Citations

Abstract Background People living with dementia (PLWD) face short‐term risks following emergency department (ED) visits. However, the long‐term impacts of ED visits on PLWD quality of life are not well characterized. Home time‐ days alive and outside hospitals or other care settings‐ is an emerging measure that can reflect longer‐term outcomes. We aimed to identify patient and ED visit characteristics associated with variation in home time after an ED visit. Method Retrospective observational study of Veteran PLWD with ≥1 VA ED visit between 10/01/2016 and 09/30/2018. We used VA and CMS data sources to define veteran characteristics and outcomes. Primary outcome was home time in the 180 days after an ED visit, defined as days alive and not in an ED, inpatient, post‐acute, or a nursing home setting. We used a negative binomial model to evaluate the associations between covariates and home time with VAMC‐level random effects to account for correlation among patients at the same VAMC. Result Our final cohort comprised 51,707 Veteran PLWD, predominantly male (97.6%) and white (73.0%), with mean age 79.9 (SD 8.59). Most lived in urban areas (74.4%), and 52.2% were married. Characteristics associated with reduced home time included older age (RR 1.06, 95% CI 1.05‐1.07), never married (RR 1.24; 1.16‐1.32) or divorced/widowed (RR 1.24; 1.20, 1.28), depression (RR 1.13; 1.09, 1.17), and ED visits for chronic conditions (RR 1.13; 1.08, 1.18). Female sex (RR 0.88; 0.79‐0.97) and lower clinical frailty (RR 0.79; 0.75, 0.83) were associated with more home time. Conclusion Patient and ED visit characteristics impact home time up to 180 days after an ED visit. Older, frailer, unmarried, male patients and those presenting with chronic conditions experienced reduced home time, suggesting directions for targeted interventions. Efforts such as enhanced discharge planning and addressing psychosocial factors (e.g., depression) could improve quality of life.

Abstract Background The polymorphic APOE gene is a susceptibility gene for Alzheimer's disease (AD). The ε4 allele is associated with increased risk for AD, particularly late‐onset disease, in a dose‐dependent manner. Additionally, homozygous ε4/ε4 individuals have increased risk of adverse events when undergoing amyloid lowering treatments. APOE genotyping is considered the gold standard for determination of ApoE4 zygosity. Recently, proteotype assays for ApoE4 have become available for high‐throughput immunoassay analyzers. These assays utilize the same specimen type as AD blood biomarkers and can potentially offer improved turnaround times compared to genotyping. In this study, we compare the performance of two automated ApoE4 proteotype research use only (RUO) immunoassays against APOE genotyping. Method EDTA‐plasma samples ( n = 65) from individuals undergoing ApoE PCR‐based genotyping for clinical purposes were evaluated. Samples were tested with the Beckman Coulter APOE ε4 RUO assay on the Access 2 and DXI 9000 instruments (Beckman Coulter, Inc), which provides algorithm calculated results for determining ApoE4 zygosity. Manufacturer generated data from 300 genotyped samples was used to calculate estimated cut‐points for ApoE4 zygosity for this study with results <0.55 classified as no E4, ≥0.55 to <4.55 as heterozygous E4, and ≥4.55 as homozygous E4. Samples were also tested with the Lumipulse G ApoE4 and Pan‐ApoE RUO assays on the Fujirebio Lumipulse G1200 analyzer. The ratio of ApoE4/Pan‐ApoE was utilized for determining zygosity with results <5% classified as no E4, ≥5% to <75% as heterozygous E4, and ≥75% as homozygous E4, as listed in the manufacturer IFU. Result APOE genotype distributions were (n, %): ε3ε4 (30, 46%), ε3ε3 (18, 28%), ε4ε4 (12, 18%), ε2ε3 (3, 5%), ε2ε4 (2, 3%). ApoE4 zygosity was categorized as no ε4 (21, 32%), heterozygous ε4 (32, 49%), or homozygous ε4 (12, 19%). The Beckman Coulter APOE ε4 RUO assay classified 65/65 (100%) patients correctly using manufacturer generated cut‐points on both instruments. The Lumipulse G ApoE4 and Pan‐ApoE RUO assays classified 61/65 (94%) patients correctly using the manufacturer listed cut‐points. Conclusion ApoE4 proteotype immunoassays may represent simplified and more accessible testing alternatives to genotyping for the assessment of ApoE4 zygosity in individuals being considered for amyloid lowering treatments.

Abstract Background Extensive evidence links cognition, tau, and neurodegeneration in Alzheimer's disease (AD). However, in U.S. POINTER imaging (a community‐recruited clinical trial cohort selected for high cardiovascular risk, ethnoracial diversity, and increased risk of cognitive decline and dementia) tau PET is more closely linked to cognition than in ADNI. Here, we further explore how ADNI and POINTER differ with respect to relationships between cross‐sectional AD biomarkers, cortical thickness, and different cognitive domains. Method U.S. POINTER imaging (Baseline; N = 775; 68.9±5.2 years, 62.8% female) and ADNI ( N = 405; 69.9±5.4 years, 58% female) were matched by age, sex, clinical status, and APOE4 genotype (Table 1). We examined associations between baseline AD biomarkers (Amyloid‐beta (Aβ) PET in centiloids, harmonized tau PET measures of MK6240 in POINTER and FTP in ADNI), regional cortical thickness, and verbal memory (Delayed Story Recall), executive function (Trail‐Making B), and global cognition (Preclinical Alzheimer's Cognitive Composite scores) across each cohort, controlling for age, sex, and education. Result Aβ burden in ADNI was associated with worse executive function ( p < .001) and global cognition ( p < .001) but not memory, whereas in POINTER Aβ burden was not associated with any cognitive domain (Figure 1A). Among Aβ+ individuals, tau burden was associated with poorer performance across domains in ADNI, but only with poorer verbal memory in POINTER (Figures 1B&1C). Additionally, there were stronger positive associations between cortical thickness and executive function and global cognition compared to verbal memory, particularly in ADNI Aβ+ individuals even after adjusting for entorhinal tau ( p < .01; Figure 2). Conclusion Cognitive performance was linked to all biomarkers (Aβ, tau, cortical thickness) but these associations were consistently stronger in ADNI compared to POINTER, particularly in Aβ+ individuals. The stronger thickness‐cognition relationships in ADNI were not driven by tau, indicating that there is a tau‐independent role of thickness in explaining cognition. In ADNI, there were subtle differences between cognitive domains such that executive function was more closely linked than verbal memory to Aβ and cortical thickness, whereas verbal memory was linked to tau in both cohorts. Our study highlights that frequently‐reported AD biomarker associations may be attenuated in heterogeneous, community‐recruited cohorts.

Abstract Background Apolipoprotein E (apoE) facilitates the fibrillization and deposition of amyloid β (Aβ) in Alzheimer's Disease (AD). Supported by robust literature from various groups, in our current study we have investigated the relative amyloidogenic properties of the three major human APOE alleles. Knowledge from such studies could provide insight into the role of ApoE protein in the deposition, evolution and maturation of parenchymal Aβ. Method We used hAbetaSAA (Jax Labs) mice crossed with human APOE targeted replacement mice to create hAbetaSAA mice homozygous for human APOE E2, E3 and E4 . Furthermore, APPsi mice (hAPPswe/indiana: Borchelt) expressing human APOE E3 or E4 were injected intracerebrally with AD brain lysates to examine the role of APOE genotype on Aβ seeding. Neuropathological examination was conducted via immunohistochemistry, immunofluorescence and immunoblotting. Result hAbetaSAA mice expressing human APOE E4 showed higher Aβ deposition relative to APOE E3 and APOE E2 by 5 months of age and progressing through 8 months and 13 months of age. In comparison, APP mice expressing humanized Aβ (Jax Labs) with human APOE E4 did not develop deposits in their lifetime. hAbetaSAA mice with endogenous mouse Apoe had the highest Aβ plaque deposition, with an approximately 60‐fold increase in Aβ burden compared to SAA APP mice expressing APOE E3 , especially in the earlier deposition phase. Removing mouse Apoe resulted in dose‐dependent reduction in Aβ deposition, consistent with previously published literature. Plaque morphology did not show any notable differences between APOE genotypes, and colocalization of apoE with Aβ were relatively equivalent across different APOE genotypes. Further, in the APPsi model seeded with AD‐derived seeds, we found that mice with APOE E4 or APOE E3 developed equal burdens of diffuse parenchymal Aβ, with no detectable changes in plaque morphology. Conclusion We conclude that apoE variants broadly influence the rate of amyloid deposition, but do not modify the morphology of the resulting deposits or colocalization with Aβ. Notably, when seeding with AD patient brain lysate, there was no significant difference in Aβ burden between APPsi mice expressing APOE E3 and E4 . Our study adds insights into the role of apoE isoforms in determining Aβ‐related phenotype.

Abstract Background Our objective is to examine the generalizability of the relationships between four MRI markers of CVD: DTI‐derived free water (FW), fractional anisotropy (FA), perivascular space (PVS) and white matter hyperintensities (WMH) volume, with vascular risk factors (VRF) and cognition in the baseline POINTER Imaging and Framingham Heart Study (FHS) cohorts. Method We studied 907 U.S. POINTER and 797 FHS Offspring participants with available baseline demographic, clinical and imaging data (Table 1). Continuous FW, FA, WMH (log‐transformed) and PVS measurements were regressed against total cranial volume (TCV). Cognitive outcomes included a Global Cognitive Composite and executive function composite score for POINTER and FHS. For each MRI marker, we used linear and logistic regressions to assess the effect of age, sex, hypertension, diabetes and smoking status, adjusting for ethnicity. We then assessed, for each cognitive outcome, the individual effect of MRI markers using separate linear regressions adjusted for demographic and clinical factors, as well as TCV‐adjusted gray matter volume to control for atrophy. Result POINTER and FHS differed across most demographic and biomarker characteristics (Table 1). Despite these differences, there were similar associations between demographic and VRF and the 4 MRI vascular markers in POINTER and FHS (Figure 1): increased age was associated with worse outcomes for the 4 markers, hypertension was associated with increased FW, PVS and lower FA, diabetes was associated with increased FW only, smoking status did not impact any of the four markers. Only exception was that female had lower FW and increased WMH in POINTER and increased PVS in FHS. Associations between CVD measures and cognition were also similar across cohorts: reduced cognitive performance was significantly associated with both decreased FA and increased FW (Figure 2), but not with WMH nor PVS. Conclusion Our study explores four imaging markers representing diverse mechanisms by which CVD could impact brain structure and function in the POINTER and FHS studies. Despite differences in cohort characteristics, we found mostly consistent CVD relationships with demographic, VRF, and cognitive measures between cohorts which supports the generalizability of the relation of these markers with VRF and cognition identified in the POINTER cohort.

Abstract Background Given low representation of diverse populations in Alzheimer's disease (AD) research, it remains unclear if AD biomarker relationships observed primarily in non‐Hispanic White (NHW) cohorts generalize to other groups. Here we evaluate associations between key AD biomarkers and cognitive performance among cognitively unimpaired non‐Hispanic Blck (NHB) and NHW participants across 2 cohorts with unique sample characteristics. Method Participants included cognitively unimpaired NHB and NHW participants with Aβ and tau PET in ADNI (69 NHB, 402 NHW) and POINTER Imaging (135 NHB, 637 NHW). We examined harmonized measures of global Aβ (in centiloids), entorhinal cortex (EC) tau (quantified with MK6240 in POINTER and FTP in ADNI) and Preclinical Alzheimer's Cognitive Composite (PACC) scores. Regression models within each ethnoracial group evaluated relationships between 1) Aβ and EC tau, and 2) EC tau and PACC performance. Interaction models within each cohort were also conducted to assess differences in these associations by ethnoracial group. All models were adjusted for age and gender. Models with PACC additionally adjusted for education. Result In US POINTER, NHBs had lower Aβ and EC tau burden compared to NHWs (Table 1). In ADNI, there was no difference in EC tau between groups, and no differenence in Aβ after adjusting for age and gender. In US POINTER, the positive Aβ‐EC tau relationship was observed in both ethnoracial groups whereas in ADNI, Aβ was associated with higher EC tau in the NHW but not the NHB group. In both cohorts, EC tau was associated with worse PACC performance in both NHB and NHW and there were no differences in this association by ethnoracial group in interaction models (Figure 1). Conclusion NHBs had lower Aβ and EC tau than NHWs in POINTER but not ADNI, and there were inconsistent associations between Aβ and EC tau across cohorts. Despite these differences, AD biomarkers appear similarly related to cognitive outcomes across ethnoracial groups in both cohorts. Future analyses will attempt to further determine the generalizability of AD biomarker relationships in diverse samples by considering matching on relevant health and demographic characteristics, and inclusion of additional cohorts with harmonized biomarker and cognitive measurements.

Abstract Background Clinically available plasma p ‐tau217 assays may be utilized in the determination of eligibility for amyloid‐lowering therapies. Our institution recently introduced a plasma p ‐tau217 assay in clinical practice using a two‐cutpoint approach that optimizes the accuracy while minimizing false positive risk and categorizing ≤20% of results as intermediate. In this study, we prospectively evaluate the performance of a plasma p ‐tau217 assay for detection of amyloid pathology using these predefined cutpoints. Method Patients recruited were being considered for lecanemab therapy at a tertiary care subspecialty clinic. Plasma p ‐tau217 was measured using the clinically available Fujirebio Lumipulse p ‐tau217 assay at Mayo Clinic, and results (pg/mL) were classified as either negative (≤0.185), intermediate (0.186–0.324) or positive (≥0.325). Amyloid pathology was determined by amyloid‐PET and/or CSF p ‐tau181/Aβ42. Result Ninety‐three patients were recruited between November 2023 and December 2024. Of these, 49 underwent amyloid‐PET, 4 had CSF p ‐tau181/Aβ42 measurements, and 40 had both PET and CSF results (with 3/40 discordant cases), for use in the assessment of amyloid pathology. The three discordant cases were considered amyloid positive for purposes of plasma p ‐tau217 comparison. Overall amyloid positivity was 90%. Plasma p ‐tau217 results were positive in 83% (77/93), negative in 6% (6/93), and intermediate in 11% (10/93) of patients. An elevated p ‐tau217 predicted the presence of amyloid positivity with a diagnostic accuracy of 96% (95% CI 90% − 99%). In the intermediate range, 80% of patients were positive for amyloid pathology. In patients with a definitive p ‐tau217 result (positive or negative), the positive and negative predictive values were 97% and 83%. There were three patients with discordant results: one PET+/p‐tau217‐, one PET‐/p‐tau217+, and one CSF‐/p‐tau217+. Clinical presentation of these discordant cases was examined, and relevant findings will be discussed. Conclusion The Lumipulse plasma p ‐tau217 assay exhibited acceptable diagnostic accuracy for the determination of amyloid pathology when compared to either amyloid‐PET or CSF p ‐tau181/Aβ42. This prospective study confirms the utility a two‐cutpoint approach for interpreting plasma p ‐tau217 for the assessment of amyloid pathology eligibility for amyloid‐lowering therapies in a heterogenous clinical cohort.

Abstract Background Anti‐amyloid therapy trials have reported changes in some Alzheimer's disease (AD) blood biomarkers (BBMs) suggesting that these BBMs may be useful minimally invasive measures of amyloid clearance and treatment outcomes. However, a better understanding of how AD BBMs changes at the individual level reflect treatment response in relation to other relevant clinical endpoints is necessary before they can be adopted for treatment monitoring. Here, several AD BBMs were assessed longitudinally in patients undergoing lecanemab therapy. Method Patients undergoing lecanemab therapy at Mayo Clinic, Rochester, MN were recruited to participate in this study. Patients were asked to provide an EDTA‐plasma sample before treatment initiation during the first infusion visit and thereafter at 3‐, 6‐, 12‐, and 18 months post‐treatment. p ‐tau217, p ‐tau181, GFAP, NfL, Aβ42, Aβ40, Aβ42/40, and p ‐tau217/Aβ42 measurements were obtained using Fujirebio Lumipulse assays. Biomarker median differences were assessed between all time points. Patients were grouped into three categories: a decreased biomarker (median decrease of at least 10%), an increased biomarker (median increase of at least 10%), and a stable biomarker (median change < +/−10%.) Biomarker data up to 6 months after treatment is presented. Result Of forty‐one patients enrolled since November 2023, twenty had time points up to 6 months. None of the biomarkers showed a statistically significant median change from baseline at 3 months ( p >0.05). At 6 months, only Aβ42/40 showed a statistically significant median change (decrease) between 0 and 6 months ( n = 20, p = 0.0058). Table 1 shows patients grouped by median biomarker changes from baseline to 6 months. GFAP, p ‐tau217, and Aβ42/40 exhibited the greatest number of patients with decreased biomarker concentrations (80%, 60%, and 60% of patients with median decreases of ‐25%, ‐26%, and ‐18% respectively), followed by p ‐tau181 (50% of patients; median decrease ‐22%), p ‐tau217/Aβ42 (45% of patients; median decrease ‐40%) and Aβ42 (45% of patients; median decrease ‐18%). None of the patients showed a decreased NfL or Aβ40 concentration. Conclusion Preliminarily analysis revealed that GFAP, p ‐tau217, and Aβ42/40 had the most frequent post‐lecanemab biomarker decreases. Additional sample collection is ongoing to assess the association of AD BBM changes with Amyloid PET over time.

Abstract Background Neighborhood socio‐economic conditions may increase Alzheimer's disease (AD) risk through amyloid, tau, atrophy or vascular pathways, potentially varying by genetic risk, race or ethnicity and sex. We examined associations between Area Deprivation Index (ADI) and cognition, AD pathology, gray matter (GM) and white matter hyperintensities (WMH) volume in cognitively unimpaired older adults by race or ethnicity, sex and APOE4 status. Method We included 1896 non‐demented older adults from US POINTER study with available cognitive evaluations, ADI level – a census–based neighborhood disadvantage metric (categorized as low, moderate and high) and a subsample with neuroimaging data ( N = 806). Linear/logistic regressions were used to assess interactions of ADI with sex, race or ethnicity, and APOE4 on (1) the Preclinical Alzheimer's Cognitive Composite, (PACC‐5), (2) MRI‐derived GM volume meta‐ROI (entorhinal, fusiform, parahippocampal, mid‐temporal, inferior temporal), (3) WMH and (4) AD pathology (amyloid and tau PET), adjusted by age, sex and intracranial volume when appropriate. Result African American participants ( p <0.001) and females ( p <0.001) were more likely to live in deprived areas. African American participants had significantly lower PACC‐5 ( p <0.001) and GM volume ( p <0.001), “Other or multiple races” participants showed significantly higher amyloid burden ( p = 0.001), and White participants higher WMH ( p = 0.013). Females showed higher PACC‐5 scores ( p <0.001), while APOE4 carriers showed lower PACC‐5 ( p = 0.042) and higher amyloid burden ( p <0.001) (Table 1). Race and ADI interacted on PACC‐5 ( p = 0.043) and showed a borderline interaction on Tau ( p = 0.079), with higher ADI linked to lower PACC‐5 in White, Hispanic, and “Other or Multiple Races” and higher Tau in Hispanic. Further, there was a borderline ADI*APOE4 status interaction on WMH ( p = 0.059) and a significant ADI*APOE4 interaction on amyloid ( p = 0.001), where APOE4 carriers in deprived areas showed higher WMH and lower amyloid burden (Figure 1). No significant ADI*sex interactions were observed. Conclusion Neighborhood disadvantage was more commonly observed in African American participants, but interaction with cognition was primarily seen in other racial/ethnic groups. APOE4 carriers showed increased amyloid burden, but those from more disadvantaged neighborhoods exhibited a higher vascular component alongside lower amyloid‐driven pathology. These results may indicate varying effects of social disadvantages across groups or sample bias.

Abstract Background Neighborhood social and built environment characteristics may promote physical activity, a modifiable factor for dementia risk, which may in turn promote cognitive and brain health. We explored the associations of the U.S. National Walkability Index ‐ a nationwide geographic data resource that ranks block groups according to their relative walkability – with cognitive function, gray matter (GM) and white matter hyperintensities (WMH), neighborhood disadvantage, sedentary behavior and frequency of physical activity in cognitively unimpaired older adults at increased Alzheimer's disease (AD) risk. Method We included baseline data from 1398 older adults (68.3 ± 5.17 years, 68.3% females, 30.5% APOE4 carriers) from the U.S. POINTER trial. Walkability was classified as: least, below average, above average and most walkable. Neighborhood disadvantage (low, moderate and high) was assessed using Area Deprivation Index (ADI) ( N = 1384). Physical inactivity was assessed using the Sedentary Behavior Questionnaire (SBQ, hours sitting/week, N = 1106), and physical activity was measured with a composite score from the Community Health Activities Model Program for Seniors (CHAMPS) questionnaire. Linear and logistic regressions examined associations between walkability and (1) physical activity and sedentary behavior; and (2) cognition assessed with the Preclinical Alzheimer's Cognitive Composite (PACC‐5), GM volume and WMHs, Additionally, associations between neighborhood disadvantage and physical activity and sedentary behavior were explored. Models were adjusted for age, sex, race, APOE4 and total intracranial volume. Result More deprived areas were generally less walkable (β = ‐0.008, p < 0.001) (Figure 1). Higher walkability (Above average: β = 0.192, p = 0.011 and most walkable: β = 0.183, p = 0.032) was associated with higher PACC‐5 (Figure 2A) scores but not with more preserved GM or lower WMH. Walkability scores were not associated with physical activity and sedentary measurements, while greater neighborhood disadvantage was linked to sedentary behavior (β = 0.126, p < 0.001) (Figure 2B). Conclusion These results suggest that physical inactivity in more deprived areas is associated with neighborhood socioeconomic disadvantages rather than built environment. Additionally, walkability scores were not associated with any measure of physical activity or brain health, suggesting the need to further investigate other health effects of neighborhood disadvantage and walkability.