bluuebunny/crossref_metadata_2025 huggingface dataset:
8‐week cognitive training intervention leads to improved mnemonic discrimination performance and near transfer from objects to scenes stimuli
Authors: Iliopoulos Panagiotis , Rong Boyan , Molloy Eóin N. , Cichy Radoslaw Martin , Maass Anne , Düzel Emrah
Published: January 2025

Background

Episodic memory declines in old age. Successful memory relies on the process of mnemonic discrimination (MD) to establish distinct representations. However, the scope for improvement in older adults’ cognitive performance using cognitive training is poorly understood. Here we investigated whether cognitive training leads to improvement in MD and whether the benefits transfer across different stimulus types, tasks and cognitive functions

Method

112 older adults (age M = 67.96, SD = 3.86) completed an 8‐week web‐based MD training intervention divided into 3 groups: one group training with object stimuli (OG), one group training with scene stimuli (SG), one active control group. The training was based on the object‐scene MD task which involves differentiating similar objects and scenes (‘lures’; correct response: ‘new’) from repeated items ('repeats’, correct response: ‘old’). Stimuli were first presented in a 2‐back set‐size: the first two stimuli were new images, while each of the subsequent two could be either a lure or a repeat trial. Then set‐size increased progressively across the training. Pre‐ and post‐training, the subjects performed a behavioral session including the 2‐back object‐scene MD task and several other transfer tasks. The latter included the mnemonic similarity task (MST; i.e. a different MD task), a pattern completion, working memory, spatial learning, and navigation task.

Result

Our results show a training‐induced improvement in the object‐scene MD task performance but not the MST. We found a bias‐corrected performance improvement (d prime) driven by the correct lures. Compared to the control group, the OG improved their MD performance in objects while the SG improved in scenes, but only the OG showed near transfer improvement to the non‐trained category (i.e. scenes). We found no significant training effect in other transfer tasks.

Conclusion

An 8‐week cognitive training intervention led to MD improvement in the trained task. We found a same modality improvement with the OG improving in objects and the SG in scenes, and evidence of near transfer from object to scenes but not vice versa. Cognitive training can lead to MD improvement in older adults. Longer‐duration interventions are needed to assess far‐transfer effects.
The Role of Sex in Post‐Mortem Neuropathology and Cognitive Decline
Authors: Dowd Rowan , Kamal Farooq , Dadar Mahsa , Oliver Michael , Morrison Cassandra
Published: January 2025

Background

Females tend to exhibit more Alzheimer’s disease (AD) pathology and have more clinical symptoms compared to males with similar levels of pathology. Post‐mortem studies in patients with AD have revealed that neuropathology is related to cognitive decline trajectories before death. However, what remains unclear is the intersection between sex differences in post‐mortem pathology and cognitive decline. These sex differences remain unstudied and may provide important treatment options in reducing pathology and delaying cognitive decline.

Method

1978 participants (females = 1354) from the RADC RUSH dataset with diagnoses at death including cognitively normal, mild cognitive impairment, and dementia were included. Pathological variables included neurofibrillary tangles (NFT), tangles, Braak staging, amyloid, and hippocampal sclerosis. Linear mixed models examined the relationship between pathology at death and rate of global cognitive decline before death between males and females.

Result

At death, females exhibited higher NFT burden (p<.001), tangles (p<.001), and Braak staging (p<.001) compared to males. Neither amyloid nor hippocampal sclerosis differed between males and females. Both females and males rate of global cognitive change was negatively associated with NFT burden (p<.001), tangles (p<.001), Braak staging (p<.001), amyloid burden (p<.001), with higher levels of pathology associating with worse cognitive decline. Only females exhibited a negative association between hippocampal sclerosis and worse cognition (p<.001). Importantly, the relationships between pathology and cognition were stronger for females than males for all pathology measures (see Fig. 1 for Braak example). To ensure the differences in rate of cognitive change associated with pathology between males and females were not due to differences in age or amount of pathology, a secondary analysis was completed on a subsample of males and females matched based on age and level of pathology. Results obtained were similar in terms of significance and effect size indicating that females are more negatively affected by AD‐related pathology.

Conclusion

Post‐mortem pathology is strongly associated with cognitive decline before death, with the relationship being stronger in females than males. To mitigate cognitive decline and alleviate stress on the healthcare system, targeting females earlier in the lifespan with interventions such as lifestyle modification reduce disparities in sex differences in AD incidence.
The X chromosome in Alzheimer’s Disease
Authors: Belloy Michael E. , Guen Yann Le , Stewart Ilaria , Herz Joachim , Sherva Richard , Zhang Rui , Merritt Victoria , Panizzon Matthew S. , Hauger Richard L. , Gaziano J. Michael , Logue Mark W. , Napolioni Valerio , Greicius Michael D ,   the VA Million Veteran Program
Published: January 2025

Background

The X‐chromosome remains largely unexplored in Alzheimer’s disease (AD). To address this gap, we performed the first large‐scale X chromosome‐wide association study (XWAS) of AD.

Method

The study overview is shown in Figure 1A. We performed a meta‐analysis of XWAS in case‐control, family‐based, population‐based, and longitudinal AD‐related cohorts from the US Alzheimer’s Disease Genetics Consortium (ADGC) and Alzheimer’s Disease Sequencing Project (ADSP), the UK Biobank (UKB), the Finnish health registry (FinnGen), and the US Million Veterans Program (MVP). Genetic data were available from high‐density single‐nucleotide polymorphism (SNP) microarrays and whole‐genome sequencing (WGS). To identify potentially causal genes in associated risk loci, statistical colocalization was evaluated between the local genetic association signal for AD and the genetic association signal for molecular traits such as expression levels of genes within that locus (R‐v.4.2.1, coloc). We leveraged public datasets where quantitative trait loci (QTL) for expression and protein levels were available for the X chromosome in brain and non‐brain tissues.

Result

The XWAS included 1,152,284 non‐Hispanic White European ancestry subjects, including 138,558 cases (Figure 1A). 6 independent genetic loci passed X‐chromosome‐wide significance (Figure 1B), with 4 showing support for causal links between the genetic signal for AD and expression of nearby genes in brain and non‐brain tissues (Table.1). One of these 4 loci passed conservative genome‐wide significance, with its lead variant centered on an intron of SLC9A7 (OR = 1.054, 95%‐CI = [1.035, 1.075]) and colocalization analyses prioritizing both the SLC9A7 and nearby CHST7 genes.

Conclusion

We performed the first large‐scale XWAS of AD, which is simultaneously the largest genetic association study of AD to date. We identified several associated loci, with the strongest support for the novel SLC9A7 locus. SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid beta accumulation. Overall, this study significantly advances our knowledge of AD genetics and may provide novel biological drug targets.
Evidence‐based Clinical Practice Guideline on the Use of Blood‐based Biomarkers in Alzheimer’s Disease: Presentation of Preliminary Evidence, and Opportunity for Public Comment
Authors: Hansson Oskar , Whitson Heather , Edelmayer Rebecca M. , Allen Laura A , Galasko Douglas R. , Karikari Thomas K , Okhravi Hamid , Paczynski Madeline , Schindler Suzanne E. , Suarez‐Calvet Marc , Teunissen Charlotte , Zetterberg Henrik , Mahinrad Simin , Pahlke Sarah , McAteer Mary Beth , Kahaleh Lara , Tampi Malavika
Published: January 2025

Background

The rapid development of blood‐based biomarkers (BBMs) has improved Alzheimer’s disease (AD) diagnostics with some tests now potentially suitable for clinical use. This aligns with the clinical availability of anti‐Aβ immunotherapies for early symptomatic AD, where BBMs can help address the increasing need for more rapid and early diagnosis. Clinical practice guidelines (CPG) can help guide healthcare professionals in incorporating BBMs into their clinical practice. The Alzheimer’s Association is collaborating with methodologists and a panel of 11 clinical and subject‐matter experts to develop a CPG for specialists, informed by a systematic review, on the use of BBMs for AD.

Method

The panel drafted several clinical questions prioritizing two questions on the use of BBMs in cognitively impaired or cognitively unimpaired individuals as the populations of immediate interest. Plasma p‐tau and Aβ biomarkers tests are index tests, and amyloid PET imaging, neuropathology, and CSF are reference standards. Experts in the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach are conducting a systematic review of the diagnostic accuracy of BBMs index tests by searching three databases (Pubmed, Embase, Cochrane Library) and will include assessments of the quality of collected evidence to inform the panel’s decision‐making process. Patients/caregivers and key external organizations will be engaged throughout.

Result

This session will cover preliminary evidence for answering the two clinical questions. At the time of abstract submission, the search strategy resulted in 880 titles/abstracts for the study selection process. Data abstraction, analysis, and evidence development are pending. Recommendations for answering clinical questions will be developed after July 2024, and all recommendations will be finalized and published by early 2025.

Conclusion

The integration of BBMs into clinical care offers the potential to improve earlier and more accurate AD diagnosis for a broader patient population and expand access to new AD therapies. The development of evidence‐based CPGs is a critical step forward in optimizing and standardizing the clinical use of BBMs. As the field of AD diagnostics and treatment continues to evolve, this CPG on the use of BBMs for AD will expand and be regularly updated to include new target audiences/settings, patient populations, and associated evidence.
Implementing a biomarker‐enabled care pathway to accelerate identification of early‐stage Alzheimer’s disease in primary care
Authors: Borson Soo , Au Rhoda , Chodos Anna H , Gandy Sam E , Jain Holly , Kerwin Diana R. , Mintzer Jacobo , Monroe Stephanie , Robinson Delecia , Wilcock Donna M. , Mielke Michelle M.
Published: January 2025

Background

New blood‐based and digital biomarkers for Alzheimer’s disease (AD) make early detection possible at stages when novel, disease‐specific therapies are likely to be most effective. These approaches may offer less invasive, more cost‐effective alternatives to traditional methods such as cerebrospinal fluid (CSF) collection or positron emission tomography (PET) imaging for diagnosing and staging AD. Building care pathways leveraging blood‐based and digital biomarkers starts with understanding the current biomarker landscape and considering opportunities for widespread implementation in primary care clinical practice.

Methods

A multidisciplinary team representing neurology, neuropsychology, geriatrics, primary care, epidemiology, laboratory programs, and patient advocacy was convened to review a summary of current biomarker research findings and discuss barriers and opportunities to implement biomarkers as part of an AD consensus‐driven clinical care pathway.

Results

The emergence of biomarkers has shifted diagnosis from primarily clinical to a biological definition of AD. However, there is currently no consensus on where biomarkers fit within an AD care pathway and when they should be utilized in primary care or dementia specialist care settings.

We found a relative paucity of published data on biomarker test accuracy in diagnosis outside tightly controlled research settings, limiting guidance around how results should be interpreted and managed in real‐world care settings. Evidence gaps are especially pressing for heterogeneous, diverse populations under‐represented in AD research.

New biomedical therapies specific to the pathobiology of AD are driving research on blood and digital biomarkers to inform optimal ways to accelerate identification. As most individuals with AD are not evaluated by specialists, accurate and usable information about the place of biomarkers in the diagnosis and treatment of cognitive impairment must reach primary care

Conclusions

With growing interest in the promise of non‐invasive biomarkers to improve detection, differentiation, and diagnosis of AD, new research is needed to generate real‐world evidence about their performance across populations, how to interpret results, and how best to use them in patient management. Effective educational strategies are needed to disseminate high‐quality evidence that engages primary care and healthcare delivery systems in implementing optimal clinical pathways. More detailed learnings for successful care pathway implementation will be shared.
The Safety, Feasibility and Effect of the APOE Mimetic Peptide CN‐105 on Neuroinflammation and Delirium after Major Non‐cardiac/Non‐neurologic Surgery in Older Adults: Results from the Phase II, Triple Blind, Escalating Dose, MARBLE Randomized Clinical Trial
Authors: Berger Miles , Timko Noah J. , Boykin Piper C. , Emerson Jacqueline M. , Woldorff Marty G. , Wright Mary Cooter , Herbert J. Taylor , Moretti Eugene W. , Devinney Michael J. , Ryu David , VanDusen Keith W. , Bunning Thomas , Hsia Bethany J. , Browndyke Jeffrey N. , Blennow Kaj , Zetterberg Henrik , Laskowitz Daniel T. ,   the MARBLE Study Investigators
Published: January 2025

Background

APOE4 leads to increased neuroinflammation, neurocognitive decline, increased risk of Alzheimer’s disease, and may be associated with increased delirium risk. However, the safety and feasibility of pharmacologic modulation of APOE to prevent neuroinflammation and postoperative delirium is unclear.

Methods

We performed a Phase II, triple blind, escalating dose, randomized controlled trial to determine the safety, feasibility, and efficacy of the APOE mimetic peptide CN‐105 for preventing postoperative neuroinflammation and delirium. We enrolled older adults (age ≥ 60 years) undergoing major non‐cardiac/non‐neurologic surgery with a planned overnight hospital stay. Patients were randomized 1:3 to placebo or intravenous CN‐105 (0.1, 0.5 or 1 mg/kg) starting within 1 hour before surgery and continuing every 6 hours (± 90 minutes) afterwards, until 13 doses were received or hospital discharge (whichever occurred first). The primary outcome was the number of Grade 2 or higher adverse events (AEs) among patients randomized to CN‐105 vs. placebo. Secondary outcomes included percent of drug doses administered within the correct time window, and postoperative delirium incidence and severity.

Results

203 patients were enrolled; 186 patients (mean [SD] age, 68.7 [5.3] years; 119 male) completed surgery on protocol (49 [26%] Placebo, 137 [74%] CN‐105; Figure 1). The groups were generally well‐matched (Table 1). Patients administered CN‐105 vs. placebo had less Grade 2 or higher AEs (median per patient [Q1, Q3] 1 [1, 3] vs. 2 [1, 5]; p = 0.025), and a lower rate of severe AEs (8.0% vs. 22.4%, p = 0.007; Table 2). The rate of doses administered within window was 95.3% (95% CI: 93.7%‐96.6%) for CN‐105‐treated patients and 93.8% (95% CI: 90.8%‐96.0%) for placebo‐treated patients. CN‐105 (vs. placebo) treated patients had a lower delirium incidence (19.3% vs 27.1%, relative risk = 0.71 [95% CI: 0.40‐1.27], p = 0.26), and lower median delirium severity (1 vs. 2; proportional odds ratio [95% CI] 0.66 [0.37, 1.20]; p = 0.178), though these effects were not statistically significant.

Conclusions

CN‐105 is safe and feasible to administer to older non‐cardiac/non‐neurologic surgery patients, and led to fewer postoperative Grade 2 or higher AEs and severe AEs. The 95% CIs for the effects of CN‐105 included clinically relevant reductions in delirium incidence and severity.
PET Imaging of Microtubules in Cognitively Impaired and Normal Older Adults
Authors: Damuka Naresh , Miller Mack , Krizan Ivan , Bhoopal Bhuvanachandra , Orr Miranda E. , Gollepalli Krishna Kumar , Lockhart Samuel N. , Whitlow Christopher T , Mintz Akiva , Craft Suzanne , Sai Kiran K. Solingapuram
Published: January 2025

Background

Although associated with early changes in Aβ and tau formations, microtubule (MT) destabilization has not yet been systematically evaluated as an early biomarker of neurodegeneration and a tool to quantify it in real‐time could provide information on these early changes in AD cascade. While current Aβ and tau PET approaches can characterize disease lesions, they fall short in capturing earlier molecular events. Our team development the first brain‐penetrant MT PET ligand, [11C]MPC‐6827. We evaluated its in vivo imaging efficacy in rodent and nonhuman primate models of AD, and subsequently conducted a first‐in‐human study. Here we show our preliminary MT‐PET and autoradiography data in cognitively impaired and age‐matched cognitively normal older adults and post‐mortem human brains respectively.

Method

Dynamic 1h brain PET imaging was conducted with [11C]MPC‐6827 in cognitively impaired (Aβ and tau PET positive) and cognitively normal (Aβ and tau PET negative) older adults (n = 5/group). MT‐PET uptake was correlated with [11C]PiB‐Aβ, and FTP‐tau SUVRs and fluid biomarker data. Autoradiography was performed in postmortem MCI/early AD (n = 3) and age‐matched cognitively normal adults (n = 2) brain tissues.

Result

[11C]MPC‐6827 uptake was higher in the frontal and prefrontal cortex, hippocampus, putamen, and pons of the cognitively impaired subjects than the controls. Uptake correlated positively with ptau181, [11C]PiB Aβ, and FTP‐tau SUVRs and inversely with their CSF Aβ42—validating its relevance to AD biomarkers. MT‐PET‐SUVRs positively correlated with calculated average PiB SUVRs (Pearson r = 0.667, p = 0.05) and with FTP SUVRs (r = 0.367, *
p = 0.047). Autoradiography uptake in AD prefrontal cortex and hippocampus was ∼39 and ∼43% (*p≤0.05) higher than that in control tissues.

Conclusion

Our [11C]MPC‐6827 human studies demonstrate (a) safety and feasibility; (b) robust brain uptake; (c) higher brain uptake in cognitively impaired subjects than in controls; (d) a highly positive correlation among PiB, and FTP uptakes; (e) autoradiography results may indicate not possibly of age confounding the imaging data. This study will be the first to image MT destabilization processes in AD. It will create a new understanding of MT‐based processes in the neurodegeneration cascade to optimize approaches of AD diagnosis and monitoring.
The Design of SPRINT MIND and SPRINT MIND 2020
Authors: Rapp Stephen R. , Supiano Mark A.
Published: January 2025

Background

The Systolic Blood Pressure Intervention Trial (SPRINT) included a specific aim on the effect of blood pressure lowering the risk of cognitive impairment (mild cognitive impairment (MCI) and dementia). Early termination of the trial and fewer than expected cases left the study under powered to detect cases of probable dementia, but the intervention reduced the risk for MCI and for a composite of MCI or probable dementia (PD). To increase the length of follow‐up and number of cases of probable dementia, two studies were funded: one from October 2017 through June 2018 and a second, the SPRINT MIND 2020 study, from December 2019 through December 2023.

Method

In the main trial, 9361 participants were randomized to either Intensive or Standard BP control, systolic BP < 120 or < 140 mmHg, respectively. For the cognitive aim, outcomes were adjudicated PD and MCI.

Result

Of the 9361 participants in the SPRINT trial, 8563 completed one or more cognitive assessment, and 325 were adjudicated to have probable dementia at the end of the first extended follow‐up. The SPRINT MIND 2020 follow‐up ascertained an additional 216 cases of probable dementia. An additional 170 cases of mild cognitive impairment were also ascertained.

Conclusion

SPRINT MIND 2020 successfully extended follow‐up time for the SPRINT MIND study and increased the number of observed cognitive outcomes substantially enabling an analysis of legacy treatment effects.
The association of frailty with cognition outcomes in SPRINT‐MIND
Authors: Callahan Kathryn E. , Jaeger Byron C , Rapp Stephen R. , Pajewski Nicholas M. , Williamson Jeff D.
Published: January 2025

Background

Frailty may moderate efficacy of interventions for Alzheimer’s disease (AD) and related dementias (ADRD), with higher efficacy at lower neuropathology burden in frailty. Using data from the Systolic Blood Pressure Intervention Trial (SPRINT) with extended post‐trial follow‐up, we assessed whether frailty moderated the effect of intensive blood pressure (BP) control and subsequent cognitive outcomes.

Methods

Primary outcomes were probable dementia (PD) and mild cognitive impairment (MCI). Intensive and standard BP control targeted systolic BP < 120 and < 140 mmHg, respectively. Frailty index (FI) was calculated using a deficit‐accumulation model. We tested for heterogeneity in the effect of intensive BP control among participants who were non‐frail (FI ≤ 0.10), pre‐frail (0.10 < FI ≤ 0.21), and frail (FI > 0.21) using Cox proportional hazards, accounting for differential baseline hazard by study site. Analyses were replicated in subgroups defined by age, sex, and race.

Results

Of the 9361 participants in the SPRINT trial, 8541 consented to follow‐up for PD/MCI and had calculable baseline FI. Over 54568 person‐years, 539 PD and 809 MCI events occurred. Participants categorized as non‐frail (N = 1412) were younger and more likely to be male versus pre‐frail (N = 4430) and frail (N = 2699) participants. Intensive versus standard BP control exhibited a heterogeneous effect for PD risk reduction (p = 0.03), with hazard ratios (HRs) ranging from 0.70 to 1.10. Among subgroups based on age, sex, and race, PD HRs ranged from 0.59 to 1.00. For MCI, heterogeneity was not detected (p = 0.23), and HRs ranged from 0.70 to 1.00. No evidence of harm (i.e., HR > 1) was detected.

Conclusions

Heterogeneity based on frailty in the effect of BP control may impact subsequent cognitive outcomes. Future studies with cognitive outcomes should consider stratifying by frailty status.
The Types and Consistency of Participant‐Specified Proxies During SPRINT
Authors: Gaussoin Sarah A. , Jaeger Byron C , Lerner Alan J. , Perdue Letitia H. , Rapp Stephen R. , Reboussin David M. , Williamson Jeff D.
Published: January 2025

Background

For clinical trials or patient care, reports from a person familiar with the trajectory of a participant’s cognitive and functional performance (i.e., proxies) may improve adjudication of events, such as mild cognitive impairment and dementia. Proxies offer a unique perspective on cognitive status that is different from what is captured through standard cognitive examinations. Clinical trials in which cognitive status is adjudicated, such as the Systolic Blood Pressure Intervention (SPRINT) trial, provide information about the contributions and consistency of proxies throughout extended follow‐up.

Method

SPRINT participants named proxies and relationship to them at study onset. Proxies provided information for the Functional Activities Questionnaire and Dementia Questionnaire. We collapsed proxy relationships into seven categories and evaluated the proportion of proxies in each category at baseline and how frequently the same proxy was retained to the last visit. We explored associations between proxy relationship and various baseline demographics and examined the association between not having a proxy, as well as proxy relationship, and adjudicated outcome.

Result

Of the 9,361 randomized SPRINT participants (35.6% female, mean age 67.9 years), 7,586 (81%) participants listed a proxy relationship from which we identified 7 categories: spouse/partner (51.7%), child (23.6%), sibling (8.7%), other family member (6.2%), and unrelated (8.8%). Male participants were more likely to name a spouse as their proxy (64%) while female participants more likely to name a child (42%). The overall consistency of proxy continuation between the baseline and final SPRINT visit (mean 6.9 years) was 90.7%. Proxy consistency from first visit to last visit for a child was 94.8%, spouse/partner (91.9%) brother/sister (87.5%), other family member (82.4%), non‐related (81.2%), and parent (78.2%). Adjudications that resulted in ‘Cannot Classify’ were greatest for proxies who were parents (15%) followed by none (12%), sibling and grandchild (9%), child and unrelated (7%), spouse and other family (6%).

Conclusion

The majority of proxies in SPRINT were immediate family members (spouse, child, or sibling). Over 90% of identified proxies at baseline continued to be available over a mean of almost 7 years of follow‐up. Not having a proxy available led to a higher rate of ‘cannot classify’ adjudications.
Empowering Communities: Examining Korean Dementia‐friendly Community Policies through a Lens of Dementia Inclusive Societies Framework
Authors: Chung Soondool
Published: January 2025

Background

As the global prevalence of dementia continues to rise, South Korea faces the imperative of developing comprehensive policies to address the multifaceted challenges posed by this condition. Creating dementia‐friendly communities is important for the inclusion of patients with dementia (PWD) and their families. Therefore, the purpose of this study is to analyze dementia‐friendly community policies in Korea using the WHO’s dementia inclusive societies framework and to suggest ways to improve such policies.

Methods

The WHO’s framework consists of key principles and actors such as key partners and target groups, etc.. The social environment, specifically Leading Institutions for Overcoming Dementia (LIOD) and Dementia Relief Members, was chosen as dementia‐friendly community policies in Korea.

Results

The Dementia‐friendly Communities Initiative was started in 2017, aiming to support social activities of PWD. Firstly, the key principle of LIOD was to make communities safe for PWD and their families, with key partners being both for‐profit and non‐profit entities such as businesses, schools, universities, and libraries. They engage in activities, campaigns, educational programs, etc., related to dementia. The target groups were employees of business, students, and user of libraries. Secondly, the key principles of Dementia Relief Members were to promptly protect and report when encountering older individuals wandering the streets, and to encourage early dementia screening and increase awareness of dementia. Key partners were small business owners such as restaurant and convenience stores after their staff received Dementia Partners education. The target groups were owners and staffs of those shops.

Conclusions

Dementia‐friendly community policy in Korea represents a critical step towards addressing the growing prevalence of dementia and promoting the rights and dignity of individuals living with the condition. However, there are some drawbacks to this policy. The system for sustaining the continuous activities of dementia LIOD is limited. Furthermore, the monitoring system for continuous activities of Dementia Relief Members is also inadequate. Dementia‐friendly establishments are only monitored for closure and changes in location, thus there is no effective management of continuous participation in activities. Further measures for improvement should be taken.
Diagnostic journey and barriers to diagnosis for patients with mild cognitive impairment or dementia due to Alzheimer’s disease in Canada: results from a real‐world survey
Authors: Glass Jennifer , Boulay Luc , Vasileva‐Metiodiev Simona , Walker Chloe , Cotton Sarah , Tarride Jean‐Eric , Laforce Robert , Gauthier Serge
Published: January 2025

Background

Alzheimer’s disease (AD) dementia progresses from preclinical brain changes, through mild cognitive impairment (MCI), to AD with dementia. Early diagnosis and confirmation of underlying AD pathology is crucial; however, there is still much to learn about patients’ diagnostic journey. We aimed to describe the diagnostic journey and barriers to diagnosis for patients with MCI or dementia due to AD in Canada.

Method

Data were collected from the Adelphi Real World AD Disease Specific Programme (DSP)™, a cross‐sectional survey of general practitioners (GPs) and specialists in Canada, from March to October 2023. GP surveys covered patient management and referral patterns. Specialists completed a survey capturing attitudes towards diagnosis, advanced testing, and future treatment landscape. Physicians saw ≥5 (GPs) or ≥10 (specialists) patients per week with MCI or dementia/AD. Analyses are descriptive.

Result

The survey was completed by 20 GPs and 30 specialists (19 neurologists, 6 psychiatrists, and 5 geriatricians). GPs reported patient difficulty remembering people’s names (65%) was the patient complaint that most often prompted further testing (Table 1). Other important patient complaints were problems concentrating on everyday tasks (45%) and worry about forgetting things, such as appointments so they have to rely on notes and calendars (45%). GPs reported referring an average of 25±22% of patients with MCI to a specialist after seeing them an average of 3.9±1.3 times. On average, 49±28% of patients with MCI or dementia/AD managed by GPs were not referred to a specialist. Specialists reported the top three barriers to early identification of patients with MCI and patients with mild dementia due to AD were delay due to lack of awareness of the condition (67% and 53%), lack of understanding what constitutes “normal” ageing (63% and 40%), and slow referral (37% and 40%) (Figure 1).

Conclusion

Many patients with MCI or dementia/AD in Canada are not referred by GPs, especially in early‐stage AD. Referrals from GPs were also often delayed, with specialists citing delay due to lack of patient awareness of MCI as the main barrier to early diagnosis. Improving awareness of early AD symptoms and AD pathology, and accelerating access to specialists, are warranted.
Sex‐specific associations between plasma biomarkers and risk factors for dementia: a 10‐year follow‐up of community‐dwelling older individuals
Authors: Ryan Joanne , Murray Anne , Wu Zimu , Mielke Michelle M.
Published: January 2025

Background

Evidence is growing supporting sex‐ and gender‐ specific differences in risk factors for dementia, and varying pathways to diagnosis. Recognized sex differences in brain structure and function could contribute to differences in plasma biomarker concentrations and in susceptibility to brain pathologies. Furthermore, differences in comorbidities between males and females (e.g. kidney function) could influence sex differences in the clearance and measurement of these biomarkers. The aim of this study was to investigate the association between risk factors and plasma biomarkers, with incident dementia, separately in men and women.

Method

In the U.S and Australia, we recruited 19,114 community‐dwelling individuals aged ≥70 years (U.S African‐Americans and Hispanics ≥65 years), without cognitive impairment and cardiovascular disease. Plasma amyloid‐beta (Aβ40 and Aβ42), phosphorylated tau (p‐tau 181), neurofilament light (NfL), and Glial Fibrillary Acidic Protein (GFAP) were measured [Simoa N4PE and Ptau181 v2 assays] at baseline. Dementia was adjudicated by an expert panel according to DSM‐IV criteria. The association between a range of factors (Table 1), and the risk of dementia was assessed using multivariable logistic regression, separately in men and women.

Result

Participants had a mean age of 74 years at baseline and plasma biomarker data was available for 7,218 women and 5,942 men. Of these participants, 824 developed dementia, with a similar proportion of men (6.4%) and women (6.2%). Age, a family history of dementia, BMI and slow gait speed were significantly associated with dementia risk, in both men and women (Table 2). All of the plasma biomarkers were associated with dementia risk, but NfL was not significant after adjustment for GFAP (particularly in women). In men only, depression and diabetes were significant risk factors, while in women poor grip strength was associated with increased risk, and U.S whites compared to Australian whites, had decreased risk.

Conclusion

Plasma biomarkers of Alzheimer’s Disease were found to be associated with dementia risk in both men and women, however associations between other risk factors and dementia varied. These findings suggest the importance of considering sex and gender differences, as this could open up possibilities for personalized prevention.
Reevaluating Melatonin’s Efficacy in Alzheimer’s Disease: A 20th‐Anniversary Updated Literature Review of Sleep Disturbances and Treatment Trials
Authors: Malhotra Alisha , Daga Vrushabh , Singer Cliff
Published: January 2025

Sleep disturbances in Alzheimer’s disease (AD) are stressful for patients and families. This review provides an update on the efficacy of melatonin and other interventions for nighttime sleep disturbances in AD patients, building on the original Alzheimer’s disease Cooperative Study trial, the first large trial for sleep disturbance in AD. The initial multicenter, randomized, placebo‐controlled study investigated the effects of two melatonin formulations – 2.5 mg sustained‐release (ML2.5SR) and 10 mg immediate‐release (ML10) –compared to placebo (PLA) in 157 participants. The primary outcomes, measured via wrist‐actigraphy, indicated no significant changes; however, secondary outcomes suggested improvement in sleep quality with ML2.5SR. This suggests the efficacy of melatonin in AD may be related to time and exposure rather than dosage, as sustained‐release formulations showed a greater trend for efficacy than immediate.

Melatonin’s antioxidant properties have been shown to be neuroprotective, balancing Aβ production and clearance, but have been equivocal in reducing sleep disturbances. Recent research has demonstrated actigraphy to be an imperfect method for measuring sleep and wakefulness, misclassifying asleep time as awake in people with AD, and overestimating sleep in others. Combined with the subjective nature and poor compliance with sleep diaries in the ADCS study, methodological questions as to how to do large studies of sleep in people with AD arose. Updated studies have looked at melatonin in comparison to interventions like bright‐light therapy and other drugs. Circadian rhythm disturbances are common in AD, and different therapies have been trialed to improve sleep onset, duration, and quality. There has also been updated information regarding the efficacy of different measure to accurately record sleep including EEG and polysomnography.

We analyzed studies in the 20 years since the ADCS trial was published. Our findings, while mixed, suggest that melatonin may be more effective improving sleep outcomes in AD, than reported in the ADCS paper‐ particularly when used in conjunction with other interventions. Suggestions for further study include finding a new way to objectively gather sleep data in a large trial so that another multicenter trial looking several sustained release formulations and other interventions may be attempted.
Sex‐Specific Effects of APOE Genotype on Contextual Fear Discrimination
Authors: Mohammed Hassan E , Coniglio Jackie , Luna Victor M.
Published: January 2025

Background

The Apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for sporadic late‐onset Alzheimer’s disease (AD). Moreover, the link between APOE4 and AD is more pronounced in women than in men. In this study, we investigate how APOE genotype and sex impact emotional pattern separation. This is a cognitive faculty that enables discrimination between highly similar emotional and non‐emotional experiences, deficits of which are key neuropsychiatric symptoms of AD progression.

Method

To determine the role of APOE alleles in emotional pattern separation, 6‐month‐old male (n = 14) and female mice (n = 15) expressing humanized APOE2, 3 or 4 alleles (CureAlz) were tested on a contextual fear discrimination (CFD) task that is dependent on the dentate gyrus and on adult hippocampal neurogenesis. Mice were evaluated on their ability to distinguish between an aversive Context A (with foot shock) and a similar yet non‐aversive Context B (no foot shock) for 5 days. For each Context, visual and olfactory stimuli in the chamber were altered while the tactile features of the floor were kept the same. As part of CFD protocol, mice also underwent standard contextual fear conditioning (CFC) testing.

Result

We found no significant effect of sex or APOE allele on CFC learning. However, in the CFD task, we found that female E2 mice performed significantly better than female E3 and E4 animals. E3 females appeared to discriminate between aversive and non‐aversive contexts better than E4. In contrast, we found that APOE allele did not impact CFD in males. Finally, we found that E2 females significantly outperformed E2 males in the CFD task. E3 and E4 females performed similar to their male counterparts.

Conclusion

Our results suggest that early in adulthood, the APOE2 allele greatly impacts emotional pattern separation in a sex‐dependent manner. To determine the underlying synaptic mechanisms for our CFD findings, we have been investigating how APOE alleles impact the expression of all glutamate receptor subunits in the dentate gyrus as well as neurogenesis levels. Most importantly, we have been aging our mouse colonies to determine how age, APOE allele, sex, and glutamate receptor composition together dictate emotional pattern separation related to AD.
Proteomic prediction of myelin water fraction using the SomaScan 7k platform
Authors: Joynes Cassandra M , Resnick Susan M. , Bouhrara Mustapha , Walker Keenan A.
Published: January 2025

Background

Myelin loss occurs as part of neurodegenerative and neuroinflammatory conditions. Myelin water fraction (MWF), a surrogate of myelin content, can be estimated using multicomponent relaxometry MRI. In this study we investigate the relationship between 7289 plasma proteins and MWF to derive a protein‐based indicator of myelin content.

Method

In the Baltimore Longitudinal Study of Aging (BLSA) plasma proteins were measured using the SomaScan proteomic platform; BMC‐mcDESPOT was used to measure MWF. Univariate analyses adjusted for age, sex, eGFR, and age2 examined the association of protein levels with MWF. Public datasets were used for determination of the cell (HPA)‐ and tissue (GTex)‐specificity used for candidate protein annotation. Multivariate analyses used stepwise linear regression, following the selection process described in Figure 1, to generate a protein‐based estimate of MWF (eMWF).

Result

64 cognitively normal participants from the BLSA (mean age at MWF visit 55.32 years [range 22.4 to 94.4], 48% males) were included in the discovery analysis. Adjusted univariate analyses found 231 proteins associated with MWF at an uncorrected p<0.05. However, none survived FDR correction. Plasma proteins CUTC (β = 0.02, p = 0.0003), COL20A1 (β = 0.04, p = 0.001), and PRSS27 (β = ‐0.03, p = 0.001) showed the strongest association with MWF (Figure 2A). Proteins positively associated with MWF were enriched for vasoconstriction, MAPK integrin signaling, amyloid‐beta binding, and complement and coagulation cascades. Proteins inversely associated with MWF were also enriched for complement and coagulation, as well as TRAIL signaling, and TP53 transcriptional regulation (Figure 2B). In a multivariable analysis of MWF, stepwise linear regression selected the proteins PRSS27, ZC4H2, IFNL3, RNF146, RFESD, PROK1, and DCAF11, as well as age and age2, for model inclusion (protein function annotated in Figure 3D). R2 of the model when fit on the full dataset was 0.86 (fivefold cross validation R2 = 0.51, Figure 3A). Observed and estimated MWF both show similar nonlinear trajectories with age (Figure 3B‐C).

Conclusion

We developed a protein‐based proxy for total myelin content and validated the predictive ability of this measure. Future studies will test eMWF in neurodegenerative and demyelinating conditions.
First‐of‐its‐kind identification of two novel tau mutations associated with cognitive resilience to Alzheimer’s disease neuropathology
Authors: Jamison Danielle , Taglialatela Giulio
Published: January 2025

Background

To date, mutations in the MAPT (i.e., tau) gene within Alzheimer’s disease (AD) patients are either benign or have an unclear effect on pathogenicity. Significant prior literature and evidence from other tauopathies support the hypothesis that mutations can alter tau’s structure and function. Approximately one‐third of neuropathological autopsies identify individuals with comparable AD neuropathology (i.e., extracellular amyloid‐beta (Aβ) plaques and intracellular tau‐containing neurofibrillary tangles (NFTs)) without similar clinical manifestations or cognitive deficits (herein referred to as non‐demented with Alzheimer’s neuropathology or NDAN). The comparable neuropathological burden with divergent clinical manifestations between AD patients and NDAN individuals led us to hypothesize that a mutation in the NDAN MAPT gene could explain, at least in part, this dichotomous presentation.

Method

RNA was isolated from the frontal cortices of seven NDAN individuals (4M, 3F) using a commercial RNA kit. Primers to amplify the tau coding sequence were found in the literature and confirmed to amplify the tau coding sequence. With assistance from UTMB’s Next Generation Sequencing core, the RNA quality was first assessed, and subsequently, library generation and sequencing were performed.

Result

Two novel somatic mutations were identified in all seven individuals with frequencies consistent with mosaic mutant frequencies. The first, an aspartic acid to alanine mutation, occurred at a position where no prior mutations have been documented. The second occurs at the serine immediately preceding tau’s amyloid motif, VQIVYK; in this mutation, the phosphoresidue is replaced by a charged and bulky arginine. Analysis using the Ensembl Variant Effect Predictor (VEP) predicted both mutations to be, at a minimum, moderately damaging to tau’s function, which is logical considering the amino acid substitutions occurring. The severity of each mutation’s effect on the tau structure and function was isoform specific.

Conclusion

We identified, to the best of our knowledge, two completely novel tau mutations uniquely associated with individuals that remain cognitively intact despite abundant AD neuropathology. These mutations may help contextualize the unique phenotype observed in NDAN individuals, such as cognitive resilience and spreading with minimal toxicity.

Funding Support: R01422460 and R0142690 to GT. Attendance at this conference was supported by an AAIC 2024 Conference Fellowship.
The Global Neurodegeneration Proteomics Consortium ‐ Biomarker and Drug Target Discovery Across >40,000 Biosamples for AD, PD, ALS, FTD, and Aging
Authors: Bringmann Martin , Imam Farhad , Krish Varsha
Published: January 2025

Background

Limited understanding of biological mechanisms behind the onset and progression of Neurodegenerative Disorders has been a burden for the discovery of novel biomarkers and treatments. Large, harmonized, patient‐derived datasets will be key in unraveling the complex biology leading to neurodegeneration. The Global Neurodegeneration Proteomics Consortium (GNPC) is a major biomarker discovery effort to unite and expand the available proteomic data for thousands of patient samples from leading dementia cohorts from around the world and comprises, to our knowledge, the largest discovery proteomics dataset to date.

Method

The GNPC has brought together over 40,000 samples from over 20 different international cohorts to create and collaborate on a fully anonymized Harmonized Dataset (HDS). The HDS spans multiple neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Secure access to GNPC data is facilitated through the Alzheimer’s Disease Data Initiative ‘s online platform, the AD Workbench. De‐identified datasets submitted by each participating cohort were harmonized and further anonymized by professional data vendors. After one year of intra‐consortium analysis, the HDS will be accessible by the broader research community as a shared, global resource.

Result

The first version of the Harmonized Dataset (HDS) includes over 40,000 unique samples on the SomaScan 5k and/or 7k proteomics array platform. All samples are accompanied by >40 phenotypic indicators including demographic, cognitive data, clinical scores, and disease‐specific genotype. Central hosting of de‐identified and harmonized data within the secure cloud environment provides the necessary data security, access to scalable compute resources, and facilitated collaboration between participants in diverse geographies and regulatory environments.

Conclusion

With over 300,000,000 unique protein measures, the GNPC represents the largest protein biomarker discovery effort for neurodegenerative diseases to date. Initial research underway is organized via several core workstreams, including cross‐sectional and longitudinal profiling, proteogenomic mapping, multivariate prediction, and combinatorial analysis across a single disease area.