bluuebunny/crossref_metadata_2025 huggingface dataset:
“I am the only one I know of who participates in research”: Promoting Equitable Research Methods for Underserved Communities in Dementia Risk Reduction Research
Authors: Booi Laura , Surr Claire , Greene Leanne , Souray Rowan , Naci Lorina , Wells Katie , Keady John , Ritchie Craig W , Lawlor Brian
Published: December 2023

Background

It is widely understood that dementia researchers need to do more to foster diversity and equitable access to research participation for underserved groups (e.g. members of racialised communities, those living in low socioeconomic status, and members of the LGBTQIA+ community). Currently, the vast majority of large‐scale dementia risk reduction research participants represent white, upper middle‐class individuals from urban areas. This project identifies the motives, facilitators, and barriers to participation in dementia risk‐reduction research in healthy middle‐aged adults who are traditionally under‐represented in research.

Methods

This is a qualitative study which worked in conjunction with the PREVENT Programme, a large‐scale, multi‐centre programme which aims to establish early biomarkers of Alzheimer’s disease. Participants for this study were healthy middle‐aged adults currently participating in the PREVENT Programme, who also identified as belonging to an underserved population. The method for data collection was semi‐structured interviews using video conference technology (N = 19). Thematic analyses was used by the research team.

Results

Findings from this study highlight motivators for participating falling in three camps: altruistic, individual health curiosity and interest in research. Facilitators to inclusion in research include strong rapport with the research team, clear understanding of the study protocol, flexible scheduling of participation (e.g., evening and weekends), monetary support to facilitate on site attendance and to support time away from paid employment, and innovative use of remote digital methods of data collection. Barriers to participation encompass a lack of awareness of opportunities to participate, and research illiteracy and stigma associated with both dementia and research participation.

Conclusion

Findings highlight individuals from under‐served communities are less likely to take part in research for a variety of reasons. The onus is on the research community to ensure equitable access to research participation amongst diverse populations. The outcome of this study is the development of guidelines for large‐scale epidemiological studies to encourage diverse, equitable, inclusive and supportive recruitment and engagement of participants from underserved from populations. This will further support the inclusion and diversity of both our research ventures and the solutions developed from them.
Which common MRI research sequences need de‐facing before research data sharing?
Authors: Schwarz Christopher G. , Kremers Walter K. , Arani Arvin , Reid Robert I. , Gunter Jeffrey L. , Senjem Matthew L. , Cogswell Petrice M , Vemuri Prashanthi , Kantarci Kejal , Petersen Ronald C. , Knopman David S. , Jack Clifford R.
Published: December 2023

Background

We have previously shown that 3D T1‐weighted and 3D T2‐FLAIR brain MRI can potentially be re‐identified using face recognition, but this has not been tested for other MRI sequences commonly used in imaging studies of aging and dementia. Here we compare match rates of automated face recognition to re‐identify 3D T1‐weighted, 3D T2‐FLAIR, 3D T2‐weighted, 2D Axial T2‐FLAIR, multi‐echo GRE (T2*), diffusion MRI, functional MRI, ASL, and T2* GRE images.

Method

We used a dataset of 182 Mayo Clinic participants each with MRI and face photographs. MRIs used Siemens and GE vendor‐product sequences similar to ADNI3 and ADNI4 protocols. We created face reconstructions (“basic”, with minimal preprocessing, and “advanced” that automatically filled missing face regions using a template) from each MRI sequence, and we trained a Microsoft Azure PersonGroup face recognition classifier to recognize these MRI‐based faces. We then queried the classifier with five face photographs for each participant, and we recorded how often the classifier chose the correct MRI as the top‐ranked match. For image types with match rates > = 10%, we then repeated the experiment after de‐facing each MRI with mri_reface, our leading software that replaces faces in each image (“re‐faces”) with an average face.

Result

Results are presented in Table 1. 3D T2‐FLAIR, 3D T1‐weighted, and 3D T2‐weighted images were matched at 96‐98%, and mri_reface reduced all to 8%. Axial T2‐FLAIR and ME‐GRE were matched at 32‐45%, and mri_reface reduced both to 1%. T2*‐GRE matched at 10%, and mri_reface reduced this to 1%. ASL matched at 8%, while dMRI and fMRI matched at only 0‐2%.

Conclusion

Among current‐generation vendor‐product sequences, we recommend that de‐facing be applied before research data sharing of T1‐weighted, T2‐weighted, T2‐FLAIR, T2*, and ME‐GRE images. Minimal match rates for current‐generation product fMRI, ASL, and fMRI images suggest that they present low risk of re‐identification and can be shared without de‐facing, but this conclusion should be re‐evaluated if they are acquired without fat‐suppression, with a larger field of view, or if newer developments reduce the current levels of artifacts and distortion around the face.
Towards a clinical timeline of Alzheimer’s disease; a multivariate cognitive perspective
Authors: Cox Timothy , Cespedes Marcela Ines , Gillis Cai , Maserejian Nancy Nairi , Maruff Paul , Fowler Christopher J , Rainey‐Smith Stephanie R , Martins Ralph N , Masters Colin L , Doecke James D ,   The AIBL Research Group
Published: December 2023

Background

Alzheimer’s disease (AD) is a multifactorial disease characterised by a long period of neuronal loss which manifests clinically as cognitive decline and ultimately dementia. Understanding the nature and magnitude of cognitive decline prior to dementia is critical to understanding the disease course. Here we quantify change in six cognitive composite scores to compare their temporal sequence and rates of change early in the AD disease course.

Method

Amyloid‐beta positive (Aβ+) cognitively unimpaired (CU), MCI and AD participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing with ≥three study visits (N = 857), were used to derive composite scores for executive function, language, attention and processing, recognition, visuospatial, and a general composite used in clinical trials (AIBL‐PACC). A multivariate method for combining cognitive change trajectory curves was used to place each composite score trajectory in a common numerical space. Using the mean AIBL‐PACC scores for the prodromal group (MCI‐Aβ+) as a reference, change over a three‐year period for each composite was estimated. Given the AIBL requirement for a minimum 1.5 SD change in two or more cognitive domains to justify progression to MCI/AD, disease time was set with the zero point at a ‐1.5 AIBL‐PACC score, representing a 1.5 SD decline in AIBL‐PACC from the mean CU Ab‐ population at baseline.

Result

The AIBL‐PACC, language and visuospatial functioning scores showed the steepest trajectories indicating AD related decline in these scores was fastest (Figure 1). AIBL‐PACC reached the ‐1.5 point on the y‐axis first followed closely by memory recognition, with steeper trajectory of decline for the AIBL‐PACC across the age range. Focusing on AIBL‐PACC, it took 2.15 years to transition from ‐1.5 to the mean of the prodromal group (‐1.87). At five years past the start of the prodromal stage, the data suggests a drop in the AIBL‐PACC to ‐2.54, an approximate decline of ∼0.22 points per year.

Conclusion

This is the first presentation of a novel multivariate disease trajectory method examining expected change across the AD continuum among Aβ+ persons. A 3‐year change in the PACC composite demonstrated here will be relevant to measure disease progression during clinical trials.
The Influence of Prior Head Injury on Late‐Life Cognition and White Matter Microstructure in Older Adults At‐Risk of Alzheimer’s disease
Authors: Chiu Larissa Kristi , Ai Meishan , Tremblay‐Mercier Jennifer , Villeneuve Sylvia , Geddes Maiya R. ,   the PREVENT‐AD Research Group
Published: December 2023

Background

The long‐term combined effects of mild traumatic brain injury (mTBI) and APOE ε4‐allele carrier status (APOE+/‐), a genetic risk factor of Alzheimer’s disease (AD), on cognition and white matter structural integrity in older adults at‐risk of AD is not fully understood.

Method

To investigate mTBI effects on late‐life neurobehavioural outcomes, a subsample of the PREVENT‐AD cohort was analyzed. Participants were cognitively normal adults over age 55 with a parental or multiple‐sibling history of AD. The mTBI group included individuals who self‐reported at least one prior mTBI with loss of consciousness and/or memory gap (n = 48, 33.3% APOE4+). Rey Auditory Verbal Learning Test measured immediate and delayed memory, Color‐Word Interference Test measured cognitive flexibility and inhibitory control, and Trail Making Test measured processing speed and attention.

The control group included demographically‐matched (age, sex, years of education) participants from the same cohort without self‐reported mTBI (n = 62, 29.0% APOE4+). Data were analyzed using 2‐way ANOVAs with weighted means on years of education, corrected for multiple comparisons. To evaluate underlying structural differences in white matter tracts between mTBI and control groups, diffusion tensor imaging (DTI) metrics, including fractional anisotropy, axial and radial diffusivity, using the JHU‐atlas parcellation.

Results

mTBI/APOE4+ individuals performed significantly worse on cognitive outcomes of delayed recall, cognitive flexibility, and inhibitory control compared to controls; however, they performed significantly better on tests of processing speed and visual attention compared to mTBI/APOE4‐ individuals. DTI results showed that the mTBI group, compared to the control group, had significantly decreased axial diffusivity in the left internal capsule, right superior longitudinal fasciculus, and superior frontooccipital fasciculus (SFOF) (p<0.05 uncorrected). Within the mTBI group, significant positive correlation between lower processing speed and decreased axial diffusivity of SFOF, accounting for age and sex.

Conclusion

Our findings suggest that prior mTBI impacts cognitive aging in older adults at‐risk of AD differentially depend on APOE4 status, where APOE4+ individuals with prior mTBI had worse working memory, cognitive flexibility, and inhibitory control but better processing speed outcomes. Lower cognitive outcomes in mTBI individuals may be supported by decreased diffusivity in specific white matter tracts. These results can inform dementia prevention in these individuals.
I‐CONECT Intervention Effects on Weekly Time Spent Outside of Home and Social Contacts among Socially Isolated Older Adults with Normal Cognition and Mild Cognitive Impairment
Authors: Yu Kexin , Wu Chao‐Yi , Silbert Lisa C , Kaye Jeffrey A , Dodge Hiroko H
Published: December 2023

Background

Social isolation has been linked to an increased risk of cognitive decline and incident dementia. Socially isolated individuals tend to lack access to cognitively stimulating activities. This may adversely impact their cognitive health. The Internet‐Based Conversational Engagement Clinical Trial (I‐CONECT) was designed to deliver online conversation sessions to socially isolated older adults to slow cognitive decline and ultimately delay the onset of dementia. The current study examined the intervention effects on participants’ weekly time spent out‐of‐home and their social interaction with family and friends as clinically meaningful functional outcomes.

Methods

Intervention group engaged in 30‐minutes video chat 4 times/week and 10‐minute weekly phone calls, while control group received only 10‐minute weekly phone calls over 48 weeks. In each call, we asked participants to report time spent out‐of‐home and whether they contacted family or friends during the week (yes/no). Linear mixed‐effect models were run for time spent out‐of‐home, and mixed‐effect models with a logistic link were performed for contact with family and friends. The intervention effect was modeled by including an interaction term of time (in weeks) and group assignments. We ran analyses separately for participants with normal cognition (NC) and mild cognitive impairments (MCI). All models controlled for age, sex, race, education, and a pre vs. post COVID‐19 pandemic indicator.

Results

As weeks passed, participants (N = 155, mean age 81, 72.3% female, 17.53% African American, 51.95% MCI) in both groups reported spending more time out of home, indicated by a significant time main effect (B = , p<.001). Among NC participants, the intervention group had a steeper increase in their reported time spent out‐of‐home compared to the control group (B = , p = .016). Among MCI participants, the intervention group had an increased likelihood of contacting friends over time (OR = 1.013, p = .001), while the intervention effect on contact with family was not significant for either the NC or MCI group.

Conclusion

Previously we reported the I‐CONECT intervention positively affected cognitive functions. The current results suggest the translational effects of I‐CONECT to functional outcomes beyond cognitive test scores, activating weekly activities among socially isolated older adults. The intervention provides a remote social interaction platform that brings cognitive stimulation to at‐risk populations.
Subjective Cognition as A Predictor of Objective Cognitive Decline Among Older Black/African Americans: A STAR Study
Authors: Chen Nancy X , George Kristen M , Lor Yi , Glymour M. Maria , Gilsanz Paola , Farias Sarah Tomaszewski , Barnes Lisa L. , Mayeda Elizabeth Rose , Gradwohl Natalie M , Peterson Rachel , Whitmer Rachel A.
Published: December 2023

Background

Subjective evaluations of cognition are convenient to administer and can be useful if they accurately identify or predict cognitive impairment. We investigated the relationship between subjective and objective measures of cognition in a cohort of Black older adults.

Method

The Study of Healthy Aging in African Americans (STAR) comprises community‐dwelling Black adults ages 50+ who are long‐term Kaiser Permanente Northern California members. Verbal episodic memory (VEM) and executive function (EF) were assessed at three interview waves by the Spanish and English Neuropsychological Assessment Scales (SENAS). We operationalized subjective cognition two ways. 1) Participants self‐rated changes in their everyday cognition using the Everyday Cognition Scale (ECog). Responses, rated 1 = “Better or no change” to 4 = “Consistently much worse, were averaged across the 16 items. 2) Participants responded (yes/no) to the question: “Are you concerned that you have a memory or other thinking problem?” (Subjective memory concerns). Linear mixed models with random intercept and slope estimated associations of ECog or subjective memory concerns with VEM and EF at baseline and over time. All models adjusted for baseline age, gender, education, parental education, and interview mode (in‐person or phone). Sensitivity models stratified by gender and age (+/‐ 65 years).

Result

Participants’ (n = 671) baseline mean age was 68.4 (SD = 8.7) years, 70.2% were women, mean ECog was 1.26 (SD = 0.3), and 40.1% reported subjective memory concerns (Table 1). Subjective memory concerns were associated with worse baseline VEM and EF, but not associated with rate of change for either domain (Table 2A; Table 3A). In contrast, ECog was associated with rate of change for VEM (b = ‐0.09, 95% CI ‐0.17,0.002; Table 2B) and EF (b = ‐0.07, 95% CI ‐0.13,‐0.003; Table 3B). Among women, higher ECog was associated with faster decline in VEM (b = ‐0.12, 95% CI ‐0.22,‐0.02; Table 2B) and EF (b = ‐0.09, 95% CI ‐0.17,‐0.02; Table 3B). Among participants ages 65 and older, higher ECog was associated with a faster decline in VEM (b = ‐0.11, 95% CI ‐0.22,‐0.001; Table 2B).

Conclusion

A well‐validated measure of subjective memory concerns, the ECog, was associated with worse objective executive function and verbal episodic memory and faster declines in both domains in this sample of middle‐aged and older Black adults.
Genetic Contributions of APOE ε4 and TOMM40 rs2075650 to Mitochondrial Dysmorphia
Authors: Wang Qian , Dove Makayla , Sanden Mckenzie , Thackery Mackenzie , Willette Auriel A
Published: December 2023

Background

Alzheimer’s disease is the most well‐known disease from ageing. On the Alzheimer’s disease (AD) side, APOE ε4 and TOMM40 rs2075650 are known risk factors from GWAS studies. On the ageing side, mitochondria are theorized to play a central role in the decrease of bioenergy production, rise of oxidative stress and inflammation activation. APOE is an apolipoprotein that facilitates the transportation of cholesterol, which affects the downstream processing of cholesterol in mitochondria. TOMM40 is the channel‐forming subunit of the translocase of the outer mitochondrial membrane complex. It is essential for the import of protein precursors into mitochondria. Interestingly, both genes are also in proximity on chromosome 19 and share linkage disequilibrium. We hypothesize that the two minor alleles work together to influence mitochondrial function.

Method

APOE ε4 and TOMM40 genes are cloned into cDNA plasmids and expressed in cells through transient transfection. Depending on the expression level, this mimics the heterozygous conditions of APOE ε4 and TOMM40 rs2075650 carriers. Mitochondria are fluorescently labeled and imaged for their morphology. The centerline length and average width of mitochondria units are measured to quantify morphology.

Result

Preliminary results showed that mitochondria in cells expressing high risk alleles were stressed. The mitochondria appeared swollen with shorter length and wider average width.

Conclusion

Since dysmorphia is a sure sign of mitochondrial dysfunction and also widely observed in specimen from Alzheimer’s patients, results from heterozygous APOE ε4 and TOMM40 rs2075650 transfected cells may provide insight into the mechanism of AD development. Future study will explore the interaction between the two alleles. The goal is to improve our understanding of the key components of mitochondrial functions and their effects on ageing.
Midpoint baseline results of the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS)
Authors: Hammers Dustin B. , Eloyan Ani , Taurone Alexander , Thangarajah Maryanne , Beckett Laurel , Gao Sujuan , Kirby Kala , Nudelman Kelly N. H. , Dage Jeff L. , Polsinelli Angelina J , Carrillo Maria C. , Dickerson Brad C. , Rabinovici Gil D. , Apostolova Liana G.
Published: December 2023

Background

Fewer than 5% of patients with Alzheimer’s disease are diagnosed between 40‐64 years old, making “early‐onset Alzheimer’s disease” (EOAD) an uncommon phenomenon (Zu et al., 2015). To date, only basic knowledge on EOAD is known, no uniform criteria for EOAD have been implemented, and sample sizes in research have been small. The Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS) aims to provide a comprehensive understanding of EOAD symptomology, with the current project profiling baseline clinical, cognitive, and basic genetic characteristics of the cohort nearing the data‐collection mid‐point.

Method

Data from 371 participants undergoing the LEADS protocol were compared based on diagnostic group classification (cognitively normal [CN], amyloid‐positive EOAD, and amyloid‐negative Early‐Onset non‐Alzheimer’s disease [EOnonAD]). Because LEADS focuses on sporadic early‐onset dementia, impaired individuals with genetic mutations in Amyloid Precursor Protein (APP), Presenilin‐1 (PSEN1) or Presenilin‐2 (PSEN2), Microtubule Associated Protein Tau (MAPT), Chromosome 9 Open Reading Frame 72 (C9ORF72), or Granulin Precursor aka Progranulin (GRN) were excluded.

Result

Demographic characteristics for each group are shown in Table 1. After adjusting for age, education, and sex, EOAD performed worse than CN for all domains (ps<.001, η2s = 0.05‐0.66), and worse than EOnonAD for all domains except language (ps<.001, η2s = 0.06‐0.29). As shown in Table 2, EOAD showed worse performance on Episodic Memory (z = ‐2.38), followed by Speed Attention (z = ‐1.93) and Executive domains (z = ‐1.43) relative to CN. An amnestic presentation was common among impaired participants, with several clinical phenotypes present. The EOAD group possessed a significantly greater proportion of apolipoprotein ε4 homozygous participants than the EOnonAD group (p = .01, Cohen’s w = 0.15), and a trend of greater proportions of ε4 heterozygous participants than both CN and EOnonAD (ps = .05‐.07, Cohen’s ws = 0.11; Table 3). Finally, LEADS participants generally consented at high rates to optional trial procedures like lumbar puncture (60%) and genetic disclosure (89%).

Conclusion

This work represents the best baseline characterization of sporadic EOAD in the U.S. to date. Early‐onset dementia presents with widespread cognitive impairment, characterized by several known clinical phenotypes. Apolipoprotein ε4 allele carrier status appears to remain important in EOAD. Future investigation will explore many potential associations between EOAD and cognition, neuropsychiatric symptoms, genetics, and imaging.
The role of FNDC5/Irisin in brain energy metabolism in models of Alzheimer’s Disease
Authors: Fonseca Ariene Soares , Chauvet Mariana Gomes , Lourenco Mychael V.
Published: December 2023

Background

Alzheimer’s disease (AD) brains present defective metabolic profiles that are associated with amyloid‐β (Aβ) accumulation. We have previously shown that physical exercise promotes the expression of FNDC5/irisin, which in turn acts in the brain to trigger neuroprotection in AD models. Here, we investigated whether irisin rescues defective mitochondrial function induced by Aβ oligomers (AβOs).

Method

Hippocampal slices from 4‐month‐old wild‐type C57BL/6J mice were prepared and exposed to AβOs (1 µM) in the presence or absence of recombinant irisin (25 nM) for 3 h. We assessed levels of proteins related to mitochondrial fusion (MFN1, OPA1) and fission (DRP1) by Western blotting and mitochondrial function, by high‐resolution respirometry. Biochemical assays were used to determine glucose uptake, lactate content and NAD levels.

Results

Acute exposure to AβOs or irisin did not trigger any significant changes in proteins associated with mitochondrial dynamics or the amount of lactate released after AβOs exposure. Initial results indicate that irisin prevents the variations caused by AβOs in NAD+ levels and glucose uptake in hippocampal slices. Slices exposed to AβOs show a trend of reduction in ATP synthesis‐, complexes II/III‐coupled O2 and in residual O2 consumption. Treatment with irisin seems to prevent these events.

Conclusion

Irisin seems to preserve against the impact of AβOs on selective mitochondrial properties in the hippocampus. Future studies will further elucidate the mechanisms by which irisin is neuroprotective in AD mice.
Comparing the efficacy of domain‐specific and general cognitive composites in Alzheimer disease research
Authors: McKay Nicole S. , Millar Peter R , Aschenbrenner Andrew J. , Nicosia Jessica , Cruchaga Carlos , Schindler Suzanne E. , Benzinger Tammie L.S. , Morris John C , Hassenstab Jason J.
Published: December 2023

Background

Balancing the need to standardize cognitive measures with the need to evolve alongside advances in scientific knowledge is an inherent challenge for longitudinal studies of Alzheimer disease (AD). The Uniform Data Set (UDS) offers a solution for this in cognitive batteries and is implemented across Alzheimer Disease Research Centers (ADRCs). Using equipercentile equating, we combined data spanning two versions of the UDS and derived domain‐specific and general cognitive composites. We compared the relationships of these measures with common biomarkers of AD, as well as their statistical power to detect cognitive change in clinical trials.

Method

Using longitudinal data from the Knight ADRC, domain‐specific cognitive composites were created using an exploratory factor analysis. The resulting four factors clustered episodic memory, semantic memory, working memory, and attention/processing speed tasks (Figure 1). We also computed a commonly‐used preclinical Alzheimer cognitive composite (PACC), an alternative Knight‐ADRC‐PACC, which did not include MMSE, and a global composite. Relationships between each cognitive composite and neuroimaging metrics of amyloid, tau, atrophy, and clinical symptoms, were compared cross‐sectionally and longitudinally (Figure 2). We also performed power analyses of all composites to calculate necessary sample sizes to observe a medium‐sized effect in a four‐year clinical trial.

Result

Overall, general metrics of cognition slightly outperformed domain‐specific composites, although the working memory composite consistently reflected a poor relationship with AD biomarkers (Figure 2). Power analyses revealed that the global, Knight‐ADRC‐PACC, and attention/processing speed composites would require the smallest sample sizes to detect cognitive change in a clinical trial, while the ADCS‐PACC, required two to three times as many individuals (Figure 3).

Conclusion

We found that data‐driven, domain‐specific, composites of cognitive performance can complement already‐established general cognitive composites, with the possible exception of the present working memory composite. In line with prior work, we highlight that attention and processing speed may be sensitive metrics of cognitive change in AD. The inclusion of the MMSE, such as in the ADCS‐PACC, may greatly reduce the sensitivity and statistical power of summary cognitive composites. Our results have important implications for the development of cognitive outcome metrics for future clinical trials.
Characterization of a R493X progranulin haploinsufficient knockin mouse model of frontotemporal dementia
Authors: Cai Wenji , Nygaard Haakon B. , Wendt Stefan , Sorrentino Stefano
Published: December 2023

Background

Frontotemporal dementia (FTD) is the second most common form of dementia in young individuals, characterized by impairments in social cognition, language processing and executive function. Heterozygous loss‐of‐function mutations in the progranulin gene (GRN) are well known as a major genetic cause of a TDP‐43‐positive subtype of FTD (FTD‐GRN). The role of progranulin in the pathogenesis of FTD is not fully understood but has been shown to be associated with lysosomal dysfunction, impaired neuronal survival, and neuroinflammation. Rodent models of FTD‐GRN have been extensively used to model disease pathophysiology, but most studies utilize mice null for GRN. Our lab recently published a comprehensive neuropathological and behavioural assessment of a GRN R493X homozygous mouse model, confirming several phenotypes relevant to human FTD.To our knowledge, haploinsufficient R493X mice have not previously been studied. Here we assessed whether haploinsufficient GRN 493X mice would demonstrate relevant phenotypes for FTD pathophysiologic studies and drug screening.

Method

We characterized behavioural and neuropathological phenotypes of aged GRN R493X+/‐, GRN R493X‐/‐ and age‐matched C57BL/6J wildtype mice. The open‐field test was used to assess anxiety phenotype. Brain lysosomal dysfunction was assessed by western blot, and neuroinflammation, including astrogliosis and microgliosis, as well as hippocampal and thalamic synaptic dysfunction were analyzed by immunohistochemistry.

Result

As expected, our preliminary data show a higher progranulin level in GRN R493X+/‐ mice in comparison with the homozygous GRN R493X mice. Behavioural data, as well as analysis of neuroinflammation, lysosomal dysfunction and brain excitatory and inhibitory synaptic function, are being analyzed and will be presented.

Conclusion

Heterozygous GRN R493X mice more closely resemble the human genetic condition. Our characterization and comparison of neuropathologic phenotypes in aged GRN R493X+/‐ and GRN R493X‐/‐ mice provide insights into the molecular mechanisms underlying the effects of GRN haploinsufficiency and the suitability of this model for drug screening studies in FTD‐GRN.
Identification of objective cognitive decline in preclinical Alzheimer’ disease
Authors: Canovas Rodrigo , Maruff Paul , Fowler Christopher J , Rainey‐Smith Stephanie R , Masters Colin L , Doecke James D ,   The AIBL Research Group
Published: December 2023

Background

In Alzheimer’s disease (AD), a long preclinical and prodromal period precedes dementia onset in which cognition declines slowly, but at variable rates for different domains. Positive AD biomarkers, (e.g., amyloid, Tau, or APOE ε4 carriage), increase rates of cognitive decline and transition to dementia. However, the extent to which cognitive decline, identified in some older adults, reflects neurodegenerative disease or normal aging in the absence of knowledge about biomarkers or genes is not well understood. We applied a novel approach to classify cognitive decline in individuals using six cognitive composite scores (AIBL Pre‐clinical Alzheimer’s Cognitive Composite (AIBL‐PACC), episodic recall, attention, executive function, language and recognition). We examine group‐wise differences across cognitive composite scores and assessed frequencies for AD biomarker positivity amongst the novel groups.

Method

Prospective data from 1,389 Cognitively unimpaired (CU) participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing were analysed using an unsupervised multivariate mixture modelling framework, accounting for age, gender and APOE ε4 allele status. Participants cognitive status was classified for their final visit. The cognitive profile and biomarker characteristics of adults with abnormal cognitive decline was compared.

Result

Differences in composite score values between cognitive decline and no decline groups were strongest for episodic recall (Cohen’s d = 1.49) and the AIBL‐PACC score (Cohen’s d = 1.45, Table 1, Figure 1A). By comparison, differences in composite scores between Aβ‐PET groups, or APOE ε4 allele carriers/non‐carriers were of less magnitude (Table 1, Figure 1). Participants with cognitive decline were more likely to be amyloid positive, (decline: 42% vs no decline: 28%, p<0.0001), but not ε4 allele carriers (decline: 28% VS no decline: 27%, p>0.05).

Conclusion

A measure of objective cognitive decline, created using flexible mixture models with six cognitive composite scores from AIBL, has utility for discerning participants with early changes in cognition. Based upon using the cognitive data alone, this method was able to detect amyloid positivity in those CU participants with cognitive decline.
Elucidating the complex role of ABCA7 in late‐onset Alzheimer’s disease
Authors: Howell Gareth R , Kotredes Kevin P , Pandey Ravi S , Rizzo Stacey J Sukoff , Carter Gregory W , Sasner Michael , Lamb Bruce T , Oblak Adrian L , Territo Paul R ,   MODEL‐AD consortium
Published: December 2023

Background

Genome‐wide association studies (GWAS) identified a locus containing the ATP binding cassette subfamily A member 7 (ABCA7) gene as increasing risk for Alzheimer’s disease (AD). ABC proteins transport various molecules across extra and intra‐cellular membranes. ABCA7 is part of the ABC1 subfamily and has high expression in hematopoietic lineage cells including natural killer cells and macrophages. More recently, ABCA7 expression has been shown in brain cells including neurons, astrocytes, microglia, endothelial cells and pericytes. However, the mechanisms by which variations in ABCA7 increase risk for AD are not known.

Method

The IU/JAX/PITT MODEL‐AD Center prioritized the A1527G variant in ABCA7 (ABCA7*A1527G) as a putative LOAD risk factor. CRISPR/CAS9 was used to introduce Abca7*A1527G variant on to B6.APOE4.Trem2*R47H mice (termed LOAD1) and transcriptional profiling of brain hemispheres from mice at 4, 8 and 12 months old (mos) was used to evaluate molecular effects of Abca7*A1527G. The Abca7*A1527G was then incorporated into B6.APOE4.Trem2*R47H.hAb mice (termed LOAD2) to further evaluate the contribution of Abca7.A1527G to LOAD. Female and male LOAD2.Abca7*A1527G and control mice were characterized at 4 and 12 mos using an established phenotyping pipeline that includes behavior, PET/CT, multi‐omics, fluid biomarkers and immunofluorescence.

Result

Brain transcriptional profiling at 12 mos showed Abca7*A1527G induced gene expression changes that are similar to some of those observed in human AD. Enriched pathways included insulin receptor signaling, and granulocyte and neutrophil migration that include myeloid (Trem2, Trem1, Csf1r) and endothelial (Pecam1) related genes. LOAD2.Abca7*A1527G mice showed no cognitive deficit at 12 mos, but did show an uncoupling of brain glycolysis and regional perfusion was observed in a sex‐ and age‐ dependent manner. Consistent with the uncoupled phenotype, IL6, IL10, and TNFα were elevated in plasma. Interestingly, TNFα, primarily expressed by microglia in the brain, was decreased. Also by 12 mos, the density of neurons, astrocytes and microglia were reduced. Additional timepoints (18‐24 mos), and assessment of LOAD2.Abca7*A1527G mice fed a high fat diet, are in progress.

Conclusion

Data support ABCA7*A1527G as a risk for LOAD that exerts its effect through interactions between cerebrovasculature, microglia and peripheral immune cells.
Alterations of Astrocytic Aquaporin 4 expression and distribution in Down Syndrome with Alzheimer’s Disease onset
Authors: Stringer Cherie A , Miyasato Haley , Camey Kevin , Andrews Elizabeth J. , Phelan Michael J. , Head Elizabeth
Published: December 2023

Background

Astrocytic Aquaporin 4 (AQP4) is a water channel that is typically expressed in astrocytic endfeet, associated with the blood brain barrier (BBB). This association is thought to facilitate the removal of waste products (e.g. beta amyloid (Aβ)) via the ‘glymphatic system’. With Aβ plaque deposition in Alzheimer’s Disease (AD), AQP4 becomes dysregulated observed as a shift in distribution from astrocytic endfeet to astrocytic processes, resulting in inefficient Aβ removal. Here, AQP4 expression and distribution within astrocytes was characterized via immunohistochemistry in human brain tissue from people with Down Syndrome without AD (DS) and with AD (DSAD). We hypothesized that AQP4 protein level would be higher and distributed along astrocytic processes as opposed to the BBB in DSAD relative to DS.

Method

AQP4 was evaluated by immunohistochemistry and quantified using QuPath (% loads, positive pixel count) for both frontal (FC) and occipital cortex (OC) in the following groups: DS (n = 17, age range = 0‐51) and DSAD (n = 20, age range = 46‐70). In addition, AQP4 distribution was classified by a blinded observer who annotated distinct AQP4 positive astrocytic morphologies, listed as follows: In WM, ‘Star,’ ‘Webbed,’ and ‘Stippled,’ and in GM, ‘Bushy,’ ‘Branched,’ ‘Globular,’ ‘Endfoot/Vascular Associated.’

Result

We show that AQP4 protein staining was higher in GM DS with AD neuropathology than in DS without AD neuropathology for both FC and OC (FC p = 0.0007; OC p = 0.0034). In addition, we observed a shift from ‘star’ shaped distribution within DS astrocytes to more ‘webbed’ and ‘stippled’ shapes in DSAD; this was not observed in OC. We found a shift in GM morphologies from ‘bushy’ morphology of AQP4 immunostaining in DS to more ‘Branched and Globular’ shapes in DSAD in OC whereas there is a shift from a ‘Bushy’ morphology in DS to more ‘Endfoot/Vascular Associated’ morphologies in the DSAD FC.

Conclusion

AQP4 expression is higher in DSAD than DS and appears to show a spectrum of astrocyte morphologies with distinct patterns based upon spatial location (FC/OC and GM/WM). Taken together, AQP4 dysfunction and shift to abnormal spatial location may reduce Aβ clearance through the glymphatic system, leading to enhanced plaque formation in DSAD.
Involvement of differential tau pathologies in late‐onset bipolar disorder assessed by PET with 18F‐florzolotau
Authors: Kurose Shin , Takahata Keisuke , Sano Yasunori , Tagai Kenji , Ichihashi Masanori , Endo Hironobu , Hirata Kosei , Matsuoka Kiwamu , Kataoka Yuko , Kubota Manabu , Moriguchi Sho , Yamamoto Yasuharu , Oyama Asaka , Oya Masaki , Matsumoto Hideki , Kokubo Naomi , Suzuki Hisaomi , Mashima Yuki , Seki Chie , Kawamura Kazunori , Zhang Ming‐Rong , Tabuchi Hajime , Tokuda Takahiko , Onaya Mitsumoto , Mimura Masaru , Higuchi Makoto
Published: December 2023

Background

Neurodegenerative pathologies, including tau depositions, have been implicated in late‐onset depression (LOD), while there is a lack of in‐vivo evidence for the neuropathological basis of late‐onset bipolar disorder (LOBD) despite postmortem findings of cerebral tau accumulations. The current study aimed to assess tau pathologies in LOBD and LOD patients positron emission tomography (PET) with 18F‐florzolotau, a radioligand for Alzheimer’s disease (AD) and non‐AD tau fibrils.

Methods

We studied LOBD and LOD patients who developed the first episode of mania or depression after age 45. Twenty‐one patients with LOBD (68.8 ± 9.6 years old; 11 females), 15 patients with LOD (73.0 ± 5.8 years old; 11 females), and 39 age‐matched healthy controls (HCs) (67.1 ± 9.1 years old; 19 females) underwent tau and amyloid PET scans with 18F‐florzolotau and 11C‐PiB, respectively. Amyloid positivity was determined by a visual read of 11C‐PiB‐PET images, and tau depositions were assessed by calculating standardized uptake value ratios (SUVRs) in 52 regions covering the cerebral grey matter and basal ganglia to the optimized reference tissue. All SUVRs were corrected for age and sex and converted to Z‐score relative to HCs. The positivity and topology of tau pathologies were determined according to the presence of a region with a Z‐score ≥ 2.0.

Results

18F‐florzolotau‐PET positivity was observed in 13 LOBD (62%), 7 LOD (47%), and 11 HC (28%) subjects, whereas 4 LOBD, 4 LOD, and no HC individuals were 11C‐PiB‐PET‐positive. A significant difference in the prevalence of tau pathologies was only found between LOBD and HCs (P = 0.043, corrected for multiple comparisons). Tau topologies in the cases with 11C‐PiB‐PET‐positive AD pathologies consisted of predominant frontal (1 LOBD and 3 LODs), lateral temporal (3 LOBDs and 1 LOD), and posterior (1 LOBD) accumulations. Meanwhile, tau pathologies in 11C‐PiB‐negative cases showed predominant frontal (2 LOBDs and 1 LOD), temporal (1 LOBD and 1 LOD), posterior (4 LOBDs and 1 LOD), and basal ganglia (2 LOBDs) localizations.

Conclusion

Our findings suggest that a significant subset of LOBD patients harbor tau lesions linked to various AD subtypes and non‐AD tauopathies indicative of distinct early‐stage frontotemporal lobar degeneration subcategories.
Prevalence of cognitive ‘super‐ageing’ in an Australian sample using different diagnostic criteria
Authors: Powell Alice , Lam Ben C. P. , Foxe David , Close Jacqueline CT , Sachdev Perminder S. , Brodaty Henry
Published: December 2023

Background

Cognitive super‐ageing, which refers to a subset of older individuals who maintain high level cognitive abilities into advanced age, has been variously defined as either superior cognitive performance for age, comparable cognitive performance to younger adults and/or maintenance of cognitive abilities over time. This study aimed to investigate the prevalence of super‐ageing in Australian older adults using different published definitions, to determine the level of agreement between these definitions and to assess the relationship of super‐ageing status with daily function.

Method

Two thousand one hundred and seven adults aged between 65 and 106 years were enrolled in three longitudinal cohort studies: Sydney Memory and Ageing Study (MAS), Older Australian Twins Study (OATS) and Sydney Centenarian Study (SCS) and underwent neuropsychological testing. The prevalence of super‐ageing in these cohorts was assessed using nine different published super‐ageing definitions. Level of agreement between definitions was calculated using unweighted kappa statistics and Gwet’s first‐order agreement coefficient. Association between super‐ageing status and daily functioning was analysed using generalised linear modelling with gamma distribution.

Result

Prevalence of super‐ageing varied between 1.3 and 47.8 per cent depending on the definition used with more stringent cut‐offs resulting in a lower prevalence. Agreement between different criteria varied from poor to good with predictably better agreement between definitions using similar tests and cut‐offs. Super‐ageing was associated with better functional performance for all definitions and this association was significant in most cases.

Conclusion

The prevalence of super‐ageing is strongly affected by the demographic and neuropsychological testing parameters used. Greater consistency in defining super‐ageing would allow for better characterisation of this exceptional minority. So long as multiple definitions prevail, operational criteria should be explicit and determined by the specific research question.
Cognitive reserve moderates Alzheimer’s disease‐related tauopathic mechanism on cognition mediated by structural connectivity networks
Authors: Song Jeong‐Yeon , Kim Sung‐Woo , Cho Hanna , Kim Han‐Kyeol , Lyoo Chul Hyoung , Seong Joon‐Kyung
Published: December 2023

Background

Cognitive reserve (CR) is the capacity of an individual to maintain cognitive function despite brain damage (Stern et al., 2002). It moderates the effect of Alzheimer’s disease (AD)‐related brain damage on cognition, which is difficult to demonstrate using residual analysis. Recent research has shown a strong effect of tauopathy on the brain damage (Renaud La Joie et al., 2020), but how the CR affects this relationship is still unknown.

Method

We obtained 121 amyloid‐positive individuals, including 15 cognitive unimpaired (CU) individuals, 44 patients with mild cognitive impairment (MCI), and 58 AD. We first identified structural connectivity subnetworks where the relationships between edges’ weights (the number of streamlines) and tauopathy (global cortical tau standard uptake value ratio, standardized by the mean and standard deviation of the amyloid‐negative CU individuals) were modified by the years of education, as a proxy for cognitive reserve, using the network‐based statistics. We chose a subnetwork where its total connectivity significantly mediated the effect of the tauopathy on memory score, based on the Baron and Kenny method (Baron, Kenny et al., 1986). Through the path analysis, we verified the moderated mediation model, in which the moderating effects of education were added to the mediation model.

Result

One subnetwork whose edges were significantly affected by the tauopathy and moderation of education showed partial mediation in the tauopathic mechanism on cognition. The moderated mediation model based on the total connectivity of the subnetwork showed an appropriate model fit (CFI = 0.999, SRMR = 0.006) and a significant moderating effect on both stages of the indirect effect path of mediation when tested using the bootstrap method with 10000 resamples. The simple slope and intercept analyses implied that the highly educated individuals on the AD continuum show higher memory function than the lower educated individuals in the absence of tauopathy, but this score decreased more rapidly as tau increased.

Conclusion

We conclude that education modifies the effect of tauopathy on structural connectivity as well as the effect of structural connectivity on cognition when AD‐related tauopathy affects memory score through the structural connectivity subnetwork.
The Amsterdam Approach: optimizing care and research
Authors: van der Flier Wiesje M.
Published: December 2023

Alzheimer Center Amsterdam of Amsterdam UMC, the Netherlands, was founded in 2000. Research is embedded in the pan‐Amsterdam research institute Amsterdam Neuroscience. Alzheimer Center Amsterdam is part of the department of Neurology, and closely collaborates with many departments including Radiology & Nuclear Medicine, Clinical Chemistry, Clinical Genetics, Clinical Neurophysiology and Medical Psychology, as well as across campus for Basic Sciences. The Amsterdam Research Ecosystem furthermore involves the Industry Alliance Office, which facilitates collaborations with private partners. For conduct of clinical trials, we collaborate with Brain Research Center, an independent organization dedicated to execution of pharmaceutical trials.

Alzheimer Center Amsterdam has a 15 person staff, including neurologists, epidemiologists and neuroscientists. We employ ∼100ft personnel, mostly PhD students, research assistants and postdocs, working on Alzheimer’s disease and other neurodegenerative diseases causing dementia.

Our mission is to achieve personalized medicine, with a particular focus on early onset dementia. Research efforts focus on (1) finding the origin of disease, (2) diagnosis & prognosis, and (3) intervention & prevention. It is our vision that patient care and research should go in hand, to achieve the urgently needed breakthroughs. Together, all patients form the Amsterdam Dementia Cohort, to date counting over 7000 individuals.

We also have a keen eye for societal outreach. All colleagues, from junior to senior, reach out to society, e.g. via lectures, blogs or (social) media. Our initiative “Alzheimersocks.nl” increases awareness, while also raising research funds. We accelerate brain research on a national level via hersenonderzoek.nl, an online platform to link Dutch citizens to brain researchers looking for participants. Hersenonderzoek.nl has been highly successful, with over 35,000 registrants, >80 studies serviced with >25.000 participants.

Alzheimer Center Amsterdam is one of five Dutch Alzheimer Centers, closely working with Alzheimer Nederland. We have initiated the Dutch Memory Clinic Network, connecting the >80 Dutch memory clinics, to foster harmonization and pave the way for implementation of research results. We take the lead in (national) consortia because collaboration accelerates research. An example is the ABOARD project (www.aboard‐project.nl), which is a public‐private consortium of >30 partners, with the mission to work towards personalized medicine for AD.