bluuebunny/crossref_metadata_2025 huggingface dataset:
The Association between the Body Fat Localization, Insulin Resistance, and Amyloid Burden in Midlife
Authors: Dolatshahi Mahsa , Commean Paul K. , Naghashzadeh Mahshid , Nguyen Caitlyn , Lloyd LaKisha , Kasani Sara Hosseinzadeh , McBee‐Kemper Abby , Weeks Jake , Sirlin Claude , Ceriani Lael , Yifei Xu , Mittendorfer Bettina , Liu Jingxia , Benzinger Tammie L.S. , Ippolito Joseph E. , Morris John C. , Raji Cyrus A.
Published: January 2025

Background

Obesity in midlife is a risk factor for developing Alzheimer disease later in life. However, the metabolic and inflammatory effects of body fat varies based on its anatomical localization. In this study, we aimed to investigate the association of MRI‐derived abdominal visceral and subcutaneous adipose tissue (VAT and SAT), liver proton‐density fat fraction (PDFF), thigh fat‐to‐muscle ratio (FMR), and insulin resistance with whole‐brain amyloid burden in cognitively normal midlife individuals.

Method

A total of 49 cognitively normal midlife individuals (Age: 50.65±5.77 years, 61.2% female, BMI: 32.0±67.34, 57.1% obese) underwent brain PET scan, body MRI, and metabolic assessment. Homeostatic Model Assessment for Insulin Resistance (HOMAIR) was used for measuring insulin resistance. Dynamic amyloid imaging was performed with a bolus injection of ∼15mCi [11C]PiB, followed by a 60‐min scan. Data from the 30–60 minute post‐injection window was used for calculating whole‐brain amyloid centiloid. VAT and SAT were semi‐automatically segmented using an in‐house MATLAB‐based software. A trained U‐Net convolutional neural network (CNN) model was used to calculate the hepatic PDFF maps from abdominal T1‐weighted images. After preprocessing and N4ITK bias correction on mid‐thigh slices between the ischial ramus and the medial knee condyle, a MATLAB program was used for segmenting thigh total fat including subcutaneous, inter‐, and intra‐muscular fat, and muscle volumes. Total thigh fat‐to‐muscle ratio (FMR) was calculated. Using Spearman correlation test, the association between whole‐brain amyloid centiloid and BMI, HOMAIR, VAT, SAT, PDFF, and FMR was assessed, with age and sex as covariates.

Result

Obese individuals had a higher amyloid burden compared to the non‐obese (p=0.011). Whole‐brain amyloid centiloid values were significantly associated with VAT (rho=0.62, p<0.0001) and HOMAIR (rho=0.56, p=0.013), but not other fat metrics. A mediation analysis showed significant direct effect of VAT (p=0.02) on amyloid burden, while the indirect VAT effects mediated by HOMAIR were non‐significant (p=0.28).

Conclusion

Obesity, higher visceral fat and insulin resistance, but not BMI, subcutaneous abdominal fat, liver fat, or thigh fat, are associated with higher whole‐brain amyloid burden in midlife. This highlights the importance of anatomical characterization of body fat for Alzheimer disease risk, where visceral fat shows a strong relationship with amyloid pathology.
The Black Male Dementia Caregiver Study: An Analysis of the Relationship between Informal Caregiving, Sleep, Depression, and Cognitive Functioning
Authors: Ali Amani L , Delong Alexander , Turner Robert W
Published: January 2025

Background

Stress associated with caregiving for a person with Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/RD) has negative health implications. However, little is known about the implications of stress on non‐Hispanic Black (NHB) informal male caregivers. This study aims to examine the relationship between sleep, depression, and cognitive function in a sample of NHB informal male caregivers in the metropolitan Washington, D.C. area.

Method

This cross‐sectional study (n = 68) included informal caregivers and non‐caregivers who participated in self‐perceived health questionnaires and a series of cognitive assessments. Data analysis consisted of logistic regression models to understand the relationship between caregiving, cognitive health, age, education, sleep (Pittsburgh Sleep Quality Index), and depression (Center for Epidemiological Studies Depression Scale).

Result

Three variables were used to explore caregiving: caregiver status, caregiver tenure, and hours per week spent caregiving. Tenure was positively associated with hours per week spent caregiving (p = 0.031). Poorer sleep was associated with caregiver status (p = 0.030) and weekly time spent caregiving (p = 0.002), while depression was associated with caregiver status (p = 0.024). Additionally, there was an association between caregiver status and the Verbal Fluency Test (VFT) (p = 0.050) and the Verbal Naming Test (VNT) (p = 0.035), which became stronger when adjusting for sleep and depression (p = 0.023). Additional hours spent per week providing care was associated with poor performance on the Number Span Test (NST) (p = 0.012), which is exacerbated when adjusting for sleep and depression (p = 0.009). Caregiver tenure was associated with lower scores on the VFT (p = 0.003), unimpacted by adjusting for sleep or depression.

Conclusion

In this study of NHB male informal caregivers, poor sleep was associated with lexical retrieval deficits, with caregiver tenure exacerbating this. Hours spent giving care per week is also associated with decreased sleep and attentivity. The results from this pilot study indicate a need for interventions to improve sleep quality among caregivers, thus reducing cognitive burden. Given this group’s unique cultural perspectives on sleep, curating targeted cognitive behavioral sleep interventions should be examined.
Associations of plasma phospho‐Tau217 with amyloid‐PET and cognitive status in adults with Down syndrome
Authors: Bettcher Brecca , Janelidze Shorena , McLachlan Max , Zammit Matthew D , McVea Andrew K , DiFilippo Alexandra H , Betthauser Tobey J. , Laymon Charles M , Tudorascu Dana , Cohen Annie , Garimella Arun , Price Julie C , Keator David B. , Brickman Adam M. , Lao Patrick J. , Klunk William E , Rosas H. Diana , Zaman Shahid , Hartley Sigan L , Head Elizabeth , Mapstone Mark , Krinsky‐McHale Sharon J. , Johnson Sterling C. , Lai Florence , Ances Beau , Handen Benjamin L , Hansson Oskar , Christian Bradley T.
Published: January 2025

Background

Blood‐based biomarkers able to detect atypical neuropathology could serve as a cost‐effective and noninvasive screening to include participants with Down syndrome (DS) in anti‐amyloid clinical trials. Accurately placing these novel biomarkers on the AD pathological cascade as proposed by the AT(N) framework informs relative disease progression of individuals. This work examines associations between plasma pTau217 accumulation, PET amyloid positivity, and cognitive status in adults with Down syndrome.

Method

Participants were recruited from the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS) study (Table 1). Amyloid positivity was determined by [11C]PiB or [18F]florbetapir (A+: Centiloids > 18) PET imaging from U01 cycle 1. Participants were classified as cognitively stable, mild cognitive impairment (MCI), or dementia (D). Plasma pTau217 concentration was measured using Lilly’s immunoassay for the Meso Scale Discovery platform. The threshold for ptau217 abnormality was derived using a subsample of amyloid negative participants. Youden’s Index (YI) was optimized to assess ptau217 sensitivity to PET A+ individuals. The time offset between PET amyloid positivity (18 CL) and ptau217 sensitivity was based on amyloid chronicity trajectories (Zammit et al, 2023). A second analysis was performed with respect to varying PET A+ thresholds.

Result

Amyloid positive participants showed elevated pTau217 levels compared to amyloid negative participants (A+: 0.82 pg/ml, A‐: 0.44 pg/ml, p < 0.05). With a data derived pTau217 threshold of 0.78 pg/ml, optimization of YI identified an optimal cut point of 48.5 CL. In a ROC analysis, AUC increased with increasing PET A+ thresholds (Figure 1). A significant separation of pTau217 with cognitive status was observed (cognitively stable: 0.51 pg/ml, MCI: 0.88 pg/ml, D: 1.50 pg/ml) (Figure 2).

Conclusion

Concordance was high between plasma pTau217 using Lilly’s immunoassay and amyloid PET status after reaching elevated amyloid levels of 48.5 CL or ∼6 years PET A+. This work suggests that elevated pTau217 levels follows Aβ neuropathology detected by PET and trends with clinical progression.
Preliminary grip strength data from an 8‐week pilot trial of creatine monohydrate supplementation in Alzheimer’s disease patients
Authors: Smith Aaron N. , Sullivan Debra K , Kelly Emma , Arora Tanu N , Waitsman Faith N , Taylor Matthew K
Published: January 2025

Background

Diminished muscle function and strength are linked to an increased risk and accelerated progression of Alzheimer’s disease (AD). Although these are direct consequences of the disease, recent preclinical evidence suggests decreased muscle function and strength may directly influence AD risk and progression via the muscle‐brain axis. Therefore, interventions to improve muscle strength may prevent functional decline related to AD. However, such specific interventions in AD are lacking. In this context, creatine monohydrate (CrM), a dietary supplement that boosts muscle strength, presents a promising intervention. This single‐armed pilot study explores the potential effects of an 8‐week creatine monohydrate supplementation on handgrip strength in AD.

Method

Data from 16 participants with AD who completed a one‐arm, 8‐week trial examining the feasibility and preliminary efficacy of 20 g/day of CrM in AD were analyzed. Handgrip strength, a reliable measure of muscle strength, was assessed on the dominant hand at baseline and at the end of the study on a calibrated hand dynamometer, measured in kilograms (kg) of force. At baseline and 8 weeks, 3 measurements were taken; the highest value was selected. We conducted a paired t‐test to test for an 8‐week change in mean handgrip strength. Statistical analyses were performed using R (v. 4.3.2; R Foundation, Vienna, Austria). Statistical significance was set at p < 0.05.

Result

Participants were 56% male with a mean age of 72.1 ± 6.4 years at baseline. The mean hand grip strength and body mass index (BMI) at baseline were 33.6 ± 11.6 kg and 25.4 ± 3.6 kg/m2, respectively. After 8 weeks of CrM supplementation, mean handgrip strength improved by 2.6 kg (36.1 ± 12.1 kg, p < 0.001). BMI did not change.

Conclusion

In this study, 20 g/day of CrM supplementation for 8 weeks was associated with improved handgrip strength in individuals with AD. Our pilot data suggests that CrM may be valuable for maintaining or preventing AD‐related functional decline by improving muscle strength.
Effects of Self‐Perceptions of Cognitive Decline on Cognitive Assessment Outcomes in the Women’s Alzheimer’s Movement Prevention Center at Cleveland Clinic
Authors: Kaplan Nikki L , Post Emily , Levine Taylor F , Caldwell Jessica ZK
Published: January 2025

Background

The Women’s Alzheimer’s Movement Prevention Center (WAMPC) at Cleveland Clinic evaluates women’s risk factors for developing Alzheimer’s disease and provides personalized recommendations for reducing risk. Previous research has established that up to 40% of Alzheimer’s disease (AD) cases might be prevented when modifiable risk factors are addressed. To better understand individual risk profiles, a wealth of information is collected, including self‐reported health conditions (both personal and familial), lifestyle factors (e.g. alcohol and tobacco use, exercise, social support), a brief cognitive test battery, and blood tests. WAMPC takes a holistic approach in helping women combat modifiable risks for AD.

Method

207 women from the WAMPC who consented to have their clinical data used for research purposes were assessed (mean age = 53.39, SD = 9.53). Requirements for participation include normal cognition and family history of Alzheimer’s disease. Patients completed the Mini Mental State Exam (MMSE), selected tests from the NIH Toolbox (Oral‐Symbol Digit, Processing Speed, Picture Vocabulary, Card Sort, and Flanker), Controlled Oral Word Association Test‐FAS (COWAT: FAS, Animal Naming), and the Trail Making Test Part B. Patients also completed the Subjective Cognitive Decline Questionnaire (SCDQ), a self‐report assessment of perceived cognitive changes. We transformed SCDQ total scores into cohort‐based z‐scores to create three SCDQ groups (“fewer cognitive concerns” = bottom third, “average cognitive concerns” = middle third, and “above average cognitive concerns” = top third. We evaluated the relationship between performance on cognitive tests and women’s perceived cognitive decline on SCDQ. We ran 9 individual ANCOVAs, one for each cognitive test, using education and age as covariates.

Result

Of the tests evaluated, the SCDQ significantly predicted scores on Animal Naming (F(2,190) = 3.602, p = .029) and NIH Toolbox Card Sorting (F(2,190) = 3.597, p = .029). No other tests demonstrated significant relationships with self‐perceptions of cognitive decline per the SCDQ.

Conclusion

Perceived cognitive decline in daily life predicted concurrent poorer performance on selected tests of language and executive function, in women who are cognitively normal, yet at increased risk for AD based on family history. Further work is needed to understand whether subjective cognitive concerns may represent risk for cognitive decline in this cohort of women with family history of AD.
Making meaning through cultural embeddedness: Advancing culture‐sensitive training for Alzheimer’s Disease and Alzheimer’s Disease Related Dementia Caregivers in Ibadan, Nigeria
Authors: Adedeji Isaac Akinkunmi , Lawal Saheed Akinmayowa , Ogunniyi Adesola , Henderson David C , Farombi Temitope Hannah , Elugbadebo Olufisayo Oluyinka
Published: January 2025

Background

Limited knowledge exists about the cultural approaches to managing the psychological and behavioral outcomes (PBO) of Alzheimer’s Disease and Alzheimer’s Disease‐Related Dementia (AD/ADRD) in Africa. Specifically, to develop a culture‐sensitive training framework for AD/ADRD caregivers, we explored AD/ADRD caregivers’ cultural embeddedness in managing people living with AD/ADRD (PLWAD/ADRD) in Ibadan, Nigeria.

Method

Using hermeneutic phenomenological qualitative research design, we interviewed 23 caregivers providing care to PLWAD/ADRD in Ibadan, a Yoruba‐speaking ethnic group of Nigeria. Caregivers participated in in‐depth interviews (IDI) to share their experiences in managing AD/ADRD PBO. To capture the interpretive value of the caregivers’ experiences, we developed inductive and deductive codes and applied them to caregivers’ narratives using Nvivo 14. Based on the reflexivity of the multidisciplinary research team, themes, and sub‐themes about the cultural elements of caregivers' response to the PBO of PLWAD/ADRD were developed.

Result

Among the 23 caregivers, 16 were female; five received a monthly salary; two were non‐members of the Yoruba ethnic group. We found five culturally sensitive themes, broadly categorized into cultural universals and specifics. The Yoruba‐specific aspects included (1) respect and filial piety, (2) non‐verbal cues, and (3) communal living arrangements and rotational care. Meanwhile, the cultural universals centered on (4) reciprocity/fear of retribution and (5) patience. Caregivers showed respect and filial piety by staying quiet, speaking in a low tone, minimizing correction, and refraining from commenting on PLWAD/ADRDs' self‐efficacy. Non‐verbal cues, like facial expressions, played a crucial role. The communal living arrangement proved valuable in managing negative behaviors like wandering. Reciprocity and retribution were embedded beliefs, and patience was a culturally universal approach requisite in the care of PLWAD/ADRD.

Conclusion

The five cultural themes are important training areas for managing the behavioral and psychological outcomes of AD/ADRD. Mixed‐methods studies are required to explore the dimensions and generalizability of the five cultural constructs to strengthen Africa’s AD/ADRD caregiving workforce.
Antisense‐mediated APP suppression as potential therapeutic for Down Syndrome Alzheimer’s Disease
Authors: Zhao Hien T , Chen Xu‐Qiao , Das Utpal , Zuo Xinxin , Ford Brittany T , Kordasiewicz Holly B , Mobley William C.
Published: January 2025

Background

Increased APP gene dosage is both necessary and sufficient to result in Down Syndrome Alzheimer’s Disease (DSAD) in humans and AD‐related degenerative changes in mouse models of DS.

Method

We tested antisense oligonucleotides (ASOs) designed to suppress APP expression via RNAseH1‐mediated degradation in the Dp(16)1Yey or Dp(16) model of Down Syndrome. Dp(16) is trisomic for human chromosome 21 syntenic regions on murine chromosome 16, containing 115 genes including APP. To evaluate efficacy of APP suppression, Dp16 and 2N euploid mice at 6‐8 months of age were treated with a mouse App ASO, and endosomal pathology and downstream pathological processes were evaluated.

Result

APP suppression reverses not only Rab5 hyperactivation in this model, but also abnormal hyperactivation of other Rab GTPases such as Rab7 and Rab11. Furthermore, tau hyperphosphorylation was ameliorated, and neurotrophin signaling was restored following APP suppression.

Conclusion

Taken together, these data support the hypothesis that APP suppression should restore normal endosomal function and neurotrophic signaling and benefit disease, and the potential of antisense‐mediated APP suppression as a disease‐modifying therapy for DSAD.
Biomarkers evaluation in olfactory neuroepithelial cells isolated from Mexican patients with and without Mild Cognitive Impairment
Authors: Silva‐Lucero Maria‐del‐Carmen , Gomez‐Virgilio Laura , Gutierrez‐Malacara Andres‐Ivan , Lora‐Marin Obed‐Ricardo , Cardenas‐Aguayo Maria‐del‐Carmen
Published: January 2025

Background

Mild cognitive impairment may increase the risk of Alzheimer's disease (AD) or probably accelerate the progression. AD is the most common cause of dementia, substantial neuronal loss, and neuropathological lesions can damage many brain regions. Symptoms of the disease begin with mild memory difficulties and evolve towards cognitive impairment. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use, but may be expensive approaches, here we propose a more affordable approach to detect biomarkers in cells isolated from the olfactory neuroepithelium.

Method

Older adults with signs of Mild Cognitive Impairment and healthy individuals of the same age were recruited. We performed a MoCA Test, a medical interview, and an olfactory test for each volunteer. A noninvasive nasal exudate was performed to obtain, isolate, and characterize Olfactory Epithelial Precursor Cells. Once the cultures were established, different biomarkers were evaluated using the Western Blot technique. We selected the biomarkers studied through a bioinformatic DEG’s analysis previously carried out by our research group.

Result

A cohort of 3 patients with cognitive impairment and 3 healthy controls were recruited. We obtained from all volunteers their clinical history, a MOCA‐cognitive test, blood samples, and the culture of the Olfactory Epithelial Precursor Cells of each patient was established. The following markers were analyzed by Western Blot Amyloid precursor protein, total tau (T‐tau) and phospho‐tau217 (p‐tau217), as well as the AD biomarkers selected by our bioinformatics analysis: calcineurin subunit, a serine/threonine phosphatase under the control of Ca2+/calmodulin; β‐synuclein, which is associated with synaptic degeneration; a‐synuclein; and FKBP prolyl isomerase 1B (FKBP1B), a chaperone involved in age‐related Ca2+ dysregulation in the brain. Our data showed no correlation between p/tau217 and cognitive impairment.

Conclusion

The search for altered genes in mild cognitive impaired patient‐derived peripheral cells will allow us to identify potential early biomarkers of AD that could be validated in blood samples from patients with AD, as a possible affordable diagnostic tool.
The impact of late‐onset epilepsy as a co‐occurring condition of Alzheimer’s disease on tau levels in older adults with Down syndrome
Authors: Queder Nazek , McMillan Liv , Sathishkumar Mithra , Taylor Lisa M. , Keator David B. , Doran Eric , Hom Christy L. , Krinsky‐McHale Sharon J. , Petersen Melissa , O'Bryant Sid E. , Brickman Adam M. , Head Elizabeth , Mapstone Mark , Silverman Wayne , Lott Ira T. , Yassa Michael A.
Published: January 2025

Background

There is an increased risk of epilepsy in Down syndrome (DS), especially after the age of 40. The onset of this co‐occurring disease is closely associated with Alzheimer’s disease (AD) related cognitive deterioration. Therefore, understanding the impact of late‐onset epilepsy on AD biomarkers in people with DS is crucial. Here, we aim to test the difference in tau levels and hippocampal volume in people with late‐onset seizures, childhood‐onset seizures, and no seizures.

Method

We analyzed data from 54 participants (52 +/‐ 6.5 years, 66% females) with DS enrolled in the Alzheimer’s disease Down syndrome study. A total of 18 participants had a history of seizures: 9 participants had recent onset of seizures in the last 5 years and 9 participants had childhood‐onset of seizures. A 2‐to‐1 match method was used to identify 36 control match participants based on age, sex, and dementia status. Magnetic resonance imaging (MRI) and flortaucipir (FTP) positron emission tomography (PET) were used to assess atrophy and tau accumulation respectively. Plasma ptau181 levels were assessed using the ultra‐sensitive single molecule array (Simoa) technology platform HDX imager. ANOVA was used to assess group differences.

Result

The results showed significant differences in ptau181 levels between individuals with late‐onset seizure disorder, individuals with childhood‐onset of seizures, and controls (F(2,51)= 9.649; p<.001). Post‐hoc analysis revealed that individuals with late‐onset seizure disorder had significantly higher levels of ptau181 compared to individuals with childhood‐onset (p<.001) and controls (p = 0.002), with no differences between childhood‐onset seizures and controls. No differences were observed in the hippocampus volume among the three groups. Differences in the temporal meta‐ROI tau SUVR were assessed in a subset of our sample. We observed a trend in individuals with history of seizures showing higher tau SUVR in the temporal meta‐ROI compared to controls.

Conclusion

Our findings suggest that the levels of ptau181 could be impacted by late‐onset seizure disorder. These results shed the light on the importance of assessing the impact of co‐occurring disorder on AD related biomarkers. Future research will explore the impact of late‐onset seizure disorder on AD‐related brain biomarkers longitudinally.
Endocrinological aging drives alterations in white matter architecture: Evidence from a humanized APOE risk model of Alzheimer’s disease
Authors: Raikes Adam C. , Bhattrai Avnish , Wang Tian , Brinton Roberta Diaz
Published: January 2025

Background

Alzheimer’s affects women 2:1 compared to men, suggesting sex‐specific factors driving risk. Menopause, a female‐specific phenomenon, induces a multi‐system response across endocrine, metabolic, and immune‐inflammatory systems. Despite known effects on these systems, the impact on the brain and AD risk remains incompletely understood, limiting preventative options. Here, we investigated the impact of the menopausal transition on white matter properties in a late‐onset AD mouse model.

Methods

6‐, 9‐ and 15‐month humanized APOEε3/ε3 (JAX #29018), ε4/ε4 (JAX #27894), and ε3/ε4 (bred in‐house) female mice were stratified into endocrine aging groups based on vaginal cytology profiles: regular (consistent 4–5 day cycles) or irregular (6–9 day cycles) cyclers or acyclic (no cycling >9 days). Ex‐vivo diffusion‐weighted imaging was used to analyze white matter fiber density (FD), cross‐section (FC), and their product (FDC), in addition to anisotropy (FA) and diffusivity (MD). Data were analyzed using generalized additive models with the main effects of endocrine aging (ref: 9‐month regular), hAPOE genotype, and total brain volume (except FD). Findings are reported at FDR corrected p<0.05.

Results

Compared to 9‐month regular cyclers, both 6‐month regular and 15‐month acyclic mice had lower FC, primarily in bilateral fimbria, stria terminalis, corpus callosum, and gray matter regions, including bilateral hippocampal subfields and cingulate cortex (15‐month acyclic mice only). 15‐month acyclic mice showed lower FD/FDC in the left cingulate, piriform, and bilateral entorhinal cortices and greater FD/FDC in the bilateral habenular commissure and dorsal tenia tecta. FA and MD were significantly lower in the 15‐month acyclic mice in most white matter regions. Compared to 15‐month irregular cyclers, 15‐month acyclic mice exhibited lower FA in white matter tracts and striatal projection fibers.

Conclusions

In these mice, menopause, rather than age or APOE genotype, altered white matter bundle properties, shifting toward smaller bundles of varying compactness and reduced bundle coherence. Pronounced differences were seen between 9‐month pre‐menopausal and 15‐month post‐menopausal mice. Differences between peri‐ and post‐menopausal mice at 15 months were only observed in FA. These findings implicate endocrine aging as a driving factor in white matter changes that may precede AD presentation. Ongoing work is focused on conducting translational analyses in the human brain.
Genome‐wide association of Amyloid imaging and plasma biomarkers in Adults with Down Syndrome
Authors: Aslam Muhammad Muaaz , Fan Kang‐Hsien , Dang Lam‐Ha T , Gorijala Priyanka , Shi Ruyu , Feingold Eleanor , Xicota Laura , Cohen Ann D , Handen Benjamin L , Christian Bradley T. , Head Elizabeth , Mapstone Mark , Cruchaga Carlos , Lee Joseph H. , Kamboh M. Ilyas ,   Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS)
Published: January 2025

Background

Adults with Down Syndrome (DS) are at higher risk for Alzheimer's disease (AD) compared to the general population due to trisomy of chromosome 21. Thus, it is important to investigate the role AD‐related biomarkers in adults with DS. Here we have performed genome‐wide association analyses on amyloid‐PET and plasma amyloid levels in the participants of the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS).

Method

Genome‐wide analyses were performed on 294 non‐Hispanic whites with DS (ranging in age from 25 to 81, Male 54.8%) having biomarker data from amyloid‐PET imaging and plasma levels of Aβ40, Aβ42, and the Aβ42/Aβ40 ratio. The association of two APOE SNPs, rs429358 (E4) and rs7412 (E2) was also examined. We used a joint model of multiple phenotypes to investigate the genetic factors contributing to all amyloid biomarkers levels simultaneously in those participants having the complete phenotypic and genotypic data.

Result

APOE4 was not associated with any Aβ biomarker, but APOE2 was significantly associated with lower Amyloid‐PET levels compared to those without APOE2 (p=0.0002). Genome‐wide association analyses identified multiple genome‐wide significant (GWS) hits including six SNPs for amyloid PET (rs532620170 on chr1, p=2.93E‐09; rs144406757 on chr3, p=3.49E‐08; rs1880432 on chr7, p=4.76E‐08; rs143578940 on chr7, p=4.95E‐09; rs8024654 on chr15, p=1.40E‐08; and rs148455801 on chr19, p=5.98E‐09), one SNP for Aβ40 on chromosome 2 (rs78338676, p=1.50E‐08) and one SNP for Aβ42/Aβ40 ratio also on chromosome 2 (rs75126438, p=1.37E‐08). The multiple amyloid phenotype analysis revealed 14 independent GWS loci on chromosomes 2, 4, 5, 7, 8, 10, 12, 15, and 16, indicating a robust association with both imaging and plasma Aβ biomarkers.

Conclusion

Despite the limited number of sample of DS, we identified a total of 22 potential GWS loci associated with Aβ. These findings highlight the potential of research with the DS population as a valuable resource for identifying genetic elements contributing to AD pathology.
Generalizability of Alzheimer’s disease plasma biomarkers phospho‐Tau and beta amyloid in individuals of diverse genetic ancestries
Authors: Griswold Anthony J. , Rajabli Farid , Gu Tianjie , Arvizu Jamie , Golightly Charles G. , Whitehead Patrice L. , Hamilton‐Nelson Kara L. , Adams Larry D. , Celis Katrina , Celis Katrina , Sanchez Jose Javier , Mena Pedro R. , Starks Takiyah D. , Illanes‐Manrique Maryenela Z. , Silva‐Vergara Concepcion , Cuccaro Michael L. , Vance Jeffery M. , Feliciano‐Astacio Briseida E. , Cornejo‐Olivas Mario , Byrd Goldie S. , Beecham Gary , Haines Jonathan L. , Pericak‐Vance Margaret A
Published: January 2025

Background

Plasma concentrations of phosphorylated threonine‐181 of Tau (pTau181) and the ratio of amyloid beta isoforms Aβ42/Aβ40 are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). However, assessment of the utility of these biomarkers has been in non‐Hispanic, European individuals. Given differences in AD risk across populations, generalizability of these findings is not assured in individuals of diverse ancestries. Here we evaluate the levels of plasma pTau181 and Aβ42/Aβ40 and assess their utility in discriminating clinically diagnosed AD from cognitively unimpaired (CU), age‐matched controls in ancestrally diverse, admixed cohorts.

Method

We measured pTau181 and Aβ42/Aβ40 with Simoa chemistry using the pTau181 AdvantageV2 and NEUROLOGY 3‐PLEX A assays, respectively. Our cohorts consisted of: 923 African Americans (319 AD, 604 CU), 149 Peruvians (49 AD, 100 CU), and 667 Caribbean Hispanics (613 Puerto Ricans (288 AD, 325 CU) and 54 Cubans (24 AD, 30 CI)). Linear mixed‐effect regression models adjusted for age, sex, population substructure and relatedness followed by Bonferroni correction was applied to identify biomarker differences. Diagnostic performance and receiver operator characteristic (ROC) curves were created from logistic regression models.

Result

Plasma pTau181 concentrations did not differ across any of the cohorts within AD or CU. There was a clear elevation of pTau181 concentration in AD compared to CU (p < 1.7x10‐13) taking into account all individuals and in each cohort separately (African Americans, p =1.9x10‐8; Caribbean Hispanics, p=3.1x10‐7; Peruvians, p=0.05). There was no significant difference in the plasma Aβ42/Aβ40 ratio, however there was a trend towards a decreasing ratio in AD. Using the area under the ROC, pTau181 was more accurate at predicting status than the Aβ42/Aβ40 ratio, but the classification improved when both biomarkers were combined.

Conclusion

These results suggest AD biomarkers are generalizable across ancestries, with baseline values being consistent across diverse populations. Ultimately, combining genomic, biomarker, and social and environmental data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses in individuals of diverse ancestries.
Development of the set of resource use items to capture costs related to informal care for people with Rare Dementia for RD‐TALK
Authors: Cullen Katherine , Brotherhood Emilie V , Fitzsimmons Deborah , Stott Joshua
Published: January 2025

Background

Non‐memory‐led dementias pose additional challenges to ‘typical dementias’ including unusual symptoms and younger onset leading to particularly high neuropsychiatric comorbidities. As part of the economic evaluation supporting the RD‐talk research programme, we require the collection of participant level resource use associated with the intervention compared with usual care. The resource use measure (RUM) needs to be sufficiently comprehensive, but still focused to capture the key items of interest (e.g., main drivers of resource use and associated cost) to balance the trade‐off between precision, effort, and burden to research participant.

Method

Initial discussion with carers of people with non‐memory‐led dementia and clinical experts informed a draft list of resource items to design a RUM. A modified Delphi survey was carried out with informal carers and healthcare professionals (HCPs). Consensus of each item, using pre‐defined levels to keep or remove items, was summarised using descriptive statistics and percentage agreement. Inter‐rater reliability between rounds was assessed using the intra‐class correlation coefficient; the stability of the raters’ responses was assessed with the Wilcoxon signed rank test.

Result

For round one, 18 participants were recruited (11 HCPs, 9 carers), 14 participants remained for round two (7 HCPs, 7 carers). For primary/community care, general practitioner appointments, psychological interventions (such as talking therapy), and rare dementia support groups or direct calls were all highly rated by both HCPs and carers. The RUM should include time taken off work or taking early retirement due to caring for someone with rare dementia. Categories of caring tasks were listed, from personal care and physical help, to helping with paperwork, financial matters, dealing with care services and benefits, and managing challenging behaviour. All categories were highly rated by HCPs and carers.

Conclusion

Resource use measures are mainly designed for the person with a disease or condition and focus on health and social care use. There can be a considerable burden on informal carers when someone is diagnosed with rare dementia, and it is important to capture key resource items in addition to health and social care relevant to this population when evaluating interventions in rare dementia management.
CU PET Aβ and Tau Positive Individuals Show Impairment in MoCA Delayed Recall
Authors: Felix Cynthia , Ferreira Pamela C.L. , Kollasserry Felix Joy , Snitz Beth E. , Rebok George , Tudorascu Dana , Rodrigues Matheus Scarpatto , Oliveira Markley , Povala Guilherme , Lemaire Peter , Bauer‐Negrini Guilherme , Medeiros Marina Scop , Abbas Sarah , Soares Carolina , Aguzzoli Cristiano Schaffer , Bellaver Bruna , Lussier Firoza Z , Amaral Livia , Pascual Belen , Gordon Brian A. , Lowe Val J. , Oh Hwamee , soleimani‐meigooni David N. , Klunk William E , Rosa‐Neto Pedro , Jagust William J. , Baker Suzanne L. , Pascoal Tharick A.
Published: January 2025

Background

Identification of cognitively unimpaired (CU) individuals who may progress to mild cognitive impairment (MCI), is a pressing issue in the Alzheimer’s disease (AD) field, since therapeutic interventions may be more effective in the absence of cognitive impairment and neurodegeneration. CU individuals positive for amyloid and tau PET are very likely in the AD pathway. In out‐patient cognitive screening, we use rapid and simple tests such as The Montreal Cognitive Assessment (MoCA) ‐ a composite of executive, visuospatial, naming, attention, language, abstraction, delayed recall, and orientation performances. We hypothesize that sub‐categorizing the CU group based on the presence of amyloid (A) and tau (T) pathologies, as measured by PET, can reveal subtle cognitive deficits, even in a clinical test with low sensitivity such as MoCA.

Method

We included 88 CU [defined as CDR global score of 0] older adults with available head‐to‐head MK6240 tau‐PET and Flortaucipir tracers from the ongoing HEAD multi‐site observational study. They also underwent Amyloid PET imaging using PiB or NAV4694. MoCA testing was done around the imaging time. To increase similarity with clinical practice, Amyloid and Tau PET positivity was defined using visual reads. Based on tracer uptake status, we categorized the individuals into A‐T‐, A‐T+, A+T‐ and A‐T‐ groups. Unpaired t‐test and one‐way ANOVA were used to test for significant differences between groups.

Result

2‐tailed p‐values were significant between the A‐T‐ group and the A+T+ group for MoCA total score [p: 0.0025 and p: 0.0025]. When we stratified MoCA in the different cognitive domains, we found that the results were driven by MoCA (memory) Delayed Recall score [p: 0.0007 and p: 0.0162]. A‐T+ vs A+T+ was also significant [p: 0.0099] for MoCA Delayed Recall. Both tau tracers (MK6240 and Flortaucipir) showed similar performance for determining T+ and identifying cognitive decline.

Conclusion

MoCA, a simple and commonly administered in‐office neuropsychological test, can detect subtle cognitive dysfunction in CU older adults who are Aβ and tau positive (A+/T+). These CU A+/T+ individuals are likely on the path to developing AD dementia.
Sex Differences in the Risk of Alzheimer’s Disease and Associated Risk Factors Among Aging Hispanics: A Cross‐country Study
Authors: Xu Yuexuan , Reyes‐Dumeyer Dolly , Weinfeld Cory , Piriz Angel , Sanchez Danurys , Soriano Belisa , Franco Yahaira , Coronado Zoraida Dominguez , Recio Patricia , Mejia Diones Rivera , Medrano Martin , Lantigua Rafael A. , Vardarajan Badri N. , Mayeux Richard
Published: January 2025

Background

Hispanics, one of the fastest‐growing populations in the United States, are disproportionately affected by Alzheimer’s disease (AD). Understanding the variations in AD risk associated with sex and the impact of relocation from their home country is crucial in designing interventions to address health disparities. This study explores the differential impact of sex and geographic relocation on dementia risk and its associated factors among Hispanics.

Method

We utilized data from two observational samples, encompassing 4,960 individuals from the Estudio Familiar de la Influencia Genética en Alzheimer (EFIGA), primarily based in the Dominican Republic, and 2,614 individuals enrolled in the Washington Heights‐Hamilton Heights‐Inwood Community Aging Project (WHICAP), based in the US. In both, we evaluated AD‐related risk factors and biomarker concentrations by sex and disease status, using two‐sample t‐tests and chi‐squared tests. We assessed AD risk across the full sample and conducted sex‐stratified logistic regression analyses, along with linear regression to compare biomarker concentrations and disease onset age among sexes.

Results

In the EFIGA study, the risk of AD was found to be lower among women (Odds Ratio [OR] = 0.86, 95% Confidence Interval [CI]: 0.75‐0.98), whereas in WHICAP, no significant sex‐based differences were observed. Concerning the age of onset, women in EFIGA exhibited an earlier onset (β = ‐1.42, p < 0.001), contrasting with a later onset in WHICAP (β = 1.02, p = 0.007). In the sex‐stratified analyses, both men (OR = 1.66, 95% CI: 1.32‐2.09) and women (OR = 1.64, 95% CI: 1.40‐1.91) in EFIGA showed distinct associations of AD with APOE ε4, a pattern only seen among women in WHICAP (OR = 1.34, 95% CI: 1.06‐1.68). With respect to biomarker concentrations, sex‐related differences were noted in Ab42/40 ratio, total tau, phosphorylated tau, glial fibrillary acidic protein, and neurofilament light, although the specific patterns varied between WHICAP and EFIGA.

Conclusion

Sex‐related differences in AD risk and associated factors among Hispanics, were evident in both EFIGA and WHICAP studies, and are potentially further influenced by geographic relocation and migration patterns.
Heneicosapentaenoic acid, a metabolite resulting from the α‐oxidation of α‐Hydroxy‐Docosahexaenoic Acid, exerts neuroprotection against Alzheimer’s disease and reduces astrocytic mitochondrial activity
Authors: Cabot Joan , Parets Sebastià , Miralles Marc , Trujillo‐Estrada Laura , Gutierrez Antonia , Fernández‐García Paula , Lladó Victoria , Escriba Pablo V. , Torres Manuel
Published: January 2025

Background

Reactive astrocytes and neuron death by excitotoxicity are observed in Alzheimer’s disease (AD). DHA‐H (2‐hydroxy‐docosahexaenoic acid; 2‐OH‐C22:6 n‐3) is a molecule under development that has demonstrated therapeutic efficacy in both cellular and 5xFAD mouse model of AD. DHA‐H is metabolized through α‐oxidation to yield HPA (Heneicosapentaenoic acid; C21:5 n‐3). This metabolic conversion is considered necessary for the neuroprotective effect of DHA‐H.

Methods

Cognitive evaluation was assessed by Radial Arm Maze in 5xFAD mice after 4 months of chronic oral treatment at a daily dose of 20 mg/kg (DHA‐H or HPA). The transformation of DHA‐H to HPA was analyzed in HEK293 cells and in 5xFAD mice by GC‐FID or GC‐MS (Gas Chromatography‐Flame Ionization Detector or Mass Spectrometry). Neuroprotective effect of DHA‐H and HPA was tested in neuron cells differentiated from SH‐SY5Y neuroblastoma cells that were stimulated with NMDA (N‐Methyl‐D‐Aspartate)/Ca to induce excitotoxicity in the presence or absence of oxythiamine (α‐oxidation inhibitor). ATP level reduction was measured with the ATP luminescence assay system ATPlite (Perkin Elmer) while mitochondrial function was assessed by measuring the oxygen consumption rate (OCR) with the Seahorse Cell Mito Stress Test kit (Agilent Technologies).

Results

Chronic oral administration of DHA‐H or HPA prevented cognitive decline in 5xFAD mice. DHA‐H is converted to HPA via α‐oxidation in cells and mice. HPA accumulates in 5xFAD mice brain instead of DHA‐H after DHA‐H treatment. Both DHA‐H and HPA prevented NMDA/Ca‐induced neuron death and the neuroprotective effect of DHA‐H was partially reversed in the presence of oxythiamine. HPA decreased ATP production and mitochondrial respiration capacity in astrocytoma cells.

Conclusions

The metabolic intermediate HPA, stemming from the α‐oxidation of DHA‐H, emerges as a prospective candidate for Alzheimer’s therapy. Although the mechanism of action behind its neuroprotective effect is still unknown, here we study the effect of HPA on ATP production and mitochondrial respiratory capacity in astrocytes as a possible mechanism.
Renal Atrophy Relates to Brain Volume Loss on 7,149 MRI Scans
Authors: Meysami Somayeh , Raji Cyrus A. , 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

Renal atrophy may reflect an end organ consequence of chronic vascular disease. Renal volume loss may therefore provide a window into brain aging and Alzheimer disease risk.

Method

We obtained whole‐body 1.5T MRI scans on 7,149 healthy individuals across four sites. The participants had a mean age of 53.06 ± 12.95 years (age range: 18‐97 years), with a gender distribution of 48% women and 52% men; 38% were non‐white. Deep learning with FastSurfer on 3D T1 volumetric MPRAGE trained on 134 participants aged 27‐66 and segmented 96 brain regions. Whole body sequences included coronal T1 that allowed for separate segmentation and quantification of renal volumes. Partial correlation analysis controlling for sex and total intracranial volume was done on kidney volumes and the following brain regions: tissue types, lobar structures and Alzheimer disease risk regions – hippocampus, precuneus, and posterior cingulate gyrus. Renal volumes were normalized to the aggregate abdominal organ volumes and tissues such as the liver, spleen and abdominal fat. Multiple comparisons were corrected for with the Bonferroni method.

Result

Lower renal volumes were correlated with lower gray matter volumes (rp = ‐0.229, p = 5.18×10−85) as well as total white matter volume (rp = ‐0.204, p = 2.51×10−67). The cerebral ventricles, demonstrated a moderate positive correlation with lower renal volumes (rp = 0.099, p = 5.28×10−16) reflective of a generalized parenchymal volume loss. Lower renal volumes also predicted lower lobar volumes in: frontal lobe (rp = ‐0.204, p = 3.34×10−67), temporal lobe (rp = ‐0.236, p = 9.76×10−90), parietal lobe (rp = ‐0.215, p = 2.69×10−74), and occipital lobe (rp = ‐0.207, p = 8.29×10−69), all showed significant negative correlations with lower renal volumes. Lower renal volumes also correlated to lower volumes in AD risk regions: the Hippocampus (rp = ‐0.203, p = 2.89×10−66) and posterior cingulate (rp = ‐0.18, p = 3.06×10−52), precuneus (rp = ‐0.171, p = 8.00×10−47).

Conclusion

This study demonstrates a strong relationship in a large sample between lower renal volumes and reduced volumes in various brain regions, including gray matter, white matter, and specific lobar structures, as well as Alzheimer's disease risk regions.
International comparison of gender differences in Informant reports of cognitive decline in older adults
Authors: Cantu Phillip A
Published: January 2025

Background

The goal of this study is to examine how gender of research participants affects informants assessments of cognitive functioning in older adults. Informant assessments are important tools when clinicians diagnose cognitive decline and dementia and have been used to characterize highly impaired adults in population studies. Contextual and social factors for men and women in different countries may make informants more or less likely to report changes in functioning and cognitive declines at different levels of cognitive impairment.

Method

his study examines gender differences in informant reports of cognitive function in different national contexts using data derived from the Harmonized Cognitive Assessment Protocol (HCAP) of the Health and Retirement Study (HRS)(n = 2,966) and the Mexican Cognitive Aging Study (MexCOG)(n = 1,750). Participants in the HCAP in each nation undergo a direct assessment of cognitive function as well as an informant assessment of cognitive functioning. The HCAP and MexCog contain 19 comparable informant questions and we control for age, gender, education, directly assessed cognition using the Mini Mental Status Examination (MMSE), informant type (spouse, child, or other) and coresidence status.

Result

Both nations have gender differences in informant reports of memory impairments, but now always in the same direction. Informants were more likely to report conversation impairments for women in Mexico. There are fewer gender differences in orientation questions for each nation, may be related to high level of impairment. There were more gender differences in reports of functional limitation in the U.S. than in Mexico. Additionally we found that the gender differences were specific to each nation.

Conclusion

Informants were MORE likely to report symptoms of cognitive decline in the U.S. than in the Mexico. Informants were more likely to report memory issues (forgets were things are kept, forgets where they put things), and difficulty with chores for women in both countries. Gender differences were not the same in each nation. Relative to Mexico, informants in the U.S. were less likely to report memory problems and talking about the past for women and more likely to report forgetting when last saw informant and difficulty handling money.