bluuebunny/crossref_metadata_2025 huggingface dataset:
Pesticides and cognitive impairment in older adults: evidence from southern Colombia
Authors: Bonilla‐Santos Jasmin , Gonzalez‐Hernandez Alfredis , Forero Eduardo A , Gomez Duvan , Cala Dorian , Parra‐Rodriguez Mario A
Published: December 2023

Background

Environmental exposure to specific chemical groups of pesticides (Carbamates, Organophosphates, Pyrethroids, and Organochlorines), as well as the non or inadequate use of personal protective equipment during pest management, have been associated to cognitive decline and increased risk of dementia (Hayden et al., 2010). This study investigated cognitive functioning in older adults exposed to pesticides in southern Colombia.

Methods

A sample of 353 older adults was recruited. Of these, 279 had not been exposed to pesticides (n‐Exp) and 74 had (Exp). They were matched according to age [n‐Ex: 63.80 (3.25), Ex: 63.30 (6.96), t = 0.618, p = 0.538] and years of education [n‐Ex: 9.29 (6.28), Ex: 8.95(6.35), t = 0.418, p = 0.676]. They were assessed with a battery of cognitive tests including CERAD (Aguirre‐Acevedo et al., 2016), The Addenbrooke’s Cognitive Examination (ACE‐R), the Free and Cued Selective Reminding Test (FCSRT) and questionnaires.

Results

FDR corrected comparisons revealed overall lower cognitive abilities in the Exp group (ACE‐R, q = 0.027). They also displayed Memory (FCSRT, q = 0.020; World List Learning q = 0.014) and Constructional Praxis (q = 0.007) impairments. Of those exposed, 73% reported no use of personal protective equipment, and neither the participants nor their family members reported concerns about cognitive decline [Self‐reported: n‐Exp: 14.27 (7.44), Exp: 14.92 (7.98), t = ‐0.654, p = 0.513; Family‐reported: n‐Exp: 10.43 (7.12), Exp: 10.26 (7.45), t = ‐0.182, p = 0.856].

Conclusion

Older adults from southern Colombia who have been exposed to pesticides show significant cognitive impairments, which have gone unnoticed by both the affected individuals and their family. Cognitive abilities found to be affected have been associated with risk of dementia caused by Alzheimer’s Disease or Parkinson’s Disease (FCSRT and Constructional Praxis). These types of dementia have been previously associated with this environmental risk factor (Chin‐Chan et al., 2015). More awareness about environmental factors and actions to mitigate their risk are urgently needed, and should be considered by future recommendations (e.g., Livingston et al., 2020).

Aguirre‐Acevedo et al. (2016). Int. Psychogeriatr, 28(3), 503‐510. https://doi.org/S1041610215001660.

Chin‐Chan et al. (2015). Frontiers in Cellular Neuroscience, 9. https://www.frontiersin.org/articles/10.3389/fncel.2015.00124

Hayden et al. (2010). Neurology, 74(19), 1524‐1530. https://doi.org/10.1212/WNL.0b013e3181dd4423

Livingston et al. (2020). Lancet, 396(10248), 413‐446. https://doi.org/10.1016/S0140‐6736(20)30367‐6
How to perform a general population‐based recruitment strategy for a multidomain intervention trial for dementia prevention—the CITA GO‐ON trial experience
Authors: Tainta Mikel , Ecay Mirian , Iriondo Ane , Barandiaran Myriam , Estanga Ainara , Altuna Miren , Clerigue Montserrat , de Arriba Maria , Lopez Carolina , Saldias Jon , Marta Cañada , Reparaz‐Escudero Imanol , Domper Jara , Mateo‐Abad Maider , Ros Naia , Garcia‐Sebastian Maite , Martinez‐Lage Pablo
Published: December 2023

Background

FINGER trial has demonstrated the potential for dementia prevention by targeting different lifestyle domains in older adults. It highlighted the importance of selecting the correct window of opportunity for preventive actions by including participants at high risk of dementia. This approach is being tested worldwide to support future public health interventions, where the selection of the appropriate target population is crucial. Here we share our approach and results in recruiting older adults with increased dementia risk and cognitive frailty from the general population for the CITA Go‐On trial.

Method

CITA GO‐ON is a single‐center randomized controlled trial in which non‐demented‐adults between 60‐80y will be allocated to receive standard care or a risk factor control and lifestyle‐based multidomain intervention. It replicates FINGER trial inclusion criteria, but the recruitment strategy is based on the community level in Gipuzkoa (Spain) instead of a previous health registry. Together with press and social media releases, mailing, and small group talks, the main recruitment strategy has been coordinated with local governments. Interested people fulfill an online form that allows identifying those who meet the pre‐established requirements (CAIDE dementia risk score ≥6) prior to attending an individualized face‐to‐face cognitive screening visit (evaluation of exclusion criteria and brief cognitive testing).

Result

By December 2022, we have reached and informed about the trial more 24000 people including all citizens older than 60 in three small municipalities in collaboration with the local town halls. Of these, 1919 completed the pre‐screening questionnaire using REDCap, 868 were screened and 450 recruited (mean age: 68,57 (6,58), 50,87% female, and mean CAIDE: 7,49 (1,39)). In person calculated (mean (sd): 6,98 (1,70)) and self‐reported (mean (sd): 7,23 (1,77)) CAIDE score is similar (p = 0,062) in our experience. Table 1 resumes age, sex, CAIDE and MMSE of the interested sample. Recruitment period is still opened.

Conclusion

CITA GO‐ON recruitment is a multi‐disciplinary population oriented efficient strategy to identify adults at high risk of dementia understanding and willing to participate in a multi‐modal intervention prevention trial. It allows to select candidates from the whole population, and not only those linked to specialized health care systems or registries.
Telomeres are associated with markers and regions sensitive to aging and not Alzheimer’s disease in cognitively unimpaired older adults
Authors: Lehodey Asrar , de Flores Robin , Palix Cassandre , Touron Edelweiss , Mézenge Florence , Landeau Brigitte , Chocat Anne , Kaliman Perla , la Sayette Vincent De , Vivien Denis , Chetelat Gael , Poisnel Géraldine , Group Medit‐Ageing Research
Published: December 2023

Background

Telomeres (protective chromosomal ends) gradually shorten over the lifespan and have been associated with the development of age‐related diseases such as Alzheimer’s disease (AD). Most studies use median telomere length as a biomarker of cellular aging, but their dysfunction is rather reflected by the load of short telomere. No study to date has assessed the links between the percentage of short telomeres (ST) and blood, neuroimaging markers of aging, neurodegeneration, amyloid and tau pathologies in healthy elderly.

Method

Baseline data from 125 cognitively unimpaired older adults (65 to 83 years old; mean ± SD: 68.9 ± 2.8) from the Age‐Well trial (NCT02977819), who completed multimodal neuroimaging and blood sampling, were analyzed. Neuroimaging data included structural T1‐weighted MRI, T2‐weighted high‐resolution scan of the hippocampus, DKI, FDG‐PET and AV45‐PET (perfusion and amyloid load). ST, as well as neurodegeneration, amyloid, and tau biomarkers (NFL, GFAP, Aβ42/40 ratio and pTau181) were measured in blood samples. Multiple linear regressions between ST and each marker were conducted corrected for age, sex, education and body mass index. Additional adjustments for APOE and amyloid status were made. Statistical significance was set to p<0.05, except for voxelwise analyses (puncorrected<0.005, kuncorrected = 500 voxels).

Result

ST was associated with lower white matter integrity (measured by kurtosis fractional anisotropy (kFA)) in prefrontal and temporal regions (Fig.1), and with the hippocampal subiculum volume, but not with total gray matter volume, mean kurtosis, glucose metabolism, brain perfusion or amyloid load; nor with blood markers of neurodegeneration, amyloid, or tau. Additional adjustments for APOE/amyloid status gave similar results.

Conclusion

Telomere dysfunctions were associated with lower white matter integrity in regions vulnerable to aging, but not to AD, nor with neurodegeneration, amyloid or tau biomarkers, and neither with AD risk factors (APOE or amyloid status). When we focused on the hippocampus, a specific link was found with the subiculum volume, an hippocampal subfield known to be the most sensitive to aging, which is not the case in AD. These results give further evidence for the tight connection between cellular and cerebral aging, but not with AD in cognitively unimpaired older adults.
Circulatory proteins relate cardiovascular disease to cognitive performance: a Mendelian randomisation study
Authors: Huang Jian , Gill Dipender , Zuber Verena , Matthews Paul M , Elliott Paul , Tzoulaki Ioanna , Dehghan Abbas
Published: December 2023

Background

Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. The objective of this study was to investigate the causal relationship between cardiovascular disease (CVD) related proteins and cognitive decline.

Method

We applied Mendelian randomisation (MR) and colocalization analysis to investigate the causal relationships of 90 CVD‐related proteins measured by the Olink CVD I panel with cognitive traits. Genetic instruments for circulatory protein concentrations were obtained from a genome‐wide association study (GWAS) meta‐analysis from the SCALLOP consortium (N = 17,747) based on three sets of criteria: 1) protein quantitative trait loci (pQTL); 2) cis‐pQTL (pQTL within ±500kb from the coding gene); and 3) brain‐specific cis‐expression QTL (cis‐eQTL) which accounts for coding gene expression based on GTEx8. Genetic associations of cognitive performance were obtained from GWAS for either: 1) general cognitive function constructed using Principal Component Analysis (N = 300,486); or, 2) g‐Factor constructed using genomic structural equation modelling (N = 11,263‐331,679). Findings for candidate causal proteins were replicated using a separate protein GWAS in Icelanders (N = 35,559).

Result

A higher concentration of genetically predicted circulatory myeloperoxidase (MPO) was nominally associated with better cognitive performance (P<0.05) using different selection criteria for genetic instruments. Particularly, brain‐specific cis‐eQTL predicted MPO, which accounts for protein coding gene expression in brain tissues, was associated with general cognitive function (βWald = 0.22, PWald = 2.4×10−4). The posterior probability for colocalization (PP.H4) of MPO pQTL with the g Factor was 0.58. Findings for MPO were replicated using a GWAS on cognitive score in an Icelandic population. Although we did not find evidence for colocalization, we found that higher genetically predicted concentrations of cathepsin D and CD40 were associated with better cognitive performance and higher genetically predicted concentration of CSF‐1 were associated with poorer cognitive performance.

Conclusion

The study suggests that proteins primarily identified for their role in cardiovascular diseases may be involved in shared pathways with cognitive reserve or cognitive decline, and may confer therapeutic targets for neurodegenerative diseases such as Alzheimer’s disease.
AD risk variants in APOE differentially affect lipid metabolism in iPSC derived neurons, astrocytes and microglia
Authors: Feringa Femke M , Elmagd Amir Abou , Kruijff Iris Daphne , Heijneman Jorin , Koppes Sascha , Mohammed Yassene , Giera Martin , van der Kant Rik
Published: December 2023

Background

Despite the clear function of APOE as a lipid carrier it is still unclear how Alzheimer’s disease (AD) risk variants of APOE affect the lipidome of individual human brain cell types. In addition, while APOE is crucial for transport of cholesterol from astrocytes to neurons, a role for APOE in lipid transport in the opposite direction from neurons to astrocytes has recently been suggested.

Method

To generate an atlas of the lipidome of the APOE genotype in a cell type specific manner, we performed lipidomic analysis on iPSC‐derived neurons, astrocytes and microglia with a different APOE genetic background. By co‐culture of these different cell types we studied the impact of APOE genotype on lipid transport between neurons and glia. We determined how the glial immune response and neuronal AD pathology are impacted by the changes in lipid transport.

Result

We find that APOE genotype affects the lipidome in all tested brain cell types. Also, we identify cell type specific metabolic adaptations to APOE genotype, emphasizing the need to study APOE biology in the context of individual cell types. In co‐culture we find that iPSC‐derived neurons can transport fatty acids and cholesterol to astrocytes as well as microglia. This neuron to glia lipid transport route is affected by the AD risk variant APOE4, which might impact immune responses in the glia.

Conclusion

AD risk variants in APOE differentially affect lipid metabolism in iPSC‐derived neurons, astrocytes and microglia and alter neuronal to glial lipid transport.
Development of a blood‐based biomarker signature for detection of cognitive impairment through a targeted metabolomics approach deciphering the association with depression
Authors: Chakraborty Manas , Dhiman Kunal , Gupta Veer
Published: December 2023

Background

A series of pathological episodes set off the development of cognitive impairment, which precede years before the onset of clinical symptoms. Disrupted glucose and fatty acid metabolism notably contributes to the development of cognitive impairment and further advancement to clinical dementia. Disrupted metabolism leads to the secretion of various inflammatory eicosanoids leading to neuroinflammation. Alteration of some specific metabolites in plasma are noted during these metabolic changes. Depression is a key risk factor of cognitive impairment, and similar changes in plasma metabolites have observed in the pathophysiology of depression. This aim of this project is to establish a blood‐based biomarker signature for early detection of cognitive impairment in individuals with depression through quantifying plasma levels of metabolites associated with glucose and fatty acid metabolism in plasma samples from the participants of the Sydney Memory and Ageing Study (MAS).

Method

Samples of 275 participants were randomly collected from baseline and 251 from an 8 year follow up study. At baseline there were 130 healthy participants, 93 participants with MCI, 36 participants with depression and 16 participants had both MCI and depression. Plasma samples were analysed to quantify the levels of fatty acids and carnitines using chemical derivatization – UPLC‐MRM/MS.

Result

Significant correlations were observed between the biomarkers like FA040 butyric acid (P: 0.034), FA224 (P: 0.032), acotinic acid (P:0.027) with MMSE. Biomarkers like C70carnitine (P:0.010), C90carnitine (P: 0.033), C150carnitine (P: 0.016), C160 carnitines (P: 0.004) significantly correlated with GDS scales. Linear regression showed significance between C90 carnitine (P: 0.021; β: 0.139) ad GDS scale. Whereas linear regression showed significant relationship between FA224 (P: 040, β: ‐.122), acotinic acid (P: 0.042, β: ‐.122), FA040 butyric acid (P: 0.036, β: ‐.193) with MMSE indicative of cognitive impairment.

Conclusion

The study will help to identify candidate metabolites of perturbed fatty acid metabolism and establish a plasma biomarker signature of early cognitive impairment, by deciphering the association with depression as a risk factor. An association will be established between central AD pathology and peripheral metabolic changes, and potential treatment options targeting the right biochemical pathways will be identified.
Co‐designing a research study with people affected by dementia: the conceptualisation and development of the ActivDem study
Authors: Ardle Ríona Mc , Barker Sandra , Dawson Annabel , Evans Cherry , Htay U Hlay , McKenzie Maisie , Ogden Margaret , Ongley Anne Ward , Pottage Mike , Rutter Ron , Simpson Leslie , Webb Karin , Din Silvia Del , Thomas Alan J , Robinson Louise , Rochester Lynn
Published: December 2023

Background

Maintaining physical activity(PA) following dementia diagnosis may decelerate decline to disability and dependency. It is unclear which socio‐ecological factors influence PA participation in people with dementia(PwD) and therefore may be effective interventional components for promotion of PA. To address this research gap, the ActivDem study was designed(see Table 1 for initial research aims). To ensure ActivDem met the needs of PwD, we aimed to co‐design the research aims, methodology and grant application with public patient involvement contributors.

Method

A call for contributors (i.e. people with cognitive impairment/dementia carers, current and former/dementia care professionals) was advertised via dementia research networks, dementia care facilities (e.g. daycares, memory cafés), charities (e.g. Alzheimer’s Society Research Network Volunteers) and social media. Interested contributors were invited to participate in either participatory workshops held on Zoom or a one‐to‐one phone call. Contributors were asked four broad questions(Table 2). Initial study aims and methods were discussed with contributors. Aims and methods were refined based on contributors’ feedback and themes raised during the discussion. Ten contributors reviewed the grant application to ensure aims, methodology and public patient involvement/engagement plans met the priorities of people affected by dementia.

Result

Thirty contributors participated in workshops/phonecalls. Contributors described experiences of PA decline in PwD post‐diagnosis; common themes expressed included loss of independence and confidence, increased feeling of burden, greater fall risk, frailty, and worse mental health. They identified potential facilitators/barriers for maintaining PA following dementia diagnosis(Table 2). They highlighted the role carers play in facilitating PA by supporting and motivating PwD to stay active and advocated for inclusion of carer‐focused investigations. Contributors felt that PA research for PwD should be prioritised and findings linked in to information/support services for carers. The study’s aims and methods were adapted to include an exploration of carers’ psychosocial wellbeing and care management strategies(Table 1). Scales relating to proposed facilitators/barriers of PA were identified, approved by contributors and implemented in the methods.

Conclusion

This work supported the conceptualisation and development of the ActivDem study. Ten contributors formed the ActivDem Public Patient Advisory Group, advising and supporting study management, data collection and interpretation, and dissemination of results.
Dementia risk reduction in the general practice: a proof‐of‐concept study evaluating the use of a brain health promotion smartphone app
Authors: Van Asbroeck Stephanie , Köhler Sebastian , Muris Jean W.M. , van Boxtel Martin P.J. , Deckers Kay
Published: December 2023

Background

During the last decades, evidence supporting the relevance of brain health promotion and dementia risk reduction has considerably expanded (1). Currently, this evidence is sufficient to take public health action (2, 3). However, implemented interventions are still scarce, especially at a large scale. In the Netherlands, evidence‐based cardiovascular risk management is already implemented in primary care. Since there is a large overlap between modifiable risk factors for dementia and those for cardiovascular disease, discussing dementia risk reduction next to cardiovascular health in the general practice seems a feasible, first step towards future large‐scale implementation of dementia risk reduction strategies.

Method

A proof‐of‐concept study is currently being conducted in ten general practices in the Netherlands in which 180 participants between 40 and 60 years old, with room for improvement on at least one modifiable risk factor, will have a consultation with their general practitioner or practice nurse. During this consultation, they will learn about brain health promotion and how they could personally improve their risk profile. Practices have been randomly allocated (1:1) to either provide the consultation only, or to additionally provide the participants with a brain health promotion smartphone app (i.e. MijnBreincoach).

Result

Feasibility will be evaluated using validated questionnaires assessing knowledge on dementia risk reduction, health behavior, motivation, usability, satisfaction, and user experience with the smartphone app. Surveys will be administered before the consultation at the general practice and three months thereafter. Further, ten participants and four healthcare professionals will be invited for a qualitative interview to get a more in‐depth view of the intervention’s feasibility.

Conclusion

Discussing dementia risk reduction in the general practice may constitute a feasible and effective, scalable approach towards dementia risk reduction. Results of the study are expected by July 2023.

References

1. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413‐46.

2. World Health Organization. Risk reduction of cognitive decline and dementia: WHO guidelines. Geneva; 2019.

3. Steyaert J, Deckers K, Smits C, et al. Putting primary prevention of dementia on everybody’s agenda. Aging Ment Health. 2020:1‐5.
Characteristics of AD‐brain tau aggregate internalisation by human astrocytes and the responses induced
Authors: Reid Matthew J , Perez‐Nievas Beatriz G. , Noble Wendy , Cao Pingting
Published: December 2023

Background

Highly phosphorylated tau aggregates are deposited in tauopathy brain as disease progresses, driven by a prion‐like spread of tau seeds. Evidence suggests that astrocytes may influence tau spread. However, the efficiency of uptake of disease‐associated tau species is not well defined, nor are the effects of tau uptake on astrocyte reactivity and function. We investigate human astrocyte ability to internalise and clear tau aggregates derived from multiple Alzheimer’s disease (AD) cases, and their impact on astrocyte function and reactivity. We further explore alterations in endogenous tau expression, APP processing and cytoskeletal proteins following tau uptake.

Method

Control human iPSC‐derived astrocytes were cultured for 70 days. Aggregated (sarkosyl‐insoluble) tau was isolated from postmortem AD brain. Post‐translational modifications (PTM) of isolated AD‐brain tau aggregates were analysed by mass spectrometry. Tau (0.1 ng/µL) and extracts from control human brain were spiked into astrocyte cultures. Internalisation of aggregated tau and the localised response of S100B and GFAP were quantified by ICC. Changes to tau, APP, functional and reactivity related genes were measured by qPCR and/or proteins by SDS‐PAGE.

Result

Aggregated tau from AD brain is readily internalised by human astrocytes, and sequesters GFAP and S100B. Differences in the rate of uptake, clearance and seeding of tau correlates with cytoskeletal protein accumulation and specific changes in astrocyte mRNA and protein levels. Work is in progress to relate these changes to characteristics of tau aggregates.

Conclusion

Our data shows that the capacity of AD brain aggregates to be internalised, cleared and induce seeding of endogenous tau varies by case. Investigations are underway to pinpoint the tau characteristics that underlie these differences. We also show that seeding ability is associated with changes in cytoskeletal elements and reactivity markers at mRNA and protein level. This work agrees with growing evidence that tau variability in AD is linked with specific cell type vulnerabilities that contribute to tau spread and disease progression.
Bilingualism in adult population without cognitive impairment: its relationship with aging in structural neuroimaging. A cross‐sectional study.
Authors: Estanga Ainara , Garcia‐Sebastian Maite , Altuna Miren , Ecay Mirian , Lopez Carolina , de Arriba Maria , Iriondo Ane , Tainta Mikel , Barandiaran Myriam , Marta Cañada , Clerigue Montserrat , Martinez‐Lage Pablo
Published: December 2023

Background

Aging is consistently associated with cortical gray matter (GM) reductions. Bilingualism has been described as a potential reserve contributor for successful brain aging and has been associated with a variety of structural changes in cortical morphology. In this study we aim to: 1) Explore differences between bilinguals and monolinguals on the whole brain cortical thickness, area and volume, 2) explore if correlations between age and cortical measures are different between bilinguals and monolinguals, and 3) to evaluate age‐bilingualism interaction effects on the cortical characteristics.

Method

Cross‐sectional study with healthy volunteers from the Gipuzkoa Alzheimer Project (GAP) cohort. Cognitively unimpaired (CDR Global Score = 0) with available 3T MRI were included and classified as bilinguals or monolinguals based on daily use of both Spanish and Basque languages or only Spanish. Subjects with diffuse white matter lesions (Fazekas scale = 3) were excluded. Cortical reconstruction was performed with Freesurfer package v5.1. as described in Montal et al., 2017. Analyses were conducted in the whole brain using linear modeling of the maps and Monte Carlo simulation corrected for multiple comparisons as implemented in FreeSurfer’s QDEC interface.

Result

Sample included 88 bilinguals and 83 monolinguals (see Table 1 for demographic and clinical characteristics). Whole brain cortical thickness, area or volume were not significantly different between groups. Age‐cortical thickness and volume correlation maps showed broader areas of negative associations in the monolingual than in the bilingual group, and inverse associations in the relationship with area characterized by negative correlations in monolinguals and positive and negative correlations in bilinguals (Figure 1). More specifically, significant age‐bilingualism interactions were found for thickness in the right superiorfrontal gyrus (p = 0.012), and for the surface area, in the inferiorparietal (p = 0.0001), supramarginal (p = 0.043) and lingual (p = 0.042) regions of the left hemisphere.

Conclusion

Cortical thickness and area variations occurring in relation to aging in cognitively healthy individuals could be modulated by bilingualism.
Towards implementing physical activity guidelines into clinical practice in persons with mild cognitive impairment
Authors: Bruderer‐Hofstetter Marina , Tomovic Sara , Ejiwoudt Emiel , Deininger Roland , Muenzer Thomas
Published: December 2023

The positive effects of physical activity and exercise on general health, well‐being, and physical and cognitive functioning in persons with mild cognitive impairment (MCI) are well documented and resulted in respective guidelines [1, 2]. To support the implementation of these guidelines into clinical practice, we developed and evaluated a training manual for physiotherapists and allied health professionals and an accompanying handout for independent training for persons with MCI.

The development process included a systematic literature search and patient and public involvement in design aspects. The training manual and handout were determined in four half‐day workshops with experienced physiotherapists. The goal was to describe specific exercises for every training dimension, i.e., endurance, strength, balance, and flexibility, including variations for progression and degression. For better comprehensibility, the handout was illustrated with pictures. Subsequently, both documents were evaluated in five geriatric clinics. The comprehensibility, acceptance, and usefulness of persons with MCI and physiotherapists’ perspectives were evaluated using structured questionnaires, including specific implementation outcomes.

Overall, both, the physiotherapists and persons with MCI found the manual useful and acceptable. However, the responses on comprehensibility indicated a need for optimization. Accordingly, we revised the training manual and handout, e.g., by simplifying the language or reducing the descriptive text. The revised documents are now freely available to physiotherapists and patients.

The training manual and accompanying handout may support the implementation of the physical activity recommendations into clinical practice and may be used in future research projects. In a subsequent project, we will implement the training manual and handout in a smartphone and tablet application to improve ease of customization and usability.

[1] Chong TWH, Curran E, Ellis KA, et al. Physical activity for older Australians with mild cognitive impairment or subjective cognitive decline ‐ A narrative review to support guideline development. J Sci Med Sport. 2020;23(10):913‐920.

[2] Izquierdo M, Merchant RA, Morley JE, et al. International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines. J Nutr Health Aging. 2021;25(7):824‐853.
Healthcare utilization prior to a diagnosis of young onset Alzheimer’s disease: A nationwide nested case‐control study
Authors: Damsgaard Line , Janbek Janet , Laursen Thomas Munk , Waldemar Gunhild , Jensen‐Dahm Christina
Published: December 2023

Background

Early symptoms of Alzheimer’s disease may be identified by altered healthcare utilization patterns in the years preceding the diagnosis. Timely diagnosis is especially important for patients with young onset Alzheimer’s Disease (YOAD), who are often in the prime of their career and whose families may be financially dependent on the patient. The aim of this study was to identify changes in healthcare utilization in the prodromal phase of YOAD, and to identify any specific types of healthcare contacts with a more pronounced association than others.

Method

We conducted a retrospective density‐matched nested case‐control study. Cases were identified using the nationwide Danish Quality Database for Dementia and included everyone diagnosed with YOAD in a Danish memory clinic during 2016‐2018. Due to the often long time‐lag between symptom onset and diagnosis, patients aged <70 years at diagnosis were included. Age‐ and sex‐matched controls were drawn from a nationwide cohort of all Danish citizens. Healthcare utilization during 10 years prior to the diagnosis was assessed in the nationwide healthcare registries. Contact rate ratios (CRR) were calculated using negative binomial regression analysis adjusted for highest attained educational level at age 40 and civil status.

Result

The study included 1082 YOAD patients and 3246 age‐ and sex‐matched controls. In the year preceding diagnosis, we found increased CRRs for all but one type of contacts (private practice medical specialists). CRRs for all types of contacts with a general practitioner were significantly increased also >1‐5 years and >5‐10 years prior to diagnosis. The highest CRR was for psychiatric emergency admissions (8.96, 95% CI 4.45‐18.05) ≤1 year prior to diagnosis. In a sensitivity analysis, we found that those with moderate/severe dementia at time of diagnosis generally had higher CRRs and showed vulnerability earlier than those with mild cognitive impairment/mild dementia at time of diagnosis.

Conclusion

Our results demonstrate that YOAD patients have an altered pattern of healthcare utilization from as much as 5‐10 years prior to the diagnosis. Awareness of the specific alterations in help seeking behavior may help healthcare professionals provide a timely diagnosis.
Receiving biomarker results is a Participant Right: why researchers should design studies with the option to learn
Authors: Walter Sarah , Taylor Angela , Tyrone Jamie , Wheaton Bonnie , Hummel Cynthia Huling , Pagan John‐Richard , Langer Sara , Gabler Sadie , Zallen Doris , Rosen Allyson C.
Published: December 2023

Background

Despite dramatic advances in the specificity and sensitivity of biomarkers for Alzheimer’s disease and related dementias (ADRD), most studies do not offer participants the option to learn their individual results. Participants and support partners view disclosure of biomarker results as a right that should be offered as part of study participation. The preferences of the participant should guide how disclosure occurs, as well as in the post‐disclosure counseling and follow‐up. With the goal of stimulating change, the Advisory Group on Risk Education for Dementia (AGREEDementia) Stakeholder Committee developed a Study Participant Bill of Rights for Disclosure of Individual Research Results. The committee includes people with a diagnosis, study participants, care partners, representatives of dementia advocacy organizations, and other stakeholders in dementia research.

Method

Three panelists will share lived experience with diagnosis, care, and research participation. Panelists will be identified by AGREEDementia and will broadly represent study participants: including individuals living with diagnosis, those at risk for dementia, care partners, and racial and ethnic groups under‐represented in research. Panelists will speak to the experience of learning their biomarker results, the personal value of those results, and share their recommendations for study design and conduct.

Result

This session will challenge ADRD researchers by offering the opportunity to understand lived experience of individuals that take part in research and their preferences in disclosure of biomarkers.

Conclusion

This Bill of Rights demonstrates the value of designing studies that are centered on the preferences of participants, towards the ultimate aim of inclusive ADRD research.
Impact of learning amyloid PET results on test‐related distress and concern about dementia in a cognitively unimpaired observational cohort
Authors: Clark Lindsay R. , Chin Nathaniel A. , Erickson Claire M , Johnson Sterling C , Basche Kristin E , Rosario Hannah , Ketchum Fred B
Published: December 2023

Background

As biomarker testing becomes more widely available, people will have opportunities to learn Alzheimer’s disease (AD) biomarker results. We developed an AD biomarker disclosure protocol to return amyloid PET results to participants interested in learning this risk‐related information. Our current objective was to evaluate the impact of returning biomarker results on longitudinal psychosocial outcomes.

Method

97 cognitively unimpaired older adults (mean age = 71.9 ± 4.8; 66% women; 29% amyloid+) were recruited from an observational cohort study. Participants completed questionnaires assessing concern about dementia, future time perspective, and cognitive complaints at baseline (pre‐disclosure) and after learning amyloid PET result (1‐ and 6‐months post‐disclosure). Participants completed measures of results‐related distress (Impact of Events Scale [IES]; Impact of Neuroimaging in AD [INI‐AD]) 1‐3 days after disclosure and then again at 1‐, 3‐, and 6‐months post‐disclosure. Linear mixed‐effects regression models were used to test for main effects of amyloid PET result and time (visit number), and an interaction of amyloid result x time on self‐reported outcomes.

Result

Participants who learned amyloid PET results were elevated or non‐elevated had similar demographic characteristics (Table 1). A significant interaction between amyloid result x time was observed for concern about dementia (β = 0.30, p = .02), whereas future time perspective and cognitive complaints did not vary by result or time in study (main effect and interaction p’s > .12; Table 2). Results‐related distress measures showed different patterns: A measure of intrusive thoughts and avoidance was initially high in elevated participants but decreased over time (IES; result x time interaction β = ‐0.83, p < .001), while a measure of psychosocial reactions to learning results was consistently high in elevated participants (INI‐AD; main effect of amyloid result β = 12.08, p < .001) (Figure 1).

Conclusion

Older cognitively healthy adults who learned elevated amyloid PET results reported increased concern about dementia and results‐related distress compared to those who learned non‐elevated results. Although intrusive thoughts/avoidance decreased over time in elevated participants, results‐related distress remained high. These indicate some increased psychosocial impacts, and possible need for post‐disclosures support, for those who learn elevated biomarker results.
Mastermind of the Alzheimer’s blood‐based biomarkers: development of cutoffs and a visualization tool for use in clinical practice
Authors: Verberk Inge M.W. , Kingma Maurice Y. , van Harten Argonde C. , den Braber Anouk , Vigneswaran Sinthujah , Gouda Mariam , van Engelen Marie‐Paule E. , Lemstra Afina W. , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Schut Martijn C. , Wilson David , Teunissen Charlotte E.
Published: December 2023

Background

Phosphorylated (P‐)tau, amyloid‐beta (Abeta)1‐42/1‐40, glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are the current key Alzheimer’s disease (AD) blood‐based biomarkers. Interpreting results of the four biomarkers simultaneously in a clinical context is challenging. A decision algorithm could aid in the interpretation, tailored to clinically relevant questions: 1) identify positive amyloid status among preclinical and prodromal AD stages, 2) discriminate AD‐dementia from frontotemporal dementia (FTD), 3) discriminate AD‐dementia from dementia with Lewy bodies (DLB). We aimed to develop such an interpretation tool.

Method

We included 1199 participants from the Amsterdam Dementia Cohort (table 1) with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD‐dementia, FTD (mixed pathologies) or DLB. Plasma P‐tau181, Abeta1‐42/1‐40, GFAP and NfL were measured with Simoa. NfL levels were adjusted for age (method: https://doi.org/10.1002/acn3.51676). We used LASSO regression with bootstrap (1000 iterations) to identify which plasma markers robustly contribute to the prediction of the outcomes of our clinically relevant questions. When a marker was selected in >95% of the iterations in at least one of the clinical scenarios, we qualified it as a contributing marker. Subsequently, we constructed UpSet plots applying Youden’s cutoffs as interpretation tool for the plasma results.

Result

P‐tau181, GFAP and NfL were selected as contributing biomarkers. Abeta1‐42/1‐40 was not selected. The panel of P‐tau181, GFAP and NfL had an AUC = 83% (95%CI: 76‐90%) to identify amyloid positivity in SCD+MCI, AUC = 87% (95%CI: 79‐94%) to differentiate AD‐dementia from FTD, and AUC = 73% (95%CI: 62‐84%) to differentiate AD‐dementia from DLB. The UpSet plots show the simultaneous interpretation of P‐tau181, GFAP and NfL results for each clinically relevant question (figure 1): e.g., when all three biomarkers are abnormal in participants with SCD+MCI, there is 83% agreement with an abnormal PET or CSF amyloid status, and when all three plasma markers are normal, there is 88% agreement with a normal amyloid status.

Conclusion

The combination of P‐tau181, GFAP and NfL in plasma could support decision making in different clinical contexts. UpSet plots enable easy interpretation of a combination of the markers, and could serve as a tool to support both detection and differential diagnosis of Alzheimer’s disease.
Soliciting Participant Program Guidance through the Development of An ADRC Participant Advisory Council
Authors: Nuttkinson Bonnie L. , SmithBA Tracy , Chin Erin , Lacey Erin , Blazel Hanna M. , Walaszek Art , Edwards Dorothy F.
Published: December 2023

Background

Studies show that including participants and community members as partnering stakeholders in research contributes to identification of pertinent research questions that might elude investigators; help recruitment, retention, and research protocols; improves the efficacy of health promotion interventions and can enhance dissemination of study results. Participant advisory boards are particularly important for clinical trials and other longitudinal research programs that want to ensure effective enrollment and retention. Participant voices and perspectives are exceedingly useful for refining protocol design, consent form design, technology solutions, and communication materials. Despite these advantages, the majority of ADRCs rely on community advisory boards rather than participant advisory boards for stakeholder input. The Wisconsin Alzheimer’s Disease Research Center (WADRC) created a Participant Advisory Council (PAC) to solicit input on design of recruitment and retention programs, refine research questions and provide input on participant experiences. The outreach and recruitment cores selected two facilitators. PAC facilitators completed an intensive 10‐day training program focused on creating an inclusive environment, encouraging multiple perspectives and full participation from members.

Method

WADRC staff identified 10 individuals enrolled in its Clinical Core to participant, eight of which volunteered. The PAC has 7 participants representing the MCI, control and IMPACT cohorts, and 1 study partner. The group is diverse with representation from 4 URG members, 1 veteran, 2 from rural communities; 7 have consented to be brain donors and 5 have completed lumbar punctures. PAC members receive a $50 honorarium each meeting and travel expenses for those living further away.

Results

The inaugural meeting took place in April 2022 where members learned about the development of the PAC, organization and goals of the WADRC. The PAC meets bi‐monthly. Meetings are hybrid, with periodic in‐person meetings. Faculty and staff learn and benefit from the feedback provided by participants on a variety of topics. To date, the PAC has discussed education programing, how to communicate such programming, and ways to increase retention. The PAC will review and comment on WADRC and ORE Core specific aims in preparation for the upcoming grant renewal.

Conclusion

Meaningful engagement of participants is essential for long‐term retention and ongoing improvement of WADRC recruitment and retention.
CSF Proteomic Signatures are Associated With Cognitive Decline in the Alzheimer’s Disease Continuum
Authors: Vromen Ellen M. , van Harten Argonde C. , Berven Frode , Teunissen Charlotte E. , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Visser Pieter Jelle , Tijms Betty M.
Published: December 2023

Background

Individuals with Alzheimer’s disease (AD) show variability in cognitive decline. Little is known about the underlying biological processes. Using an untargeted CSF proteomics approach, we explored the biological processes associated with cognitive decline throughout the AD continuum.

Method

We included 280 AD individuals from the Amsterdam Dementia Cohort (median age 66 (IQR:60‐70) years, 124 (44%) female, n = 34 preclinical AD, n = 77 MCI due to AD, n = 169 AD‐dementia, all abnormal CSF amyloid, Table 1). The CSF proteome was quantified at baseline using LC‐MS/MS in an untargeted manner based on TMT labelingWe included n = 2318 proteins measured in ≥50% individuals. We used the MMSE score as a proxy for global cognition, and created summary scores for cognitive domains (i.e., episodic memory, executive functioning, attention and language) using neuropsychological test scores. We applied linear mixed models to test the association between each protein and cognitive decline over time, with age, sex and education as covariates, a random intercept for patient ID, and a random slope for time; stratified for syndrome diagnosis. We performed pathway enrichment analysis on proteins associated with cognitive decline.

Result

Individuals with preclinical AD showed most decline on episodic memory compared to other domains. In preclinical AD, 150 proteins, enriched for cell death and cell adhesion, were associated with memory decline. Individuals with MCI showed most decline on episodic memory and executive functioning. Proteins associated with decline on memory (n = 188, Figure 1) and executive functioning (n = 213) were enriched for complement and coagulation cascade and innate immune processes. Proteins associated with memory decline were also enriched for synaptic plasticity. Individuals with AD‐dementia showed more decline on attention and language compared to other AD‐stages. In AD‐dementia, 69 proteins, enriched for innate immune processes, were associated with decline on the MMSE and 127 proteins, enriched for synaptic plasticity, were associated with decline on language.

Conclusion

Proteins involved in innate immune processes, synaptic plasticity and cell death were associated with cognitive decline in AD, with different processes involved in different stages. These results provide insight into the pathophysiology of cognitive decline and hint towards potential therapeutic targets for prevention of cognitive decline in AD.
Late, but not too late, is better than never: late‐life literacy is not associated with lower prevalence of dementia and cognitive impairment no dementia
Authors: Bertola Laiss , Suemoto Claudia Kimie , Ferri Cleusa P
Published: December 2023

Background

Education is a major modifiable risk factor for dementia and is usually considered an early‐life intervention. However, low‐ and middle‐income countries usually have high rates of illiteracy among older adults, and some became literate after childhood. Therefore, we aimed to investigate whether there were any associations between the age of literacy with the prevalence of cognitive impairment no dementia (CIND) and dementia, compared to illiteracy, regardless of the educational attainment.

Method

We used baseline data from the Brazilian Longitudinal Study of Aging (ELSI‐Brazil), a population‐based nationally representative cohort of people aged 50 years or older, and the first Health and Retirement Studies (HRS) partner study in South America. For this study, we restricted our analysis to those aged 60 years or older, who had been classified as cognitively normal, CIND, or dementia. Participants were stratified into five groups: four according to their age when started schooling (early‐life literacy (EL) (<11 years), adolescent literacy (AdL) (11‐19 years), adulthood literacy (AhL) (20‐59 years) and late‐life literacy (LL) (≥60 years)) and illiteracy (IL). CIND and dementia classification prevalence ratios (PR) according to literacy status were assessed using Poisson regression, and adjusted for sociodemographic (age, sex/gender, educational attainment, race/ethnicity) and clinical confounders (memory complain, depressive symptoms, heavy drinking, smoking status, hypertension, and diabetes).

Result

Our final sample comprised 5,244 older adults (mean age 70.1±7.8 years, mean education 4.6±4.4 years, 60% female, 55% Black/Brown, 6% with dementia and 8% with CIND) (Table 1). Fifteen percent of the sample started their literacy after childhood, and 21% remained illiterate. EL and (PR = 0.22, 95%CI = 0.09;0.53) and AdL (PR = 0.42, 95%CI = 0.18;0.98) groups had lower dementia prevalence compared to IL group (Table 2). However, there was no prevalence difference between IL and those who started literacy after adolescence.

Conclusion

We found a lower prevalence of dementia among participants with early‐life and adolescent literacy compared to illiteracy. Adulthood and late‐life literacy were not associated with lower dementia prevalence. Literacy after childhood might have same beneficial impact if it is not started too later in life. Further studies should be conducted to better understand the impact of late‐life literacy interventions on reducing dementia risk.