bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual Cognitive Assessment Test (VCAT): A language‐neutral test to detect mild cognitive impairment and dementia in multinational cohorts
Authors: Ng Kok Pin , Ong Gwen Cui Fann , Saffari Seyed Ehsan , Bernardes Marina Musse , de Carvalho Antonella Brun , Schilling Lucas Porcello , Ranganathan Anandhi , Raghu Rema , Rosa‐Neto Pedro , Gauthier Serge , Liu Yidan , Li Xiaofeng , Baek Min Jae , Kim SangYun , Kandiah Nagaendran
Published: January 2025

Background

Cognitive assessments are essential for the diagnosis of mild cognitive impairment (MCI) and dementia. However, existing tests are mostly developed in English‐speaking cohorts. Hence, their application in multilingual populations will need translation which may affect their test psychometrics. VCAT is a language‐neutral visual‐based assessment that is developed to address this issue. While VCAT was validated in Southeast Asian countries, its performance in diverse language cohorts remains unclear. Here, we aim to compare the utility of VCAT with established screening tests, Montreal Cognitive Assessment (MoCA) and Mini‐Mental State Examination (MMSE), in distinguishing MCI and dementia from cognitively normal (CN) individuals in a multinational study.

Methods

This study supported by the Alzheimer’s Association has recruited 670 participants (294 CN, 244 MCI, 132 Dementia) from Brazil, Canada, China, India, Korea and Singapore and recruitment is ongoing. We standardized the administration of MMSE, MoCA and VCAT across all study sites. Participants answered a questionnaire on their demographics and underwent cognitive assessments (MMSE, MoCA and VCAT) on the same day. The performance of VCAT in distinguishing MCI and dementia from CN were assessed within each sites using the area under the curve (AUC) analysis.

Results

The demographics, diagnosis and cognitive scores of the participants from each site were summarized in Table 1. The AUCs of VCAT in detecting MCI+Dementia vs CN were 0.979 for Brazil, 0.708 for Canada, 0.929 for China, 0.956 for Korea, 0.808 for India and 0.731 for Singapore. In comparison, the AUCs of MoCA in detecting MCI+Dementia vs CN were 0.771 for Brazil, 0.751 for Canada, 0.899 for China, 0.964 for Korea, 0.806 for India and 0.682 for Singapore, while the AUCs for MMSE in detecting MCI+Dementia vs CN were 0.896 for Brazil, 0.721 for Canada, 0.891 for China, 0.895 for Korea, 0.712 for India and 0.640 for Singapore.

Conclusion

VCAT showed satisfactory discriminative validity in differentiating MCI+Dementia from CN participants within multinational, multilingual cohorts. VCAT was also comparable to the MoCA and MMSE. Further analysis in a larger cohort within our study will be performed to validate the utility of VCAT globally.
Informant characteristics are associated with the Clinical Dementia Rating Sum of Boxes scores in the Alzheimer’s Disease patients participating in the National Alzheimer’s Coordinating Center Uniform Data Set
Authors: Vargas‐González Juan‐Camilo , Santuccione Antonella , Castro Laura , Ferretti Maria Teresa , Tartaglia Maria Carmela
Published: January 2025

Background

The Clinical Dementia Rating Sum of Boxes (CDR‐SB) is a widely used measurement score to stage dementia severity; it has become one of the most common outcome measurements in Alzheimer’s Disease (AD) research. The CDR‐SB requires an informant to provide information to stage a patient’s dementia severity. The effect of the informant’s characteristics including sex and relationship with patients on the CDR‐SB is unknown. We aimed to evaluate the effect of the informant’s sex and relationship to the patient on the CDR‐SB scores in patients with Alzheimer’s Disease with mild cognitive impairment or dementia included in the National Alzheimer’s Coordinating Center Uniform Data Set (NACC‐UDS).

Method

We included all participants from the NACC‐UDS that had AD as the principal diagnosis, with information about the Mini‐Mental State Examination or Montreal Cognitive Assessment scores, and informant sex and relationship to patient; we also analyzed the possible interaction between these characteristics, and the outcome was the CDR‐SB. We performed a conditional growth model using multilevel linear regression analysis.

Result

We included data from 20636 participants, totalling 47727 visits with a median of 2 (1‐4) visits. Patients' age at the initial visit was 74.0±9.4 years and 54.1% were females. Informant characteristics were mean 66.2±13.2 years of age, 69.1% were females, and the relationship to patients was 60.5% spouse or partner, 26.7% children and 12.8% other relation. The CDR‐SB scores were 0.20 (CI 95%: 0.11 to 0.29) higher when the informant was female. When comparing to informant’s relationship with the baseline being spouse or partner, the CDR‐SB was 0.39 (CI 95%: 0.25 to 0.53) higher when the informant was the child of the patient and 0.18 (CI 95%: ‐0.35 to ‐0.01) lower if other relationship. The only significant interaction was between informant relationships other than spouse or child and female patients where the scores were 0.24 (CI95%: 0.03 to 0.46) higher.

Conclusion

We found that the CDR‐SB scores are significantly modified according to informant characteristics in the NACC‐UDS patients with AD diagnosis. These results are clinically relevant because informant characteristics should not affect AD patient staging, and future research should evaluate how to manage these confounding variables.
Affective symptoms and quality of life in persons experiencing subjective cognitive decline: A cross‐sectional analysis
Authors: Watry Rebecca Ann‐Maria , Hadidi Niloufar , Kreitzer Mary Jo , Bhimani Rozina , Yu Fang , Salisbury Dereck L.
Published: January 2025

Background

Subjective Cognitive Decline (SCD) is a prevalent condition impacting 11.7% of older adults, which increases the risk for mild cognitive impairment and dementia. The transition to SCD and dementia is often accompanied by an increase in affective symptoms (i.e., anxiety and depression) and decreased quality of life (QoL). Affective symptoms in SCD increase the risk of Alzheimer’s disease (AD) compared to SCD alone. SCD plus (SCD+) is a condition that is known to increase the likelihood of preclinical AD, including amyloid‐beta and pathologic tau deposition. The relationships among SCD symptoms, affective symptoms, and QoL have been observed; however, they remain poorly understood. We aimed to explore the associations between SCD, affective symptoms, and QoL and identify any differences within the SCD+ subset of individuals.

Methods

Community‐recruited individuals with SCD (n = 38) were divided into two groups SCD+ (those with >3 SCD+ features [Table 1]) and non‐SCD+. We used correlational analysis to determine relationships among SCD symptoms, affective symptoms, QoL overall, and four QoL domains.

Results

The mean age of participants was 74.6 (7.5) years of age (Table 2). Demographic variables were not significantly different between groups. In the entire sample, significant correlations were found between anxiety and depressive symptoms (r = 0.44, p = <0.01); anxiety symptoms with overall (r = ‐0.38., p = 0.02), physical (r = ‐0.39, p = 0.02), and psychological QoL (r = ‐0.57, p <0.01); and depressive symptoms with overall (r = ‐0.49, p = <0.01), physical (r = ‐0.49, p = <0.01), psychological (r = ‐0.53, p = <0.01), and social (r = ‐0.35, p = 0.03) QoL (Table 3). Some of these correlations remained significant in the SCD+ group.

Conclusion

A significantly positive correlation exists between anxiety and depressive symptoms in SCD. Multiple negative correlations exist between affective symptoms and QoL in SCD. Some of these remain significant in those with SCD+. This research provides preliminary information on the relationships between SCD symptoms, affective symptoms, and QoL. Further research with a larger sample is necessary to better understand the interactions between SCD and SCD+ with affective symptoms and QoL.
Characterizing accelerated long‐term forgetting in preclinical Alzheimer’s disease using the Boston Remote Assessment for NeuroCognitive Health (BRANCH)
Authors: Molinare Cassidy , Soberanes Daniel , Dubbelman Mark A. , Hsieh Stephanie , Johnson Keith A , Sperling Reisa A , Rentz Dorene M , Marshall Gad A , Amariglio Rebecca E , Papp Kathryn V , Jutten Roos J
Published: January 2025

Background

Accelerated long‐term forgetting (LTF) is characterized by unimpaired retention of information after short‐term delays (e.g., 20‐30 minutes) with increased forgetting at longer intervals (e.g., weeks to months). Previous studies have suggested that assessing LTF may provide a useful marker of preclinical Alzheimer’s disease (AD). However, assessing LTF over longer intervals is challenging using standardized in‐clinic paper‐pencil cognitive tests. Here, we leverage remote, digital cognitive testing to investigate LTF at different timepoints and its association with AD biomarkers in cognitively unimpaired (CU) older adults.

Method

N = 61 CU older adults (age = 76.5±8.5, 67.2% female, 18% Aβ+) with amyloid (PiB) and tau (FTP) PET completed the Boston Remote Assessment for NeuroCognitive Health (BRANCH) at‐home on a personal device for seven consecutive days, including a Face‐Name Matching Task with identical stimuli each day. Learning across seven days was quantified using a previously validated multi‐day learning curve (MDLC) metric. Participants were asked to recall previously learned face‐name pairs after 1‐week (Median = 8(IQR = 7‐35) days) and after 6 months (Median = 6.67(IQR = 6.35,7.85) months). LTF was computed by dividing the percentage of correctly recalled face‐name pairs by a participant’s maximum performance during the 7‐day learning phase. We used linear regression models to examine the associations between LTF and initial MDLCs, global amyloid burden, entorhinal cortex (EC) and inferior‐temporal (IT) tau deposition, correcting for age, sex, and education when needed (covariates with a p‐value > 0.1 were excluded).

Result

Better initial MDLCs were associated with less accelerated LTF after 1 week (β = 0.55,95%CI[0.00‐1.09],p = 0.048), but not after 6 months (β = 0.34,95%CI[‐0.35–1.02],p = 0.329). There were no associations between LTF and global amyloid burden. However, higher EC tau was associated with accelerated 1‐week LTF (β = ‐0.18,95%CI[‐0.31—0.05],p = 0.009) but not with extended LTF(β = ‐0.14,95%CI[‐0.35–0.07],p = 0.172). In contrast, higher IT tau was associated with accelerated LTF after 6 months (β = ‐0.38,95%CI[‐0.75—0.01],p = 0.045), but not after 1 week (β = ‐0.15,95%CI[‐0.43–0.13],p = 0.280) (Figures 1‐2).

Conclusion

We showed that 1‐week LTF is associated with initial learning and EC tau, and LTF at an extended interval of 6 months was associated with IT tau. This suggests that accelerated LTF may be an early cognitive sign in preclinical AD, but that assessing LTF over different time intervals may reveal unique information.
The role of negative affect, depression, and perceived disease susceptibility in self‐reported dementia worry
Authors: Gehling Jacklyn , Jacova Claudia , Robertson Frank , Dhaliwal Ravneet K.
Published: January 2025

Background

Worry about developing Alzheimer’s disease and related dementias (ADRD), otherwise known as dementia worry, is a construct of significant interest in ADRD‐related health behaviors. In the present analysis, we aimed to understand dementia worry in the framework of the Health Belief Model by investigating the contribution of perceived risk/susceptibility and psychological factors including depression and negative affect.

Method

An English‐speaking community sample free of neurocognitive diagnoses (n = 279) who were aged 60‐96 (M = 73.8), 52% women, and had a mean education of 14.9 years (range = 10‐20) completed a Qualtrics online survey probing their perceptions of ADRD. Participants rated their worry about developing ADRD on a 5‐point scale (1 = not at all worried to 5 = very worried) and indicated which of 10 evidence‐based risk factors they believed contributed. Endorsed risk factors were summed for analysis. Participants also completed the Patient Health Questionnaire (PHQ‐2) and the Positive and Negative Affect Schedule (PANAS). A three‐step hierarchical regression analysis with age and education entered in step 1, ADRD Risk Sum entered in step 2, and PHQ‐2 and PANAS‐Negative Affect scores entered in step 3 was conducted predicting ADRD Worry. We first tested depression and negative affect in separate models in step 3 and found that each contributed. We then combined them into a single model to better understand the contribution of each.

Result

Participants had a mean score of .51 on the PHQ‐2 (SD = 1.07), a mean score of 7.11 on PANAS‐Negative Affect (SD = 3.26), endorsed on average 2.77 ADRD risk factors (SD = 1.83), and ranked their worry at 2.05 on average (SD = .93). In the final model, age and education did not predict ADRD Worry, whereas ADRD Risk Sum did (R‐squared change = .03, B = .09, p<.05), and negative affect and depression scores contributed further (R‐squared change = .04), but only PHQ‐2 scores were predictive (B = .16, p<.05). The contribution of ADRD Risk Sum remained significant after entry of the affective variables in step 3.

Conclusion

We found that in a community sample of adults aged 60 and above, higher levels of dementia worry were associated with higher perceived disease susceptibility and poorer emotional status indexed by negative affect and, more importantly, depression.
Examination of intrapersonal and affective characteristics associated with everyday function among older adults with subjective cognitive decline
Authors: Farias Sarah Tomaszewski
Published: January 2025

Background

The purpose of this study was to evaluate a variety of intrapersonal factors that may also be associated with everyday functional outcomes in older adults with subjective cognitive decline (SCD).

Participants and Methods

Participants included 127 older adults with SCD (age M = 73.1, SD = 4.9; education M = 15.4, SD = 2.2; 80% female, 89% White) who were enrolled in an NIH funded randomized controlled trial teaching memory support strategies and healthy lifestyles (R01AG066748). This study utilized baseline data from the trial, prior to the start of the intervention. Everyday function was measured across a variety of instrumental activities of daily living (IADLs). Key independent variables of interest included self‐rated positive and negative affect, life satisfaction, resiliency, life purpose, health literacy, and perceived competence. Linear regression was used to assess associations between key independent variables and each outcome. Model building began with simple models including one key independent variable in addition to demographics (age, education, gender). A final model was then built including all variables that met a trend level association in those models (p<.15). Correlations between variables were assessed for collinearity. All analyses were conducted in R and a p‐value less than 0.05 was considered statistically significant.

Results

When examining predictors of IADLs, positive affect (.001), negative affect (p = .05), resiliency (p = .1) and life purpose (p = .03) were all identified in individual models as having a potential association with IADLs after controlling for demographics. When all four variables were included in a final model, along with demographics, positive affect (p = .03) remained significantly associated with IADLs. Specifically, higher positive affect was associated with greater independence in IADLs.

Conclusions

In this study we show that positive affect is an important predictor of better self‐reported IADL functioning in a group of older adults at risk for cognitive and functional decline. Positive affect has previously been associated with a host of health outcomes, but to our knowledge this is the first finding showing it may bolster everyday functioning and reduce disability. Findings may have important implications for interventions that focus on improved well‐being as a way to bolster everyday functioning among older adults with SCD.
Association of Majority versus Minority First Language Multilingualism and Socioeconomic Status on Cognition among Older Indian Adults
Authors: Strangmann Iris M. , Avila Justina F , Petrosyan Sarah , Meijer Erik , Nichols Emma , Narayanan Shrikanth , Aksman Leon M. , Lee Jinkook , Rentería Miguel Arce
Published: January 2025

Background

Some research suggests that multilingualism confers a cognitive advantage, but this association may be confounded by linguistic and socioeconomic factors. Multilinguals can differ on their first language such that it could be a societal majority‐ or minority‐language, resulting in distinct reasons for‐ and experiences with‐ becoming/being multilingual, along with different socioeconomic opportunities. We evaluated the association of multilingualism (Monolingual, Multilingual‐Majority, Multilingual‐Minority) and socioeconomic status (SES) on cognition among older adults.

Method

The analytic sample included 3,918 older adults (65% Monolingual, 23% Multilingual‐Majority, and 12% Multilingual‐Minority) from the Longitudinal Aging Study in India – Diagnostic Assessment of Dementia (LASI‐DAD). Participants reported their first and (any) additional language(s), and completed a cognitive battery assessing executive function, language, memory, and visuospatial domains. Majority language within residential state was determined per the Indian Census. SES was defined by years of education, caste, consumption, and parental education. SES scores were derived through factor analysis and grouped into tertiles (High‐, Medium‐, Low‐SES). The associations of multilingualism and SES were evaluated using Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy (MAIHDA), adjusting for age, sex/gender, and rurality.

Result

Multilingual‐majority status was associated with better cognitive performance across all domains compared to monolinguals, while multilingual‐minority status performed better on all domains except memory (Table 1). Relative to high‐SES, lower‐ and medium‐SES were associated with worse performance across all domains. Results suggest an interaction between language group and SES (Figure 1). While high‐SES monolinguals performed worse than their multilingual counterparts in all domains ‐ except for memory when compared to high‐SES multilingual‐minority participants ‐ they outperformed low‐ and medium‐SES multilinguals. Although high‐SES multilinguals outperformed low‐/medium‐SES multilinguals in all domains, there were no differences between majority/minority‐multilinguals of equal SES.

Conclusion

Both multilingualism, regardless of majority‐minority first language, and socioeconomic status were associated with cognitive benefits. While a multilingual cognitive advantage was more apparent among those with high SES, this advantage did not surpass the independent benefit of high SES, since monolinguals with high‐SES outperformed multilingual older adults with low‐ and medium‐SES. These results suggest that the potential benefits of multilingualism on cognition differs across life‐course socioeconomic determinants of health.
Floor‐effect in the performance of the Spanish‐language MoCA by cognitively unimpaired Peruvian individuals with low educational background
Authors: Custodio Nilton , Calandri Ismael Luis , Montesinos Rosa , Custodio Belen , Malaga Marco , Chambergo‐Michilot Diego , Bustamante‐Paytan Diego , Aguero Katherine , Verastegui Graciet , de la Colina Adrián Noriega
Published: January 2025

Background

The Montreal Cognitive Assessment (MoCA) stands as a prominent cognitive impairment screening tool, finding widespread use globally and existing in official versions across 14 languages, including Spanish. Despite this, the challenges emerge due to the extensive variations within the Spanish language, which is not only the fourth most spoken language worldwide but also possesses significant geographic diversity, particularly evident in regions like Peru. Here, the intersection of regional nuances, low educational backgrounds, and culturally distinct tasks complicates the application of a standard MoCA version. We aimed to assess MoCA performance in individuals with both high and low education levels from an urban region of Peru to investigate the applicability of MoCA in low‐educated population.

Methods

A total of 40 cognitively healthy individuals with low education (less than 6 years, mean = 3.8 ±1.8) and 40 individuals with higher education (more than 6 years, mean = 14.1 ±3.5) participated in the study. We assessed them with the Spanish version 7.0 of MoCA and estimated total score and domain indices. We fitted linear regression models to evaluate age‐ and sex‐adjusted differences between groups. We examined the presence of a floor effect in the low education group, defining it as the test’s minimum possible score surpassing the mean minus three standard deviations. This observation indicates a lack of sensitivity in capturing normal inter‐individual variation at lower values. To delve deeper, we employed a three‐parameter Item Response Theory model (IRT) to estimate the difficulty of each test item.

Results

We observed significant differences in the total MoCA score (b = 9.3, 95% CI: 7.7,11, p<0.001) as well as in the memory index (MoCA‐MIS, b = 5.9, 95% CI: 4.4, 7.5, p<0.001), executive function (MoCA‐EIS, b = 5.0, 95% CI:4.0,6.0 p<0.001), attention (MoCA‐AIS, b = 5.5, 95% CI: 4.4, 6.6, p<0.001), and the remaining subscores (Figure 1). Floor effect was detected in memory, executive, language, and visuospatial indices. (Table 1) The more complex items identified were repetition and abstraction tasks (Figure 2)

Conclusion

Our results shows that MoCA indices can be significantly influenced by education, floor effect is present even in healthy individuals, and certain items need to be reconsidered due to their difficulty in this context.
Potential of dual orexin receptor antagonists to prevent Alzheimer’s disease
Authors: Lucey Brendan P , Musiek Erik S.
Published: January 2025

Sleep disturbances, such as insomnia, are associated with Alzheimer’s disease pathology and future risk of cognitive impairment. This raises the exciting possibility of repurposing existing drugs to prevent or delay Alzheimer’s disease since there are multiple drug approved by the Food and Drug Administration for the treatment of insomnia. Dual orexin receptor antagonists (DORAs) are one such class of medications. The orexin system regulates sleep‐wake activity and individuals with orexin deficiency have narcolepsy, a sleep disorder resulting in excessive daytime sleepiness, sleep paralysis, sleep‐related hallucinations, and cataplexy. Based on its role in narcolepsy pathophysiology, DORAs were developed as a treatment of insomnia. Growing evidence suggests that DORAs may be effective at preventing Alzheimer’s disease pathology. In amyloid precursor protein (APP) transgenic mice that develop amyloid deposition, treatment with a DORA decreased the soluble amyloid‐beta concentrations and prevented amyloid deposition. Recent evidence in humans shows that a DORA, suvorexant, acutely decreases amyloid‐beta and phosphorylated tau levels in human cerebrospinal fluid within hours. In this presentation, we will review recent advances testing the effects of DORAs on biomarkers for Alzheimer’s disease pathology, examine additional potential mechanisms that DORAs may reduce Alzheimer’s disease pathology, and discuss current knowledge gaps regarding the effects of other sleep drugs on Alzheimer’s disease biomarkers. Finally, we will discuss on‐going studies planned to test the effects of DORAs in preclinical animal models and humans to lay the groundwork for future phase III clinical trials to prevent or delay the onset of symptomatic Alzheimer’s disease.
Rescue of FTLD‐associated TDP‐43 pathology and neurodegeneration by peripheral AAV‐mediated expression of brain‐penetrant progranulin
Authors: Haass Christian
Published: January 2025

Background

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐GRN). Multiple therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD‐associated pathologies may be their inefficient brain exposure and biodistribution.

Method

We therefore developed an adeno‐associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain‐penetrant (b) PGRN variant (AAV(L):bPGRN) in two mouse models of FTLD‐GRN, namely Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS‐administered AAVs while maintaining sustained levels of PGRN in the brain following a single dose.

Result

AAV(L):bPGRN treatment reduced several FTLD‐GRN associated disease pathologies including severe motor function deficits, aberrant TDP‐43 solubility and phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis and neurodegeneration in the brain. Translatability of our findings was confirmed in a novel human in vitro model using co‐cultured human induced pluripotent stem cell (hiPSC)‐derived microglia lacking PGRN and TMEM106B and wild‐type hiPSC‐derived neurons. As in mice, aberrant TDP‐43, lysosomal dysfunction and neuronal loss were ameliorated after treatment with exogenous TfR‐binding protein transport vehicle fused to PGRN (PTV:PGRN).

Conclusion

Together, our studies suggest that peripherally administered brain‐penetrant PGRN replacement strategies can ameliorate FTLD‐GRN relevant phenotypes including TDP‐43 pathology, neurodegeneration and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD‐GRN and potentially other CNS disorders.
Mechanistic links between TMEM106B and TDP‐43 dysfunction in AD‐related dementias
Authors: Prudencio Mercedes
Published: January 2025

Background

Inclusions of TAR DNA binding protein of 43kDa (TDP‐43) constitute the main characteristic pathology in the majority (∼97%) of amyotrophic lateral sclerosis (ALS) cases and approximately 50% of patients with frontotemporal lobar degeneration (FTLD). TDP‐43 is a nuclear RNA binding protein; however, in disease, it becomes hyperphosphorylated and/or insoluble, hindering its nuclear function in maintaining RNA homeostasis. Importantly, the incidence of TDP‐43 proteinopathy extends to aging brains (LATE) and may be concomitant with Alzheimer’s disease (AD) neuropathological changes (LATE/AD) in up to 70% of AD patients. Interestingly, LATE/AD cases are characterized by worse memory and greater hippocampal atrophy than AD alone. Therefore, TDP‐43 dysfunction could have diverse, disease‐specific effects on pathogenesis, making it imperative to elucidate the mechanism of TDP‐43 deposition in the brain and its role in AD‐related dementias (ADRDs).

Method

We used standardized molecular biology techniques and single‐nuclei RNA sequencing to evaluate TDP‐43 dysfunction across brain regions in both LATE/AD and FTLD‐TDP, identify common and distinct molecular mechanisms involved in each ADRD, as well as assess the relevance of TMEM106B rs3173615, a genetic variation linked to risk of FTLD haplotype, in TDP‐43 pathology.

Result

We detected misspliced, TDP‐43‐regulated cryptic RNAs in the amygdala and hippocampus of LATE/AD and FTLD‐TDP. FTLD‐TDP, but not LATE/AD, frontal cortex also showed significant accumulation of these aberrant transcripts. The topographic distribution of cryptic RNAs mimicked that of insoluble, phosphorylated TDP‐43, regardless of TDP‐43 subtype classification. Despite common misregulated transcripts in these ADRDs, we also identified unique transcriptome changes, even within each TDP‐43 subtype. Finally, we observed that TMEM106B core deposition, which is linked to the presence of the risk TMEM106B rs3173615 haplotype, was associated with enhanced TDP‐43 dysfunction and pathology, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD‐TDP.

Conclusion

Our results emphasize the use of cryptic RNAs to identify cases with TDP‐43 pathology, and raises the possibility that unique transcriptome signatures may further distinguish FTLD‐TDP from LATE/AD and within different TDP‐43 subtypes. We showed a relationship between increased TMEM106B core deposition and greater susceptibility to TDP‐43 dysfunction, potentially through dysregulation of endolysosomal function.
Asymmetrical hippocampal atrophy: an arrow in the quiver of imaging markers for LATE‐NC
Authors: Woodworth Davis C. , Greenia Dana E. , Bukhari Syed A. , Montine Thomas J. , Ezzati Ali , Kawas Claudia H. , Corrada María M. M. , Sajjadi S. Ahmad
Published: January 2025

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) denotes TDP‐43 deposition in older age and is consequential for cognitive function. Currently there is no way to identify LATE‐NC during life. Some forms of TDP‐43 deposition in younger age, related to frontotemporal dementia (FTD), are associated with pronounced asymmetrical atrophy of the temporal lobe. Given the similar underlying proteinopathy of TDP‐43 in both LATE‐NC and FTD, we hypothesized LATE‐NC would be associated with asymmetrical hippocampal atrophy.

Methods

We included participants from The 90+ Study with both MRI and autopsy data. All participants were assessed for LATE‐NC, Alzheimer’s disease neuropathologic change (ADNC), and hippocampal sclerosis of aging (HS‐A). 3D‐T1w MRIs were segmented using FreeSurfer. We examined hippocampal asymmetry, and minimum and average hippocampal volumes (across left and right), in relation to LATE‐NC stages. We defined asymmetry as asym = log(100*abs(left. hipp. vol.‐right. hipp.vol)/(ave. hipp. vol)). We fit multiple linear regression models for each outcome, accounting for HS‐A presence and ADNC severity. Lastly, we examined prediction performance using area under the curve (AUC) for LATE‐NC stage 2 or higher, considering dementia status alone or including asymmetry, minimum, or average hippocampal volume. All models were adjusted for age at death, sex, education, and intracranial volume.

Results

Table‐1 displays participant characteristics (N = 104), with N = 37 (36%) having LATE‐NC. Increasing LATE‐NC stage was associated with increasing hippocampal asymmetry and decreasing minimum and average hippocampal volumes (Figure‐1). LATE‐NC stages 2 and 3 showed significant associations with hippocampal asymmetry (Figure‐2). HS‐A trended towards an association with, but ADNC was not associated with, hippocampal asymmetry (Figure‐2). Both asymmetry and minimum hippocampal volume appeared to be more strongly related to LATE‐NC compared to average hippocampal volume (Figure‐2). AUC analysis indicated that, for predicting LATE‐NC stage 2 or greater, the model which included asymmetry (AUC = 0.79) outperformed both the model with dementia status alone (AUC = 0.64, P = 0.005) and the models with average (AUC = 0.65, P = 0.007) and minimum (AUC = 0.69, P = 0.014) hippocampal volumes.

Conclusion

LATE‐NC is associated with asymmetrical hippocampal atrophy in a stage‐dependent fashion, independent of HS‐A and ADNC. Using measures of hippocampal asymmetry may lead to better identification of LATE‐NC during life.
Developing and Tailoring a Nutrition Intervention for Dementia Risk Reduction
Authors: Sheffler Julia L
Published: January 2025

Background

Nutrition and other lifestyle interventions hold promise for reducing dementia risk; however, significant barriers remain in translating these programs and recommendations to individuals at the greatest risk. We discuss application of the NIH Obesity‐Related Behavioral Intervention Trials (ORBIT) to the development and tailoring of a nutrition program for high‐risk older adults.

Method

A mixed methods approach was used to evaluate factors that contribute to adherence and engagement with the nutrition program. Quantitative and qualitative data were drawn from two early phase clinical trials. Additionally, focus group data is reported to supplement the trial data.

Result

Program‐specific factors (e.g., group cohesion, delivery methods, quality of materials, and support for change) and personal factors (e.g., supportive family, health conditions, food‐related habits/experience) were identified as potential contributors to adherence and engagement. Further, focus groups provided specific feedback and recommendations about updates that can enhance adherence and engagement with the nutrition program.

Conclusion

Intervention development and adaptation is an iterative process that can be enhanced through mixed methods approaches that provide qualitative context for quantitative trial results.
Targeting Aging‐Related Neuroinflammation and Autophagy as Interventions for Late Onset Alzheimer’s Disease
Authors: Santos Diogo Francisco Silva , Haynes Katy A , Williams Sean‐Paul Gerard , Willis Jenny M , Nepali Umesh , Reddy Aman , Heaton Nicholas , Hart Jason T , Letica Leila , Dubberley Lauren R , Choi Sang‐Ho , Schaeffer David J , Silva Afonso C , da Silva Lais , Territo Paul R , Quinney Sara K , Liu Yuan , Chen Bill , Finkel Toren , Santos Diogo J Sukoff
Published: January 2025

Background

The bi‐directional autophagy and inflammation network becomes progressively dysregulated with age, with systemic inflammation as a biomarker of this dysregulation including in Alzheimer’s Disease (AD). We hypothesize that interventions which target the shared feature of systemic inflammation in the biology of aging and AD, via regulation of the autophagy‐inflammation network, will prevent the conversion to disease pathogenesis in AD as well as improve healthspan and longevity in aging populations. While previous studies report benefits of mTOR inhibition including rapamycin in transgenic mouse models of familial AD, the present studies aim to evaluate this pathway in a model of sporadic, late onset AD (LOAD) and test the contribution of AMP‐activated protein kinase (AMPK) as a critical regulator of the mTOR pathway.

Method

A novel brain penetrable AMPK activator compound (BC1618) and the prototypical mTOR inhibitor rapamycin were administered chronically to male and female mice with genetic and environmental risk for LOAD. LOAD mice (APOE4/TREM2R47H/hAPP; JAX #030670) were conditioned on High Fat Diet (HFD) from 2 months of age which induced sustained inflammation. Drug exposure levels were measured by HPLC‐MS/MS for PK analysis. Subjects were evaluated through a comprehensive battery of tests longitudinally at 6‐month intervals throughout lifespan including motor, sensorimotor, cognitive behavior, frailty, blood‐based biomarkers, and PET/MR.

Result

Treatment with rapamycin and BC1618 resulted in the expected appreciable exposure levels in brain and plasma. Interim analysis of LOAD+HFD mice at 22 months of age (10+ months treatment) revealed reduced survival and healthspan relative to non‐LOAD controls with no benefit of RAPA or BC1618 treatment. Ongoing studies evaluating translationally relevant PET/MR, biomarkers, pathology, and behavior throughout lifespan to evaluate effects on healthspan and lifespan are in progress.

Conclusion

LOAD+HFD mice model genetic x aging x environmental risk of sporadic late‐onset AD and provide a more translationally relevant model to study potential benefits of interventions that target the mTOR pathway. These studies are poised to inform influence of AMPK on autophagy and inflammation to attenuate disease progression in LOAD; which may be better predictive of effects on sporadic AD than previous studies in young transgenic early‐onset models of brain amyloid overexpression.
Subtle Inefficiencies in Everyday Tasks are Significantly More Frequent in People with Mild Cognitive Impairment and Associated with Episodic Memory Performance: Implications for Clinical Practice and Research
Authors: Mckniff Moira , Kaplan Marina , Holmqvist Sophia L. , Tassoni Molly B. , Simone Stephanie M. , Giovannetti Tania
Published: January 2025

Background

Mild functional difficulties begin in mild cognitive impairment (MCI) and precede functional disability, but people with MCI generally perform at ceiling on performance‐based tests of everyday function. This study examined whether inefficient reaching, touching, and extra movements (i.e., micro‐errors) on a performance‐based test (Naturalistic Action Test [NAT]) are more frequent in people with MCI vs healthy cognition and whether micro‐errors are associated with cognitive abilities, reflecting cognitive failures.

Method

Community dwelling older adults over the age of 65 (N = 89; MAge = 73.54; SD = 6.9) completed tests of global cognitive status, episodic memory, executive functioning, language, and attention and were classified as having healthy cognition (n = 74) versus MCI (n = 15) using Jak/Bondi criteria. Participants also completed the NAT, which includes a breakfast and a lunch task, at two time‐points separated by 4‐6 weeks. NATs were scored for subtle, inefficient actions (i.e., micro‐errors) by coders who were blind to cognitive status and timepoint.

Result

An ANCOVA (controlling for age) showed participants with MCI made significantly more micro‐errors than participants with healthy cognition at both timepoints [Timepoint 1: F (1, 87) = 7.368, p = .008, η2 = .079; Timepoint 2: F (1, 87) = 15.167, p < .001, η2 = .151]. Micro‐errors at time 1 were correlated with global cognitive status [r = ‐.229, p = .031], episodic memory [r = ‐.223, p = .036], and micro‐errors at time 2, but were not correlated with measures of executive function, language, or attention. A Spearman’s rank order correlation to establish test‐retest reliability did not reach our .7 cut‐off, though the correlation was significant (r (87) = .465, p < .001), and both time‐points did not significantly differ from each other (p = .086)

Conclusion

Although people with MCI are functionally independent, they make more inefficient actions (micro‐errors) than healthy controls on highly familiar everyday tasks, and this difference was stable over time. Micro‐errors, which correlations suggest reflects cognitive failures, may be useful markers for early detection of MCI, identification of risk for conversion to dementia or functional disability, and may be used as functional outcomes in clinical trials.
A Computerized Cognitive Assessment Battery Optimized for At‐Home Testing
Authors: Hall Kathleen , Baldo Juliana , Pebler Peter , Herron Timothy J , Geraci Kristin , Blank Michael , Schendel Krista , Lwi Sandy J. , Chok Jas M. , Kahly Omar , Miranda Miranda , Jaramillo Isabella , Curran Brian , Santavicca Isabella , Thomas Lexie , Spinelli Maria G , Williams Garrett , Johnson David K , Woods David L.
Published: January 2025

Background

The administration of cognitive tests in patients’ homes facilitates access by underserved communities and increases testing capacity and efficiency. However, the validity of at‐home computerized cognitive tests is often questioned because of limitations in examiner monitoring, distractions, environmental noise, and potential cheating. Here, we compare performance of the computerized and proctored California Cognitive Assessment Battery (CCAB) when administered at‐home or in the laboratory using otherwise identical procedures.

Method

The California Cognitive Assessment Battery (CCAB) includes 17 verbal and 15 non‐verbal tests that have been optimized and normed for at‐home assessment on tablet computers (Figure 1). To reduce the influence of distractions and noise, CCAB verbal stimuli are adjusted for hearing loss and delivered at high intensities through noise‐attenuating circumaural headphones. Verbal responses are digitally recorded using a noise‐cancelling head‐mounted microphone. Most importantly, CCAB test administration is proctored through a control interface that warns of potential error conditions (e.g., performance failures, excessive noise, etc.), displays test performance in real time, facilitates patient observations, and incorporates video chat and test‐control capabilities to readminister tests should problems arise.

During the COVID pandemic 310 participants (mean age 70.1 years) successfully completed three 90‐minute enrollment test sessions in their homes. Omnibus z‐scores were obtained by averaging z‐scores from 70 individual test measures. At 6 months, 277 participants were retested, 46% of them in the laboratory. At 18 months, 200 participants were retested, 57% in the laboratory.

Result

Table 1 shows Omnibus z‐score correlations at enrollment, 6‐, and 18‐ months as a function of retest location: test‐retest reliability was similar for at‐home/in‐lab and at‐home/at‐home pairs. Table 2 shows mean z‐scores for at‐home and in‐lab assessments at 6‐ and 18‐months, estimated with a model that included Omnibus z‐scores at enrollment. No significant differences were observed as a function of test site at 6‐months (t(273) = ‐0.56, NS) or 18‐months (t(172) = 0.44, NS).

Conclusion

The CCAB produces results with similar means, variances, and distributions whether assessments are administered at‐home or in a laboratory.
Does the correlation between informant ratings of function and cognitive assessment scores differ based on informant gender?
Authors: Stradtman Megan , De Vito Alyssa N. , Price Ashley N. , Strenger Jennifer , Thompson Louisa I. , Sinoff Stuart , Snyder Peter J. , Alber Jessica
Published: January 2025

Background

Informant reports can complement standardized cognitive assessment and improve accuracy of dementia diagnosis. Although informant reports correlate moderately with objective measures of decline, the influence of informant factors, such as gender, on these relationships is unclear. This study assessed the hypothesis that informant gender would emerge as an independent predictor in the relationship between informant ratings of cognitive function (i.e., Clinical Dementia Rating Scale) and cognitive assessment scores.

Method

204 adults aged 55‐80 (124 F, 80 M) completed the CDR with study partners (106 F, 95 M). Participants completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and CDR at screening, and the Free and Cued Selective Reminding Test (FCSRT) within 12 weeks of screening. RBANS delayed memory index scores were available for 203 participants, and the RBANS total scores for 200 participants. 148 participants had FCSRT immediate free recall and delayed free recall scores available. Linear regression analyses were used to evaluate whether informant gender significantly predicted the relationship between the CDR sum of boxes (SOB) and: RBANS total score, RBANS delayed memory index score, FCRST immediate recall score, and FCRST delayed recall score, while controlling for age and education.

Result

The CDR SOB was negatively associated with RBANS total score (R2 = .547, β = ‐.511, p< .001), RBANS delayed memory index score (R2 = .640, β = ‐.643, p< .001), FCRST immediate free recall (R2 = .220, β = ‐.162, p = .025), and FCRST delayed free recall (R2 = .667, β = ‐.646, p<; .001). Informant gender was not associated with any cognitive outcome (p’s> .05).

Conclusion

These results did not support the hypothesis that participants with female study partners would show a stronger correlation between informant ratings of cognitive function and cognitive assessment scores. Future work will: 1) use qualitative analysis to investigate potential gender differences in informant reporting and 2) examine additional informant‐related factors that may impact the relationship between informant ratings and neuropsychological testing such as informant level of education, culture, and family history and/or experience with dementia.
Heterogeneous clinical phenotypes of sporadic Early‐onset Alzheimer’s disease: A data‐driven approach
Authors: Putcha Deepti , Katsumi Yuta , Touroutoglou Alexandra , Dage Jeffrey L. , Eloyan Ani , Nudelman Kelly N. , Carrillo Maria C. , Rabinovici Gil D. , Apostolova Liana G. , Dickerson Bradford C. , Hammers Dustin B. , Consortium LEADS
Published: January 2025

Background

Early‐onset Alzheimer’s disease (EOAD) manifests prior to the age of 65. Clinical presentation of EOAD is distinct from that of late‐onset Alzheimer’s disease, and is characterized as having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS) described their sample as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the range of EOAD presentation, we applied a neuropsychological data‐driven method to phenotypic subtyping within the LEADS cohort.

Method

Data from 169 amyloid‐positive EOAD participants with composite data in all cognitive domains (Episodic Memory, Executive Functioning, Speed/Attention, Language, and Visuospatial) were analyzed. Our approach consisted of comparing the relative levels of baseline impairment in each cognitive domain. Education‐corrected normative comparisons were made using a sample of 98 aged‐matched cognitively normal participants. A cut‐off of 1 SD below all other composite domain scores was applied to indicate a phenotype of “predominant” impairment in a given cognitive domain. Individuals were otherwise considered to have a phenotype best characterized by multidomain impairment.

Result

We identified 6 phenotypic subtypes of EOAD (Table 1): Dysexecutive‐predominant (22% of sample), Amnestic‐predominant (11%), Language‐predominant (11%), Visuospatial‐predominant (15%), Mixed Amnestic/Dysexecutive‐predominant (11%), and Multidomain (30%). These subtypes did not differ on age, age‐at‐symptom‐onset, sex, or overall clinical severity (p>0.05). Groups differed on global cognitive functioning (MMSE) such that the Amnestic‐predominant group performed better than other domain‐predominant subtypes of EOAD (p>0.05). In contrast to the heterogeneity observed from our data‐driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic‐predominant, 9% were non‐amnestic, 4% were visuospatial‐predominant, and 5% were language‐predominant.

Conclusion

Applying a neuropsychological data‐driven method of phenotyping EOAD individuals uncovered a more detailed understanding of the diversity of presenting heterogeneity in this atypical AD group compared to clinical judgment alone. These results suggest that clinicians and patients may over‐prioritize memory dysfunction during subjective reporting at the expense of non‐memory symptoms, which has important implications for diagnostic accuracy and treatment considerations. We plan to investigate the patterns of cortical atrophy and network dysfunction subserving this heterogeneity.