bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal Association of Perceived Stress with Cerebrospinal Fluid Alzheimer's Disease Biomarkers in a Biracial Cohort
Authors: Trammell Antoine R , Goldstein Felicia , Lah James J. , Parker Monica W , Davis Crystal P , Dorbin Cornelya D , Saleh Sabria , Murphy‐Tchivzhel Elizabeth , Rose Alecia Michella , Osborne Amber , Ahmad Adiva , Al‐Amin Jahmila , Hajjar Ihab
Published: January 2025

Background

African American (AA) persons have a higher Alzheimer's disease (AD) prevalence and report more perceived stress than White persons. Our previous cross‐sectional study (JAD, 2020, 77:843‐853) demonstrated an association between self‐reported stress levels and cerebrospinal fluid (CSF) AD biomarkers. Using a biracial cohort, the current study investigates the association between stress and longitudinal CSF AD biomarkers over time.

Method

We analyzed data from a biracial cohort of community‐dwelling adults 50 years or older who completed baseline, Year 1, and Year 2 visits at the Emory Goizueta Alzheimer’s Disease Research Center. Participants underwent a lumbar puncture and cognitive testing and completed the perceived stress scale (PSS) questionnaire at each visit. We created 4 groups by self‐reported race (AA vs. White) and cognitive classification (normal vs. impaired). Using ANOVA or chi‐square, we compared baseline characteristics, cognitive classification status, and CSF AD biomarkers in the 4 groups (white/normal, white/impaired, AA/normal, and AA/impaired). Next, we tested associations between baseline PSS scores (predictor) and CSF AD biomarkers (outcome) over time using mixed models adjusted for factors confounding racial differences in AD. The significance level for all tests was p < 0.05.

Result

Data for 583 participants were analyzed (mean age:64.2; AA:49.7%; female:61.1%; impaired:68.6%). The AA participants were younger (63.6 vs. 67.7, p=.004) than white participants and had less neuropathology (Aβ42: 278 vs. 249, p<.0001; T‐tau: 47.9 vs. 74.7, p<.0001; P‐tau: 16 vs. 23.3, p<.0001; TAR: .21 vs. .37, p<.0001; PTAR: .07 vs. .11, p<.0001). AA/impaired participants reported higher stress (PSS=23.1, p=.04) than other groups. Regression, after adjusting for age, sex, education, BMI, and vascular comorbidities, showed higher baseline PSS scores were associated with higher P‐tau (F=8.22, p=.008) and PTAR (F=9.29, p=.005) over time in AA/impaired participants.

Conclusion

Higher baseline PSS scores were associated with Tau accumulation in the AA/impaired group over time. These results confirm previous findings and further suggest a biological connection underlying the stress‐AD link and its racial disparity. Future work exploring potential mechanisms is needed.
Differential Patterns of Brain and Body Aging on MR Imaging
Authors: Raji Cyrus A. , Meysami Somayeh , Hashemi Sam , Garg Saurabh , Akbari Nasrin , Gouda Ahmed , Chodakiewitz Yosef Gavriel , Nguyen Thanh Duc , Niotis Kellyann , Merrill David A. , Attariwala Rajpaul
Published: January 2025

Background

Comparative information on how whole‐body organs are linked with age and the brain is lacking.

Method

Overall, 7,149 healthy participants from four sites (Mean age 53.06 ± 12.95 years, 18‐97 years; 48% women; 52% men; 38% non‐white) were scanned on 1.5T MR machines with a whole‐body protocol. Whole body sequences utilized in the quantitative analyses were coronal T1 for organ, fat and muscle segmentation. Deep learning with FastSurfer on MPRAGE trained on 134 participants aged 27‐66 and segmented 96 brain regions. Partial correlation analysis was done controlling for sex and total intracranial volume for brain regions and total abdominal organ volume for abdominal organs. Multiple comparisons were accounted for using the Bonferroni method.

Result

Age negatively correlated with gray matter (rp = ‐0.38, p = 6.31×10−244) and white matter (rp = ‐0.263, p = 4.03×10−112). Age positively correlated to cerebral ventricle volume (rp = 0.493, p < .001). Increasing age was also inversely correlated with the lobar structural volumes: frontal lobe (rp = ‐0.420 p = 2.70×10−302), temporal lobe (rp = ‐0.378 p = 4.50×10−240), parietal lobe (rp ‐0.373 with p = 2.22×10−233), occipital lobe (rp = ‐0.259; p = 1.58×10−108). Age negatively correlated with AD risk regions: hippocampus (rp = ‐0.288 and p = 9.79×10−136), posterior cingulate (rp = ‐0.338, p = 4.37×10−189), precuneus (rp = ‐0.321, p= 1.44×10−169). Beyond the brain, the kidney and psoas muscle showed significant negative correlations with age (kidney; rp= ‐0.114, p = 1.23×10−211) and the psoas muscle (rp = ‐0.353, p= 1.13×10−208). Strikingly, visceral fat (vfat) was found to have a strong positive correlation with age, (rp = 0.416, p= 8.81×10−297). Subcutaneous fat (sfat), by contrast, showed a null correlation (rp = ‐0.01, p=1.0). Increasing age showed negative correlations with liver volumes (rp = ‐0.226, p = 2.21×10‐82), spleen (rp = ‐0.262, 5.46×10‐112) and total muscle volume (rp = ‐0.317, 3.17×10‐165).

Conclusion

Differential patterns of brain and body organ aging may lend insight into how age can increase the risk for common brain disorders in the elderly such as Alzheimer’s.
Association between brain metabolism and anxiety in long COVID in an underrepresented cohort
Authors: de Souza Débora Guerini , Silveira Maiele Dornelles , Borelli Wyllians Vendramini , Senger Joana Emilia , Machado Luiza Santos , Ferrari‐Souza João Pedro , de Bastiani Marco Antônio , Povala Guilherme , da Silva Ana Paula Bornes , de Mello Guilherme Bastos , da Ros João Pedro Uglione , Jotz Arthur Viana , Kadan Matheus Fakhri , Radaelli Graciane , de Paula Faria Daniele de Paula , Coutinho Artur Martins , Lourenco Mychael V , Pascoal Tharick A. , Rosa‐Neto Pedro , Matushita Cristina Sebastião , Soder Ricardo Benardi , Schumacher‐Schuh Artur Francisco , Souza Diogo O. , da Costa Jaderson Costa , Zimmer Eduardo R.
Published: January 2025

Background

Long COVID is an under‐characterized disorder that affects a wide range of individuals after COVID‐19 resolution. Long COVID individuals report persistent neurological manifestations, such as anxiety. Understanding its effects in the brain might help uncover the actual burden imposed by the pandemic sequelae and either define or discard long COVID as a risk factor for neurodegenerative diseases. Here, we aim to identify whether there is an association between brain metabolism and anxiety in an underrepresented population.

Method

Community‐dwelling individuals, above 50 years old, from Porto Alegre, Brazil, were divided into long COVID (n=39) and control groups (n=10) were evaluated with a battery of neuropsychological testing, including the GAD‐7 scale of anxiety. Then, they underwent a brain [18F]FDG‐PET scan (images normalized by the pons). We conducted a voxel‐wise linear regression testing the association between [18F]FDG metabolism and GAD‐7, and corrected for education, sex, and age. The analysis was corrected for multiple comparisons using the cluster‐wise random field theory method (significant t<‐3.34 and t>3.34, p<0.001, df=35).

Result

We found that GAD‐7 score presented a widespread negative association with [18F]FDG metabolism in multiple gray and white matter regions (Figure 1). Specifically, hippocampus (tmax =‐3.34, p=0.002), amygdala (tmax=‐3.82, p=0.0005), cerebellum (tmax=‐4.28, p=0.0001), and lateral occipitotemporal gyrus (tmax=‐5.26, p=0.0001) had the most relevant associated clusters in gray matter, while temporal lobe (tmax=‐3.9, p=0.0004) and frontal lobe (tmax=‐4.33, p=0.0001) presented the most relevant associated clusters in white matter.

Conclusion

Anxiety symptoms are a highly self‐reported symptom in long COVID. Here we show that anxiety is widely associated with reduced brain glucose metabolism in crucial areas for the limbic system and cognition, such as the hippocampus and amygdala. The peculiar associations between anxiety and FDG metabolism in white matter may suggest inflammatory responses triggered by long COVID. These data provide new insights into the mechanisms underlying long COVID symptoms in the brain.
Exploring the utility of Plasma GFAP as a secondary endpoint in Alzheimer's disease Clinical trials to monitor disease progression
Authors: Abbas Sarah , Ferreira Pamela C.L. , Bellaver Bruna , Povala Guilherme , Rohden Francieli , Aguzzoli Cristiano Schaffer , Zalzale Hussein , Bauer‐Negrini Guilherme , Soares Carolina , Ferrari‐Souza João Pedro , Leffa Douglas Teixeira , Lussier Firoza Z , Madeiros Marina Scop , Rodrigues Matheus Scarpatto , Oliveira Markley , Felix Cynthia , Tissot Cécile , Therriault Joseph , Benedet Andrea L. , Ashton Nicholas J. , Cohen Ann D , Lopez Oscar L. , Tudorascu Dana , Villemagne Victor L , Saeed Anum , Karim Helmet T. , Hong Chang Hyung , Roh Hyun Woong , Karikari Thomas K , Zetterberg Henrik , Blennow Kaj , Zimmer Eduardo R. , Rosa‐Neto Pedro , Son Sang Joon , Pascoal Tharick Ali
Published: January 2025

Background

Recent anti‐amyloid clinical trials have incorporated plasma glial fibrillary acidic protein (GFAP) as an exploratory endpoint, reporting a notable decrease in plasma GFAP levels over time. Additionally, plasma GFAP has been associated with Aβ pathology and cognitive decline in individuals with cognitive impairment, making it a robust biomarker of neuroinflammation for Alzheimer’s disease (AD). Here, we tested the utility of changes in plasma GFAP as a secondary endpoint in AD clinical trials focusing on cognitively impaired (CI) individuals.

Method

We evaluated CI Aβ+ individuals from two distinct cohorts: TRIAD (n=29, mean age (SD) = 71.5 (6.48), %MCI=44.8 and BICWALZS (n=65, mean age (SD) = 71.5 (6.48), %MCI=66.1]. All individuals had Aβ PET measurements at baseline. Paired t‐tests compared plasma GFAP levels between baseline and follow‐up. Cox proportional‐hazards analysis was performed to assess whether changes in plasma GFAP levels were predictive of increased odds for increasing CDR sum of boxes score over time. Sample size estimation was based on a hypothesized 25% drug effect on plasma GFAP reduction.

Result

We found a significant increase in plasma GFAP levels compared to baseline in both cohorts (Figures 1A and 1B). The percentage change in the research‐based cohort was slightly higher, likely attributed to a higher proportion of AD individuals compared to the memory clinic cohort (Figure 1C). Longitudinal plasma GFAP was associated with an increased risk of worsening cognition over time (Figures 2A and 2B). The effect size was slightly higher in the memory clinic cohort likely due to a relatively smaller standard deviation (Figure 3A). Inclusion of CI Aβ + individuals in a clinical trial testing a hypothesized 25% drug effect would necessitate 1354 participants in the research‐based cohort and 977 participants in the memory clinic cohort per study arm (Figure 3B).

Conclusion

Changes in GFAP are associated with worsening cognition over time in CI Aβ + individuals. Our findings suggest Plasma GFAP as a robust biomarker to be used as a secondary endpoint to monitor disease progression in CI Aβ + in AD clinical trials. Our findings, replicated in both research and clinical settings, may have implications in AD clinical trials composed of a real‐world population.
Cognitive training related changes in fMRI activations: a neural mechanism of transfer to executive functions in normal aging
Authors: Skolasinska Paulina , Qin Shuo , Lee Hyun Kyu , Voss Michelle W , Basak Chandramallika
Published: January 2025

Background

Improvement of cognitive functions is often accompanied by changes in brain function after cognitive training in older adults. In this large‐scale dual‐site fMRI study we investigated the effects of BrainHQ cognitive training (CT; ®Posit Science Inc.) and an active control (AC) group on brain activations during a demanding executive control (EC) task among cognitively normal older adults. CT was an adaptive, speed‐based program, with conflict resolution and switching, Participants in the AC arm played non‐timed casual games with low demands on EC. We expected changes in the activations of brain regions related to motor processing and control mechanisms on a hybrid block/event‐related Task‐switching fMRI paradigm alongside improvements in performance.

Methods

We identified brain regions differentially sensitive to the effects of CT and AC interventions using group‐by‐time generalized linear models to determine block‐related (single and dual blocks), and event‐related activations. The latter determined regions sensitive to varieties of cognitive and motor control processes, including local switch cost (switch‐nonswitch trials) and compatibility switch cost (CSC; incompatible‐compatible trials). The resulting activations were subjected to linear mixed models (LMM) to determine post‐training group differences, after controlling for differences in baseline activation.

Results

Compared to AC, CT showed consistently increased activations in the premotor and right prefrontal cortices–regions related to higher‐order motor planning and EC, following the intervention. Increased activation of this region was correlated to gains in Task‐switching accuracy and the EC construct. A CSC‐sensitive region was a large right‐lateralized frontoparietal area including both EC areas and regions involved in sensorimotor function. Post‐training, CT showed lower activation than AC, who showed an increase, but only during the compatible condition. Increased activation observed in AC was maladaptive to cognition as it correlated with reduced gains in the EC construct. Group‐by‐time interactions favoring CT were also observed in cognitive and motor processing cerebellar regions.

Conclusions

Compared to AC, CT showed compensatory adaptive changes in fMRI activations that were beneficial to cognition beyond the fMRI task. Training‐related changes on the Task‐switching paradigm can provide meaningful information on neural underpinnings of transfer to tasks of similar cognitive functions in normal aging.
Exploring Peripheral Blood Biomarkers for Dementia Diagnosis in Latin American Populations
Authors: Caviedes Ariel , Orellana Paulina , Hernandez Hernan , Slachevsky Andrea , Behrens María Isabel , Matallana Diana , Lopera Francisco , Custodio Nilton , Bruno Martin Alejandro , Funes José Alberto Avila , Takada Leonel Tadao , Pina‐Escudero Stefanie D , Valcour Victor , Kosik Kenneth S. , Miller Bruce L. , Yokoyama Jennifer S. , Ibañez Agustin , Duran‐Aniotz Claudia
Published: January 2025

Background

Dementia, encompassing Alzheimer's disease (AD) and frontotemporal dementia (FTD), poses a substantial public health challenge in Latin America. Barriers such as a shortage of healthcare professionals, limited medical accessibility, and underdiagnosis contribute to the complexity. While biomarkers aligned with the ATN framework (Amyloid, Tau, Neurodegeneration) have revolutionized diagnosis, their cost limits adoption in Latin America. Existing research focuses predominantly on North American or European cohorts, leaving a significant gap for the region. Our groundbreaking study aims to investigate, for the first time, ATN‐related proteins in AD, FTD, and control subjects using blood samples from the ReDLat cohort. This research addresses critical gaps in dementia diagnosis specific to Latin America, guided by insights from the ATN framework.

Method

We enrolled 500 participants (AD, FTD, and healthy controls‐HC) from Argentina, Chile, Colombia, Mexico, and Peru through the Multi‐Partner Consortium to Expand Dementia Research in Latin America (ReDLat). Plasma samples were collected in EDTA tubes, aliquoted, shipped on dry ice, and stored at ‐80°C following standard methods. We assess the plasma levels of Aβ40, Aβ42, p‐tau181, and NfL across groups (AD, FTD, HC) using Lumipulse G600II from Fujirebio, an advanced automated system which detects proteins via chemiluminescence.

Result

Our analysis revealed a significant decrease in the Aβ1‐42/40 ratio between AD and FTD patients compared to HC. Additionally, we observed a significant increase in p‐tau181 levels in both AD and FTD patients relative to HC, with a significant difference between AD and FTD. NfL levels were significantly higher in AD and FTD patients compared to HC.

Conclusion

Our findings demonstrate substantial differences in Aβ1‐42/40 ratio, phosphorylated Tau, and NfL levels between AD, FTD, and control subjects. These distinct biomarker profiles hold promise for distinguishing between various forms of dementia and healthy individuals. Importantly, our study addresses the critical gap in dementia research within LA populations, offering valuable insights into the potential impact of regional factors on biomarker dynamics.
Association of Plasma Alzheimer’s Disease Biomarkers with White Matter Hyperintensity Volume in Diverse Populations: A HABS‐HD Study
Authors: Trammell Antoine R , Lah James J. , Goldstein Felicia , Parker Monica W , Hales Chadwick M , Davis Crystal P , Dorbin Cornelya D , Saleh Sabria , Murphy‐Tchivzhel Elizabeth , Rose Alecia Michella , O'Bryant Sid E.
Published: January 2025

Background

Older African American (AA) and Hispanic American (HA) adults have a higher risk for Alzheimer’s disease (AD) than older non‐Hispanic white (NHW) adults. Cerebrovascular disease reflected by white matter hyperintensity (WMH) lesions on magnetic resonance imaging (MRI) may influence ADRD risk in these groups. Amyloid and tau PET data from studies of mostly NHW participants show a relationship between AD pathology and WMH lesions. Using a diverse cohort, this study investigates relationships between plasma AD biomarkers and WMH volume.

Method

We analyzed plasma AD biomarkers, WMH volume, and self‐reported participant race (NHW, HA, AA) obtained during baseline visits for the Health and Aging Brain Study: Health Disparities. Plasma AD biomarkers included amyloid‐beta40 (Aβ40), amyloid‐beta42 (Aβ42), total tau (T‐tau), phosphorylated tau181 (P‐tau181), and neurofilament light (NfL) from single‐molecule enzyme‐linked immunosorbent assays. From self‐reported race and baseline global Clinical Dementia Rating scores (normal=0, impaired≥0.5), we created race/cognitive groups (white/normal, white/impaired, AA/normal, AA/impaired, HA/normal, HA/impaired). Using ANOVA and chi‐square, we compared baseline characteristics, plasma AD biomarkers, and WMH volume in the groups. We tested associations between plasma AD biomarkers and WMH volume with linear regression adjusted for age, education, and sex.

Result

Data from 3,035 participants was analyzed (mean age: 65.2; female: 62.3%; impaired: 20.1%). AA persons were younger (NHW: 68.6, AA: 62.9, HA: 62.3. p<.0001) and had the highest WMH volume (NHW: 4.16, AA: 18.4, HA: 3.18, p<.0001). AA and HA participants had the lowest Aβ42 (NHW:10.9, AA:10.2, HA:10.1, p<.0001), while HA persons had the lowest Aβ40 (NHW: 223, AA: 220, HA: 207, p=0.0003). NHW persons had the highest P‐tau181 (NHW: 2.38, AA: 1.95, HA: 1.92, p<.0001) and NfL (NHW:19.1, AA: 12.3, HA: 17.1, p<.0001). Regression showed higher WMH volume was associated with higher Aβ40 (β=.02, p=.02), P‐tau181 (β=.29, p=.01), and T‐tau (β=1.55, p=.0002) in the HA/impaired group.

Conclusion

Our results show associations between plasma AD biomarkers and WMH volume in cognitively impaired HA adults who also have low WMH burden compared to other groups. Further studies to discern potential mechanisms and the potential diagnostic prognostic utility of plasma AD biomarkers on AD risk are needed.
The impact of lecanemab and donanemab on future Alzheimer’s disease clinical development
Authors: Dickson Samuel P. , Mallinckrodt Craig , Burstein Aaron H , Nisenbaum Laura , Fillit Howard M , Hendrix Suzanne B.
Published: January 2025

Background

A new era of Alzheimer’s disease (AD) research is beginning now that multiple monoclonal antibodies (mABs) are on the market. Their use may not be widespread initially but will be more common in clinical sites likely to participate in clinical trials and will continue to grow. Many AD investigational treatments have been studied as add‐on to acetylcholinesterase inhibitors; however, putative disease‐modifying therapies (DMTs) like mABs are expected to alter the underlying rate of progression, potentially reducing our ability to detect effects of other DMTs on top of mABs. In addition, if the mechanism of action (MOA) also targets amyloid, the treatment effect may be further reduced by co‐administration (antagonism). Alternatively, treatments that target complementary mechanisms may actually perform better (synergy). This new context requires careful consideration when powering clinical trials.

Method

We consider two clinical trial design scenarios. The first is a two‐arm trial to test a treatment as an add‐on to a mAB. The second is a four‐arm combination trial to represent the scenario where the mAB is started at the same time as investigational treatment. We calculate the required sample sizes for studies in three different patient populations: secondary prevention (MSDR = 0.34, 2‐year study), early AD (MSDR = 0.55, 18‐month study), and mild‐to‐moderate AD (MSDR = 0.67, 1‐year study). We consider scenarios with additivity, 30% antagonism, and 30% synergy.

Result

As shown in the table, the expected interaction with mAB treatment can have a large effect on study design decisions, with antagonistic treatment effects requiring more than three times the sample size of a synergistic treatment in most scenarios. The four‐arm scenario also usually requires around a threefold increase in sample size compared to a simple add‐on study.

Conclusion

Studies evaluating investigational therapies as add‐on to mABs are complex, and their cost to run will depend on how interactive the two treatments are. Treatments that are likely to work better with amyloid removed will be easier to study in this new context due to their complementary MOA. Symptomatic treatments may require fewer additional subjects than disease‐modifying treatments given the same expected effect size in the absence of mABs.
In vivo 18F‐MK6240 tau PET imaging in relation to peripheral inflammation and episodic memory in late middle‐aged adults
Authors: Malarte Mona‐Lisa , Chiotis Konstantinos , Ioannou Konstantinos , Rodriguez‐Vieitez Elena
Published: January 2025

Background

Detecting early stages of Alzheimer's disease (AD) remains a crucial yet complex challenge. While recent interest has surged in detecting biomarkers linked with the disease preclinical phase, a comprehensive understanding of the concomitant peripheral biological pathways before the potential disease onset is necessary. We aim to explore the associations between the 18F‐MK6240 tau PET tracer with plasma inflammatory markers, other AT(X)N biomarkers and episodic memory.

Method

The cross‐sectional sample consisted of n=132 cognitively unimpaired late middle‐aged Hispanic individuals (64.5 ± 3.4 years old, 34.1% APOE4 carriers, 69.7% female, 10.7 ± 4.0 years of education) from Northern Manhattan (AD Knowledge Center database). All individuals underwent multi‐modal imaging with T1‐weighted MRI, T2‐weighted FLAIR MRI, Aβ PET (18F‐florbetaben), tau PET (18F‐MK6240), plasma measures of inflammation (OLINK panel of 92 markers), plasma neuronal injury (NfL), and neuropsychological assessments. Data on demographics: age, sex, education, APOE, body mass index (BMI), and diabetes mellitus, were also included. Using the median split to dichotomize global Aβ and NfL measures, the study sample was stratified into four groups: “Aβ‐low, NfL‐low” (Group 0); “Aβ‐high, NfL‐low” (Group 1); “Aβ‐high, NfL‐high” (Group 2); and “Aβ‐low, NfL‐high” (Group 3).

Result

Our results revealed that 18F‐MK6240 tau PET is sensitive in detecting early neocortical tau pathology, even without evident neuronal injury (Figure 1). Plasma inflammation was not directly linked with Aβ or tau pathologies but strongly associated with NfL (Figure 2). Markers of neuronal injury (NfL), cerebrovascular injury (WMH) and specific inflammatory markers were associated with lower episodic memory (Figure 1). High NfL correlated with factors such as high inflammation, BMI, diabetes and older age.

Conclusion

The study emphasizes the complex nature of early AD markers suggesting that, aside from Aβ and tau, peripheral markers of NfL and inflammation are also central. Our findings call for a broader perspective in identifying early AD markers, underscoring the interplay between neuronal damage, inflammation, comorbidities and early cognitive changes.
Prior infections and polymorphism in NECTIN2 gene are synergistically associated with reduced hippocampal volume, a biomarker of neurodegeneration, in older women
Authors: Ukraintseva Svetlana , Popov Vladimir , Duan Hongzhe , Yashkin Arseniy , Akushevich Igor , Arbeev Konstantin , Yashin Anatoliy
Published: January 2025

Background

A growing body of research suggests a connection between Alzheimer’s disease (AD) and prior infections, although the mechanisms are not well understood. We recently reported a significant association between a history of adult infections and smaller brain hippocampal volume (HV), a major biomarker of neurodegeneration, in female participants of the UK Biobank (UKB). Here we further investigate this connection, taking into account the rs6859 polymorphism in the NECTIN2 gene, an established genetic risk factor for AD that is also involved in vulnerability to infections.

Methods

We estimated the associations between adult history of infections and HV assessed later in life, at ages 65‐80 years, in the presence and absence of the AD risk variant (A) of rs6859, using the UKB subsample with respective information (N=11,765; 48% women). Infectious disease diagnoses were based on ICD‐10 codes. The left/right HV was measured by magnetic resonance imaging (MRI) in cubic millimeters (mm3) and normalized. Analysis of variance (ANOVA), Tukey’s test, Welch test, and regression were used to examine statistical significance.

Results

Prior infections and carrying the AD risk variant rs6859 (A) were synergistically associated with a significant reduction in the left HV by ∼2.1% (p‐value=0.03) and in the right HV by ∼2.2% (p‐value=0.01) in women aged 65‐80 years. Results for men did not reach statistical significance.

Conclusion

Results of our study suggest that prior infections and rs6859 in the NECTIN2 gene synergistically contribute to neurodegeneration in older women. A potential explanation of this effect could be that carrying the rs6859 (A) may aggravate AD‐related brain pathology triggered by infections because this genetic risk factor for AD also increases the brain’s vulnerability to infections. This hypothesis needs confirmation in biomedical research. The observed sex difference may reflect a higher vulnerability of the female brain to infection‐related factors due to hormonal or other differences between males and females, which deserves further investigation.
Synthetic γ‐AApeptides as Targeting Ligands for Immunomagnetic separation of Alzheimer’s disease (AD) Biomarkers
Authors: Li Yuancheng , Mao Hui , Cai Jianfeng , Ma Hedi , Padelford Jonathan
Published: January 2025

Background

Liquid biopsy for Alzheimer’s disease (AD) biomarkers in cerebral spinal fluid (CSF) or blood samples is becoming a significant sector in the management of AD and AD related dementia (ADRD). Whereas different types of molecules, such as small molecules, peptides, and antibodies, have been used as ligands for targeting AD biomarkers/pathologies such as amyloid beta peptides (Aβs), current liquid biopsy approaches mostly use antibodies. However, the activity and affinity of the antibodies can vary depending on the source and preparation as well as the stability in storage. This study reports the application of Aβ40‐specific synthetic γ‐AApeptides, consisting of N‐acylated‐N‐aminoethyl amino acid units, as targeting ligands for immunomagnetic separation of Aβ40.

Method

A γ‐AApeptides library was developed using combinatorial chemistry, and screened for Aβ40‐targeting candidates following published methods. Chemical structures of γ‐AApeptides were solved by nuclear magnetic resonance (NMR) spectroscopy and tandem mass spectrometry (MS/MS). Conjugation of γ‐AApeptides with ultra‐magnetic iron oxide nanorod Magfiniti® was performed using the terminal thiol groups on γ‐AApeptides and amine groups on Magfiniti®, facilitated by a sulfosuccinimidyl 4‐(N‐maleimidomethyl)cyclohexane‐1‐carboxylate (sulfo‐SMCC) linker. Conjugation was validated by the change of hydrodynamic size and zeta‐potential of Magfiniti®. Human serum spiked with fluorescence‐labeled Aβ40 (100 to 2000 pg/mL) was used to test the detection sensitivity of γ‐AApeptide‐Magfiniti®, with Aβ40‐targeting 6E10‐antibody‐conjugated Magfiniti® used as control.

Result

We found three structures of γ‐AApeptides specific for Aβ40, namely A‐28, C‐231, and F‐12, all of which contained a backbone of four monomeric γ‐peptide units but different N‐acylated‐N‐aminoethyl sidechains. With similar chemical structures, successful conjugation of each γ‐AApeptides on Magfiniti® was confirmed by the increased hydrodynamic sizes from 58.8±8.0 nm to 91.3±11.9 nm, along with the decrease of zeta potentials from 25.4±7.7 mV to 14.1±5.6 mV. The detection sensitivity for 100 pg/mL Aβ40 by each γ‐AApeptide‐Magfiniti® was 96.1±2.7% (F‐12), 92.2±4.4% (C‐231), and 78.8±6.9% (A‐28), whereas 6E10‐Magfiniti® captured 98.4±2.1% of Aβ40 under same condition.

Conclusion

We synthesized and identified three Aβ40‐specific γ‐AApeptide that can be used as targeting ligands for immunomagnetic separation of AD biomarkers. The γ‐AApeptide F‐12 achieved a similar sensitivity to that of Aβ40‐targeted antibody.
BOLD fMRI signal changes in preclinical Alzheimer’s disease
Authors: Hrybouski Stanislau , Das Sandhitsu R. , Xie Long , Lyu Xueying , Wisse Laura E.M. , Kelley Melissa , Lane Jacqueline , Sherin Monica , DiCalogero Michael , Nasrallah Ilya M. , Detre John A. , Yushkevich Paul A. , Wolk David A
Published: January 2025

Background

Previous work suggests functional abnormalities in the human brain in preclinical Alzheimer’s disease. However, little has been explored about the relationship between BOLD fMRI signal amplitude/energy over time and AD pathology. In this work we analyzed the effects of AD progression on amplitude of low‐frequency fluctuations (ALFF) during resting‐state fMRI scans both at the whole‐brain level and at a more granular level, focused on regions of the medial temporal lobe (MTL) that are most vulnerable to AD pathology.

Method

In this cross‐sectional study, we analyzed data from 224 individuals from the Penn ADRC cohort (Table 1). All participants underwent structural and functional MRI on a Siemens 3T Prisma system, and 18F‐Florbetaben or 18F‐Florbetapir amyloid‐PET imaging. 125 participants also underwent 18F‐Flortaucipir tau‐PET scans. Functional images were preprocessed using a custom implementation of fMRIprep and ALFF was extracted using Conn software. In the whole‐brain analyses we performed voxelwise GLMs with age and sex as covariates.

Results

We observed reduced ALFF in both preclinical AD (Amyloid‐positive (Aβ+) cognitively unimpaired, CU) and Aβ+ cognitively impaired (CI) individuals. Relative to Aβ‐ controls, individuals with preclinical AD displayed lower ALFF in frontal, parietal and temporal association cortices (Figure 1, top left). CI individuals displayed lower ALFF in most of the brain, except in inferior temporal cortex, temporal pole, and MTL. The effect of AD progression on ALFF was characterized by a progressive reduction primarily in frontal and parietal regions that roughly align with the anatomy of the default mode network. In contrast, transentorhinal tau pathology was negatively associated with ALFF in frontal and anterior temporal lobes, as well as insula and MTL (Figure 1 bottom right). Negative association between tau burden and MTL ALFF was observed in all main MTL subregions, and strongest in the transetorhinal cortex (Figure 2).

Conclusion

We conclude that: (1) ALFF might be a promising biomarker for studying functional abnormalities in preclinical AD, and (2) based on the spatial topography of amyloid and tau effects on ALFF (Figure 1 bottom), there is likely a differential effect of of the two on ALFF that needs to be further explored.
Biomarkers, clinical status, and cognitive performance in a Caribbean Hispanic cohort
Authors: Honig Lawrence S. , Kang Min Suk , Reyes‐Dumeyer Dolly , Franco Yahaira , Medrano Martin , Piriz Angel , Recio Patricia , Mejia Diones Rivera , Soriano Belisa , Lantigua Rafael A. , Mayeux Richard
Published: January 2025

Background

Plasma biomarkers may be utilized to assist in diagnosis of Alzheimer's disease. However, in a cohort of Caribbean Hispanic individuals we have shown that there are both individuals who are biomarker positive but without dementia, and biomarker negative but diagnosed with dementia. Here we examine education and neuropsychological testing performance in these subgroups with biomarker‐inconsistent dementia diagnosis.

Method

Adults of Caribbean Hispanic ethnicity were recruited in both New York City and the Dominican Republic. The group reported here includes 1173 individuals. Plasma biomarkers including AB40, AB42, total tau, phosphorylated‐tau181, Neurofilament light chain (NfL), and Glial Fibrillary Acidic Protein (GFAP) were measured in samples processed, stored at ‐80°C, and thawed for analysis. Measurements were made using the Simoa Quanterix HD‐X platform.

Result

In this group of 1172 individuals, 885 (75.5%) were assessed as clinically without dementia, and 288 (24.5%) as clinically with dementia. Of those without dementia, 627 (70.8%) were biomarker negative, and 258 (29.2%) were biomarker positive for p‐tau181. Of those with dementia, 173 (60.1%) were biomarker positive, and 115 (39.9%) were biomarker negative for p‐tau181. For those without dementia, there was no significant difference in education level or performance on most neuropsychological measures between those biomarker positive or negative, except that delayed recall on the SRT word‐list‐learning test was lower in those with higher p‐tau181 (mean 4.25 ± 2.27 vs. 4.65 ± 1.98; p=0.009). For those with dementia, education was significantly lower in those that were p‐tau181 negative (2.87 ± 3.36 vs. 4.18 ± 4.73 yr;p=0.011), but these individuals also performed significantly better in neuropsychological tests including SRT immediate (p=0.003) and delayed recall (p<0.001), orientation (p=0.002), and Benton‐matching (p=0.012).

Conclusion

Plasma biomarkers may perform well in diagnosis of dementia in clinic populations, but less well in underserved populations, with more persons without dementia but with positive biomarkers, and with dementia but with negative biomarkers. For those without dementia but with positive biomarkers, likely many have pre‐symptomatic Alzheimer's; lower performance on memory tests supports this explanation. For those with dementia, but without positive biomarkers, explanations may include lower cognitive reserve/educational attainment level, increased comorbidities affecting functional status, and the presence of non‐Alzheimer's brain disorders.
Meta‐analysis of Alzheimer’s disease clinical trial time savings results
Authors: Hendrix Suzanne B. , Hendrix Kent , Haaland Benjamin A , O'Keefe Patrick P , Knowlton Newman , Mallinckrodt Craig , Dickson Samuel P.
Published: January 2025

Background

Alzheimer’s disease (AD) clinical trials led to the recent successes with monoclonal antibodies targeting amyloid, which opens up many new directions for research into treatment for AD in the future. Gaining greater understanding from these successes and failures will help researchers to focus their efforts on avenues that have the highest potential benefit.

Method

We performed a meta‐analysis of over a hundred studies of 70+ AD treatments. A global statistical test (GST) combining ADAS‐cog, ADCS‐ADL and CDR‐sb was used to assess the overall efficacy in these studies, in a fair way across multiple outcomes. Disease modifying treatment effects and symptomatic effects impacting all disease symptoms will perform better on this GST than treatments impacting only one symptom. In addition, a false positive effect is less likely to occur on all 3 outcomes simultaneously, making the GST a more reliable outcome for detecting true treatment effects. Composite scores, ADCOMS and iADRS, were used to target true disease progression in the lecanemab and donanemab phase 2 studies, respectively, and have similar advantages to a GST. A similar approach would have possibly averted much of the controversy surrounding the aducanumab approval.

Result

Some studies that were previously determined to be failures show some indication of positive effects. And conversely, some studies previously thought to be promising are shown to be more clearly failures. Meta‐analyses combining similar treatments across programs illuminate overlooked mechanisms as well as more conclusive failures.

Conclusion

The success and failure of Alzheimer’s treatments is partly hidden by including 3 different domains of clinical efficacy: cognition, function and global. True treatment efficacy and true lack of efficacy are much easier to detect with multiple, combined outcomes.
Group Singing Programs for Well‐being of Older Adults: An In‐Person Quantitative Follow‐up
Authors: Bonakdarpour Borna , Schafer Rhiana , Miller Jonathan , Miller Sandra Siegel
Published: January 2025

Background

Singing improves mood, social, and physical well‐being (Pentikainen et al., 2021). Choral singing has therefore gained recognition as a highly recommended activity for older adults and persons with dementia to fight isolation (Petrovsky et al., 2020; Sakamoto et., 2023). In a previous study, using qualitative measures, we demonstrated virtual sing‐along and choral singing offered by the Chicago‐based Sounds Good Choir and were associated with improved anxiety, emotional, and physical well‐being (Schafer et al., 2023) using qualitative, but not fully quantitative measures. The goal of this study was to determine whether in‐person choral singing and virtual sing‐along programs would improve older‐adults well‐being as measures by 7 quantitative surveys.

Methods

Participants were aged 55 and older. The sing‐along program engaged participants in virtual singing‐along to familiar music weekly for a year. The choir program consisted of 14 in‐person rehearsals to learn different parts of choral pieces. Following the program, self‐report assessments were solicited via 21 Likert scale questions covering 7 areas of well‐being (Table 1). Questions were developed from previous program evaluations and modeled off existing validated assessments of well‐being (Topp et al, 2015; Barrett & Murk, 2006; Dunn, 2008). Data were compared across program types using ANOVA, with Bonferroni corrected post‐hoc pairwise t test comparisons.

Result

Participants reported improvements in all aspects of well‐being in both programs (Figure 1). Two areas improved across the board with no effect of program type ‐ normalcy/structure and emotional. ANOVA indicated four well‐being areas were improved significantly more in choir participants than sing‐along (Figure 2) ‐ social (Q2‐4, p<0.001), intellectual (Q1‐4, p<0.001), physical (Q2, p<0.01), and spiritual (Q1, p<0.01). Connection to past was endorsed significantly more by sing‐along participants (p<0.01).

Conclusion

Both choral and sing‐along programs improved all aspects of well‐being with choral singing showing more effect in social, intellectual, physical, and spiritual well‐being, and sing‐along achieving more connection to the past. Our results provide preliminary evidence that our quantitative measures can capture participants’ experiences. While a larger controlled study is necessary for confirmation, our findings may suggest that depending on feasibility, either program may be utilized for measurable well‐being effects in older adults.
Limbic predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is associated with lower volume in gray and white matter of the temporal and frontal lobes and basal ganglia: A deformation‐based brain morphometry study
Authors: Tazwar Mahir , Evia Arnold M , Ridwan Abdur Raquib , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos
Published: January 2025

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is common in older adults and has been associated with substantial cognitive impairment. However, the association of LATE‐NC with brain morphometry has not been thoroughly investigated. In this work, we examined the association of LATE‐NC with brain morphometric anomalies using deformation‐based morphometry (DBM) in a large community cohort of older adults that came to autopsy (N=897).

Method

Cerebral hemispheres were acquired from 897 deceased older adults participating in Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core. Hemispheres were imaged ex‐vivo on 3T MRI scanners, which was followed by detailed neuropathologic examination. The participant scans were non‐linearly registered to an ex‐vivo template, and the resulting deformation fields were used to calculate the logarithm of the Jacobian determinant in each voxel (LogJ maps). Voxel‐wise linear regression was used to test the association between deformations shown in the LogJ maps and LATE‐NC stages, controlling for other age‐related neuropathologies (Alzheimer’s disease, Lewy bodies, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts), age at death, sex, education, postmortem intervals, and scanners. To identify the earliest LATE‐NC stage exhibiting morphometric abnormalities, LogJ values were compared between LATE‐NC stages 1–5 and stage 0. Statistical significance was set at p<0.05.

Result

Voxel‐wise analysis revealed an independent association of LATE‐NC with significantly lower volume in both gray and white matter regions within the temporal and frontal lobes and basal ganglia (p<0.05), including amygdala, hippocampus, entorhinal, parahippocampal, temporal pole, inferior temporal, middle temporal, fusiform, medial orbitofrontal, lateral orbitofrontal, insula, accumbens, and putamen cortices. Groupwise comparison of LogJ values revealed significant morphometric anomalies in small temporal lobe areas in stages 1–2, more temporal lobe as well as basal ganglia tissue in stage 3, and finally also included frontal lobe areas in stages 4–5.

Conclusion

The morphometric anomalies were detected as early as LATE‐NC stage 1, suggesting that MRI is sensitive to the early stages of the disease. This pattern is consistent with the known pathological distribution of LATE‐NC in the brain and may potentially be used in the development of a marker of this devastating neuropathology.
Evaluating brain age using functional connectivity in autosomal dominant Alzheimer disease
Authors: Macharia Kiana Angela , Gordon Brian A. , Wisch Julie K. , Metcalf Nicholas V , Roman June , Benzinger Tammie L.S. , Cruchaga Carlos , Goate Alison M. , Hassenstab Jason J. , Ibanez Laura , Karch Celeste M. , Llibre‐Guerra Jorge J. , Morris John C. , Perrin Richard J. , Renton Alan E. , Supnet Charlene B , Xiong Chengjie ,   Dominantly Inherited Alzheimer Network (DIAN), Bateman Randall J. , McDade Eric , Ances Beau , Millar Peter R
Published: January 2025

Background

Brain‐predicted age estimates are used to quantify an individual's brain age compared to a normative trajectory. We have recently shown that brain age from structural MRI is elevated in autosomal dominant Alzheimer disease (ADAD), a unique sample that allows the study of AD progression independently of age‐related confounds. Resting‐state functional connectivity (FC) may capture a biphasic response to sporadic AD, and thus may complement structural measures of brain aging in ADAD.

Method

We trained a Gaussian Process Regression (GPR) model to predict age from FC in 271 regions of interest in 779 cognitively unimpaired, amyloid‐negative, non‐ADAD participants. We applied the model in a cohort of 256 ADAD mutation carriers (MCs) and 200 familial non‐carrier controls (NCs) from the Dominantly Inherited Alzheimer Network (DIAN). We then assessed whether the brain age gap (FC‐BAG; difference between predicted and actual age) varied based on mutation status, cognitive status, or estimated years until symptom onset (EYO). We also explored its associations with markers of amyloid (PiB PET, CSF amyloid‐ß‐42/40), phosphorylated tau (CSF and plasma pTau‐181), neurodegeneration (CSF and plasma neurofilament light (NfL)), and cognition (global neuropsychological composite and CDR®‐sum of boxes).

Result

The model accurately predicted age in the training set (r = 0.77), validation set (r = 0.76), and DIAN NCs (r = 0.82), Figure 1. FC‐BAG was elevated in symptomatic MCs (p < .001), but only marginal elevation was observed in asymptomatic MCs (p = 0.047), Figure 2. In symptomatic MCs, FC‐BAG weakly associated with pTau‐181 in CSF (r = 0.34, p = 0.0046) and plasma (r = 0.26, p = 0.02), but no other associations with AD biomarkers or cognition were observed, Figure 3.

Conclusion

FC‐BAG was elevated in symptomatic ADAD, consistent with recent demonstrations in sporadic AD. However, we did not detect a predicted biphasic response to presymptomatic ADAD pathology. This inconsistency may be driven by differences between AD forms or by low reliability of FC, which may result in low statistical power and inconsistent brain‐behavior relationships. FC‐based BAG offers unique benefits but ultimately does not function as a reliable model for observing advanced aging in preclinical ADAD.
Correlation between ERP and CSF biomarkers in Mild Cognitive Impairment and Dementia patients in a general neurological clinic population
Authors: Levy Igor
Published: January 2025

Background

We have recently reported on the use of Event‐Related Potentials (ERP) biomarkers to separate Amyloid PET positive vs Amyloid PET negative patients with mild cognitive impairment (MCI) and dementia. A large body of evidence shows that low levels of beta amyloid and increased tau in the CSF are highly correlated with Alzheimer’s pathology in the brain. We investigated the correlation between amyloid and tau in the CSF, and ERP responses in patients with MCI and dementia.

Method

Patients with MCI and Dementia in a general neurological outpatient clinic underwent ERP testing. CSF analyses for Amyloid and TAU were also performed, and the results correlated with the output from the ERP test. When CSF studies were indeterminate, readings for brain amyloid brain load were obtained through PET analysis as part of the IDEAS (Imaging Dementia ‐Evidence for Amyloid Scanning) study when feasible

Result

Data will be presented at the conference with correlation between ERP markers and CSF amyloid and tau levels in patients with MCI and dementia.

Conclusion

Study results will provide valuable insights into the use of ERPs in a general neurological population with Alzheimer’s disease and cognitive impairment.