bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of a binding site on the SORLA‐retromer complex that augments endosomal recycling: Implications for a novel class of AD drugs
Authors: Merchant Kalpana M. , Andersen Olav M. , Lefker Bruce , Withka Jane , Small Scott A. , Petsko Gregory A. , Klein Joel , Armstrong Rob
Published: January 2025

Background

Genetic studies have established that loss of function SORL1 gene variants are associated with Alzheimer’s disease (AD). SORL1 encodes an endosomal trafficking receptor, SORLA, which regulates endosomal protein recycling through its interaction with the retromer core complex (consisting of VPS26, VPS35 and VPS29). Deficits in the levels and function of the SORLA‐retromer complex are thought to underlie AD. We set out to identify and validate potential small molecule binding sites on the SORLA‐retromer complex that may restore endosomal recycling and lead to disease‐modifying therapies for AD.

Method

We engineered HEK293 stable cell lines expressing a SORL1 reporter construct to monitor shedding and production of soluble SORLA (sSORLA), as indicators of endosomal recycling activity. In parallel, we synthesized cell‐permeant derivatives (R8 and TAT‐conjugations) of a retromer stabilizing cyclic peptide, RT‐L4 (Chen et al., Sci Adv, 2021), and its analogs, M10 and M7, that bind to the VPS26‐VPS35 interface in vitro at range of potencies. These peptides and several controls were tested for their ability to augment the shedding of SORLA in the cell media. Cell viability was assessed using CellTiter‐Glo and DRAQ7 staining.

Result

Using a Homogenous Time‐Resolved Fluorescence (HTRF) binding assay, we confirmed that the cell‐permeant derivatives of RT‐L4, M10 and M7 bind to the retromer heterotrimer at affinities similar to the parent cyclic peptides. Treatment of HEK293 cells with cell‐permeant derivatives of these peptides, but not unmodified peptides and controls, increased sSORLA levels in the media at potencies that correlated with their binding affinity for the VPS26‐VPS35 interface. These effects were seen at concentrations that did not produce significant cell toxicity monitored by two different methods.

Conclusion

These data validate the VPS26‐VPS35 interface as a target for small molecules to enhance SORLA‐retromer‐mediated recycling. The results provided a compelling rationale to conduct a high throughput screen to discover and develop a novel class of AD drugs.
Investigating the relationships between cognitive impairment score, cerebrospinal fluid measures and dementia diagnosis
Authors: Ilchovska Zlatomira Georgieva , Jung JeYoung , Mukaetova‐Ladinska Elizabeta , Hosseini Akram A.
Published: January 2025

Background

Cerebrospinal fluid (CSF) dementia markers are sensitive to cognitive decline, particularly memory (Hosseini et al, 2023).

Methods

We performed preliminary analyses on a neurodegenerative and non‐neurodegenerative patient dataset, collected as part of the CogNID study (IRAS reference: 250525, clinical trial reference: NCT03861884). We explore two questions, the first of which regards whether cognitive profile measured by the Addenbrooke’s cognitive examination (ACE‐R III) can predict diagnosis category, clustered into three groups: 1) Alzheimer’s Disease (AD; N=50), 2) non‐AD dementia conditions (e.g., frontotemporal dementia, Vascular Cognitive Impairment, Parkinson’s disease; N=46), and 3) a mixed, non‐dementia group serving as “control” (e.g., subjective cognitive impairment, post‐Covid‐19 brain fog; N=64). The second question asked whether, for a smaller subset of our participants with CSF dementia measures, there is any correlation between CSF dementia biomarkers and cognitive impairment. We explored these using regression analysis and Pearson’s correlation tests.

Results

For our total sample with recorded ACE‐R III scores (N=160, Mage=59.3, SDage=6.4), participants’ memory (t=‐2.31, p=.02) and language (t=2.16, p =.03) scores predicted their diagnosis category. Post‐hoc split‐data regression analyses revealed only a significantly lower memory score for the AD group compared to control group (t=‐2.482, p=.015). None of the other comparisons showed a significant difference after multiple‐comparisons corrections. For our second question, we selected a subsample of our data with recorded CSF measures (N=56). We assessed the CSF measures of total 181‐Tau, phospho‐Tau and Amyloidß1‐42 in these participants in relation to their memory, attention and visuospatial, obtained from the ACE‐R III scores. We found a significant negative correlation between 181‐phospho‐Tau (but not total Tau) and memory scores (r=‐.37, p=.005), indicating that higher 181‐phospho‐Tau measures were significantly associated with impaired memory performance.

Conclusions

The preliminary analysis is limited by the high diversity of our neurodegenerative non‐AD group. A more detailed exploration of memory is crucial during diagnostic assessments of suspected AD.

Disclosure and funding: AAH is funded by the UK Medical Research Council (MR/T005580/1).

Reference: https://alz‐journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.054530
Physical frailty and brain health: a prospective cohort study
Authors: Gao Pei‐Yang , Tan Lan , Yu Jin‐Tai
Published: January 2025

Background

Physical frailty is characterized as functional degeneration across multiple systems, which has been proposed as a risk factor for various health outcomes. However, the correlation between physical frailty and brain health, including brain function, brain disorders, and brain structure, remains unclear.

Method

Here, 316905 participants from the UK Biobank were included in this prospective longitudinal study. Physical frailty was assessed by five phenotypes, including exhaustion, low grip strength, low physical activity, weight loss, and slow walking speed. Linear regression model and cross‐lagged panel model were firstly applied to evaluate the cross‐sectional and longitudinal relationship of physical frailty with brain function, including mental health and cognitive function. Cox proportional hazard model and Mendelian randomization analyses were further conducted to examine the longitudinal association and causal relationship between physical frailty and eight brain disorders. Finally, the cross‐sectional correlation between physical frailty and brain cortical and subcortical regions were assessed using linear regression model.

Result

Over a median of 14.47 years follow‐up, 5943 (1.88%) new‐onset dementia were assessed. After adjusted covariates, a significant cross‐sectional and longitudinal relationship of physical frailty and five phenotypes with mental unhealth (four depression scales, life satisfaction, general mental status, and traumatic events) and worse cognition (reaction time, numeric memory, and fluid intelligence). Cox model and MR analyses revealed significant associations of physical frailty and five phenotypes with risk of incident dementia, Parkinson’s disease, stroke, sleep disorders, anxiety, major depressive disorder, and schizophrenia. Moreover, neuroimaging analyses emphasized the correlation of physical frailty with the cortical frontal cortex and subcortical regions including the thalamus, lateral ventricle, and hippocampus.

Conclusion

This study provides evidence from multiple perspectives suggesting that physical frailty intervenes brain health and presents a strategy that early modification of physical frailty states may benefit the prevention of brain health.
Therapeutic potential of beta‐carotene on intracisternal injection of glucose oxidase‐induced senile dementia in diabetic rats
Authors: Muthuraman Arunachalam , Lim Khian Giap
Published: January 2025

Background

Senile dementia (SD) is a deteriorative organic brain disorder and it comprises Alzheimer’s disease (AD) as a major variant. SD is shown impairment of mental capacities whereas AD is degeneration of neurons. According to World Health Organization (WHO) report; more than 55 million peoples have dementia and it is raising 10 million new cases every year. Further, it is expected to rise to 78 million in 2030 and triple by 2050. The glucose oxidase (E.C. 1.1.3.4; GOD) is an oxidoreductase enzyme and it oxidizes the β‐d‐glucose to d‐glucono‐δ‐lactone and hydrogen peroxide (H2O2). In the neuronal system, GOD & H2O2 cause rapid fluctuations of glucose levels, insulin resistance, oxidative stress along with microglial activation and neurodegenerations. Besides, only a few medications were approved for the symptomatic relief of SD i.e., donepezil, galantamine, rivastigmine, and memantine. Moreover, the most efficient and potential agents are not discovered yet. Hence, the present study was designed to investigate the beta‐carotene (BC) actions against the GOD‐associated SD in diabetic rats.

Method

Male Sprague Dawley rats were used for the induction of diabetes by intraperitoneal injection of nicotinamide (50 mg/kg and streptozotocin 50 mg/kg), and SD was induced by intracisternal administration of GOD (50 U/5 µl at 1 µL/minute). The BC (50 and 100 mg/kg; p.o.) and donepezil (1 mg/kg; p.o.) were administered for 15 consecutive days. The cognitive function was assessed by the Morris water maze test and biomarkers i.e., blood glucose & insulin; serum nitric oxide (NO); tissue acetylcholinesterase (AChE), galectin‐1 (G1), NADPH oxidase (NOX4) activity & glucose transporter 1 (GLUT1) levels were evaluated.

Result

GOD potentially changes the neurovascular unit in the brain which leads to a rise the insulin resistance (IR), NO, G1, & GLUT1 levels; and decreases the NOX4 activity. The GOD causes the potential cognitive dysfunctions. However, the treatment of BC attenuated the GOD‐associated cognitive dysfunction and biomarker changes.

Conclusion

The present results revealed that BC possesses the ameliorative potential against GOD‐induced neurotoxicity and SD due to its anti‐oxidative, anti‐cholinesterase, reduction of IR, prevention of microglial activation, and enhancement of the glucose update actions.
Aryloxypropanolamine mitigates Alzheimer‐like phenotype by directly removing amyloid aggregates
Authors: Yoon Soljee , Lee Hee Yang , Cho Illhwan , Lee Donghee , Shin Jisu , Kim Kyeonghwan , Kim Jimin , Kim Hye Yun , Kim Ikyon , Kim YoungSoo
Published: January 2025

Background

The accumulation of amyloidogenic proteins is recognized as a primary biomarker, initiator of pathology, and a potential therapeutic target for Alzheimer’s disease (AD). An unbiased screening of a small molecule library was conducted to identify new chemical compounds exhibiting amyloid‐dissociative properties.

Method

The ability of aryloxypropanolamine derivatives to dissociate amyloid‐β (Aβ) aggregates was evaluated through in vitro assays. Subsequent assessments involved immunostaining, immunoblotting, and Morris water maze to examine the anti‐Alzheimer properties of the molecules using 5XFAD and transgenic APP/PS1 mice. Characterization of the target‐ligand interaction was also carried out through peptide mapping assay and constrained docking simulations.

Result

Among 11 derivatives, YIAD002 demonstrated the most significant dissociative effect against β‐sheet‐rich Aβ aggregates. Oral administration of the compound led to a significant reduction in amyloid burden, improved cognitive performance in the Morris water maze, and mitigated key clinical symptoms of AD, including tauopathy, neuroinflammation, and synaptic protein loss. Mechanistic studies indicated that YIAD002 directly interacted with the KLVFFA and IGLMVG domains of Aβ.

Conclusion

Collectively, our results demonstrate the potential of chemical‐driven dissociation of amyloidogenic proteins as a promising disease‐modifying treatment for AD.
Effect of increasing cognitive activity participation on functional connectivities within default mode network– a randomized controlled trial
Authors: Lee Allen TC
Published: January 2025

Background

We previously reported that increasing participation in Chinese calligraphy handwriting, one of the “Four Arts” traditionally mastered by intellectuals in China and currently widely practiced by older adults in the Chinese community, led to better working memory among individuals with subjective cognitive decline (but without mild or major neurocognitive disorder). Given that the default mode network (DMN) is closely correlated with the clinical symptoms and progression of Alzheimer’s disease, we aimed to investigate the effect of increasing calligraphy practice on the DMN.

Method

Community‐living older adults who had been practicing Chinese calligraphy handwriting regularly (at least one hour of calligraphy practice per week) and experiencing subjective cognitive decline (but without mild or major neurocognitive disorder) were randomly allocated into either the control group, where they continued their usual practice of calligraphy, or the intervention group, where they doubled their amount of practice for 6 months. Functional connectivities within DMN were assessed before and after the intervention. This randomized controlled trial was funded by the Research Grants Council in Hong Kong (grant number: 24114519), registered with the Chinese Clinical Trial Registry (ChiCTR1900024433), and approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong (CREC Ref. No.: 2019.054).

Results

By the end of 6 months, nearly all the functional connectivities that we examined within the DMN weakened in the control group, whereas those in the intervention group either strengthened or showed a lesser degree of weakening. Statistical significance was reached in the between‐group differences of the functional connectivities between medial prefrontal cortex and right lateral temporal cortex, medial prefrontal cortex and right inferior parietal lobe, left hippocampal formation and right lateral temporal cortex, and left hippocampal formation and right inferior parietal lobe.

Conclusion

Increasing cognitive activity participation may have a positive neuromodulatory effect on functional brain network in older adults who are not yet having mild or major neurocognitive disorders. Our findings highlight the importance of staying cognitively active in late life for better brain health.
Peruvian healthcare system readiness for dementia: First insights from an ongoing research study
Authors: Serruto Francisco Tateishi , Porras Maria Lazo , Hawkins Jemma , Cuba María Sofía , Butler Christopher , Bernabe Antonio , Moore Graham , Landeiro Filipa , Cardenas Maria Kathia , Canseco Francisco Diez , Flores Miriam Lucar , Quinoso Silvana Perez León
Published: January 2025

Background

Peru does not have official prevalence data of dementia, however, particular studies indicate that in urban areas 6.85% of the population over 65 years of age has it. Countries such as Peru have significant drivers of the condition such as low socio‐economic (monetary poverty 27.5%) and educational levels (21.9% of the population has only primary education). In order to prepare the health system and society in general, it is necessary to start multisectoral studies to understand the complexity of the challenge ahead. The IMPACT project aims to contribute to this.

Method

Mixed methods approach. Semi‐structured interviews with different stakeholders as well as secondary data review to cover 11 themes from the health system (policy environment, financing, infrastructure, service delivery in prevention and management issues, etc.) in three levels (macro, meso and micro) nnd in four different areas of Peru

Result

The presentation still does not show results, as it is still ongoing. However, we are sharing some of the insights and learnings we have gained so far. Some of these are the following: limited and heterogeneous response due to the highly fragmented system, lack of political support, first level of care not designed or prepared to deal with dementia cases, reduced amount of specialists, adequate training for health providers attending this group, no guidelines for medical practices and limited research about its characteristics and needs. Also, age stereotypes and lack of awareness about dementia as a medical condition persist in all levels of the health system and society, negatively affecting the effectiveness of its response to their needs

Conclusion

These are some preliminary Conclusions: more research is needed, to address stereotypes, increase training for health providers, use technology to facilitate access to services, create models of effective implementation to generate impact on urgent issues and inclusion of preventive and long‐term care approaches
ApoE4 antibody ameliorates cognitive impairments and synapse loss in ApoE4/Tau‐P301S mice
Authors: Song Ha‐Lim , Kim Min‐Seok , Cho Mi‐Hyang , Mun Yeon‐Seon , Kim Na‐Young , Shin Jung‐Su , Kim Jun‐Sub , Kim Dong‐Hou , Yoon Seung‐Yong
Published: January 2025

Background

The Apolipoprotein E4 isoform (ApoE4), encoded by the APOE gene, stands out as the most influential genetic factor in late‐onset Alzheimer’s disease (LOAD). The ApoE4 isoform contributes to metabolic and neuropathological abnormalities during brain aging, with a strong correlation observed in APOE4‐positive Alzheimer’s disease cases between phosphorylated tau burden and amyloid deposition. Despite compelling evidence of APOE‐mediated neuroinflammation influencing the progression of tau‐mediated neurodegeneration, the molecular mechanisms underlying these phenomena remain largely unknown.

Method

Utilizing Tau‐P301S mice crossed to APOE4‐knockin mice expressing human APOE4 (TauP301S/APOE4), the investigation tested the impact of anti‐mouse ApoE4 antibody, ADEL‐Y04, on memory enhancement and tau pathology reduction.

Result

We developed ADEL‐Y04, an anti‐mouse ApoE4 antibody specifically recognizing human ApoE4. Administration of ADEL‐Y04 in TauP301S/APOE4 mice demonstrated improvements in memory impairment. Synapse loss and pathological tau accumulation was also inhibited by ADEL‐Y04 administration.

Conclusion

Our findings suggest the potential for improving APOE4‐mediated tau pathology and memory impairment through the modulation of ApoE4. This provides avenues for intervention, indicating the possibility of ameliorating tau pathology and memory deficits by targeting APOE4.
Traumatic brain injury and cognitive resilience in the Framingham Heart Study
Authors: Hwang Phillip H , Durape Shruti , Price Eden , Gurnani Ashita S. , Ang Ting Fang Alvin , Devine Sherral A. , Choi Seo‐Eun , Lee Michael L. , Scollard Phoebe , Gibbons Laura E. , Mukherjee Shubhabrata , Trittschuh Emily H. , Sherva Richard , Dumitrescu Logan C. , Hohman Timothy J. , Saykin Andrew J. , Crane Paul K. , Tripodis Yorghos , Alosco Michael L. , Katz Douglas I , Dams‐O'Connor Kristen , Au Rhoda , Farrer Lindsay A. , Mez Jesse
Published: January 2025

Background

Some evidence supports an association between traumatic brain injury (TBI) and greater risk of dementia, but the role of cognitive resilience in this association is poorly understood.

Method

2,050 participants from the Framingham Heart Study Offspring cohort who were aged ≥60 year and had a plasma total tau (t‐tau) measure at Exam 8 (2005‐2008), and a neuropsychological (NP) exam visit within five years were included. Plasma t‐tau was measured using the Simoa assay (Quanterix). NP factor scores were previously derived for memory, language, and executive function using confirmatory factor analysis. Information on TBIs was collected by comprehensive review of medical records, health history updates, exams, and self‐report. TBI occurrence and severity were operationalized using modified ACRM & VA/DoD criteria, respectively. Cognitive resilience was operationalized using a residual approach by regressing each NP factor score on the plasma t‐tau measure, adjusting for age at Exam 8, sex, education, time from blood draw, and APOE ε4 genotype. The adjusted residuals were then regressed on history of TBI (yes versus no), and severity of TBI (moderate‐to‐severe versus mild versus none).

Result

The sample was, on average, 67 years of age at Exam 8, 54% female, and college educated. No differences were observed in plasma t‐tau levels between those with and without TBI. Having a history of TBI was significantly associated with a reduction in resilience in executive function (β: ‐0.110; 95% CI: ‐0.175, ‐0.044; p: 0.001) as compared to not having a history of TBI. No significant associations were observed between history of TBI and resilience in memory or language. Greater TBI severity was significantly associated with worse resilience in executive function in a dose‐response manner (Ptrend: <0.001), with the association being strongest in the moderate‐to‐severe TBI group (β: ‐0.209; 95% CI: ‐0.340, ‐0.078; p: 0.002) followed by the mild TBI group (β: ‐0.082; 95% CI: ‐0.155, ‐0.010; p: 0.026).

Conclusion

Having a TBI was associated with worse resilience to neurodegeneration in executive function, and most strongly among individuals with moderate‐to‐severe TBI. These results suggest that having a TBI may increase vulnerability to late‐life executive dysfunction after accounting for a primary neurodegenerative disease process.
A Prospective Study of Long‐Term Red Meat Intake, Risk of Dementia, and Cognitive Function in US Adults
Authors: Li Yuhan , Li Yanping , Gu Xiao , Liu Yuxi , Dong Danyue , Kang Jae H. , Wang Molin , Eliassen Heather , Willett Walter C. , Stampfer Meir J. , Wang Dong D.
Published: January 2025

Background

Previous studies yielded inconsistent results regarding the association between red meat intake and cognitive health. We aimed to prospectively examine the associations between processed and unprocessed red meat intakes and various cognitive outcomes.

Method

We assessed diet intake every 2‐4 years using food‐frequency questionnaires and ascertained incident dementia cases through self‐report and death records in 87,424 participants free from Parkinson’s disease or baseline dementia, stroke, cancer from the Nurses' Health Study (NHS). In a subset of 17,458 NHS participants, cognitive function was assessed using the Telephone Interview for Cognitive Status (1995‐2008). We longitudinally collected information on subjective cognitive decline from 33,908 NHS participants and 10,058 participants in the Health Professionals Follow‐Up Study.

Result

During a follow‐up of 38 years (1980‐2018) in the NHS, we documented 6,856 dementia cases. Participants with processed red meat intake ≥ 0.25 serving/day, as compared to < 0.10 serving/day, had 15% higher risk of dementia (HR = 1.15; 95% CI: 1.08‐1.23; P
linearity <0.001). We found significant associations between higher processed red meat intake and accelerated aging in global cognition [1.61 years per 1 serving/day increment (95% CI: 0.20, 3.03)] and verbal memory [1.69 years per 1 serving/day increment (95% CI: 0.13, 3.25), both P
linearity = 0.03]. Participants with processed red meat intake ≥ 0.25 serving/day had a 14% higher likelihood of subjective cognitive decline compared to those with intake < 0.10 serving/day (OR = 1.14; 95% CI: 1.04–1.24; P
linearity = 0.004), while unprocessed red meat intake of ≥ 1.00 serving/day compared to < 0.50 serving/day was associated with a 16% higher likelihood of subjective cognitive decline (OR = 1.16; 95% CI: 1.04–1.30; P
linearity = 0.02). In substitution analyses, replacing 1 serving/day of processed red meat with 1 serving/day of nuts and legumes was associated with a 23% lower risk of dementia (HR = 0.77, 95% CI: 0.69–0.86), 1.37 fewer years of cognitive aging (95% CI: ‐2.49—0.25), and a 20% lower odds of subjective cognitive decline (OR = 0.80, 95% CI: 0.69–0.92).

Conclusion

Higher intake of red meat, particularly processed red meat, is associated with a higher risk of developing dementia and worse cognition.
Models for Predicting Dementia Risk in Low‐ and Middle‐Income Countries
Authors: Alshahrani Maha , Stephan Blossom CM , Siervo Mario , Sabatini Serena , Tang Eugene Yee Hing , Brain Jacob , Naheed Aliya , Pakpahan Eduwin , Robinson Louise , Mohan Devi
Published: January 2025

Background

Most people with dementia reside in low‐ and middle‐income countries (LMICs) where resources, research, services, and support are often very limited. Research into dementia risk prediction is scarce in LMIC settings, and those prediction models developed in high‐income countries generally do not transport well to LMICs. This suggesting a dire need for LMIC specific dementia risk models.

Method

We synthesised the evidence from our three previous systematic reviews (covering all literature from inception to 2023 from PubMed, Embase, and PsychInfo) on dementia risk prediction modelling. The aim was to identify models that have been specifically developed and tested specifically in LMICs. There were no language or time restrictions applied.

Result

To date, over 50 different dementia risk prediction models have been developed and tested with only 7 models reported from two LMICs including five studies from China and two studies from Mexico. The models incorporated variables typically linked to dementia including demographics (e.g., age, sex, education), health (e.g., diabetes, hypertension, heart disease) and lifestyle (e.g., smoking and alcohol) variables. The 7 models also have varying degrees of predictive accuracy (c‐statistic range 0.65 [95%CI: 0.64–0.67] to 0.92 [95%CI: 0.88‐0.95]) and none has undergone external validation. These models have been developed using traditional statistical approaches including Cox and Logistic Regression. Further, model development has not considered factors such as socioeconomic status, literacy, access to healthcare, diet, stress, pollution, and workplace hazards that may be crucial in predicting dementia risk in LMICs.

Conclusion

There is an urgent need to create context‐specific dementia prediction models to inform the development of risk reduction and preventative interventions in LMICs where dementia case numbers are greatest. Dementia risk model development and testing need to be extended to LMICs across different regions (e.g., Asia, Middle East, Global South, Africa) and income levels (e.g., low, lower‐middle, and upper‐middle income).

Recommendations

Greater investment is needed into understanding dementia, and its risk factors in LMICs to inform the development of risk mitigation programs. Research should focus on developing accurate, resource‐conscious models with affordable and obtainable variables for identifying those individuals likely to benefit the most from interventions targeting risk reduction.
Feasibility of and association between plasma total tau with MCI and AD across racial/ethnic groups utilizing multiple datasets
Authors: McEligot Archana J , Xiao Cally , Cummins Kevin , Pappas Ioannis , Toga Arthur W.
Published: January 2025

Background

Circulating plasma total tau (t‐tau) concentrations are increasingly being utilized for Alzheimer’s disease (AD) diagnoses. Nonetheless there is a dearth of data on the use of t‐tau in diverse groups, including Hispanic populations who are at elevated risk for AD. Therefore, we investigated the feasibility of biomarker data availability in diverse groups and subsequently assessed the relationship between t‐tau with mild cognitive impairment (MCI) and AD/dementia in Hispanic participants across multiple datasets available via the Global Alzheimer's Association Interactive Network (GAAIN).

Method

Initially, we explored demographic (age, gender, ethnicity), APOEε4 and t‐tau, as well as MCI and AD/dementia data from nine studies (ADNI, HABS‐HD, TARCC, NACC, APOE4, ALFA, ADNI‐ARG, ACE and 10/66) via GAAIN. Multiple logistic regression analyses, adjusted for co‐variates [(age, sex, education, BMI and APOEε4 (for TARCC)], were conducted to investigate the relationship between t‐tau and AD/dementia in non‐Hispanic white (NHW) and Hispanic participants.

Result

Three studies provided biomarker data, and two (HABS‐HD and TARCC) had sufficient Hispanic sample sizes for model estimation (nADNI = 9; nHABS‐HD = 793; nTARCC = 867). Among NHW participants, plasma t‐tau was associated with AD (TARCC: OR = 7.88, 95% CI = 3.28, 20.8, p < 0.001) and dementia (HABS‐HD: OR = 1.71, 95% CI = 1.17, 2.47, p = 0.005). However, for Hispanic participants, the association between t‐tau and AD (OR = 2.42, 95% CI = 1.38, 4.21, p = 0.002) was weaker (interaction p = 0.03) in TARCC, and no significant relationship was detected with dementia in HABS‐HD.

Conclusion

Increasing tau concentrations by one pg/ml was associated with nearly an eight‐fold higher odds of AD dementia and 71% increase in AD among NHW participants; however, for Hispanic participants, increasing t‐tau was associated with nearly a two and a half‐fold increase in AD only, suggesting that Hispanic participants may potentially be more susceptible to non‐AD dementia. Although plasma biomarker data are available for Hispanic participants, large population‐based studies need to further recruit diverse groups in order to more feasibly study the role of plasma biomarkers in AD and non‐AD dementia and/or etiology in diverse, at‐risk populations.
Prehospital treatment decisions for critically ill patients with dementia
Authors: Pollack Lauren R , Nomitch Jamie T , Kiker Whitney , Engelberg Ruth A , Dotolo Danae , Brumback Lyndia , Reed May , Johnson Nicholas , Sayre Michael , Kross Erin
Published: January 2025

Rationale

Prior work has shown a preference among most people with dementia and their families for comfort‐focused care near the end‐of‐life. Nonetheless, intubation and mechanical ventilation are increasing over time without concurrent trends in improved survival, including among those with advanced dementia. A better understanding of prehospital decision‐making about intubation for people with dementia will guide efforts to increase goal‐concordant care at onset of critical illness.

Methods

We identified eligible patients using the UW Medicine electronic health record (EHR) applying the following inclusion criteria: (1) age ≥ 55, (2) ICD‐code indicating dementia, (3) admission to a medicine service between 2011 and 2021, (4) treatment by paramedics, and (5) National Early Warning Score ≥7 indicating critical illness. We performed automated and manual abstraction of demographic and clinical variables from the EHR. We conducted a qualitative content analysis of emergency medical services (EMS) treatment narratives for patients with dementia, abstracting the number of cases in which there was documentation of: (1) the patient’s history of dementia, (2) presence of a surrogate decision‐maker, and (3) discussion of advance directives.

Results

In a preliminary sample of 81 patients, the mean age was 80 years (SD 12) and 42% were female. About half (48%) were residing in a nursing home and 73% had clinical markers of advanced dementia. The mean Glasgow Coma Score at time of EMS assessment was 11 (SD 3.9). The most common documented reasons for EMS activation were respiratory complaints (30%), altered mentation (20%), and suspected sepsis (19%). Awareness of patients’ history of dementia was documented in about a third (31%) of cases, the presence of a surrogate decision‐maker in 21% of cases, and assessment of whether the patient had an advance directive in 22% of cases.

Conclusion

Content analysis of EMS treatment narratives for critically ill patients with dementia suggests challenges faced by paramedics in eliciting patients’ treatment preferences, including having limited access to a surrogate decision‐maker with knowledge of the patient’s medical history, values and goals, and existing advance directives. Future work should elicit paramedic perspectives on challenges faced in providing goal‐concordant care for this patient population.
Targeted degradation of a‐synuclein via the AdPROM system prevents PFF‐induced a‐synuclein aggregation
Authors: Carton Bill , Gelders Géraldine , Kocaturk Nur , Roth Sascha , Macartney Thomas , Van Elsen Joke , De Muynck Louis , Buist Arjan , Moechars Diederik , Sapkota Gopal
Published: January 2025

Background

Accumulation of misfolded a‐synuclein protein in intracellular inclusion bodies of dopaminergic neurons underlies the pathogenesis of synucleinopathies, which include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). Therefore, clearance of misfolded α‐synuclein from dopaminergic neurons could in principle offer a an approach for modifying synucleinopathies, which currently remain untreatable.

Method

In this study, we employ the Affinity‐directed PROtein Missile (AdPROM) system consisting of the substrate receptor of the CUL2‐E3 ligase complex VHL and a nanobody selectively recognising the human α‐synuclein protein

Result

We demonstrate targeted degradation of endogenous α‐synuclein from human cell lines with exquisite selectivity. We further demonstrate that targeted degradation of α‐synuclein prevents the pre‐formed fibril‐ (PFF‐) induced aggregation of α‐synuclein in primary neurons derived from rats expressing human α‐synuclein. We will report at the meeting our progress on ongoing in vivo studies in a mouse model of α‐synucleinopathy

Conclusion

Our findings demonstrate that targeted degradation of α‐synuclein in vitro and in vivo with AdProms is feasible.
Imaging biomarker of beta‐amyloid pathology limits cognitive plasticity in healthy aging: A multi‐center intervention study
Authors: Bischof Gérard N , Fellerhoff Tim , Giehl Kathrin , Drzezga Alexander
Published: January 2025

Background

Experience‐dependent cognitive plasticity can be induced by cognitive training well into the later decades of life. Although some prerequisites (education, intelligence) and constraints (age, genetic predisposition) on the extent of cognitive plasticity have been discussed, the impact of molecular age‐related changes in the form of fibrillar amyloid pathology on plasticity remains to be investigated. Expanding our knowledge of potential contributors to the observed heterogeneity in intervention benefits may allow us to improve non‐pharmaceutical interventions

Method

Seventy‐six healthy older adults (mean age = 68.5, SD = 5.8) participated in a cognitive intervention study with twelve 60‐minute sessions. Tasks targeted executive function, memory, attention, and processing speed. Neuropsychological tests were conducted at baseline, posttraining, and three months. Outcome measures included training improvement, immediate transfer task improvement, and long‐term transfer maintenance. Positron emission tomography (PET) with 18F‐florbetaben imaged beta‐amyloid plaques. General linear models, controlling for age, education, and intelligence, assessed the influence of global SUVR on intervention outcomes.

Result

We observed significant negative effects of global amyloid on training improvement, controlling for baseline effects, age, education, and intelligence, with individuals with higher SUVRs showing significantly less training improvement. Similarly, significant amyloid deposition was negatively associated with transfer maintenance to follow‐up, again controlling for post‐training, age, education, and intelligence. Interestingly, immediate transfer improvement at follow‐up was not related to amyloid depositio

Conclusion

Our study reveals that amyloid pathology significantly hinders cognitive training benefits in healthy older adults. Amyloid limits cognitive plasticity induction, posing challenges for long‐term maintenance of training effects. The interplay between cognitive resilience and amyloid emerges, emphasizing the need for tailored cognitive interventions considering neuropathological factors. While cognitive training stimulates plasticity, its efficacy is constrained by amyloid presence, emphasizing the necessity of comprehensive strategies for addressing cognitive decline in aging individuals.
Determining the association between intracranial arterial calcification and cerebral amyloid deposition – A population imaging‐based approach
Authors: Streiber Anna M , Neitzel Julia , Ho Phuong Thuy Nguyen , Vernooij Meike W. , Bos Daniel
Published: January 2025

Background

Arteriosclerosis is linked to an increased risk of dementia and Alzheimer’s disease. However, the underlying pathological mechanisms remain unclear. We investigated the association between intracranial arteriosclerosis and cerebral Amyloid beta (Aß). Calcification of the intracranial internal carotid‐ (ICAC) and the vertebrobasilar arteries (VBAC) were used as a proxy of arteriosclerosis. We hypothesized that calcification presence, burden, and subtypes, differentially relate to changes in cerebral Aß.

Method

Analyses were based on 633 participants from the population‐based Rotterdam Study (mean age 69.3 ± 5.46 years, 51.2% female) who underwent an amyloid PET‐CT scan to quantify both calcification in the intracranial arteries (on low dose CT) and cerebral Aß accumulation. Calcification volume (in mm3) and subtypes (Figure 1) have been assessed by two independent raters. Aß burden was quantified using the standardized uptake value ratio (SUVR). Based on a clinically defined SUVR cutoff, participants were classified as Aß positive or Aß negative. The association between the presence, burden, and type of intracranial calcification and Aß was assessed by applying logistic and linear regression models. In Model 1, we adjusted for age, sex and APOE‐e4 carriership. In Model 2, we additionally corrected for cardiovascular risk factors.

Result

In total, 78.4% of the participants presented with ICAC and 13.3% with VBAC. In 16.43% of the participants, we detected Aß levels that were above the defined SUVR cutoff. Overall, calcification presence, and higher calcification volume were associated with lower odds of being Aß positive and a lower Aß SUVR (Figure 2 and 3). However, none of the results were statistically significant. The results did not differ per calcification subtype. We employed sensitivity analyses to account for potential selection bias and confounding, which did not change the overall results.

Conclusion

We found no significant association between intracranial arterial calcification and cerebral Aß accumulation. Future research should explore other potential neuropathological links to further understand the etiology underlying Alzheimer’s disease.
Exploring barriers and facilitators for the implementation of Alzheimer’s disease blood‐based biomarkers in primary care: The CANTATE‐Perspectives study
Authors: Claessen Thomas , Visser Fleur C.W. , van Munster Barbara C. , van der Flier Wiesje M. , Jiménez‐Mausbach Martí , van Harten Argonde C. , Visser Leonie N.C. , Teunissen Charlotte
Published: January 2025

Background

Adequately diagnosing Alzheimer’s disease (AD) in primary care can be challenging. Early symptoms often go unrecognized and other (neurodegenerative) diseases may be misdiagnosed as AD. AD blood‐based biomarkers could improve the diagnostic process for cognitive complaints in primary care. To prepare for implementation of these biomarkers in different contexts, we investigated barriers and facilitators from the perspective of general practitioners (GPs).

Method

In this qualitative, semi‐structured interview study, we used purposive sampling to select a heterogeneous group of 18 Dutch GPs (Figure I & Table I). The interview guide was based on the “Theoretical Domains Framework (TDF). Interviews were audio‐recorded and transcripts analyzed using MaxQDA software. By means of directed content analysis, a multidisciplinary research team (TC, FV & LV) identified barriers and facilitators for implementation of AD blood‐based biomarkers in primary care and categorized these into TDF‐domains.

Result

We identified 8 relevant TDF‐domains (Table II). Barriers could be mapped on the environmental context and resources (e.g. AD blood‐based biomarkers not being in GP guidelines) and knowledge domains (e.g. GPs perceived AD‐dementia as a syndromic diagnosis, not a biological diagnosis and were unaware of AD blood‐based biomarkers). Other important domains were emotion and beliefs about consequences (e.g. AD blood‐based biomarkers could result in over‐ or underdiagnosis of AD).

Facilitators could be mapped onto the environmental context and resources domain (e.g. availability of (disease‐modifying) treatment for AD, availability of education and accessible information for GPs and patients). Furthermore, facilitators could be mapped onto the social influences, beliefs about consequences & memory, attention and decision processes domains (e.g. GPs believed that AD blood‐based biomarkers would be useful in primary care as biomarkers could initiate further care, facilitate decision‐making and provide clarity regarding the diagnosis).

Conclusion

We identified a large variety of barriers and facilitators that can help to further understand and enable the implementation of AD blood‐based biomarkers in primary care. Important barriers and facilitators include the need for education and accessible information to enhance GPs’ knowledge about AD blood‐based biomarkers. Our next step is to further explore and confirm relevant factors for successful implementation by means of focus groups and a large scale questionnaire.
An observational multi‐clinic implementation science study to evaluate barriers and enablers of real‐world use of confirmatory blood‐based biomarkers for the diagnosis of early Alzheimer’s disease
Authors: Zullig Leah , Mattke Soeren , Vandercappellen Jo , Jones Daryl , Hampel Harald , Batrla Richard
Published: January 2025

Background

New innovations take a long time to be utilized into routine healthcare due to intrinsic and practical barriers. Implementation science can identify such barriers and offer potential solutions to speed up this process. Blood‐based biomarkers (BBBMs) may enable scalable confirmation of amyloid pathology in the Alzheimer’s disease (AD) care pathway with test performance similar to cerebrospinal fluid (CSF) testing and positron emission tomography (PET), so‐called confirmatory biomarkers as they can corroborate amyloid pathology with high certainty. However, establishing effectiveness does not guarantee translation into the care pathway. The objective of this study is to evaluate the feasibility of implementing BBBMs as confirmatory diagnostic tools for early AD in real‐world clinical practice.

Method

This prospective, multi‐clinic study will use the updated Consolidated Framework for Implementation Research to guide the implementation strategy. Consenting participants with first referral for evaluation of progressive cognitive decline will be assigned to: Arm 1 (standard‐of‐care [SOC]) or Arm 2 (confirmatory BBBM). Laboratory, cognitive and magnetic resonance imaging assessments will be performed in both arms as per the SOC in a memory clinic where BBBMs are accessible. Amyloid biomarkers will be confirmed by PET or CSF assessment in Arm 1 and confirmatory BBBMs in Arm 2. Implementation science questionnaires (clinicians) and qualitative interviews (clinicians and patients) will be conducted at baseline and at end of study in both arms.

The following implementation science outcomes will be evaluated: feasibility, acceptability and appropriateness of BBBMs using validated questionnaires; proportion of patients and reach (diversity representativeness [e.g., sex/race/age]) with a biomarker‐confirmed diagnosis; barriers and facilitators of BBBM implementation; time, number of visits and costs for a biomarker‐confirmed diagnosis. An estimated 60 subjects will participate in qualitative interviews based on information saturation guiding principle.

Result

The study will generate real‐world data on implementation of confirmatory BBBMs into clinical practice, specifically into a memory clinic set‐up. Interim results will be presented as available.

Conclusion

This study will provide a rationally and systematically tested and studied blueprint and recommendations for implementing confirmatory BBBMs into healthcare systems by identifying facilitators and barriers. The outcomes are intended to be used in educational programs for accelerated uptake of BBBMs.
Cost‐effectiveness of an online randomised controlled trial for dementia prevention, Maintain Your Brain, to improve cognition and lower dementia risk after 3 years
Authors: Welberry Heidi , Ku Li‐Jung Elizabeth , Shih Sophy TF , Jorm Louisa , Singh Maria A. Fiatarone , Valenzuela Michael , Ginige Jeewani Anupama , Heffernan Megan , Chau Tiffany , Brodaty Henry
Published: January 2025

Background

The Maintain Your Brain (MYB) randomised controlled trial (RCT) examined the effect of a multi‐domain internet‐based dementia prevention program against a control group (information only) over three years among Australians aged 55‐77 years. A cost‐effective analysis (CEA) quantified the differences in costs (direct healthcare and program costs) and effectiveness outcomes between the intervention and control groups from a health care sector perspective.

Method

An economic evaluation was conducted alongside the MYB trial. The intervention comprised a personalised schedule of online coaching in physical activity, nutrition, cognitive activity, and depression or anxiety. MYB trial data were linked to the 45 and Up Study and administrative health data using uniquely assigned identifiers to obtain healthcare utilisation and costs data. The two effectiveness outcomes were global cognition composite (GCC) scores and the Australian‐National University Alzheimer’s Disease Risk Index (ANU‐ADRI) short form questionnaire scores. Costs analysed included MYB program costs and the direct healthcare costs of MYB participants. All costs were reported on actual nominal values in Australian dollars ($AUD) during the trial period. The time horizon of this analysis was 3 years follow‐up after randomization. Incremental cost effectiveness ratio (ICERs) between the intervention and the control were calculated for GCC and ANU‐ADRI and compared using bootstrapped means and bias corrected and accelerated 95% Confidence Intervals.

Result

There were 3025 in the intervention group and 3033 in the control with available linked healthcare data. The average program cost per person was $1,572 for the intervention group and $538 for the control. Incremental cost‐effectiveness ratios at three years were calculated by comparing the average marginal difference in costs to a mean difference in z score of 0.18 (95%CI: 0.13, 0.23) and in ANU‐ADRI of ‐0.57 (95%CI: ‐0.95, ‐0.24) for the intervention versus control. The base case ICERs calculated were $2568 per 1 standard deviation in Z score and $823 per reduction of 1 ADRI point. After 1000 bootstrapped replications, the scatter‐plots of ICER ellipses suggests that the MYB intervention was effective and relatively cost‐neutral.

Conclusion

The MYB program showed potential cost‐effectiveness for preventing dementia. Longer‐term follow‐up is needed to confirm our initial findings.