bluuebunny/crossref_metadata_2025 huggingface dataset:
Minority Stress, Caregiving Experiences, and Health of Bi+ Informal Caregivers of People with Alzheimer’s Disease and Related Dementias
Authors: Kittle Krystal R. , Cicero Ethan C. , Pelkmans Jordan , Flatt Jason D. , Anderson Joel G
Published: January 2025

Background

Bi+ people, those with non‐monosexual identities (e.g., bisexual, pansexual, sexually fluid) are more likely to experience poor physical and mental health compared with monosexual minority (i.e., gay[G], lesbian[L]) people. These poor health outcomes stem from minority stress related to their sexual minority status (e.g., discrimination, victimization). Due to minority and caregiver stress, LGB+ people providing care to someone with ADRD are more likely to have worse health than their straight counterparts. Little is known about how minority and caregiver stress affect the health of bi+ ADRD caregivers versus monosexual minority ADRD caregivers.

Method

Cross‐sectional survey data from a non‐probabilistic sample of sexual minority ADRD caregivers (bi+, n = 125; gay/lesbian, n = 161) were used to examine associations between minority stress (discrimination, victimization, microaggressions, perceived stress), caregiver stress (caring for spouse/partner, respite use, distress from care recipient’s neuropsychiatric symptoms, care recipient’s level of independence) on overall self‐rated health and if these associations differed among bi+ and monosexual minority ADRD caregivers. Multivariable regression, adjusting for demographic characteristics, was used to investigate if sexual orientation (bi+ vs. gay/lesbian) moderated the association between minority/caregiver stress variables and health.

Result

All minority stressors and two caregiving stressors (caring for spouse, care recipient’s level of independence) were associated with overall health. In our adjusted model, three variables (lifetime victimization, day‐to‐day discrimination, caring for spouse/partner) moderated the association between sexual orientation and overall health. As lifetime victimization scores increased, bi+ overall health decreased while monosexual minority overall health increased (B = ‐0.56; 95% CI = 1.06,0.05; p = 0.03). Caring for a spouse/partner, protective for both groups (B = 5.11; 95%CI = 3.04,7.17; p<0.001), had a greater effect on health for monosexual minorities (B = ‐4.26; 95% CI = ‐7.49,‐1.03; p<0.001). Higher day‐to‐day discrimination scores predicted worse health for both groups (B = ‐0.61; 95% CI = ‐0.91,‐0.32; p<0.001), but the magnitude was greater for monosexual minorities (B = 0.41; 95% CI = 0.01,0.80; p = 0.044).

Conclusion

The effects of lifetime victimization, day‐to‐day discrimination, and caring for one’s spouse/partner on health differ significantly dependent on being bi+ or gay/lesbian. Qualitative inquiries may help illuminate the underlying mechanisms for this phenomenon, informing interventions and policy development aimed at supporting the health and well‐being of bi+ ADRD caregivers.
Relationships between Diabetes, Vitamin D Status, Neuropsychological Functioning, and Hispanic Ethnicity in Older Rural West Texans: A Project FRONTIER Study
Authors: McCready Riley , Morris Claudia , Antwi‐Adjei Philip , Pourghaed Mohammad , Ramirez‐Velandia Felipe , Kopel Jonathan , Culberson John , Ashworth Gabriela , Singer Jonathan , Molinar‐Lopez Veronica , Sabbagh Marwan N. , Neugebauer Volker , Decourt Boris , Lawrence J. Josh
Published: January 2025

Background

Diabetes, a chronic metabolic disease leading to damage to multiple organs and the nervous system, is associated with cognitive decline. Moreover, Vitamin D (VD) insufficiency/deficiency is implicated as a risk factor for diabetes. However, the specifics of the relationships between these variables remain unclear. Previous studies also have suggested that Hispanic individuals have a higher risk of VD deficiency, diabetes, and cognitive decline. We aimed to determine associations between VD level, diabetes, cognitive functioning, and Hispanic ethnicity (HE) amongst a sample of aging, rural West Texans from Project FRONTIER (PF; Facing Rural Obstacles to Health Care Now Through Intervention, Education, and Research).

Method

Data were obtained from a cohort of 292 PF participants (mean age 62.6±11.8, 70.5% female, 40.1% HE). We examined relationships between consensus diabetes diagnosis, blood‐based diabetes‐related biomarkers, VD level, Repeatable Assessment for Neuropsychological Status (RBANS) total score, and HE status. Logistic and linear regression analyses were performed on binary and continuous variables, respectively. We utilized Spearman correlation for bivariate comparisons and Mann‐Whitney U tests for between‐group comparisons.

Result

Regression analyses indicated significant negative associations between VD and HbA1c (p=0.0004), fasting blood glucose (p=0.0003), and consensus diabetes diagnosis (p=0.0060). Regression analyses also indicated significant negative associations between overall cognitive functioning and HbA1c (p=0.0282) and consensus diabetes diagnosis (p<0.0001). A significant positive correlation emerged between VD levels and overall cognitive functioning score (p=0.0439). HE was associated with significantly lower VD levels (p<0.0001), higher HbA1c (p=0.0003), and higher fasting blood glucose levels (p=0.0011) compared to non‐HE participants. HE was associated with lower overall cognitive functioning scores (p<0.0001), indicating greater cognitive impairment.

Conclusion

Our results suggest that, in a rural West Texas cohort, HE is associated with lower VD levels, higher levels of diabetic indicators, and greater levels of cognitive impairment. These disparities are important to consider when investigating areas to improve healthcare in West Texas. Further investigation is necessary to elucidate the connection between VD, diabetes, and cognitive decline in minority, rural populations.
Early life factors and dementia risk: A study of adverse childhood experiences and later‐life cognition and behavior
Authors: Mudalige Dinithi M , Guan Dylan X. , Smith Eric E. , Ismail Zahinoor
Published: January 2025

Background

Of the 12 modifiable dementia risk factors established by the Lancet Commission, only one addresses early life. However, the brain is highly plastic in early life. Adverse childhood experiences (ACE)–physical, emotional, and sexual abuse and neglect–can result in long‐term reductions in brain volume. These alterations increase susceptibility to neurodegenerative diseases like Alzheimer’s disease. We investigated associations between the severity of ACE and cognitive and behavioral risk for dementia, operationalized as later‐life cognitive impairment and mild behavioral impairment (MBI), respectively.

Method

Data were from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behavior, Function, and Caregiving in Aging (CAN‐PROTECT) study. Measures included the Childhood Trauma Screener (for ACE), neuropsychological tests (objective cognition), Everyday Cognition (ECog)‐II (subjective cognition), and the MBI Checklist (MBI‐C, later‐life behavioral changes). Linear regressions modeled associations between ACE severity and neuropsychological test scores. Multivariable negative binomial regressions (zero‐inflated, if appropriate) modeled associations between ACE severity and ECog‐II and MBI‐C scores. Models adjusted for age, sex, education, and ethnocultural origin. Clinical diagnosis of depression and/or anxiety were explored as covariates and mediators of the observed associations.

Result

Participants (n = 1102) were 64.6 (SD = 7.3) years old; 883 (80.1%) were female, 290 (26.3%) had a bachelor’s degree or equivalent, and 939 (85.2%) were of European origins. Every 1 standard deviation (SD) increase in ACE score was associated with worse performance on Trail Making B (b = 0.10, 95%CI:0.05–0.16), Switching Stroop (b = ‐0.08, 95%CI:‐0.14—0.03), Paired Associates Learning (b = ‐0.08, 95%CI:‐0.13—0.02), and Digit Span (b = ‐0.08, 95%CI:‐0.14—0.02). Every 1 SD increase in ACE score was associated with higher ECog‐II (b = 1.1, 95%CI:1.0‐1.1, p = 0.007) and MBI‐C (b = 1.2, 95%CI:1.1–1.3, p<0.001) scores, not mediated by previous psychiatric history (ECog II p = 0.16; MBI‐C p = 0.13).

Conclusion

Greater ACE severity predicted more later‐life cognitive and behavioral symptoms, representing higher dementia risk, not mediated by psychiatric history. These findings extend the public health importance of ACE to brain aging and emphasize the importance of incorporating early‐life risk factors into dementia risk assessment. ACE are potential targets for risk reduction and identify persons who should be screened for cognitive and behavioral risk markers.
Which Nursing Homes Received Paycheck Protection Program Funding?
Authors: Coe Norma , Sun Chuxuan , Travers Jasmine , Chen Kevin , Burke Robert , Pogorzelska‐Maziarz Monika , Castle Nicholas , Falvey Jason
Published: January 2025

Background

Nearly 90% of nursing homes in the US experienced severe staffing shortages during COVID‐19, which disproportionately affected over 50% of nursing home residents living with Alzheimer’s Disease and Related Dementia (ADRD). One major federal policy to support the maintenance of staffing levels during the COVID‐19 pandemic was the Paycheck Protection Program (PPP), a $75 billion program that provided loans to small businesses, including nursing homes. Loans were forgivable if at least 60 percent of the loan was spent on payroll providing an incentive to apply resources toward staffing. This paper examines the organizational and staffing characteristics of nursing homes that received PPP loans, including the prevalence of residents living with ADRD and Serious Mental Illness (SMI).

Method

We examine a national cohort of non‐VA nursing homes eligible for PPP funding. We compare those who received a PPP loan to nursing homes that did not receive a PPP loan. PPP loan receipt was captured in the US Small Business Administration (SBA) PPP data from April 2020 to June 2021. We primarily use datasets from 2019 to examine baseline characteristics, including Nursing Home Compare data, the Minimum Dataset (MDS), LTC Focus, and the Payroll‐Based Journal data.

Result

3,536 nursing homes received a PPP loan in any of the three rounds; 9,943 eligible nursing homes never received a PPP loan.

More than 50% of nursing home residents were living with ADRD, and nearly 1 in 3 had a serious mental illness. These rates were slightly higher among facilities receiving PPP loans.

Staffing in 2019 was inferior in nursing homes receiving PPP loans than those who did not on all measures: lower‐star ratings on both quality and staffing measures, higher turnover rates at the RN (9.7% vs. 9.0%), LPN (11.2% vs. 10.3%), and CNA levels (11.4% vs. 11.0%). COVID‐19 affected PPP‐receiving nursing homes more in terms of confirmed cases (522 vs. 511), resident deaths (107 vs. 97), and staffing shortages (22% vs. 18%).

Conclusion

This first‐ever direct federal funding effort to support nursing home staff during a pandemic appears to have supported the most vulnerable nursing homes.
Elucidation of tRNA‐Derived Fragments in Alzheimer’s Disease: Cell‐Type Implication for New Biomarkers and Regulators
Authors: Rippee‐Brooks Meagan D , Vedder Hannah , Wu Wenzhe , Dong Jianli , Pappolla Miguel A , Fang Xiang , Bao Xiaoyong
Published: January 2025

Background

Alzheimer’s disease (AD), the most common type of dementia, affects at least twenty‐four million people globally, yet, the causation, mechanisms of progression, and therapeutic strategies remain elusive. Currently, tRNA‐derived RNA fragments (tRFs), a family of recently discovered small non‐coding RNAs (sncRNAs), have surfaced as promising biomarkers for many diseases, including AD. Our work revealed that several AD‐impacted tRFs in human hippocampus, CSF, and serum.

Method

Herein, we further characterized the expression of tRFs in AD through elucidating exactly which cell types of the brain contribute to the higher expression of tRFs, using human induced pluripotent stem cells (iPSCs)‐derived cells. We further delve into the identification of tRFs, commonly affected by emerging SARS‐CoV‐2 infection and AD, for a future study on the influence of SARS‐CoV‐2 infection on AD.

Result

Our results indicate that neurons derived from AD iPSC have significantly enhanced tRF expression than neurons derived from healthy adult donor. The impacted tRFs include tRFs derived from the 5’‐end of mature tRNA encoding ProAGG (tRF5‐ProAGG), GluCTC (tRF5‐GluCTC), and GlyGCC (tRF5‐GlyGCC). Such a difference did not show in iPSC‐derived astrocytes. Interestingly, among AD‐impacted tRFs in neurons, two of them are also inducible by SARS‐CoV‐2 infection.

Conclusion

tRF5‐ProAGG, ‐GluCTC, and ‐GlyGCC continue to show the potential as AD biomarkers originating from neurons from within the brain. Commonly impacted tRFs by SARS‐CoV‐2 and AD, combined with our recently published data showing the impact of tRF5 on the regulation of genes important for neuronal functions, implicates SARS‐CoV‐2’s influence on AD.
Persistent functional impairments in cognitively normal older adults and risk of cognitive decline and dementia
Authors: Ghahremani Maryam , Ismail Zahinoor
Published: January 2025

Background

Maintaining functional independence is an essential aspect of healthy aging. In fact, functional dependence to perform activities of daily living (ADL) is a fundamental part of a dementia diagnosis. Newer diagnostic criteria for MCI also consider functional impairments (FI) but not to the extent of compromising functional independence. Therefore, accurate characterization of FI across the cognitive spectrum could help identify individuals who may be at a greater risk of cognitive decline and dementia, thereby improving treatment strategies. Here, we explored the utility of capturing persistent FI, in contrast to transient FI, to identify a higher‐risk group for cognitive decline and dementia.

Method

Data from cognitively normal (CN) older adults from the National Alzheimer’s Coordinating Center were analyzed. From the Functional Activities Questionnaire four items were used (assembling tax records, paying bills, shopping alone, and traveling). Persistent FI was operationalized as FI present at more than two‐thirds of all study visits (TTV) prior to cognitive decline and dementia. The two comparator groups either had transient FI not meeting TTV criteria or no FI in advance of cognitive decline and dementia. Kaplan‐Meier survival curves were generated for all FI groups. Cox proportional hazard models compared incidence rates for cognitive decline and dementia across FI groups, adjusted for age, sex, education, race, APOE‐e4 status, and presence of subjective cognitive decline and neuropsychiatric symptoms.

Results

The CN sample comprised 1,612 Persistent‐FI (age = 77.3±9.7; 61.7% female), 3,195 Transient‐FI (age = 72.9±8.8; 63.7% female), and 7,284 No‐FI participants (age = 69.7±8.4; 66.0% female) (Table 1). Persons with persistent FI had lower survival (p<0.0001) and a 3.89‐fold greater incidence rate for cognitive decline and dementia compared to No‐FI (CI:3.45‐4.38, p<0.001); persons with transient FI had a 2.04‐fold greater incidence rate than No‐FI (CI:1.84‐2.27, p<0.001) (Figure 1).

Conclusions

CN older adults with persistent FI had greater incidence of cognitive decline and dementia than transient FI or no FI. Operationalizing FI‐related risk based on the persistence of functional impairments improves the prognostication of cognitive decline and dementia and allows for the identification of individuals who are at a greater risk in the absence of objective cognitive impairments.
Association Between MIND Diet Score and Cortical Thickness in an Aging Population
Authors: Dempsey Desarae A. , Apostolova Liana G. , Brosch Jared R. , Clark David G. , Farlow Martin R. , Mathew Sunu , Unverzagt Frederick , Wang Sophia , Gao Sujuan , Clark Daniel , Saykin Andrew J. , Risacher Shannon L.
Published: January 2025

Background

The Mediterranean diet has been associated with decreased brain atrophy (Staubo et al. 2016,Alz&Dem), but the MIND (Mediterranean‐Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay) diet, designed for dementia prevention (Morris et al. 2015, Alz&Dem), remains underexplored for its impact on brain atrophy. We investigated the MIND diet’s association with cortical thickness (CT) in the Indiana Alzheimer’s Disease Research Center (IADRC) sample.

Methods

134 participants (49 CN, 45 SCD, 30 MCI, 10 AD/other) completed a self‐report MIND diet questionnaire at the IADRC, which was coded into high, medium, or low intake groups for each food (5 ‘unhealthy’ food groups were reverse scored) and completed an MRI scan on a 3T scanner. The cortical surface was parcellated using FreeSurfer v6. We selected two regions of interest (ROIs) reflecting AD‐associated neurodegeneration: temporal and global CT. We examined the association of MIND diet scores (0‐15) and food groups with CT using regression models adjusted for age, sex, race, education, and diagnosis.

Results

Higher MIND diet scores were associated with greater mean temporal CT (r = 0.269, p = 0.002) and greater mean global CT (r = 0.230, p = 0.008). In multivariable‐adjusted models, the association persisted for temporal but not global CT. Among the 15 food components, greater olive oil (r = 0.034, p<0.001), fish (r = 0.181, p = 0.040), beans (r = 0.237, p = 0.008), and nuts (r = 0.214, p = 0.014), and reduced fast food intake (r = 0.188, p = 0.035) were significantly associated with temporal CT. These associations, except for nuts, remained significant in multivariable‐adjusted models, with an additional relationship found for chicken (r = 0.189, p = 0.038). Among the 15 food components, greater olive oil (r = 0.243, p = 0.008), and beans (0.180, p = 0.044), and reduced fast food (r = 0.212, p = 0.017) were significantly associated with global CT. Only reduced fast food retained significance in the multivariable‐adjusted models.

Conclusions

Greater adherence to the MIND diet was associated with greater CT in both global and temporal regions. Specific components, including increased olive oil, beans, nuts, fish, and reduced fast food, showed significant associations with CT, suggesting elements within the diet driving this association. These findings highlight the potential neuroprotective effects of the MIND diet, emphasizing the importance of dietary patterns in preserving brain health during aging.
Blood‐brain barrier breakdown and abnormal brain microstructure in older adults with COVID‐19‐related cognitive impairment are modified by sex and APOE4
Authors: Reas Emilie T. , Alderson‐Myers Austin T , Solders Seraphina K. , Shen Qian , Wang Xin , Rivera Charlotte S. , Banks Sarah , Graves Jennifer
Published: January 2025

Background

Persistent neurological symptoms including cognitive impairment can follow SARS‐CoV‐2 infection, a condition termed neurological post‐acute sequelae of COVID‐19 (Neuro‐PASC). Structural brain differences have been observed in individuals with Neuro‐PASC, raising concern that COVID‐19 may promote age‐related neurodegeneration. However, the mechanisms by which COVID‐19 impairs cognition and its impact on brain aging, remain poorly characterized. Blood‐brain barrier (BBB) dysfunction has been observed in Alzheimer’s disease and has been hypothesized to contribute to Neuro‐PASC, implicating potential acceleration of Alzheimer’s disease pathogenesis by COVID‐19. The present study evaluated BBB permeability and brain microstructure among older adults with Neuro‐PASC, along with modification by sex and APOE4, risk factors for Alzheimer’s disease that have also been associated with COVID‐19 outcomes.

Method

Older adults (50‐90 years; 54% women) with (N=16) or without (N=43) Neuro‐PASC underwent neuropsychological testing as well as multi‐shell diffusion MRI and dynamic contrast‐enhanced MRI to measure restriction spectrum imaging (RSI) metrics of brain microstructure and BBB permeability in subcortical, white matter, and gray matter regions of interest. ANCOVA compared cognitive and MRI measures between Neuro‐PASC and healthy controls, and models were repeated assessing interactions with sex or APOE4. Partial correlations examined associations between brain microstructure and BBB permeability. Models were adjusted for age and sex, with further adjustment for education for cognitive scores, and for MRI software for RSI measures.

Result

Neuro‐PASC participants had worse episodic memory performance, higher white matter BBB permeability, and lower neurite density and hindered diffusion than controls. APOE4 carriers demonstrated more pronounced PASC‐related cognitive impairment and microstructural abnormalities than non‐carriers. PASC‐related BBB leakage was stronger among men, whereas women showed stronger PASC‐related increases in free water and decreases in restricted diffusion. Among Neuro‐PASC, but not controls, hippocampal BBB permeability correlated with greater hippocampal free water.

Conclusion

Older adults with persistent COVID‐19‐related neurological complaints demonstrate objective cognitive impairment accompanied by BBB dysfunction and microstructural brain abnormalities. PASC‐related cognitive decline, BBB breakdown, and microstructural injury differ by sex and are magnified among APOE4 carriers. Longitudinal investigation is warranted to determine whether PASC heightens risk for Alzheimer’s disease by accelerating cerebrovascular and neurodegenerative changes, particularly among high‐risk populations.
Poor sleep is adversely associated with MRI markers of AD‐specific neurodegeneration
Authors: Shi Hui , Archer Derek B. , Perry Arden , Pechman Kimberly R. , Shashikumar Niranjana , Landman Bennett A. , Hohman Timothy J. , Jefferson Angela L. , Full Kelsie M
Published: January 2025

Background

Poor sleep has emerged as a potentially modifiable risk factor for Alzheimer’s disease (AD) and related dementias (ADRD). Few previous studies have incorporated objectively‐measured sleep and structural neuroimaging to understand if poor sleep relates to changes in brain structure. In a cohort of older adults, we investigated actigraphy‐measured sleep health and associations with well‐established magnetic resonance imaging (MRI) markers of AD‐specific neurodegeneration.

Method

Participants from the Vanderbilt Memory and Aging Project (n=390, Mean age: 69.5± 9.3 year; 47.4% women) wore ActiGraph GT9X accelerometers on their wrist daily for 10 days. Data were processed to estimate sleep regularity, wake after sleep onset (WASO), average awakening length, sleep fragmentation index, sleep timing, and sleep duration. 3T brain MRI was used to quantify hippocampal volume and to estimate the McEvoy AD signature (calculated according to published guidelines). We used cross‐sectional multivariate linear regression to assess the associations between individual sleep measures and neuroimaging markers. Models adjusted for age, sex, race, education, APOE‐ε4 status, cognitive status, sleep medication use, body mass, index, physical activity, depressive symptoms, and cardiovascular risk. For sleep timing and duration, quadratic terms were added in regression models. Models examining the total hippocampal volume also adjusted for intracranial volume.

Result

In the fully adjusted models, we found abnormal sleep duration (β = ‐2.35, 95% CI = ‐4.58, ‐0.11) and greater sleep irregularity (β = ‐0.34, 95% CI = ‐0.62, ‐0.07) were associated with lower AD signature values. Additionally, greater sleep irregularity (β = ‐262.36; 95% CI = ‐451.71, ‐73.00), greater WASO (β = ‐2.76; 95% CI = ‐5.30, ‐0.21) and greater average awakening length (β = ‐74.20; 95% CI = ‐128.47, ‐19.94) were associated with lower hippocampal volumes.

Conclusion

Our results suggest that several measures of poor sleep, including greater sleep irregularity, wake time, and sleep fragmentation, are cross‐sectionally linked to smaller hippocampal volume and smaller brain volumes in regions most affected by AD neuropathology. Longitudinal studies are needed to clarify if poor sleep contributes to brain atrophy over time.
Extended Exposure to Alzheimer's Risk Factors Increases Alzheimer's Diagnosis Risk Amplified in APOε4 Carriers: Implication for Delayed Onset of Alzheimer's Risk Factors
Authors: Merlini Simona , Vitali Francesca , Brinton Roberta Diaz
Published: January 2025

Background

Obesity, diabetes, hypertension, hyperlipidemia, and depression are relevant Alzheimer’s Disease (AD) modifiable risk factors (RFs). However, little is known about how the duration of these conditions, influenced by unmodifiable AD risk factors, such as chromosomal sex and APOE genotype, affects the associated risk. Modeling interactions between patient’s temporal and clinical patterns, integrated with the probability of developing AD remains challenging, particularly when considering the multifactorial progression of AD. To address these challenges, we conducted a retrospective analysis using longitudinal data from the UK Biobank.

Methods

Inclusion criteria were age older than 55 years, no prior history of neurodegenerative disease, neurosurgery, or cancer, and enrollment with at least 3 years of follow‐up. Propensity score matching was performed based on age at recruitment, educational level, center, and Charlson comorbidity index. Extended Cox proportional hazard models (CPHMs) for time‐to‐event prediction were used to evaluate the impact of the age‐specific effect of multiple AD‐RFs, in combination with sex and APOEε4 carrier status. Age stratification was evaluated when a violation of the hazard ratio (HR) proportionality assumption occurred during aging.

Result

Preliminary findings revealed RF‐specific differences in AD on‐set based on the age of RF diagnosis. After age stratification, the risk of developing AD was significantly greater than the APOEε4 effect if hypertension and diabetes were diagnosed before 62yo, while if diagnosed after 72yo, APOEε4 was the major contributor to increased AD risk. Obesity had a 54% increased risk of developing AD if diagnosed before 62yo and was associated with nearly 3 times increased risk if diagnosed between 62‐72yo. Lastly, hyperlipidemia and depression were associated with an age‐strata‐independent increased AD risk of 33% and 69%, respectively.

Conclusions

This study identified critical tipping points indicating a decline in the hazard ratio of modifiable RFs with aging and a stronger association of APOEε4 with late‐onset AD. Age stratification within CPHMs provided valuable insights into age‐specific hazard ratios and identified age‐dependent RFs. Furthermore, these results highlight interactions between age, sex, and APOE genotype which could inform a precision medicine approach for AD prevention.
Metabolic syndrome severity score associates with structural brain features and functional connectivity of Default Mode Network subsystems in the HABS‐HD study
Authors: Green Zachary D. , O'Bryant Sid E. , Johnson Leigh A. , Burns Jeffrey M , Morris Jill K
Published: January 2025

Background

States of altered metabolic health such as metabolic syndrome (MetS), obesity, and insulin resistance increase Alzheimer’s Disease (AD) risk. Individuals with these conditions, like those with AD, have demonstrated changes in the structural and functional features of the Default Mode Network (DMN). Here, we characterize associations between systemic metabolic dysfunction, brain structure (Cortical Thickness and Hippocampal Volume) and functional connectivity of DMN subnetworks.

Method

We leveraged data from the Health and Aging Brain Study: Health Disparities (HABS‐HD) dataset, an ongoing longitudinal study that characterizes AD biomarkers across diverse populations. Specifically, we used data from the initial visits of the Hispanic and Non‐Hispanic White (NHW) cohorts. Individuals were categorized as cognitively healthy (n=1192; age=66.1 years, 65% female) or cognitively impaired (n=307; age=67.4 years, 50% female). We used a continuous measure of metabolic risk (Mets‐Z) that is more sensitive and ethnicity‐specific than categorical definitions of MetS. Mets‐Z a weighted composite of systolic blood pressure, triglycerides, HDL cholesterol, glucose, and waist circumference. Structural measures were acquired using FreeSurfer. Functional connectivity was measured via resting‐state fMRI, and pre‐processed using FSL. We utilized both summary metrics (ROI‐based connectivity estimations) and voxel‐wise approaches (FSL’s randomise).

Result

MetS‐Z differed between diagnostic groups (t=‐2.387, p=.017) and between Hispanics and NHWs (t=‐11.864, p<.001). Meta‐ROI cortical thickness was negatively associated with both cognitive status (β = ‐.152, p < .001) and MetS‐Z (β = ‐.085, p < .001). Hippocampal volume was found to have a negative relationship with MetS‐Z (left, β = ‐.073, p < .001; right, β = ‐.072, p < .001). Functional connectivity, specifically of the posterior DMN, was significantly associated with MetS‐Z. There was a high degree of overlap between the clusters of voxels in which MetS‐Z and pDMN connectivity associated, and the clusters demonstrating decreased connectivity to due to age and cognitive status.

Conclusion

We present evidence of altered DMN connectivity due to a higher load of metabolic risk in an ethnoracially diverse cohort of older adults, with and without cognitive impairment. Future studies should leverage the longitudinal HABS‐HD dataset to examine if higher metabolic dysfunction predicts differences in the trajectory of DMN connectivity.
APOE4 moderates the association between cerebral small vessel disease and cortical tau accumulation in midlife
Authors: Espinoza Liliana , Scott Matthew R , Beiser Alexa S , Banh Andy Q , Philip Vinu , Ghosh Saptaparni , Thibault Emma G , Maillard Pauline , Decarli Charles , Fakhri Georges El , Johnson Keith A , Seshadri Sudha , Satizabal Claudia L
Published: January 2025

Background

Recent research suggests that soluble pathogenic tau accumulates in the brain microvasculature of patients with Alzheimer’s Disease (AD) and primary tauopathies, driving cerebrovascular impairments and further tau accumulation. However, little is known about the interplay of these processes before dementia onset. In the present study, we investigated the association between free water (FW), an early biomarker of cerebral small vessel disease, and tau accumulation in the rhinal, entorhinal, and inferotemporal cortices derived from PET imaging in middle‐aged adults. Additionally, given the known increased risk of AD among APOE‐ɛ4 carriers, we further explored the interaction between FW and APOE‐ɛ4 carriership on tau accumulation.

Method

We included 281 cognitively healthy participants (mean age 55±9 years, 49% male, 23% APOE‐ɛ4 carriers) from the Third Generation Cohort of the Framingham Heart Study who had undergone brain MRI and tau PET imaging. We used linear regression models to relate FW to regional tau, adjusting for potential confounders. Model 1 was adjusted for age, age2, sex, camera, and time interval between MRI and PET scans. Model 2 was additionally adjusted for cardiovascular risk factors (i.e. systolic blood pressure, antihypertensive medication use, type 2 diabetes, body mass index, smoking, and prevalent cardiovascular disease).

Result

Although we did not find a significant association between FW and regional tau, we observed significant interactions between FW and APOE‐ ɛ4 genotype on tau accumulation in the rhinal (p=0.079) and entorhinal cortices (p=0.071) in fully adjusted models (Table 1). Among APOE‐ɛ4 carriers, we found a significant association between higher FW and increased rhinal tau levels (β=1.49, p=0.031), and a borderline significant association between higher FW and increased entorhinal tau (β=1.25, p=0.061). No significant associations were observed in non‐APOE‐ɛ4 carriers.

Conclusion

Our findings suggest that the APOE‐ɛ4 genotype is a moderator in the association between cerebrovascular injury and tau accumulation in brain regions typically affected earlier in the pathological spreading of tau in AD. These findings may help further elucidate underlying early processes leading to tau propagation. Replication studies in larger samples are needed to confirm these findings.
Regional Difference in Dementia Incidence in Older Adults
Authors: Dintica Christina S. , Bahorik Amber L , Xia Feng , Boscardin W John , Yaffe Kristine
Published: January 2025

Background

Studies in prevalence and incidence in the United States have been limited to clinical populations and single site studies, therefore, there is a notable lack in estimates of regional differences in dementia incidence and the drivers of such disparities.

Methods

We included 1,268,599 US Veterans Health Administration (VHA) dementia‐free patients aged 65 years or older living within the U.S. with a residential zip code from year 2000‐2021. Dementia incidence was estimated according to US geographical areas from residential zip codes, based on the 10 Centers for Disease Control and Prevention (CDC) National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP) regions, labeled from A to J. Incident diagnosis of dementia was ascertained using the 9th and 10th editions of the International Classification of Diseases. Poisson regression models adjusted for age were used to asses differences in dementia incidence based on geographical regions, and the sensitivity of the findings were evaluated by accounting for competing risk of death.

Results

Among the 1,268,599 study participants (mean age 73.9 [SD, 6.1] years; 25 335 women [2%]; 15.5% received a diagnosis of dementia over a mean follow‐up of 12.6 years. Unadjusted incidence of dementia per 1000 person‐years was the lowest for the Northeast region, B and the highest in in the Southeastern region D (Figure 1). Residence within the Southeastern region D was associated a 27% higher risk of dementia, 19% higher risk in the Southern region F, 17% the midwestern region H and Northwestern region J, 12% for Southeastern region C; the remaining regions had an increased risk <10% compared to region B (Table 1). Additional adjustment for sex and race, and accounting for the competing risk of death produced similar results.

Conclusion

Among older adults who received care at VHA medical centers, there were significant geographical differences in dementia incidence across the U.S, suggesting important roles for geographically patterned risk factors. Identifying geographical differences in dementia incidence allows for a more strategic and targeted approach to healthcare planning, public health interventions, and policy development.
Cognition Four Decades After High School: Does School Context Matter for Cognitive Disparities at Midlife?
Authors: Manly Jennifer J. , Hung Koit , Brickman Adam M. , Grodsky Eric , Muller Chandra , Warren John Robert , Culbertson Michael
Published: January 2025

Background

Structural racism shapes educational quality by perpetuating unequal access to school resources, creating disproportionate exposure to disciplinary actions, and limiting access to advanced courses among racially minoritized children. School quality is linked to later life ADRD risk, but the benefit may vary across groups. We asked 1) whether the same high school social contexts and academic resources predict midlife cognitive functioning across race, ethnicity, and gender, and 2) how much could disparities in midlife cognitive function be narrowed if everyone had equal access to high quality high schools?

Method

Data was from the nationally representative High School and Beyond cohort, which prospectively followed 12,530 Americans from high school through age ∼60 and administered telephone‐ and web‐based measures of memory, language, and attention in 2021‐22. Extensive information about family, high school social and academic context, and student achievements was gathered directly from students and their schools in 1980‐1982. OLS regression models estimated associations between specific school variables and an IRT‐derived cognitive composite, before and after adjustment for confounders in race, ethnicity, and sex stratified models.

Result

Higher average SES of students in each high school predicted better midlife cognitive test scores among White people and Latina women, but not among Latino men or Black participants. This association weakened after adding school academic context variables. A composite measure capturing school‐level academic engagement and rigor (academic press) predicted better cognition among White and Latinx participants but not among Black participants. If everyone had access to high schools of the same quality as the group with the highest test scores (White women), and adjusting for family confounders, disparities between White women and participants from racially minoritized groups would be substantially reduced (by 9% among Black women, 5% among Black men, and 6% among Latino men and Latina women).

Conclusion

Investment in high schools that serve Black and Latinx children could meaningfully narrow disparities in cognition four decades later, particularly among Black women. Later life cognitive benefit of specific aspects of school context, such as high SES peers and academic rigor, had differential benefit depending on race, ethnicity, and sex.
Urine dicarboxylic acid as a potential AD biomarker associated with fusiform gyrus volume in older cognitively healthy adults
Authors: Fonteh Alfred N , Maldonado Salvador , Butler Ryan , Kang Jimmy , Macias Thomas , Nolty Anne , Yu J , Mack Wendy J , Chui Helena C , Minazad Yafa , Kloner Robert A , Arakaki Xianghong
Published: January 2025

Background

Our study aims to determine if urine dicarboxylic acids (DCA) concentrations might be associated with specific brain region volumes in older cognitively healthy (CH) adults.

Method

We recruited CH study participants (> 65 years) and acquired MRI data analyzed using NeuroQuant. Urine DCAs were quantified using GC‐MS. For n=62 participants, DCA variables of interest—C4+C5 and C7+C8+C9 (% of the sum of C4 to C10), and their ratio—were assessed for association with each of six intracranial volume (icv)‐normalized brain region volumes; C4+C5 with 61 additional regions. We modeled volume as a function of a discretized DCA variable (sample tertiles), age, and sex, for each pair. Pairs with a statistically significant estimated association were assessed by fitting natural cubic spline models with a range of spline degrees of freedom in a second stage of analysis. The Benjamini–Hochberg procedure was used to control the false discovery rate below q1 = 0.2 in the first stage and q2 = 0.05 in the second stage.

Result

There was a significant estimated inverse association of categorical C7+C8+C9 with the fusiform gyrus (FG) volume (Table 1). Similarly, there was a significant estimated positive association between categorical (C4+C5)/(C7+C8+C9) and FG volume (Table 1). The FG was estimated to decrease by 0.004 for every one‐unit increase in C7+C8+C9, and this estimated association remained significant after adjusting P values for all tests (95% CI ‐0.007 to 0.002; adjusted P = .035, Table 2). The observed Cohen’s f2 for the DCA variable was 0.18. For the (C4+C5)/(C7+C8+C9)–FG couple, it was the 2‐df natural cubic spline model that had the lowest Bayesian information criterion values among the spline models considered, with a significant estimated association of the DCA variable with the FG (spline adjusted P = 0.035). Figure 1 depicts the estimated spline. The observed Cohen’s f2 for the spline was 0.29.

Conclusion

Our analysis suggests that DCA metabolism may be associated with FG volume differences between individuals. Since the FG participates in visual processing, memory, and multisensory integration, urinary DCA levels may be biomarkers to monitor AD pathophysiology associated with differences in these functions.
Longitudinal Plasma pTau217 Measurements in Preclinical Alzheimer’s Disease
Authors: Wilson Rachael E , Reyes Ramiro Eduardo Rea , Langhough Rebecca E. , Jonaitis Erin M. , Du Lianlian , Legois Emily , Keske Elysse , Fredricks Aaron , Marshall Martie , Jensen Cindy , VandenLangenberg Monica , Jeffers Beckie , Wheelock Bailey , Mershon Max , Kaseno Jo , Betthauser Tobey J. , Christian Bradley T. , Okonkwo Ozioma C , Bendlin Barbara B. , Engelman Corinne D. , Gleason Carey E. , Hogan Kirk J. , Chin Nathaniel A. , Carlsson Cynthia M. , Asthana Sanjay , Johnson Sterling C. , Zetterberg Henrik
Published: January 2025

Background

Plasma pTau217 (tau phosphorylated at threonine 217) assays will expand access to screening for Alzheimer’s disease (AD). However, clinical interpretation is not well‐established, particularly during the preclinical window when interventions may be most effective. Using plasma samples from primarily late‐midlife, cognitively unimpaired Wisconsin Registry for Alzheimer’s Prevention (WRAP) and Wisconsin Alzheimer’s Disease Center (WADRC) participants, we investigated pTau217 agreement with amyloid and tau PET then compared trajectories between participants grouped by baseline pTau217.

Methods

EDTA plasma samples from 428 participants were analyzed using the ALZpath pTau217 Simoa assay on a Quanterix HD‐X (Table 1). Amyloid and tau positivity were defined as global [11C]‐PiB DVR>1.19 (21.6 centiloids) and [18F]‐MK6240 temporal meta‐ROI SUVR>1.3, respectively. In separate receiver operating characteristic (ROC) analyses using pTau217 to classify amyloid and tau PET, the area under the curve (95% CI) and optimal (Youden) cutoffs were, respectively: 0.91 (0.87‐0.94), 0.37 pg/mL; and 0.89 (0.83‐0.94), 0.53 pg/mL. To characterize pTau217 rates of change based on baseline measurements, participants were clustered into low (≤0.37 pg/mL), intermediate (0.37 < pTau217 < 0.53 pg/mL), and high (≥0.53 pg/mL) groups according to the ROC thresholds. Linear mixed models were then run with group and age as fixed effects and including random person‐level intercept and age slopes.

Results

Mean pTau217 concentration was 2.5 times higher for amyloid positive participants compared to amyloid negative (Figure 1A; p < 0.001). Significant differences were also observed between CU, MCI, and dementia groups (Figure 1B; CU‐MCI: p < 0.001, CU‐MCI: p<0.001, Dementia‐MCI: p<0.001). Mixed effects models indicated that pTau217 increased at a higher rate in the high group compared to other groups (Figure 2; simple slopes low‐high: t(361)=‐7.010, p<0.001, intermediate‐high: t(318)=‐5.712, p < 0.001). No differences were observed between simple slopes for low and intermediate groups (t(235)=‐0.314, p=0.9470).

Conclusion

These results suggest that plasma ALZpath pTau217 is a very good proxy for molecular PET for detecting AD pathology prior to symptoms. Strategies such as assigning an indeterminate zone for secondary confirmation (Brum, W., et al, 2023) would improve accuracy and lessen the burden on existing resources while expanding access to the broader community.
Multi‐Component and Cognitive Skills Training in Mild Cognitive Impairment: Outcomes from a South American Study
Authors: Martin Maria Eugenia , Martinez Carlos , Worff Iris , Belucci Maria Agustina , Keller Greta , Arruabarrena Micaela Maria , Corvalan Nicolas , Clarens Maria Florencia , Allegri Ricardo , Crivelli Lucia
Published: January 2025

Background

Dementia represents a significant health challenge, with evidence suggesting that it can be potentially delayed or prevented through non‐pharmacological interventions. There are different types of non‐pharmacological interventions for Mild Cognitive Impairment (MCI). The Aging Well through Interaction and Scientific Education (AgeWISE) Program is a notable cognitive intervention designed to educate both individuals experiencing normal aging and those with age‐related diseases. It offers strategies for managing age‐related cognitive changes and provides skill training.

Goals

This study aims to evaluate the effects of a multi‐component psychoeducation intervention (AgeWise) in patients with MCI, focusing on the aging brain, lifestyle factors associated with successful brain aging, and strategies to compensate for age‐related cognitive decline.

Method

A group of 25 amnesic and amnestic‐multidomain MCI patients (mean age: 75.26±5.5, 65.38% female, education level: 14.46±2.8, MOCA: 22.96±2.91) were recruited from a Memory Clinic in Buenos Aires. Patients underwent 10 treatment sessions based on the AgeWISE program. Pre‐treatment (week 0) and post‐treatment (week 10) assessments included the Multifactor Memory Questionnaire (MMQ) for various memory dimensions and the Depression, Anxiety, and Stress Scale (DASS‐21) to assess mood. The Wilcoxon‐Mann‐Whitney model was used to analyze the impact of treatment on each outcome.

Result

The pre and post‐treatment measures were compared, revealing an improvement in the total DASS‐21 (P = 0.05), with a significant reduction in depression (DASS‐21‐Depression P = 0.02). While changes in the MMQ scale did not reach significance, there was a trend towards improved satisfaction with memory performance (P = 0.083).

Conclusion

In regions with limited access to clinical and pharmacological trials, non‐pharmacological interventions emerge as a viable option for MCI patients. The AgeWISE intervention specifically demonstrated improvements in mood among MCI patients, with significant changes were observed in specific items (DASS‐21‐Total and Depression) related to initiative, tolerance for interruptions, and enthusiasm, suggesting positive outcomes for individuals undergoing this intervention. These findings highlight the potential benefits of non‐pharmacological interventions for individuals with MCI.
Risk factors and baseline cognition. Preliminary results from the LatAm‐FINGERS cohort
Authors: Corvalan Nicolas , Keller Greta , Surace Ezequiel Ignacio , Calandri Ismael Luis , Brucki Sonia Maria Dozzi , Salinas‐Contreras Rosa Maria , Suemoto Claudia Kimie , Velilla Lina M , Yassuda Monica Sanches , Allegri Ricardo , Caramelli Paulo , Lopera Francisco , Nitrini Ricardo , Sosa Ana Luisa , Sevlever Gustavo , Crivelli Lucia ,   LatAm‐FINGERS Consortium
Published: January 2025

Background

LatAm‐FINGERS ‐ the first non‐pharmacological multicenter randomized clinical trial in Latin America ‐ is a valuable opportunity to study lifestyle in a heterogeneous and multiethnic population exposed to a large number of cardiovascular risk factors. Our aims are to study the risk distribution in the LatAm‐FINGERS cohort and to explore the relationship between LIfestyle for BRAin Health (LIBRA) and cognition.

Method

We calculated the risk of dementia using the LIBRA score in the entire cohort (n = 1200). LIBRA consists of a weighted sum score (higher scores indicating greater dementia risk) of 12 modifiable risk and protective factors for cognitive decline. Cognition was assessed using the Latin America Neuropsychological Test Battery (LatAm‐NTB). We constructed mixed‐effects linear regression models to examine the relationship between the LIBRA and cognition as a fixed effect, with country as a random effect.

Result

The LIBRA ranged from ‐4.5 to 10, with a mean of 2.39 (±2.75). Men had significantly higher LIBRA scores than women (w = 125887, p = .003). Those with more education (>9 years) scored significantly lower in LIBRA compared to those with less education (w = 57458, p < .001), possibly due to the established association between education and health outcomes. No differences were found in LIBRA between individuals with and without APOE4 (w = 17475, p = 0.57). A significant relationship was observed between LIBRA and global cognition measured by LatAm‐NTB (β = ‐0.03, std. error = 0.004, t value = ‐9.28, p < .001). There was a relationship between LIBRA and memory (β = ‐0.05, std. error = 0.007, t value = ‐7.06, p < .001), executive functions (β = ‐0.02, std. error = 0.004, t value = ‐5.49, p < .001), and processing speed composites (β = ‐0.01, std. error = 0.005, t value = ‐3.30, p < .001).

Conclusion

Our results shed light on sex differences, revealing that men tend to exhibit higher LIBRA. The negative relationship between higher levels of education and LIBRA underscores the protective role of education on cognition. This highlights the significance of LIBRA as a useful risk composite for elucidating cognitive outcomes within the LatAm‐FINGERS cohort, characterized by its ethnic and cultural diversity.