bluuebunny/crossref_metadata_2025 huggingface dataset:
Impacts of cardiovascular risk factors and APOE on cognitive decline in late‐life
Authors: Wang Xinhui , Asante Isaac , Yu Lei , Wilson Robert S. , Bennett David A. , Arvanitakis Zoe , Yassine Hussein N
Published: January 2025

Background

Apolipoprotein E (APOE) is a known genetic risk factor for dementia. Midlife cardiovascular risk factors are associated with lower cognitive performance and increased dementia risk. However, little is known whether cardiovascular risk factors mediate or modify the associations between APOE and cognitive decline in late‐life.

Method

We conducted longitudinal data analyses on 1180 participants (aged 79.3±6.9 years at baseline) from Religious Orders Study and Rush Memory and Aging Project. Participants had ≥4 cognitive assessments with the last one within 2 years before death and APOE genotyped as ε4 carrier (ε3/ε4 or ε4/ε4) or non‐carrier (ε3/ε3). Annual global cognitive function was assessed via a battery of 19 tests and averaged into a summary measure. Cardiovascular risk factors included depression, hypercholesterolemia, and hypertension defined by corresponding medication usage in last 2 weeks at baseline, and diabetes based on self‐report or medication use. We constructed random change point models to analyze cognitive trajectories before death and estimate the subject‐specific change point, slopes before (pre‐terminal decline) and after (terminal decline) the change point, and level of cognition at death. We used linear regression to analyze the associations between APOE, cardiovascular risk factors, and these trajectory parameters adjusting for age at death, sex, and education. Interactions between APOE and risk factors were also examined.

Result

On average, the onset of terminal decline happened at 2.9 years before death and the decline speed increased 5.6 times afterwards. Compared to non‐carriers, ε4 carriers had significantly lower cognition at death, earlier onset of terminal decline, faster pre‐terminal (β = ‐0.017, 95%CI = [‐0.023,‐0.012]) and terminal declines (β = ‐0.026, 95%CI = [‐0.044,‐0.008]) – equivalent to 2 years and 0.9 years of age effect respectively. Treated hypercholesterolemia and hypertension showed protective effects on cognitive trajectories, while depression showed adverse effect and no effect observed for diabetes. None of them changed the APOE adverse effects. No interactions were found between risk factors and APOE either (all p>0.05).

Conclusion

APOE ε4 carriers were associated with worse global cognitive trajectories before death and these were not impacted by depression, hypercholesterolemia, hypertension, or diabetes. The protective effects of treated hypercholesterolemia and hypertension on cognitive trajectory did not differ by APOE genotype.
Epidemiology of cognitive impairment in rural and urban settings in southern Peru
Authors: Rivera‐Fernandez Claudia , Herrera‐Perez Eder , Soto‐Añari Marcio F.
Published: January 2025

Background

In Peru, the prevalence of dementia is associated with a significant number of social, ethnic, and demographic factors. Data on prevalence is still limited, especially in regions distant from major urban centers. Our objective was analyze the prevalence of dementia in the southern population of Peru.

Method

We conducted an epidemiological study on cognitive impairment and dementia in southern Peruvian populations. A total of 314 older adults (mean age = 68.45, SD = 9.57), comprising 74.03% women and 25.96% men, were recruited from the city of Arequipa in the southern region of Peru. We applied a clinical protocol that included brief cognitive tests (Addenbrooke Cognitive Examination and Rowland Universal Dementia Assessment Scale (RUDAS)). Functional status measures were evaluated using the Pfeffer questionnaire (PFAQ). Additionally, a brief questionnaire on social determinants of health and clinical health information was administered. The cut‐off point of the brief cognitive test and functional measurement was applied to approximate the diagnosis. Binary logistic regression was performed with positive and negative cases as the dependent variable and gender, education, and ethnicity as predictors.

Result

We observed a global prevalence of 7.35%, which can vary according to the number of years of education. Individuals with more than 6 years of education showed a prevalence of 10.71%, while low‐educated populations exhibited a higher prevalence (23.53%). Additionally, we observed some minor variations based on ethnicity, health issues, and emotional states.

Conclusion

We identified a lower prevalence of cognitive impairment compared to previous reports. Social determinants of health appear to exert a significant impact on prevalence. This initial study in the southern Peruvian population highlights a noteworthy interaction between nature and nurture in the risk of dementia.
Age adjustment approaches to estimating the association of neuroimaging biomarkers and cognition in the oldest‐old, LifeAfter90 Study
Authors: Lor Yi , Posis Alexander Ivan B. , George Kristen M. , Peterson Rachel , Gilsanz Paola , Corrada María M. M. , Whitmer Rachel A.
Published: January 2025

Background

Appropriate methods for age adjustment in associations of neuroimaging and late‐life cognition is not well defined, especially among those 90+ years old. We examined how different age adjustment approaches affect the associations of MRI/PET‐based regional brain markers and cognitive change in the oldest‐old.

Method

LifeAfter90 is a diverse cohort study of adults ages 90+ in Northern California. We evaluated the associations of volumetric MRI/PET brain regions of interest (ROI) with change in executive function and verbal episodic memory over 8 visits (∼6 months apart) using linear mixed models. The cognitive domains were assessed with the Spanish and English Neuropsychological Assessment Scales. All ROI were adjusted for total cranial volumes while free water, fractional anisotropy, and amyloid standardized uptake ratio (SUVR) were not. Age‐adjustment was assessed using five approaches: 1) no adjustment, 2) residual age at MRI scan estimated from regression models on total cranial volume, 3) within model adjustment for age at baseline cognitive interview, 4) age at MRI scan, and 5) age at both baseline interview and MRI scan. All models adjusted for practice effects and interview mode (telephone/in‐person).

Result

Among 209 participants (mean age at baseline cognition = 91.7±2.0, mean age at imaging = 93.2±2.2), 58% were female, and 74% had some college or more. Older age at baseline cognitive assessment was associated with larger volumes in certain ROI (hippocampus, parietal, third ventricle), but lower in other ROIs (cerebrum gray, frontal) (Figure 1). Older age was also associated with higher white matter hyperintensities (WMH), free water, and amyloid SUVR. Adjustment for age using approaches 2‐5 resulted in no significant changes in the estimated association for each measure of ROI (e.g. hippocampus, third ventricle, WMH, amyloid SUVR) with baseline cognition and longitudinal cognitive change compared to approaches 1 (Figure 2). Model fit statistics (AIC, BIC, and log‐likelihood) indicate that approach 1 yielded the best fit.

Conclusion

Age adjustment does not meaningfully change the magnitude of the estimated association of neuroimaging biomarkers with baseline cognition and cognitive change. In those 90+, adjustment for age in models may not be necessary potentially due in part to the narrow age range and smaller age variation in this group.
Associations of several common infections with amyloid‐β pathology in vivo: a population‐based study
Authors: Felici Caterina , Green Rebecca E , Warren‐Gash Charlotte , Butt Julia , Waterboer Tim ,   Insight 46 study Team, Hughes Alun D , Schott Jonathan M , Keshavan Ashvini , Chaturvedi Nishi , Richards Marcus , Williams Dylan M
Published: January 2025

Background

Associations of common infections with Alzheimer’s disease have been reported, but potential mechanisms underlying these relationships are unclear. A hypothesised mechanism is amyloid‐beta (Aβ) aggregation as a defense mechanism in response to infection, with subsequent tau accumulation. However, no studies have assessed associations of infections with cerebral Aβ and tau pathology in vivo. We investigated relationships between serum antibodies to common infections and Aβ pathology quantified using PET in the Insight 46 neuroimaging cohort.

Method

Circulating antibody levels against 14 pathogens, measured at age 60‐64, were modelled as pathogen serostatus, cumulative pathogen burden, and seroreactivity tertiles. Their associations with Aβ‐PET positivity, assessed 7.3(±1.3) years after serology measurement, were modelled using multivariable logistic regression. Model 1 adjusted for sex and ages at serology and PET scan, models 2‐4 additionally adjusted for APOE ε4 carriage, education, and inflammatory markers respectively. We tested for interactions in associations by APOE ε4 carriage and education, and interactions between herpes simplex virus 1 and both cytomegalovirus and varicella‐zoster virus. Analyses were repeated using Aβ‐PET deposition as a continuous variable.

Result

424 individuals had serology and Aβ‐PET data (Tables 1 and 2). Individuals seropositive to Epstein‐Barr virus (EBV) had higher odds of Aβ‐PET positivity in all models, with a large point estimate but wide confidence intervals including null (Model 2: OR 3.11; 95% CI: 0.96,10.09; Figure 1). Similar patterns were observed when analysing Aβ‐PET continuously (Model 2: 22% higher burden; 95% CI: ‐4, 47%). Individuals seropositive to Toxoplasma gondii (T.gondii) had a higher likelihood of Aβ‐PET positivity with large confidence intervals including null (Model 2: OR 1.60; 95% CI: 0.87, 2.94; Figure 1). There was modest evidence for an interaction between human herpesvirus 7 (HHV7) and education in relation to Aβ‐PET positivity (lower Aβ risk among HHV7 seropositives with higher education). No other pronounced findings were observed.

Conclusion

Results suggest potentially strong associations of EBV and T.gondii seropositivity with Aβ burden, however, the large CIs including null suggest the study lacked power to generate precise estimates. Findings warrant replication in other larger cohorts and with other neurobiomarkers. We plan to expand our analyses to plasma p‐tau217 as another outcome (N≤1454).
Salivary biomarkers for the molecular diagnosis of Dementia with Lewy Bodies
Authors: D'Antonio Fabrizia , Vivacqua Giorgio , Serrentino Marco , Podgajna Martyna , Kaczynska Aleksandra , Peconi Martina , Bartolo Maria Ilenia De , Panigutti Massimiliano , Sepe‐Monti Micaela , Talarico Giuseppina , Fabbrini Giovanni , Bruno Giuseppe
Published: January 2025

Background

Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia. Although its prevalence, DLB is under‐investigated and frequently misdiagnosed and there are no available biomarkers. The aim of this study was to investigate salivary a‐synuclein (a‐syn) and tau species in DLB patients as potential disease biomarkers and to assess their potential in differential diagnosis with Alzheimer’s Disease (AD) and Parkinson’s Disease (PD).

Method

We measured total‐ and oligomeric a‐syn, total‐tau and S199‐phosphorylated‐tau (pS199‐tau) in the saliva from 21 DLB, 20 AD, 20 PD patients and 20 Healthy subjects (HC), using quantitative enzyme‐linked immunosorbent Assay (ELISA) analyses.

Result

Salivary total a‐syn was higher in DLB compared to PD, whereas all pathological groups had higher concentration of oligomeric a‐syn compared to HC. Salivary total‐tau concentration was higher in all the pathological groups compared to HC, whereas the concentrations did not differ among patients’ groups. Conversely, salivary levels of pS199‐tau were higher in DLB and AD patients in comparison to both HC and PD patients. Both correlation matrix and Principal Component Analysis showed that core clinical DLB features were related to a‐synuclein pathology, while the cognitive decline was associated with salivary levels of pS199‐tau. Receiver operating characteristic analysis reported high diagnostic accuracy for both a‐syn oligomers and pS199‐tau, between DLB and HC and an adequate accuracy between DLB and PD.

Conclusion

Salivary total and oligomeric a‐syn were accurate in differentiating DLB from HC, whereas pS199‐tau might represent a marker of cognitive decline. These findings provide a preliminary evidence that salivary a‐syn and tau species might be promising in identifying DLB patients with potential implications for early diagnosis and disease modifying therapies.
Association of Blood‐Based Biomarkers: GFAP, Amyloid 42/40 and Perivascular Spaces in Relation to Cognitive Domains in Vascular Cognitive Impairment Participants
Authors: Wang Jia Dong James , Leow Yi Jin , Vipin Ashwati , Sandhu Gurveen Kaur , Tanoto Pricilia , Azam Mohammed Adnan , Zailan Fatin Zahra , Lee Faith Phemie Hui En , Ghildiyal Smriti , Liew Shan Yao , Tan Isabelle Yu Zhen , Kandiah Nagaendran
Published: January 2025

Background

Perivascular spaces (PVS) are fluid‐filled spaces in the brain, hypothesized in promoting clearance of metabolites implicated in dementia through glymphatic system drainage. PVS are classified according to Grades (0‐4). Blood‐based biomarkers including Glial fibrillary acidic protein (GFAP), Amyloid β 42/40 (Aβ42/40) ratio have shown promise in diagnosing and prognosing dementia.

However, the association between blood‐based biomarkers and PVS remains relatively unexplored in Vascular Cognitive Impairment (VCI) participants. Thus, this study aims to characterize association between blood‐based biomarkers and PVS in relation to cognitive domains in VCI participants.

Method

Participants from the Biomarkers and Cognition Study, Singapore were included and VCI was defined in participants with confluent white matter hyperintensities (WMH), >1 lacunae and Montreal Cognitive Assessment (MoCA) score <26.

108 participants (mean age 67.3, education years 13.3, 51.9% females) were included.

Normality tests, multivariate ordinal correlation analysis was performed to understand association between blood‐based biomarkers and PVS grade, with correction for age, diastolic blood pressure and WMH.

Aβ42/40 and GFAP ratio values of 0.05 and 54.1pg/ml were utilized to segregate VCI participants to different subgroups (high vs low levels) and their association with cognitive domain performance was assessed.

Result

Higher GFAP (p=0.026) and lower Aβ42/40 ratio (p=0.049) was associated with higher PVS grade.

In the low Aβ42/40 ratio subgroup, higher PVS grade was most significantly associated with executive function impairment (p = 0.045, β = 0.612). For the subgroups of high Aβ42/40 ratio (p=0.017, β = 0.325), low GFAP (p = 0.027, β = 0.610), high GFAP (p = 0.006, β = 0.375), higher PVS grade was most significantly associated with learning and memory impairment.

Conclusion

These results demonstrate that low Aβ42/40 ratio, high GFAP levels were associated with higher PVS grade in VCI participants, suggesting their utility as markers for VCI.

Furthermore, higher PVS Grade in VCI participants with low Aβ42/40 ratio were associated with executive function impairment compared to other subgroups which were associated with learning and memory impairment. This could be an important clinical marker when examining patients with high PVS Grade as it could be associated with a more sinister disease progression.
Dynamic functional connectivity evolution across the Alzheimer's Disease spectra
Authors: Carrasco‐Gómez Martín , Cabrera Jesús , García‐Colomo Alejandra , Fernández Ricardo Bruña , Maestú Fernando , Santos Andrés ,   Center for Cognitive and Computational Neuroscience
Published: January 2025

Background

Recent studies in brain functional connectivity (FC) have shifted focus to dynamic functional connectivity (dFC), exploring transient aspects of FC over time. This shift is particularly relevant for Alzheimer's Disease (AD), as it involves altered cognition‐supporting networks. Our study aims to characterize the evolution of dFC across the entire pre‐dementia AD spectrum using Amplitude Envelope Correlation (AEC) recurrence matrices and to link this to cognitive decline.

Method

We analyzed 143 healthy controls (HC), 72 subjective cognitive decline (SDC) participants, and 106 Mild Cognitive Impairment (MCI) patients. Leakage‐corrected AEC was computed in alpha (8‐12 Hz) and beta (12‐30 Hz) bands from resting eyes‐closed magnetoencephalography (MEG) signals. Recurrence matrices representing dFC stability over time were obtained by correlating AEC matrices over signal segments. Between‐group differences were tested via linear regression, controlling for sex and age. Group differences were further explored with cluster‐based permutation tests (CBPT), and MCI whole‐brain stability was correlated with mini mental state evaluation (MMSE) scores. All results are FDR corrected (q = 0.05).

Results

Significant decreases in dFC stability between the HC and MCI groups were observed in both alpha and beta bands (Figure 1, alpha: p‐value < 0.001, β‐value = 0.0265; beta: p‐value < 0.001, β‐value = 0.0135). CBPT analyses identified significant differences in orbitofrontal and left temporal cortices in alpha (Figure 2A; p = 0.028), and in the left orbital and temporal regions and in several areas related to the Default Mode Network (DMN), including the hippocampus and precuneus in beta (Figure 2B; p = 0.009). Additionally, a significant inverse correlation between MCI whole‐brain stability and MMSE scores was found in both frequency bands (alpha: R = ‐0.27, p‐value = 0.0084; beta: R = ‐0.26, p‐value = 0.0117).

Conclusion

Our findings suggest a decrease in dFC dynamics along the AD continuum, particularly affecting orbitofrontal and temporal regions, as well as DMN‐related areas like the hippocampus and inferior parietal gyrus. These changes are inversely correlated with cognitive performance in MCI patients. This indicates that dFC parameters derived from AEC recurrence matrices could be valuable in identifying early AD progression.
Measurement of Blood GFAP Concentration to Evaluate KDS2010 (MAO‐B Inhibitor) Drug in APP/PS1 Mice Using a Magnetic Bead‐based Electrochemical Sensor
Authors: Cho Hana , Park Sang‐Heon , Jeong Yeeun , Park Jong‐Hyun , Lee Soo Hyun
Published: January 2025

Background

Blood GFAP levels have the potential to reflect and predict worsening disability in individuals with degenerative diseases such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). Recently published research suggests that blood GFAP levels can be used to detect even subtle damage to the degenerative disease. In this study, we evaluated the effectiveness of the KDS2010 (MAO‐B inhibitor) drug targeting AD by measuring blood glial fibrillary acidic protein (GFAP) levels in APP/PS1 mice using a magnetic bead‐based electrochemical sensor.

Method

Magnetic beads were coated with a primary antibody that was specifically bound to the antigen. Subsequently, the magnetic beads were incubated with 3 blood different samples from: 1) wild‐type (control, WT), 2) APP/PS1 model (TG), and 3) APP/PS1 + KDS2010 drug (TGD). The magnetic beads coated with the samples were measured using a nano‐gap based electrochemical sensor.

Result

The TG sample exhibited much lower impedance values compared to the WT sample due to the high concentration of GFAP in the blood. On the other hand, the TGD samples showed a value (‐8.1%) similar to that (‐5.6%) of the WT samples, as shown in Figure 1. This result means that KDS 2010 (MAO‐B inhibitor) plays a good role in suppressing the reactivity of astrocytes. And then, blood GFAP levels can be lower after KDS 2010 treatment.

Conclusion

We validated the effectiveness of the KDS2010 in APP/PS1 mice with a magnetic bead‐based electrochemical sensor. Successful validation of a point‐of‐care platform for blood GFAP could increase the diagnostic reliability of AD, which could have a significant economic impact on the dementia diagnostics market.
Initial evaluation rate invariance for Alzheimer’s Disease drug trials after first appointment modification
Authors: Lee Ralph , Huoh Yu‐Jay , Martinez Brenda , Lee Elly
Published: January 2025

Background

Recruiting large numbers of study participants for Alzheimer’s Disease (AD) drug trials remains a significant challenge in need of more effective approaches. Advertising can be an effective way to reach large numbers of prospective participants, but can suffer from low attendance rates. This study examined the relationship between the initial behaviors of prospective AD trial participants who did not attend their first scheduled appointment and their overall likelihood of eventually attending an in‐person consultation.

Method

In 2023, 4,043 potential participants were identified through online advertising and scheduled for 5,561 appointments for an in‐person pre‐screen at a commercial research site. Only 45.0% attended their first scheduled appointment. In lieu of attending their first scheduled appointment, 32.3% (n = 1,307) called in to the clinic to modify (i.e. cancel or reschedule) their first scheduled appointment and the remaining 22.7% (n = 915) simply did not attend their first scheduled appointment. Recruiters attempted to reschedule the latter group for another appointment.

Result

Of the 4,043 potential participants who were ever scheduled for an in‐person pre‐screen, 55.8% of these participants eventually attended an appointment, whether during the first or subsequently scheduled appointments.

Of the 1,307 potential participants who called in to modify their first scheduled appointment, 506 of these potential participants were scheduled for a subsequent appointment, with 57.3% of these persons eventually attending. This deviation from the 55.8% overall attendance rate is not statistically significant (p = 0.50).

However, of the 915 potential participants who simply did not attend their first scheduled appointment, 352 were scheduled for a subsequent appointment. Of these 352, only 43.5% eventually attended an appointment. This deviation from both the overall attendance rate and the attendance rate for those who modified their first appointment were highly significant (p < 1e‐4 for both).

Conclusion

Potential AD trial participants who modify their first appointment are adequately engaged in the process, and so not attending their first appointment does not adversely affect their chances of attending a pre‐screen. In contrast, potential participants who simply do not show up are much less likely to ever attend any appointment (almost 25% relative, >13% absolute).
Is the residual approach reliable to estimate resilience to Alzheimer’s disease pathology? Comparison among different methods
Authors: Mutel Sophie , Quattrocchi Lara , Altomare Daniele , Scheffler Max , Chicherio Christian , Blennow Kaj , Zetterberg Henrik , Garibotto Valentina , Ashton Nicholas J. , Frisoni Giovanni B , Ribaldi Federica
Published: January 2025

Background

Resilience, the ability to maintain normal cognition (cognitive resilience, CR) or brain integrity (brain resilience, BR) despite neuropathological burden, is often quantified using the residual approach. This method calculates residuals from a linear regression where the dependent variable is brain volume or cognition, and the independent variable is neuropathology. Residuals can be corrected to render them independent from the dependent variable, but comparative analyses of residual correction methods within memory clinic populations are scarce. Our study aims to bridge this gap by comparing non‐corrected and corrected residual approaches.

Methods

112 MCI patients from the Geneva Memory Center who underwent amyloid‐PET (A), tau‐PET (T), MRI (N), and clinical and neuropsychological assessments were included. Standardized residuals were extracted from linear regression models between hippocampal volume and AT (BR) or MMSE scores and ATN (CR). We compared: (i) non‐corrected residuals (nBR and nCR); (ii) residuals corrected by regressing the dependent variable out of the residuals (cBR and cCR); (iii) non‐corrected residuals with the dependent variable included as covariate (covBR and covCR). Associations between CR or BR and demographic, clinical, cognitive, and biomarker variables were investigated. Linear mixed models explored the impact of CR and BR on cognitive trajectories over time. Results were compared with non‐residual based statistical models.

Results

Corrected and non‐corrected approaches yielded significantly different results. Several factors were associated with nBR, but not with cBR or covBR, such as age (nBR: β = ‐0.399, p < 0.001; cBR: β = ‐0.048, p = 0.641; covBR: β = ‐0.012, p = 0.614). Conversely, several factors were associated with cBR and covBR, bur not nBR, such as female sex (nBR: β = ‐0.102, p = 0.619; cBR: β = ‐0.506, p = 0.012; covBR: β = ‐0.108, p = 0.013). Similar results were observed with CR. Longitudinal assessments also indicated differences in the relationship between corrected/non‐corrected resilience and cognitive trajectories. For example, there was a significant interaction of time x cBR on MMSE scores (p < 0.001), but not of time x nBR (p = 0.226)

Conclusion

Researchers should be aware that the choice of residual correction method significantly influences study conclusions. Our findings emphasize the necessity of adopting sophisticated modeling approaches to accurately capture resilience.
Translation and Cultural Adaptation of Tools to Assess Diverse Asian American and Asian Canadian Populations: The Asian Cohort for Alzheimer’s Disease Study
Authors: Lee Haeok , Tzuang Marian , Chow Tiffany W , Kang Younhee , Tee Boon Lead , Li Clara , Ho Pei‐Chuan , Gu Yian , Lu Anna T. , Choi Yun‐Beom , Jun Gyungah R , Wang Li‐San , Yu Haung (Ho) , Park Van Ta ,   The Asian Cohort for Alzheimer’s Disease Study
Published: January 2025

Background

Socio‐cultural and language‐appropriate study materials and instruments are critical for accurate assessment of cognitive function in people from diverse backgrounds. Most research uses cognitive tests based on Western, industrialized, English‐speaking cultures and may not reflect global experiences. The purpose of this study was to describe the translations of study materials and cultural adaptations that were developed for the Asian Cohort for Alzheimer’s Disease (ACAD).

Methods

Multi‐lingual researchers, clinicians, and community leaders with extensive practical translation experience created materials and instruments in accordance with World Health Organization (WHO) guidelines, using a translation process that consisted of preparing materials, translating materials, conducting a committee review, conducting a pretest (as appropriate), and conducting necessary revisions. The ACAD study population speaks Chinese (Simplified and Traditional), Korean, or Vietnamese. The majority of instruments in the protocol harmonize with the National Alzheimer’s Coordinating Center purposefully, warranting both literal and conceptually cultural‐appropriate translations for our older Asian American and Asian Canadian participants.

Results

We have developed Asian language versions of the ACAD informed consent, data collection packet, and community outreach materials for all our target groups. Many cognitive tools had been previously translated into Asian languages and made minor modifications. Some items required cultural adaptations to reflect the socio‐cultural background of the targeted Asian languages, e.g., the types of physical activities or dietary choices surveyed.

Conclusion

This multi‐stage translation process accounts for the distinctive socio‐cultural and language backgrounds of each Asian population. Alzheimer’s disease and related dementias researchers interested in engaging with these populations may apply this translation process to reduce health disparities in these underrepresented populations. To ensure fidelity across different languages, ACAD will continue to engage in this comprehensive translation process with our diverse community stakeholders.
Results from a Phase 2a Proof‐of‐Concept Double‐Blind, Randomized, Placebo‐Controlled Trial of Lomecel‐BTM in Mild Alzheimer’s Disease Dementia
Authors: Ramdas Kevin N. , Agafonova Nataliya , Hare Joshua M. , Naioti Eric , Kopcho Steven , Cummings Jeffrey L. , Carballosa Raul , Patel Paayal , Brody Mark , Herskowitz Brad , Fuquay Ana , Rodriguez Savannah , Botbyl Jeffrey , Rash Brian , Oliva Anthony A.
Published: January 2025

Background

Lomecel‐B is a novel cell‐based therapy with potential to demonstrate clinical benefit on Alzheimer’s disease (AD) and its progression. Here we present the results of a phase 2a proof‐of‐concept trial (n = 49) to further define the potential of Lomecel‐B in patients with mild AD dementia.

Methods

This double‐blind, randomized, placebo‐controlled 45‐week trial (ClinicalTrials.gov: NCT05233774) enrolled patients (60‐85 yrs.) with mild AD dementia (MMSE score 18‐24); with evidence of amyloid on positron‐emission tomography (PET) and brain MRI consistent with AD. There were 4 study arms of Lomecel‐B intravenous infusion: 25 million (25M) cells once followed by 3 infusions of placebo (N = 13); 25 million (25M) cells (N = 13) or 100 million (100M) cells (N = 11) monthly for 4 months; 4 IV infusions of Placebo (N = 12). The primary endpoint was safety, secondary endpoint was change from baseline to Week 39 in Composite AD Score (CADS) that equally incorporated z‐scores of CDR‐SB, ADAS‐Cog‐13, ADCS‐ADL, and left hippocampal volume.

Results

The trial achieved its primary endpoint of safety and tolerability (no infusion‐related reactions, ARIA or death). One SAE occurred within 30 days post‐infusion for each Lomecel‐B group with none for placebo. Lomecel‐B 25Mx1 demonstrated a trend toward slowing of disease progression relative to placebo on the CADS score (0.38 [‐0.06, 0.82], p = 0.091 (pre‐specified level of significance for CADS is p = 0.1)). While CADS declined by ‐0.25 [95% CI, ‐0.56, 0.07] in placebo, no decline occurred in the individual or pooled Lomecel‐B treatment groups. Regarding cognitive function, MoCA improved vs placebo (25Mx1: (4.90 [95% CI, 1.26, 8.55], p = 0.009) and (pooled: 3.74 [95% CI, 0.73, 6.75] p = 0.015). ADRQL and QOL‐AD were numerically improved in Lomecel‐B treatments; with significant improvement observed in the ADCS‐ADL for the 100M×1 (10.74 [95% CI, 0.50, 20.98] p = 0.040) and pooled group at Week 39 p = 0.047). Lomecel‐B slowed whole brain volume loss by 49% (100Mx4 (8.31 [95% CI, 0.12, 16.50] p = 0.034) with significant preservation of left hippocampal volume (pooled: 0.0253 [95% CI, 0.0015, 0.0492] p = 0.038), Week 39 compared to placebo.

Conclusion

Together, the study achieved proof‐of‐concept in a small sample size. Accordingly, these findings support further development of Lomecel‐B in a larger dose‐finding study.
Attributable fractions of risk factors for cognitive impairment in the ELSA‐Brasil cohort
Authors: Castilhos Raphael Machado , Leotti Vanessa Bielenfeldt , Feter Natan , Duncan Bruce , Schmidt Maria Inês
Published: January 2025

Background

Attributable fractions (AFs) of the modifiable risk factors of dementia are usually calculated using population‐based samples. Nevertheless, assessing AF within cohorts offers a more nuanced perspective on the impact of these factors. We aimed to estimate the relative risks (RRs) for cognitive impairment (CI) for eight risk factors for dementia and their respective AF in the Longitudinal Study of Adult Health (ELSA‐Brasil).

Methods

A global cognitive function score was established by averaging Z scores from six standardized tests. Risk factors and sociodemographic variables were collected between 2008 and 2010, while CI (defined as < ‐1.5 SD on the global cognition Z score) was assessed approximately 10 years later. Participants with CI in the baseline were excluded. We calculated the RR for CI of eight risk factors (physical inactivity, depression, tobacco use, excessive alcohol consumption, obesity, low education, diabetes and hypertension) using a robust Poisson model. AFs were computed using the average attributable fraction method.

Results

Of the 15,105 individuals of the ELSA‐Brasil, 10,058 were included in this analysis. At baseline, the median (IQR) age was 50 (44‐56) years and 56.7% (5,704) were women. The incidence of CI was 5.5% (n = 549). RRs for CI were significant for low education (4.37, 3.61‐5.29), hypertension (1.43, 1.21‐1.7), smoking (1.37, 1.09‐1.71), diabetes (1.27, 1.05‐1.54), in addition to male sex (1.31, 1.11‐1.55) and older age (1.07, 1.06‐1.08). Adjusted risks for depression, physical inactivity, excessive alcohol consumption and obesity were not significant. Low education had the highest AF (CI 95%), 14.3% (10.8‐17.7), followed by hypertension, 13.1% (6.8‐19.4), diabetes, 4.3% (0.4‐8.1) and smoking 3.3% (0.5‐6.1). The total AF for CI was 35% (28‐42).

Conclusions

This is the first assessment of AF of the modifiable dementia risk factors in a Brazilian cohort, with RR calculated directly from the sample. In the ELSA‐Brasil, assuming causality, around one‐third of cognitive impairment cases could be prevented if these four risk factors were eliminated.
The Relationship between Cancer Diagnosis Timing and Cognition in Older Adults in the National Health and Nutrition Examination Survey
Authors: Chen Annie , Bowles Erin J Aiello , Chubak Jessica , Cosentino Stephanie , Genkinger Jeanine M , Levine Deborah A , Tehranifar Parisa , Wolfova Katrin , Tom Sarah E.
Published: January 2025

Background

Cancer diagnosis is related to poor short‐term cognition, reflecting the condition, stress, and management. Less is known about long‐term relationships between time since cancer diagnosis and cognition. We evaluated the association between recency of cancer diagnosis and cognition.

Method

The National Health and Nutrition Examination Survey is a nationally representative, cross‐sectional survey of community‐dwelling people in the United States. In 2011‐2012 and 2013‐2014, the study included questions on the timing of cancer diagnosis. Participants age ≥ 60 years completed the Digit Symbol Substitution Test and the Consortium to Establish a Registry for Alzheimer’s Disease Total Learning Test and Recall Test. Our analytic sample included individuals age ≥ 60 years who reported a cancer diagnosis and completed all cognitive tests. We calculated z‐scores for each cognitive test and a global score (sum across individual z‐scores). We used linear regression to assess the relationship between time since cancer diagnosis (current ‐5 years, >5 years) and cognition. We estimated an age and sex‐adjusted model and included potential confounders in a series of nested models, with each step adding: race and ethnicity, education level, marital status, and health insurance status. Analyses were weighted such that results represent the US community‐dwelling population.

Result

The analysis sample included 477 participants who ever had a cancer diagnosis, excluding unknown and non‐melanoma skin cancers, corresponding to an implied population of 9,027,595 (including 11% melanoma skin, 23% breast, 16% prostate) with a mean age of 71.2 years (SD = 6.6). A total of 31% of participants reported a cancer diagnosis within the past five years. Demographic characteristics were similar based on cancer diagnosis timing. Adjusting for age and sex, participants greater than five years from cancer diagnosis had a higher cognition level, compared to those with a cancer diagnosis within five years (coefficient = 0.22, 95% CI = 0.05, 0.39). Results were similar when adjusting for additional covariates.

Conclusion

Among older adults who ever had a cancer diagnosis, a diagnosis that occurred more than 5 years ago was related to better cognition. Future studies should investigate the roles of cancer site, treatments, and stage at diagnosis in this relationship.
Risk Factors and Brain Substrates of Motoric Cognitive Risk Syndrome in Rural and Urban Residents: Results from the Kerala‐Einstein Study
Authors: Emmeline Ayers , Blumen Helena M , Delpratt Natalie A , Adhikari Dristi , Verghese Joe
Published: January 2025

Background

Rural populations are under‐represented in cognitive studies worldwide. The few extant studies report differences in risk profiles for pre‐dementia and dementia syndromes among urban and rural residents. We compared risk factors and brain substrates of Motoric Cognitive Risk (MCR) syndrome, a pre‐dementia syndrome identified by slow gait speed and subjective cognitive concerns, in urban and rural participants in the Kerala‐Einstein study.

Method

Participants (aged 60+) are recruited from rural and urban sites in Kozhikode district, Kerala, India. Participants with possible dementia were excluded (score ≤4 on the Picture‐Memory Impairment Screen). Logistic regression was used to identify risk factors of MCR in rural and urban residents. Multivariate general linear models were used to examine the relationship between MCR and brain structures as a function of residency.

Result

334 rural (M age = 68.7±5.1; 64% male, 20% high school graduates) and 299 urban (M age = 68.7±6.1; 60% male, 25% high school graduates) participants without dementia were examined. MCR prevalence was similar in rural (10%) and urban (9%) settings. Individuals with MCR in both samples reported more depressive symptoms and fewer years of education. Urban MCR participants were more likely to use a hearing aid, have apathy, and have occupations that involved manual labor. Modeled simultaneously, hearing aids (p = 0.05) and manual labor (p = 0.027) were associated with MCR in urban settings, and education years (p = 0.010) in the rural setting. In a subset of participants with MRI (N = 213; 145 Urban; 68 rural; 15% MCR), significant interactions between MCR and residency were observed for the right frontal cortical thickness (p = 0.005) and left hippocampal volume (p = 0.018) such that a significant association was only observed in the urban residents – after adjusting for age, sex, education, overall white matter lesion burden, total intracranial volume, and depressive symptoms. After adjusting for apathy, only the association between MCR and left hippocampal volume remained significant.

Conclusion

The risk factors and the brain substrates associated with MCR differ in urban and rural residents from Kerala, India, and have implications for designing interventions and understanding the pathophysiology of MCR.
Event‐based modeling of T‐N mismatch reveals distinct spatio‐temporal trajectories of subtypes with likely co‐pathology in Alzheimer’s disease
Authors: Lyu Xueying , Yushkevich Paul A. , Hrybouski Stanislau , Li Yue , Duong Michael Tran , Xie Long , Wisse Laura E.M. , de Flores Robin , Irwin David J , Dickerson Bradford C. , Nasrallah Ilya M. , Das Sandhitsu R. , Wolk David A
Published: January 2025

Background

The heterogeneity of Alzheimer’s disease (AD) and lack of well‐validated markers of co‐pathologies present a substantial challenge for therapeutics. We previously found phenotypes defined by Tau (T) ‐ Neurodegeneration (N) discordance linked to non‐Alzheimer’s pathologies (e.g. TDP‐43, vascular disease). In this work, we aim to leverage T‐N mismatch for identifying distinct spatial‐temporal progression patterns of non‐AD pathologies.

Method

We performed T‐N regression on 1040 scan pairs (n=722 individuals) from ADNI, using cortical thickness (N) and 18F‐Flortaucipir uptake (T) in 20 bilateral cortical regions of interest. As in previous work, residuals were identified as canonical (T∼N), vulnerable (N>T) and resilient (N<T). Here, we apply SuStaIn, a phenotype discovery and stage inference algorithm, to standardized T‐N residuals in canonical and vulnerable cases (n=608), expecting the latter would reflect co‐pathologies.

Result

Besides the "canonical" subtype (S0), SuStaIn identified three subtypes with distinct T‐N mismatch (N>T) progression profiles (Figure 1). Two exhibited different but progressively diffuse spatial patterns of T‐N mismatch — the anterior subtype (S1) starting from frontal, and the posterior subtype (S2) initiating from occipital/temporal regions. The third subtype (S3) exhibited temporal‐limbic mismatch patterns, with spreading to anterior limbic regions.

The three mismatch subtypes had worse cognition, greater age and larger rate of amyloid positivity than canonical subtype (Table 1). SuStaIn‐identified stage was associated with age and worse cognition but not tau severity (Figure 2A‐C), indicating the stages do not represent AD progression. The anterior subtype had the largest white matter hyperintensity (WMH) volume, increasing with higher stages (Figure 2D), suggesting an association with vascular disease. The temporal‐limbic subtype demonstrated poorest memory performance (Figure 2E) and may be associated with TDP‐43 pathology, as suggested in our prior work. 90.1% with longitudinal scans did not change subtype or transitioned from canonical to mismatch subtypes (Figure 2F), supporting the stability of classifications.

Conclusion

We identified distinct T‐N mismatch progression trajectories in AD, potentially reflecting progression of co‐pathologies. It is important to better define these groups in the context of anti‐amyloid therapies to better understand their effectiveness in populations with likely co‐pathology and whether these mismatch trajectories driven by non‐AD factors would continue independent of treatment.
Reduction in Alzheimer’s disease brain atrophy by MRI measures in a phase 2a clinical trial of Lomecel‐BTM
Authors: Ramdas Kevin N. , Agafonova Nataliya , Hare Joshua M. , Naioti Eric , Kopcho Steven , Carballosa Raul , Patel Paayal , Brody Mark , Herskowitz Brad , Fuquay Ana , Rodriguez Savannah , Botbyl Jeffrey , Rash Brian , Oliva Anthony A.
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized by progressive atrophy of the cerebral cortex and hippocampus, with concomitant increase in ventricular volume. Lomecel‐B is a novel cell‐based therapeutic approach to AD that targets neuroinflammation, microvascular dysfunction, and has the potential to stimulate endogenous tissue regeneration. We conducted MRI analysis of brain morphology in the CLEAR‐MIND study, a 49‐patient proof‐of‐concept study that tested 3 different dosing regimens of Lomecel‐B vs placebo in patients with mild AD dementia.

Methods

This double‐blind, randomized, placebo‐controlled 45‐week proof‐of‐concept trial (ClinicalTrials.gov: NCT05233774) enrolled patients (60‐85 yrs.) with mild AD dementia (MMSE score 18‐24); with evidence of amyloid on positron‐emission tomography (PET) and brain MRI consistent with AD. There were 4 study arms of Lomecel‐B intravenous infusion: 25 million (25M) cells once followed by 3 infusions of placebo (N = 13); 25M cells (N = 13) or 100 million (100M) cells (N = 11) monthly for 4 months; 4 IV infusions of Placebo (N = 12). Lomecel‐B treatment groups were evaluated for individual and pooled (25Mx1, 25Mx4, 100Mx4) groups vs placebo, n = 32.

Results

Patients receiving Lomecel‐B exhibited slowing of whole brain atrophy (pooled: reduced by 48% vs placebo, p = 0.005). Lomecel‐B exhibited reduced left, right and bilateral hippocampal atrophy by 62%, p = 0.021, 53%, p = 0.073 and 59%, p = 0.013, respectively. At Week 39, left, right and bilateral ventricular enlargement were reduced in Lomecel‐B pooled group by up to 34%, p = 0.097, 40%, p = 0.044 and 37%, p = 0.066 respectively, compared to placebo. Moreover, diffuse tensor imaging (DTI) used to index neuroinflammation indicated increased inflammation in AD placebo but substantial reduction in the Lomecel‐B pooled group, particularly the cingulate cortex (100% reduction, p = 0.002).

Conclusion

Brain MRI in this proof‐of‐concept study with small sample size reveals that Lomecel‐B was associated with measurable neuroanatomical and neuroinflammatory improvements compared with progressive AD pathology observed in placebo. Accordingly, these findings support further development of Lomecel‐B in a larger dose‐finding study.
Community‐based centers for people living with dementia and family caregivers: implementation and adaptation from pilot to national policy
Authors: Gajardo Jean , Aubert Josefina , Moreno Ximena , Aravena Jose M , Carcamo Felipe , Barrientos Carolina , Abusleme Maria T , Mascayano Franco
Published: January 2025

Background

Community‐based centers for people living with dementia (PLWD) have been implemented as part of the National Plan of dementia in Chile, delivering a multicomponent and multiprofessional intervention to support the PLWD and their families, integrating social and clinical aspects. We sought to examine the implementation and adaptation of these centers, transitioning from adult day services to a community‐based dementia care model that has escalated to a public policy.

Method

We conducted a realistic evaluation using multiple qualitative data collection strategies and informants to analyze complex interventions, in 4 of a total of 9 centers. Key informants of the centers’ implementation were identified and participated in individual interviews or focus groups, at different levels (macro‐level of centralized policy, n:4; meso‐level of intervention deliverers and center coordinators, n: 27; and micro‐level of user family caregivers, n:14). Interviews and focus groups were audio‐recorded and transcribed. Rapid qualitative analysis was used with predetermined codes describing implementation according to the Active Implementation Frameworks and Implementation Outcomes.

Result

At a macro‐level of implementation, the centers have not experienced relevant transformations, and fidelity is tensioned due to lack of updated centralized technical orientations. At a meso‐level, the centers’ intervention has been adapted to improve sustainability and appropriateness, which has enhanced their scalability. Engagement with the local service network and tailoring according to geographic and cultural context, emerged as implementation drivers. Relevant points of agreement and disagreement regarding implementation among actors were identified.

Conclusion

The implementation of community centers for PLWD in Chile, at a policy macro‐level the program has been continuous and stable. Most relevant implementation drivers and adaptations are identified at a meso‐level, which stresses the need to identify core components and processes for standardization and later evaluation and monitoring. Points of agreement and disagreement among the three levels are key for understanding priorities for improvement and impact.