NfL and p‐tau217, have equally high performance to AD pathology in Down Syndrome individuals with possible applications in clinical practice and clinical trials. Moreover, GFAP and NfL may act as important biomarkers in an off‐site finger prick collection which will increase inclusion and easier monitoring in the Down Syndrome community.
Preliminary performance of the Lumipulse G pTau 217 Plasma prototype assay on plasma samples
Authors: Vandijck Manu , Dekeyser Filip , Lambrechts Charlotte , Hasumi Yurina , Van Loo Maxime , Accou Flore , Sato Hideo , Inaoka Daigo , Nojima Hisashi , Degrieck Rosina , Bastard Nathalie Le , Vanbrabant Jeroen , Stoops Erik , Vandenbroucke Ina
Published: December 2023

Background

Multiple publications demonstrated that plasma pTau species (e.g., 181, 217, and 231) have the potential to be a good predictor of amyloid status by either PET or cerebrospinal fluid (CSF). Such blood‐based biomarker testing could be used as a simple, accessible, and scalable approach to help support the diagnosis of Alzheimer’s disease (AD), avoiding the complexity of CSF sampling, and the high costs and limited availability of PET imaging. Multiple plasma pTau assays, established on different immunoassay platforms, are currently being evaluated in research settings with variable outcomes in terms of analytical and clinical performance. At Fujirebio, an assay for the measurement of plasma pTau217 was developed on the LUMIPULSE G platform to complement the commercially available plasma pTau181 RUO assay. The aim of this study was to determine the preliminary performance of the Lumipulse G pTau 217 Plasma prototype assay.

Method

The LUMIPULSE G System is a fully automated chemiluminescent enzyme immunoassay platform processing samples in ready‐to‐use immunoreaction cartridges in about 30 minutes. The assay uses an in‐house developed monoclonal antibody for capturing of pTau217. Analytical assay characteristics such as sensitivity, precision and dilutional linearity were determined. The analytical studies included a series of buffer and K2EDTA plasma samples, each tested in several replicates. Preliminary clinical performance was explored on a small set of patient and control samples.

Result

All analytical parameters tested were within the acceptance criteria. All clinical samples tested had a result above the limit of quantification (LoQ). The LoQ was obtained based on the evaluation of low concentrated plasma pTau217 samples. Imprecision was less than 15% CV on buffer‐based as well as plasma samples. Dilutional linearity on spiked samples was within ±20%. The Lumipulse G pTau 217 Plasma prototype assay outperformed the Lumipulse G pTau 181 Plasma RUO assay in a ROC curve analysis of clinically typed patients and controls.

Conclusion

This preliminary performance evaluation of the Lumipulse G pTau 217 Plasma prototype assay indicated good results in terms of high sensitivity, low variability, dilutional linearity and clinical capability. More studies on well‐characterised and diverse cohorts are needed to confirm the assay’s clinical performance.
Baseline Frailty and Domain‐specific Cognitive Declines in Healthy and MCI Older Adults
Authors: Liu Albert C. , Chiang Grace Shu Hui , Carlson Michelle C , Xue Qian‐Li
Published: December 2023

Background

Both physical frailty and cognitive decline increase with age and each place adults at elevated risk for loss of independence. Inconsistent associations have been found between frailty and risk for cognitive declines across cognitive domains. However, most studies were cross‐sectional and did not include a comprehensive battery of neuropsychological tests. We hypothesized that frail older adults, whether with or without Mild Cognitive Impairment (MCI) at baseline, are at risk for accelerated domain‐specific cognitive declines.

Method

The Ginkgo Evaluation of Memory Study (GEMS) was a prospective study of 3069 dementia‐free older adults aged 72‐96 years, followed for up to 7.5 years or a diagnosis of dementia, 482 of whom were diagnosed with MCI at baseline. A modified physical frailty phenotype was constructed using GEMS baseline data. A Neuropsychological Battery consisted of 13 tests reflecting global cognition, memory, visual‐spatial construction, language, psychomotor speed/attention, and executive function were administered annually. Linear random effects models were used to compare differences in baseline and rate of change in domain scores among individuals with and without baseline frailty.

Result

Overall, frail participants showed poorer baseline cognitive function in all domains, and greater declines in all cognitive domains. When stratified by baseline MCI, among non‐MCI participants, those with frailty revealed poorer baseline psychomotor speed/attention and executive function, and greater declines in all cognitive domains. Among MCI participants, those with frailty exhibited lower baseline visual‐spatial construction, and greater declines in all cognitive domains except for visual‐spatial construction and executive function. In all cognitive domains, the estimated effect of frailty on cognitive decline was greater in MCI participants than non‐MCI participants.

Conclusion

Frailty was predictive of accelerated cognitive declines across domains and more so in those with baseline MCI. The results from this study highlight the importance of assessing frailty as a risk factor for accelerated cognitive declines, particularly among those at elevated preclinical cognitive risk. These individuals may be at the greatest risk of transitioning to dementia.
Alzheimer’s disease biomarker profiling in a memory clinic cohort without common comorbidities
Authors: Daniilidou Makrina , Eroli Francesca , Alanko Vilma , Goikolea Julen , Leal Maria Latorre , Rodriguez Patricia Rodriguez , Griffiths William J , Wang Yuqin , Pacciarini Manuela , Brinkmalm Ann , Zetterberg Henrik , Blennow Kaj , Rosenberg Anna , Bogdanovic Nenad , Winblad Bengt , Kivipelto Miia , Ibghi Delphine , Minguez Angel Cedazo , Maioli Silvia , Matton Anna
Published: December 2023

Background

Comorbidities such as hypertension, hypercholesterolemia and diabetes are known contributors to Alzheimer disease (AD) progression. However, their mechanistic contribution to pathology and neurodegeneration has not been clarified. The aim of this study was to investigate cerebrospinal fluid (CSF) levels of markers reflecting brain changes in synaptic integrity, inflammation, oxidative stress, glucose homeostasis and cholesterol metabolism in memory clinic patients without known AD comorbidities.

Method

CSF samples from 90 memory clinic patients without diagnosed hypertension, hypercholesterolemia, or diabetes nor other neurodegenerative disorder, were used to investigate 13 molecular markers representing key mechanisms underlying AD pathogenesis. Associations were analyzed by linear regression. Two‐step cluster analysis was used to determine patient clusters. Two key markers were analyzed by immunofluorescence staining in hippocampus from control and AD individuals.

Result

CSF angiotensinogen, thioredoxin‐1, and interleukin‐15 had the most prominent associations with AD pathology, synaptic and axonal damage. SNAP‐25 and NFL were increased in MCI and AD cases. Grouping biomarkers by biological function, showed that inflammatory and survival components were associated with AD pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In data‐driven analysis, two patient clusters were identified; cluster 1 had increased CSF markers of oxidative stress, vascular pathology and neuroinflammation and was characterized by elevated synaptic and axonal damage, compared to cluster 2. Clinical groups were evenly distributed between the clusters. Analysis of post‐mortem hippocampal tissue, showed that, compared to non‐demented controls, angiotensinogen staining was higher in AD and co‐localized with phosphorylated‐tau.

Conclusion

The identification of biomarker‐driven endophenotypes of cognitive disorder patients, further highlights the biological heterogeneity of AD and the importance of tailored prevention and treatment strategies.
Tele‐Dementia in Africa: Setting roadmap for implementation
Authors: Farombi Temitope Hannah , Akinyemi Rufus O. , Ogunniyi Adesola , Consortium Africa Dementia
Published: December 2023

Background

Alzheimer’s disease and dementia related disorder incidence and prevalence continue to increase in Africa due to changing ageing demographics. Despite this rise, overall quality and quantity of available evidence to inform best practices in recruitment, retention and inclusion of underrepresented population in ADRD research is very low. Africa needs creative innovations to bridge the dementia care gap and telemedicine offers a unique opportunity for prompt diagnosis, follow up and care support

Method

This was an observational study of remote video assessment of persons living with Dementia and their caregivers. Mobile phone and web‐based applications for virtual consultation and health information management system were built to engage patients with various clinical conditions across multiple specialties. The assessment and follow up were done between September 2020 and December 2022.Cognitive assessment tools were administered via telemedicine platform for screening and post diagnostic management due to the COVID‐19 lock down

Result

A total of 50 patients with Dementia and their caregivers attending Neurology clinic at the Geriatric centre UCH were engaged on the platform for clinical follow up. Mean(+SD) age of was 74.0(+7.2) year and 56% were females, 82.8% had some form of formal education, 67.2% married and 97.9 lived with other persons. Over 31.9% participants had at least one comorbidity. 93% of the participants expressed satisfaction with video conferencing platform. 87% retention rate on follow up on the platform,13% of drop out rate due to technical fault and poor internet connection

Conclusion

we believe implementation of telemedicine will improve recruitment and retention of persons living with dementia and it offers a promising dementia management strategy for Africa
Including drawings in future dementia research: identification and modification of negative stereotyping
Authors: Bormans Kasper , Zwakhalen Sandra , Pate Melannie
Published: December 2023

Background

Most countries in Western civilization are segregated societies with little or no contact between generations. Elementary schools and nursing homes are separated worlds in proximity. Children alienate further from the elderly and rely on indirect experiences with old age and dementia. The elderly can embody negative stereotypes from media and society leading to disparities in health care, social isolation and loss of functional ability.

Method

In this study we collected 796 drawings from 98 children in 4 elementary schools in Belgium and The Netherlands. The 10‐y‐old pupils made portraits of grandparents and the elderly in neutral, happy and unhappy conditions. The standardized drawing assignments were repeated after a psychosocial intervention program of 16 weeks to connect generations. The effects of non‐pharmacological interventions in Alzheimer’s research are mostly studied with classical questionnaires. These tools are insufficient to detect unconscious motives and subtle mental representations of old age and dementia. Before and after drawings are an added value to the field of research. The implicit measurements circumvent social desirability, go beyond the level of awareness and give a clearer picture of negative stereotypes of old age and dementia.

Result

The content analysis of the drawings demonstrated that children represent ‘happy elderly people’ as: outdoors, active, and surrounded by others, while ‘unhappy elderly people’ are generally portrayed indoors, sedentary and lonely.

Conclusion

Children’s drawings as implicit measurement are an added value for non‐pharmacological interventions. The act of drawing is pleasant, easy and effective for the identification and modification negative stereotyping of old age and dementia.
Medical‐assistance in Dying (MAiD) for Dementia Patients in Canada and Netherlands: A Literature Review
Authors: Shrestha Lucy , Shrestha Hom Lal
Published: December 2023

Background

Dementia is the seventh leading cause of death worldwide. The notion of Medical‐assistance in Dying (MAiD) among dementia and Alzheimer’s patients has been legalized in Canada and Netherlands. However, there has been little research dedicated to clinical intervention and clinical ethics in MAiD as well as policy, legal, ethical barriers and challenges, and research gaps for physicians, dementia care specialists, healthcare providers, and carers. In Canada, MAiD accounts for 2.5% of all deaths, including dementia.

Method

A comprehensive search in Google Scholar, PubMed, and the National Library of Medicine was conducted to discover evidence‐based MAiD practice, legislation, and ethical protocols among dementia and Alzheimer’s patients worldwide through peer‐reviewed research articles published between 2012 and 2022 that focused on quantitative, qualitative, and mixed methods. This includes MAiD education, clinical practices, legislation, attitudes and experiences of physicians, geriatricians, dementia care specialists and health care providers and barriers in MAiD in dementia for patients and their decision‐making capacity in the early or late stages of dementia.

Result

Three Canadian studies demonstrate knowledge and experiences of dementia care specialists for advanced requests for MAiD in British Columbia; capture physicians' characteristics and attitudes toward MAiD for non‐competent dementia patients in Quebec; and reflect insight into the current practises of MAiD among dementia patients focused on their autonomy and mental capacity of consent in Canada. Studies in the Netherlands reveal physicians' experiences and workload, pressure and expectations of relatives and societies to access end‐of‐life options and care for MAiD; and argue on early vs. late stages in Dutch practices and decision‐making and consent among incompetent dementia patients.

Conclusion

The roles of Alzheimer’s societies, stakeholders, MAiD assessors and providers, and social support systems are critical in educating, advocating for, and empowering dementia patients and carers to MAiD in the early and late stages. More research is needed to inform policymakers and legislators in developing a roadmap for educational interventions to MAiD assessors and providers, health care providers, medico‐legal practitioners, stakeholders, and family carers on ethical, cultural, spiritual, and legal issues, as well as legislative process related to MAiD any changes to the law in societies.
Transcriptomics similarities between Alzheimer’s Disease and Cardiovascular Disease
Authors: Da Ros Lucas Uglione , Bastiani Marco Antônio De , Lobato Lara Willers , Zimmer Eduardo R.
Published: December 2023

Background

Cardiovascular disease, such as coronary artery disease (CAD), is considered a risk factor for the development of dementia, especially due to Alzheimer’s Disease (AD). The mechanisms through which these two entities interact are not totally elucidated, even with some evidence indicating a role of microinfarcts and white matter lesions. CAD is a severe form of cardiovascular disease, in which the arteries that irrigate the heart are compromised. Here, we aimed to assess altered biological processes that are shared between CAD and AD using blood transcriptomics.

Method

We used the GEO repository to search for available transcriptomics studies of whole peripheral blood for CAD and AD; for CAD we selected GSE20680, GSE20681, GSE98583, GSE42148 and GSE12288, and for AD GSE63063 and GSE85426, together with the ADNI database. All CAD patients had angiographic confirmation of coronary stenosis. The data was downloaded using the GEOquery package and the differentially expressed genes (DEG) were defined as having p‐value < 0.05 and logFC > 0.27. We then proceeded to determine the intersection of DEGs present both in CAD and AD and these DEGs were submitted to Gene Ontology (GO) enrichment analysis using the clusterProfiler package (v3.16.1) and enrichGO function. GO terms were clustered using semantic similarity with the package GOSemSim. All analyses were performed in R.

Result

We found a total of 3561 DEGs for AD and 1873 for CAD, with an intersection of 352 of those. After the functional enrichment analysis, these were translated into 32 GO terms enriched in both diseases. These terms were clustered based on semantic similarity into 9 groups: myeloid cell differentiation; homeostasis of number of cells; positive regulation of I kappa B kinase/NF‐κB signaling; regulation of immune effector process; positive regulation of cell adhesion; positive regulation of proteolysis; positive regulation of cytokine production; phospholipid biosynthesis process; miscellaneous biological processes.

Conclusion

Here we provide evidence that shared systemic pathological changes, including inflammatory processes, may also contribute to the development of both cardiovascular disease and dementia.
APOEε4 potentiates the effects of Aβ pathology on the deposition of neurofibrillary tangles via tau phosphorylation
Authors: Ferrari‐Souza João Pedro , Bellaver Bruna , Ferreira Pamela C.L. , Benedet Andrea Lessa , Povala Guilherme , Lussier Firoza Z , Leffa Douglas Teixeira , Therriault Joseph , Tissot Cécile , Soares Carolina , Wang Yi‐Ting , Chamoun Mira , Servaes Stijn , Macedo Arthur C. , Vermeiren Marie , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Poltronetti Nina Margherita , Cohen Annie , Lopez Oscar L. , Klunk William E , Soucy Jean‐Paul , Gauthier Serge , Souza Diogo O. , Triana‐Baltzer Gallen , Saad Ziad S. , Kolb Hartmuth C. , Karikari Thomas K , Villemagne Victor L , Tudorascu Dana , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick A.
Published: December 2023

Background

The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences Alzheimer’s disease (AD) pathophysiological progression are poorly understood. Here, we tested the association of APOEε4 carriership and amyloid‐β (Aβ) burden with longitudinal tau pathology progression.

Method

We studied 104 individuals across the aging and AD clinical spectrum from the McGill TRIAD cohort. Study participants underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aβ ([18F]AZD4694) and tau ([18F]MK6240) at baseline, as well as an additional follow‐up tau‐PET scan (mean follow‐up, 2.4 years). We further assessed longitudinal changes in tau phosphorylation (plasma phosphorylated tau at threonine 217 [p‐tau217+]), brain atrophy (gray matter density), and clinical function (clinical dementia rating scale sum of boxes).

Result

We found that APOEε4 carriership potentiates Aβ effects on longitudinal tau tangle accumulation over two years (Figure 1). Interestingly, the APOEε4‐potentiated Aβ effects on tangles were mediated by longitudinal plasma p‐tau217+ increase (Figure 2). In addition, this longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline during the follow‐up period (Figure 3).

Conclusion

Our results support a model in which the APOEε4 allele plays a key role in Aβ downstream effects on the aggregation of phosphorylated tau in the form of neurofibrillary tangles in the living human brain, which is a key factor in the development of dementia. These observations have important implications for the design of future trials by suggesting that the combination of therapies targeting both ApoeE4 and Aβ pathology might have the potential to synergistically halt tau progression in AD.
Association of human brain‐age with genetically predicted plasma levels of brain rejuvenating and aging factors identified in mice
Authors: Anastasi Federica , Genius Patricia , Escalante Armand González , Rodríguez‐Fernández Blanca , Cumplido‐Mayoral Irene , Falcon Carles , Minguillon Carolina , del Campo Marta , Esteller Manel , Navarro Arcadi , Gispert Juan Domingo , Suárez‐Calvet Marc , Vilor‐Tejedor Natalia
Published: December 2023

Background

Aging is the primary risk factor for Alzheimer’s disease. Experiments in mice have identified circulating proteins with an “aging/rejuvenating” effect on the brain. However, whether these proteins have an effect on the human brain remains unknown. Here, we leverage genetic data to study links between the predicted plasma levels of these proteins and human brain age.

Methods

This study includes 1,394 cognitively unimpaired individuals of the ALFA study. Plasma proteins with an effect on mice brain aging were identified through a systematic review [Figure 1]. Summary statistics data of protein quantitative trait loci (pQTLs) associated to these proteins in human (inclusion threshold<5×10−5) were acquired from a previous study (Pietzner et al.,2021), and used for computing protein genetic scores (pPRS). For each ALFA cohort participant, DeltaAge scores was calculated by subtracting chronological age from MRI‐based estimation of brain age (Cumplido et al.,2022). Positive values are interpreted as brain age older than chronological age, and viceversa. The associations between brain DeltaAge measurements and pPRSs were assessed through general linear regression models stratified by sex, amyloid‐β (Aβ) status (CSF‐Aβ42/40<0.071 [Milà‐Alomà et al.,2020]) and APOE‐ε4 carriership. Results were reported for nominal and group‐correction (two experimental aging groups) level of significance (p<0.05, p<0.025, respectively). All pQTLs included in the significant pPRS were functionally annotated and an enrichment analysis was performed.

Results

Genetically predicted plasma levels of CSF2, VCAM1, HP, GHRH and BGLAP were associated with negative values of brain DeltaAge, while KLOTHO with positive values. Results for GHRH (Aβ+ and APOE‐ε4 non‐carriers) and BGLAP (APOE‐ε4 carriers) remained significant after p‐value correction, with an effect in agreement with their brain rejuvenation role as found in mice [Figure 2]. Enrichment analysis found immune response and complement activation processes associated with negative values of DeltaAge [Figure 3].

Conclusions

These results show that plasma levels of the brain aging/rejuvenating proteins discovered in mice may also influence human brain aging. In particular, genetically predicted levels of two rejuvenating factors in mice (BGLAP and GHRH) were associated with a younger brain age than chronological age. Follow‐up analyses will include protein level measurements to unravel the molecular complexity of brain aging.
The role of lifecourse socioeconomic status and midlife brain health in Black adults
Authors: Turney Indira C , Lao Patrick J. , Rivera Andres M. , Berroa Joncarlos , Brickman Adam M. , Manly Jennifer J.
Published: December 2023

Background

A recent study showed that middle‐aged Black participants exhibited the magnitude of brain aging observed during late life, suggesting accelerated brain aging. Lifecourse socioeconomic status (SES) is an important predictor of health status, like cognition and Alzheimer’s disease (AD), and may help us understand some of the underlying mechanisms that contribute to accelerated brain aging in middle‐aged Black adults. SES predicts health outcomes throughout the lifespan, and there may be a period of susceptibility where SES is most impactful (e.g., SES in childhood vs adulthood). This study assessed whether childhood or midlife SES better predicts midlife brain health in Black adults.

Method

Participants were 140 middle‐aged Black adults from the Offspring study of Racial/Ethnic Disparities in AD with MRI (mean age = 54.9 (SD = 9.2) years; 63% women). We used general linear models to examine the relationship of childhood SES (e.g., composite of parent’s income, education, occupation) and Midlife SES (e.g., midlife income) with MRI‐based cerebrovascular disease (e.g., white matter hyperintensity volume; WMH) and neurodegeneration (e.g., AD signature cortical thickness), controlling for sex/gender and age, and additionally household size in midlife SES models only. We also assessed whether health factors (e.g., hypertension, diabetes) attenuated the effects of lifecourse SES on MRI markers.

Result

Childhood SES was not associated with midlife cortical thickness or WMH volume. For midlife SES, participants making less than $35k/year (New York City median income) had lower cortical thickness (B = ‐0.39, CI = ‐0.075,‐0.002) and greater WMH volume (B = 0.192, CI = 0.048,0.336). Estimated marginal means predicted that if these participants made $35k+/year, they would instead show a 1.5% increase in cortical thickness and 32.8% reduction in WMH volume. History of hypertension (47%) and diabetes (22%) was unrelated to MRI markers and did not attenuate the relationship between midlife SES and MRI markers.

Conclusion

Midlife SES, but not childhood SES, was associated with midlife brain health in people racialized as Black. Results did not show a direct association between vascular risk and brain health or suggest that vascular risk was in the pathway from SES to brain health. Rather, higher income may maintain vascular and structural brain health in midlife.
Combined effect of persistent cytomegalovirus infection and Tumor Necrosis Factor‐α Polymorphism on age‐related cognitive decline
Authors: Vacher Michael , Lee Silvia , Ha Phuongnhi , Waters Shelley , Laws Simon , Price Patricia
Published: December 2023

Background

Human cytomegalovirus (HCMV) is a ubiquitous infectious agent, widely distributed in human populations. Its infection has been correlated with a number of age‐related disorders but associations with neurocognitive decline are not seen consistently. The Tumor Necrosis Factor‐α (TNF) is a cytokinine playing a key role in inflammation and TNF polymorphisms have been associated with various autoimmune diseases. In this study, we investigated the impact of TNF genotype and HCMV on age‐related cognitive decline.

Method

The study cohort consisted of 200 Caucasian Australians (aged 59‐89 years) drawn from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. We used linear regression models to assess the effect of TNF genotype, HCMV and their interaction on a series of domain‐specific composite scores (Preclinical Alzheimer Cognitive Composite; PACC, Recognition, Attention Processing, Language). The models accounted for the potential effect of age, education level and Apolipoprotein E genotype.

Result

The interaction between HCMV and TNF genotype significantly predicted PACC (b = 5.3; SE = 2.56; p = 0.04) and Recognition scores (b = 1.9; SE = 0.78; p = 0.01). Interactions were not significant in the other domains investigated (attention processing & language).

Conclusion

The results suggest that the presence of TNF polymorphism, combined with HCMV infection have a protective effect against cognitive loss. Further research is needed to understand the underpinning mechanisms.
Alzheimer’s disease plasma markers and depressive symptoms: an IPD meta‐analysis
Authors: Twait Emma L. , Kamarioti Maria , Verberk Inge M.W. , Teunissen Charlotte E. , Nooyens Astrid C.J. , Verschuren Monique WM , Visser Pieter Jelle , Huisman Martijn , Kok Almar A.L. , Slagboom P. Eline , Beekman Marian , Ikram M. Arfan , Schuurmans Isabel K , Wolters Frank J. , Moonen Justine E. , Gerritsen Lotte , van der Flier Wiesje M. , Geerlings Mirjam I.
Published: December 2023

Background

Depression has been associated with an increased risk of Alzheimer’s disease (AD), but the biological mechanisms are still not fully understood. Plasma biomarkers, such as amyloid‐beta, tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL), have been associated with AD pathophysiology. However, the relationship with depression is unclear. Assessing these biomarkers in the blood allows for the opportunity to assess if AD pathology is related to depressive symptoms on a large‐scale. We hypothesized if depression is part of the AD process, then these markers will be associated with depressive symptoms.

Method

A two‐stage IPD meta‐analysis was performed based on eight cohorts of individuals without dementia as part of the Netherlands Consortium of Dementia Cohorts (NCDC). We examined the cross‐sectional association between each plasma marker for AD (amyloid‐beta42/40 ratio, p‐tau181, NfL, and GFAP) with depressive symptoms (the GDS‐15, PHQ‐9, CES‐D, and SF‐36). Plasma markers were assessed using Single Molecular Array (Simoa; Quanterix) assays. Both plasma markers and depressive symptoms were standardized. We estimated the effect per plasma marker with depressive symptoms using linear regressions, correcting for age, sex, education, and APOE e4 allele presence, in each cohort. The effect estimates were entered into a random‐effects meta‐analysis. We also performed subgroup analyses assessing sex differences and between those with and without an APOE e4 allele.

Result

This study involved 7210 participants with an age range of 38 to 102 years. Based on clinical cut‐offs per questionnaire, high depressive symptomology ranged from one to 22% per cohort. None of the plasma markers were associated with depressive symptoms in the meta‐analysis. However, subgroup analyses found an association with NfL and depressive symptoms in women (beta 0.07; 95% CI: 0.03‐0.10, p < 0.001) and in those with an APOE e4 allele (beta 0.11; 95% CI: 0.05‐0.17, p = 0.001).

Conclusion

AD pathology did not show an overall relationship with depressive symptoms. However, in women and in those with a genetic risk for AD, NfL showed an association. As NfL is a marker of overall neurodegeneration, this pathology in plasma may be specific to depressive symptoms in certain subgroups.
Effects of Physical Activity, Vascular Burden and Clinical Diagnosis on White Matter Integrity
Authors: Konwar Srijan
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common type of dementia. Both degenerative and vascular pathology tend to contribute to dementia as AD coexists with single or multiple cardiovascular risk factors (vascular burden). Modifiable lifestyle factor such as physical activity has been associated with lower vascular burden (VB) and a lower risk of dementia. To test whether physical activity characterised as being inactive or active helped preserve white matter microstructure in a sample consisting of healthy controls and patients from the clinical AD continuum (mild cognitive impairment to dementia) with either low or high VB.

Method

213 participants were recruited from three memory clinics and were classified as being either physically active (n = 113) or inactive (n = 100) based on the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) questionnaire. Voxel‐wise tract‐based spatial statistics (TBSS) was carried out using a set of 5000 permutations and threshold‐free cluster enhancement (TFCE) to find significant clusters for fractional anisotropy (FA), axial diffusivity (AxD), mean diffusivity (MD) and radial diffusivity (RD).

Result

Participants who were physically active had higher FA and lower AxD, MD and RD values relative to the inactive participants. Changes in indices of WM integrity were widespread across the brain covering mainly association and projection tracts but a few commissural tracts. A three‐way interaction effect between Group × Physical Activity × VB was found for FA that was present in mainly projection tracts with a rightward asymmetry along with some association and commissural tracts. Post hocs revealed greater FA in physically active patients with high VB compared with inactive patients with high VB in projection and association/limbic tracts with a rightward asymmetry. Furthermore, the patients with high VB showed higher FA in bilateral projection fibers and cerebellar regions compared with inactive controls with high VB.

Conclusion

TBSS analysis revealed that high risk patients such as those with high VB achieved the maximum benefit by being physically active as it led to a much greater preservation of white microstructure relative to controls with high VB. This preservation of white matter microstructure was only observed in patients but not in controls.
Clinical Phenotypes of Alzheimer’s Disease: Pathological Correlates of Regional Cortical Volume
Authors: Reijner Niels , Frigerio Irene , Bouwman Maud M.A. , Guizard Nicolas , Jubault Thomas , Lin Chen‐Pei , Hoozemans Jeroen , Rozemuller Annemieke J.M. , Bouwman Femke H. , Barkhof Frederik , Gordon Elizabeth , Berg Wilma D.J. , Jonkman Laura E.
Published: December 2023

Background

Recent studies highlight distinct patterns of cortical atrophy in amnestic (typical) and non‐amnestic (atypical – behavioural, dysexecutive and visuospatial) clinical phenotypes of Alzheimer’s disease (AD). The current study aimed to assess regional phenotypic MRI patterns of cortical atrophy, and their association with Amyloid‐beta (Aβ), phosphorylated Tau (pTau), and axonal degeneration (NfL).

Method

Postmortem In‐situ 3DT1 3T‐MRI data were collected for 28 AD (14 typical, 14 atypical) and 10 control brain donors. Images were segmented using QyScore® and regional volumes according to the AAL3 atlas were obtained. At subsequent autopsy, Eight brain regions from the right hemisphere were selected and immunostained for Aβ (4G8), pTau (AT8), and Neurofilament light (NfL), and quantified for area% load. Group comparisons and MRI volume‐pathology associations were analyzed using linear models with covariates age, gender, postmortem delay, and intracranial volume when applicable.

Results

When assessing regional cortical volumes, compared to controls, typical AD showed a more parietal‐temporal, while atypical AD showed a more a frontal‐temporal atrophy pattern (fig1).

Typical and atypical phenotypes showed different pathological load across all selected regions in both Aβ and NFL (p = 0.032,p = 0.0007, respectively). Subsequent explorative assessment indicates a difference in regional pTau distribution between behavioural, dysexecutive and visuospatial subtypes, specifically in the occipital region (fig2).

Addressing MRI‐pathology associations across all selected regions, we observed a positive association between cortical volume and Aβ in typical AD (β = 1.98,p = 0.026), while both pTau and NFL showed a negative association (β = ‐0.26,p = 0.004; β = ‐2.00,p = 0.001, respectively). In atypical AD, only NFL showed a significant negative association (β = ‐2.27,p<0.001) with cortical volume. Regionally (fig3), only NfL associated with MRI volume; with the precuneus in both typical and atypical AD (β = ‐2.81,p = 0.044; β = ‐3.81,p = 0.011, respectively), and with posterior cingulate cortex volume in atypical AD (β = ‐3.24,p = 0.045).

Conclusion

This study found varying atrophy patterns in AD phenotypes when compared to controls. Across all selected regions, typical AD showed volume‐pathology associations with Aβ, pTau and axonal damage, while atypical AD only showed associations with axonal damage, indicating a possible difference in volume‐pathology associations between phenotypes. Regionally, cortical volume was predominantly associated with axonal damage, rather than Aβ or pTau protein accumulation, in parietal regions.
Trajectory of MRI and FDG‐PET biomarkers in Alzheimer’s disease
Authors: Heeman Fiona , Moscoso Alexis , Dunås Tora , Schöll Michael
Published: December 2023

Background

Alzheimer’s disease (AD) has a long preclinical phase, which is hypothesised to start with the accumulation of β‐amyloid (Aβ) plaques, followed by tau neurofibrillary tangles and neurodegeneration. Despite presenting quite different types of information, MRI‐derived volumetric measures and FDG‐PET‐derived metabolism are both commonly used as proxy of neurodegeneration in AD. The aim of this work is to assess the trajectory of both of these biomarkers in AD, relative to time to amyloid‐positivity.

Method

3289 MRI scans (682 participants) and 2472 FDG‐PET scans (1296 participants) were included from the ADNIGO, 1,2 and 3 cohorts. For MRI scans, total volume was calculated for a meta‐ROI consisting of entorhinal, inferior, middle temporal and fusiform gyri. For FDG‐PET, standardized uptake value ratios (SUVR) were calculated from 30‐60 min post injection for a meta‐ROI consisting of the angular, posterior cingulate and inferior temporal gyri, normalised to the pons. All metrices were transformed into z‐scores using the references values of the Aβ‐negative subjects. Age of amyloid‐positivity was determined by fitting a nonlinear mixed effects model to 3607 Centloid values corresponding to 1690 participants. Next, time to amyloid‐positivity was calculated for each scan. The relationship between time to amyloid‐positivity and (z‐scored) SUVR or cortical volume values was modelled using a non‐linear mixed effects model with spline function and trajectories from both modalities were compared.

Results

Baseline demographics can be found in Table 1. Figure 1 shows the trajectory of amyloid deposition that was used to determine age of amyloid‐positivity. Cortical volume and SUVR showed similar trajectories over time, with steeper decline in both measures after the event of amyloid‐positivity (Figure 2). The overlay of both biomarker trajectories shows that for the meta‐ROI, there is no difference in when these biomarkers become abnormal.

Conclusions

The present results suggest that measures of neurodegeneration from MRI and FDG‐PET scans corresponding to a meta‐ROI, follow very similar trajectories. Future work will investigate if this also holds true for smaller regions of interest.
Investigating drug repurposing for the prevention of Alzheimer’s disease and related dementias using electronic health records in the University of Pennsylvania Health System
Authors: Li Lu , Wu Qiong , Lundin Sori Kim , Naj Adam C. , Gur Ruben C , Rascovsky Katya , Wolk David A. , Tao Cui , Chen Yong
Published: December 2023

Background

Alzheimer’s disease and related dementias (ADRDs) are a group of complex neurodegenerative diseases and disorders that pose a growing global public health burden. Developing new treatments for ADRDs has been difficult and there is a pressing need for new therapeutic options. Drug repurposing, which involves finding new uses for existing drugs, has gained increasing attention as a potential strategy for ADRD prevention. Here we aimed to identify drugs that may be repurposed for Alzheimer’s disease (AD) or ADRD prevention using a data‐driven approach from a large multi‐site electronic health record (EHR) database.

Method

Using structured EHR data from the University of Pennsylvania Health System (UPHS) between January 2012 and March 2022, we constructed a cohort of 13,091 individuals with mild cognitive impairment (MCI) and hypertension. We conducted multivariate Cox proportional hazard analyses to investigate the effect of exposure to medications on time to AD/ADRD adjusting for potential risk factors, including age at MCI diagnosis, sex, race, and several comorbidities. We identified and investigated five classes for the treatment of hypertension, including beta‐blockers (BBs), Renin‐angiotensin‐system (RAS), calcium channel blockers (CCBs), Diuretics, and antihypertensives (AHM). To ensure adequate statistical power, generic drugs with more than 500 users were identified and examined.

Result

Multivariate analyses revealed that two drug classes (Table 1) had significantly reduced hazard ratios (HR) for developing dementia including Diuretics (HR = 0.885, P = 0.038) and BBs (HR = 0.881, P = 0.027). Additionally, furosemide in the Diuretics category (HR = 0.723, P < 0.001) and propranolol in the BBs category (HR = 0.529, P = 0.045) demonstrated protective effects on developing dementia. On‐going secondary analyses stratified by gender, age group

Conclusion

This study identifies 2 drug categories and 2 generic drugs that may confer protection against the onset of AD/ADRDs. Further follow‐up, such as a randomized trial, is needed to confirm these associations and explore potential therapeutic applications. This study’s approach to harmonizing and analyzing records from a large multi‐site EHR database approach represents a promising data‐driven strategy for identifying drug repurposing opportunities for AD/ADRD prevention.
Mitophagy biomarkers are changed in the continuum of Alzheimer’s disease
Authors: Veverova Katerina , Katonova Alzbeta , Horakova Hana , Angelucci Francesco , Laczó Jan , Hort Jakub , Shi Liu , Fang Evandro Fei , Vyhnalek Martin
Published: December 2023

Background

Autophagy is a cellular self “garbage clearance ”system through which cells eliminate and recycle dysfunctional cytoplasmatic components, such as defective organelles and misfolded protein aggregates. Mitophagy is the sub‐type of autophagy that recognizes and degrades damaged or superfluous mitochondria to maintain cellular homeostasis. Emerging evidence demonstrates that autophagy and mitophagy are impaired in Alzheimer’s disease (AD); its upregulation ameliorates Aß pathology and slows down the cognitive decline in animal models of AD, thus representing a potentially treatable target. The change in the mitophagy biomarkers in individuals with AD needs to be clarified. We aimed to explore the changes of mitophagy biomarkers in biomarkers‐defined individuals in various stages of AD and compare them to cognitively unimpaired individuals (CU).

Method

We included 228 biomarker‐defined individuals from the Czech Brain Aging Study:98 AD dementia (ADD), 88 mild cognitive impairment due to AD (MCI‐AD), and 42 CU individuals. They underwent clinical examination, complex neuropsychological assessment, and brain MRI. Commercial ELISA kits were used to measure standard AD biomarkers in CSF (Aß42, Aß40, pTau, tTau), a biomarker of neurodegeneration (neurofilament light chain – NfL), synaptic dysfunction (neurogranin, Ng), and mitophagy biomarkers in CSF (PINK1‐ mitochondrial kinase crucial for mitophagy) and in serum (BNIP3L‐ mitophagy receptor, TFEB‐ transcription factor critical for lysosomal degradation).

Result

We found a significant increase in PINK1 CSF and BNIP3L serum levels in ADD compared to MCI‐AD and CU (ps<.001). TFEB serum levels were decreased in ADD compared to MCI‐AD and CU (ps<.05). Additionally, in ADD, PINK1 correlated with NfL (r = 0.27) and Ng (r = 0.47). In MCI‐AD, there was a correlation between PINK1 and Ng (r = 0.51), but not with NfL. There was no correlation in CU individuals with NfL or Ng.

Conclusion

We identified candidate proteins of mitophagy that are changed in various cognitive stages of AD. In the ADD stage, there is an upregulation of the mitophagy inducers, PINK1 and BNIP3L, together with decreased levels of TFEB, a master regulator of lysosomal biogenesis. One of the possible explanations is that these findings reflect impairment in the final stage of autophagy–lysosomal degradation. Further research is needed to clarify its pathophysiological importance in the AD cascade.
The diurnal variation of Alzheimer’s disease plasma biomarkers: a 25h study with hourly sampling
Authors: Brum Wagner S. , van Doorn William , Zimmer Eduardo R. , Zetterberg Henrik , Ashton Nicholas J. , Meex Steven JR , Blennow Kaj
Published: December 2023

Background

Novel plasma biomarkers can accurately reflect key pathological features of Alzheimer’s disease (AD). To ensure their safe clinical implementation in the near future, determining whether they present a diurnal rhythm is a key pending task in the field. This would help to elucidate whether the time of day in which blood samples are collected could influence blood biomarker results in clinical trials, research studies and clinical practice. Thus, we aimed to determine the diurnal rhythm of novel AD plasma biomarkers.

Method

In this study, we included n = 24 cognitively unimpaired older adults (median age [IQR]: 73 [64‐83] years). After overnight fasting and refraining from exhaustive physical activities for 2 days, volunteers were restricted to a standardized experimental environment from 8:30AM to 9:30AM on the following day (NCT02091427). Plasma‐EDTA samples were collected hourly (n = 26 time points), and we quantified biomarkers of tau pathology (p‐tau181), amyloid‐β (Aβ42, Aβ40, Aβ42/Aβ40), glial activation (glial fibrillary acidic protein, GFAP) and neurodegeneration (neurofilament light, NfL) with Simoa HD‐X instruments (UGOT assay: p‐tau181; Quanterix Neurology‐4‐Plex‐E for others). For visualization, biomarker concentrations were CV‐transformed, a standard procedure in which each measurement corresponds to the percent variation from each individual’s mean value over a day.

Result

Biomarkers generally demonstrated stable values during a day’s period (Figure 1). When evaluating CV‐transformed concentrations, the observed 5th and 95th quantiles of within‐individual variation over a day were: Aβ42, ‐18.4% to 15.4%; Aβ40, ‐13.7% to 14.4%; Aβ42/Aβ40, ‐9.4% to 8.7%; P‐tau181, ‐15.7% to 21.5%; GFAP, ‐24.0% to 26.8%; NfL, ‐16.2% to 19.9%. Plasma Aβ42 and Aβ40 increased during the day, reaching a peak during sleep (2:00AM), with a similar pattern but much smaller in magnitude for Aβ42/Aβ40 (Figure 2A‐C). P‐tau181 presented a peak in the morning, while GFAP and NfL also presented a peak during sleep (Figure 2D‐F).

Conclusion

Novel AD plasma biomarkers seem to present a diurnal rhythm. A night‐time biomarker peak, such as observed for plasma Aβ42 and Aβ40, could be explained by sleep‐related clearance of certain proteins from the brain. Nevertheless, the clinical impact of our findings will depend on the analyte of interest and clinical context of their application.