Background
Polygenic risk scores (PRS) provide an overall estimate of the individual’s genetic propensity to a trait by combining sparse information scattered across multiple genetic loci which often ...display small effect sizes. Most genetic studies are of European ancestry, ultimately limiting the use of PRS in other ethnicities. Here we constructed and validated a PRS for late‐onset Alzheimer’s Disease (LOAD) in Caribbean Hispanics (CH).
Method
We employed genome‐wide association summary statistics from 4,312 CH to construct an ancestry‐specific PRS (“CH‐PRS”) in an independent validation CH cohort (N=1,850). CH‐PRS performance was evaluated using the area under the receiver operator characteristic (ROC) curves and logistic regression to evaluate strength of the association with LOAD and statistical significance. We sought to further replicate the CH‐PRS in an independent CH dataset (Alzheimer’s Disease Research Center “ADC‐CH”, N=200) and in a brain autopsy cohort (N=33). We also studied the CH‐PRS performance in predicting conversion to LOAD in a subset of non‐demented individuals at baseline with longitudinal data (N=600), employing a Cox regression model. Finally, we tested the effect of ethnicity on PRS performances by employing European (EUR) and African American (AA) ancestry studies as discovery datasets to construct alternative PRSs (“EUR‐PRS”, “AA‐PRS”) in our validation cohort.
Result
In the full model (LOAD ∼ CH‐PRS + sex + age + APOE‐ɛ4), the AUC reached 74.02% (OR=1.51 95%CI=1.36‐1.68), raising to >75% in APOE‐ɛ4 non‐carriers. In the autopsy cohort, higher CH‐PRS was significantly associated with pathological AD diagnosis (AD ∼ CH‐PRS; AUC=72%; OR=2.35, 95%CI=1.0‐5.52), and AUC=83% in the full model. In ADC‐CH, the PRS showed significant association with LOAD (OR=1.61, 95%CI=1.19‐2.17). CH‐PRS significantly predicted conversion to LOAD over time (HR=1.96, CI=1.61‐2.39). EUR‐PRS and AA‐PRS reached lower prediction accuracy (AUC=58% and 53%, respectively).
Conclusion
PRS is an effective strategy to delineate individual risk profiles as shown by our cross‐sectional and longitudinal analyses as well as associations with well‐established AD‐hallmarks. Enriching diversity in genetic studies is indeed critical to provide a PRS tool that is effective in predicting LOAD risk across ethnic populations.
We examined the social impact of the telemedicine intervention effects in lower- and higher-socioeconomic status (SES) participants in the Informatics for Diabetes Education and Telemedicine ...(IDEATel) study.
We conducted a randomized controlled trial comparing telemedicine case management with usual care, with blinded outcome evaluation, in 1665 Medicare recipients with diabetes, aged 55 years or older, residing in federally designated medically underserved areas of New York State. The primary trial endpoints were hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol, and systolic blood pressure levels.
HbA1c was higher in lower-income participants at the baseline examination. However, we found no evidence that the intervention increased disparities. A significant moderator effect was seen for HbA1c (P = .004) and systolic blood pressure (P = .023), with the lowest-income group showing greater intervention effects.
Lower-SES participants in the IDEATel study benefited at least as much as higher-SES participants from telemedicine nurse case management for diabetes. Tailoring the intensity of the intervention based on clinical need may have led to greater improvements among those not at goal for diabetes control, a group that also had lower income, thereby avoiding the potential for an innovative intervention to widen socioeconomic disparities.
Supported by a supplement to our Clinical and Translational Science Award, we studied the feasibility of implementing clinical research in Northern Manhattan community practices that primarily serve ...Hispanic patients.
We applied a mixed-methods approach (surveys, focus groups, interviews) based on the PRECEDE-PROCEED model to determine the level of interest in clinical research among community clinicians (both practice-based research network PBRN members and non-PBRN members), the perceived barriers that hamper participation in clinical research, and the perceived facilitators for conducting research in such practices.
Survey and qualitative data indicated strong interest in clinical research among current and potential PBRN members if it was relevant to improving quality of care in their practice or community. They also identified important perceived barriers (lack of time, inadequate training in research methods, lack of collaborators and support staff, institutional review board hurdles, and community distrust of research) and the necessary requirements for overcoming barriers to conducting research in busy clinical settings, which included collaborators, mentors, research support staff, and a trusting patient-clinician relationship.
It is feasible to conduct clinical research studies in urban community medical practices if the topics are relevant to the community and appropriate enabling structures and processes are put into place.
Cerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited.
To ...assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity.
In this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023.
Main outcomes were the association of plasma biomarkers amyloid-β 1-42 (Aβ42), amyloid-β 1-40 (Aβ40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests.
Exposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index.
This study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 95% CI, 0.32-0.60), NfL (r = 0.57 95% CI, 0.44-0.68), and P-tau181/Aβ42 (r = 0.44 95% CI, 0.29-0.58). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aβ42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aβ42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aβ42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD.
In this cross-sectional study, plasma P-tau181 and P-tau181/Aβ42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.
Abstract
Background
Presence of the APOE‐ε4 allele is the most consistently confirmed genetic risk factor for late‐onset Alzheimer’s disease (AD) in white, non‐Hispanic populations, but the ...associated risks observed in African Americans and Hispanics are somewhat lower. The objective of this study was to identify protective variants that could modify or reduce the effect of APOE‐ε4 on AD risk.
Methods
We analyzed WGS data in over 3500 individuals from 600 multiplex AD families of non‐Hispanic White (NHW) and Caribbean Hispanic (CH) ancestry to identify protective variants in AD. APOE ε4 homozygosity was found in 48 healthy individuals over the age of 70, and APOE ε4 heterozygosity was found in 155 healthy individuals over the age of 80 were present in families with two of more affected samples. Protective variants were found segregating in the APOE ε4 homozygote and heterozygote individuals. We required that these variants be rare (MAF<0.1%) in GnomAD and prioritized exon coding variants that were putatively damaging to the resulting protein product. Novel or rare coding mutations segregating in ε4 unaffected subjects were tested for the effects on the age of onset of symptoms.
Results
We identified 632 putatively protective variants that were present in at least 1% of APOE ε4 carriers and were absent in those with other APOE genotypes. 67 protective variants were present in both NHW and CH families. Pathway analysis of these segregating variants in APOE ε4 carriers are enriched in pathways involved in biological pathways and molecular functions such “actin binding”, “microtubule binding”, “extracellular matrix structural constituent”. These results suggest that protective variants promote activity of the extracellular matrix and cytoskeletal proteins leading to enhanced clearing of Aβ peptides. Variants in NBEAL1 delayed the age of onset in AD by 8.33 years respectively.
Conclusions
WGS in CH and NHW families multiply affected by AD identified some healthy elderly, non‐demented APOE ε4 carriers with rare coding variants associated with delayed age of onset. Characterizing the functional role of these protective variants in AD will facilitate the creation of tractable models for investigation of disease mechanisms and potential therapies.
Objective To determine whether a diabetes case management telemedicine intervention reduced healthcare expenditures, as measured by Medicare claims, and to assess the costs of developing and ...implementing the telemedicine intervention. Design We studied 1665 participants in the Informatics for Diabetes Education and Telemedicine (IDEATel), a randomized controlled trial comparing telemedicine case management of diabetes to usual care. Participants were aged 55 years or older, and resided in federally designated medically underserved areas of New York State. Measurements We analyzed Medicare claims payments for each participant for up to 60 study months from date of randomization, until their death, or until December 31, 2006 (whichever happened first). We also analyzed study expenditures for the telemedicine intervention over six budget years (February 28, 2000- February 27, 2006). Results Mean annual Medicare payments (SE) were similar in the usual care and telemedicine groups, $9040 ($386) and $9669 ($443) per participant, respectively (p>0.05). Sensitivity analyses, including stratification by censored status, adjustment by enrollment site, and semi-parametric weighting by probability of dropping-out, rendered similar results. Over six budget years 28 821 participant/months of telemedicine intervention were delivered, at an estimated cost of $622 per participant/month. Conclusion Telemedicine case management was not associated with a reduction in Medicare claims in this medically underserved population. The cost of implementing the telemedicine intervention was high, largely representing special purpose hardware and software costs required at the time. Lower implementation costs will need to be achieved using lower cost technology in order for telemedicine case management to be more widely used.
In order to provide a comprehensive evaluation of the non‐genetic factors involved in the development of Alzheimer’s disease and related disorders it is necessary to develop a systematic process to ...capture the range of environmental and social influences. Exposomics has emerged as an approach to do this. Using high‐resolution mass spectrometry and geospatial techniques it is possible to evaluate thousands of external factors (chemical, nutritional, social, environmental) and their corresponding impact on biology. In this presentation, we will describe the steps we are taking to build the required infrastructure. The first aspect is to improve the identification of exogenous and endogenous chemical features by expansion of our high‐resolution mass spectrometry capabilities (automated liquid handling with ThermoFisher Orbitrap‐based technology: HFX, LC‐Exploris 240, GC‐Exploris 240, and IQX Tribrid Mass Spectrometer). We are in the process of analyzing thousands of samples from WHICAP, EFIGA, and RANN using our combined LC/GC Orbitrap platform, to identify significant associations with disease traits (existing and next generation biomarkers, pathology, imaging, clinical features). Initial results from these studies will be presented to demonstrate feasibility of the approach. We have also initiated a series of pilot studies for other AD cohorts, which cover a range of populations with diverse ethnicity, disease stage, and age. These studies have extensive clinical phenotyping and deep molecular phenotyping. The addition of exposomics will leverage these existing studies to uncover novel environmental contributors to AD. We also also developing a platform to distribute workflows via an online EXCEL AD Community Dashboard to other ADRCs and AD research groups interested in incorporating exposomics into their studies. We will also provide guidance on quality control materials, including providing standards as needed. The Community Dashboard would also compile information on ongoing AD studies that are incorporating exposomics, as well as relevant publications. Various tools will be developed to encourage the utilization of this new platform such as user manuals, training programs (in‐person, online) exposomics bootcamps, and scholar exchange through on‐site visits to laboratories. We will deploy an academic research consultancy that will help other interested laboratories to establish the exposomics workflow.
Background
The utility of plasma‐based Alzheimer’s biomarkers in differentiating cognitively healthy individuals from those with Mild Cognitive Impairment (MCI) or Alzheimer’s disease (AD) has been ...widely investigated in cross‐sectional studies. There are fewer data on longitudinal change of these biomarkers over time, particularly in multi‐ethnic cohorts.
Method
Based on a community‐based, multi‐ethnic cohort study, the Washington Heights Inwood Columbia Aging Project, we included 610 cognitively normal individuals with three plasma samples collected over a mean period of 6.7 years. We used AD biomarkers, including Aβ40, Aβ42, tau, phosphorylated tau‐181 (P‐tau181), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL), and two calculated ratio measures (Aβ42/Aβ40, P‐tau181/Aβ42). During the follow‐up, 156 individuals developed MCI, 50 developed AD, and 404 remained cognitively unimpaired. We used generalized estimating equations to examine whether those who developed MCI and AD had different rates of change in plasma biomarkers than controls. Analyses were adjusted for age, years of education, sex, race and ethnicity, and APOE ɛ4 status. Similar analyses were performed to examine whether the rate of biomarker change differed by race and ethnicity, sex, and APOE ɛ4 status.
Result
The initial mean age of individuals was 73.1 (SD = 5.6) years, 419 (69%) were women, and 25.9% carried APOE e4. Individuals self‐identified as non‐Hispanic White (28.9%), non‐Hispanic Black (25.4%), or Hispanic (45.7%). Compared to controls, individuals with incident MCI had an accelerated increase in P‐tau181 (b = 0.029, p = 0.048), NfL (b = 0.027, p = 0.010), GFAP (b = 0.029, p = 0.002), and a more rapid decrease in Aβ42/Aβ40 ratio (b = ‐0.015, p = 0.033). Individuals with incident AD also had a greater increase in NfL (b = 0.041, p = 0.027) and GFAP (b = 0.04, p = 0.006) than controls. Hispanics had a faster increase in NfL (b = 0.033, p = 0.002) and GFAP (b = 0.034, p<0.001), and Black participants had a faster increase in NfL (b = 0.028, p = 0.023), compared to Whites. Neither sex nor APOE ɛ4 genotype affected rates of biomarker changes.
Conclusion
Longitudinal change in plasma biomarkers may have clinical utility, since incident MCI and AD are accompanied by faster increases in P‐tau181, NfL, and GFAP, and a faster decrease in Aβ42/ Aβ40 ratio. The trajectories of AD biomarker change may also vary by race and ethnicity.
Background
Genetic Studies of Alzheimer’s Disease in Caribbean Hispanics (CH) has been ongoing for over 20 years. Our primary goal was to identify genes in large well‐phenotyped, multiplex families, ...and sporadic cases and controls. This longitudinal collection of data represents a unique resource for the scientific community. The project is led by collaborators in the United States (US) and the Dominican Republic (DR). For the past three years, our efforts have been centered on the collection of cerebrospinal fluid (CSF), plasma, serum and Paxgene tubes for RNA to study core biomarkers. Collection of blood samples for DNA to conduct genetic analyses is also ongoing.
Method
The cohort consisted of participants aged 50 and older from the DR, including those living in the New York City area, willing and able to provide a blood and CSF samples. Interviewers in the DR were trained to collect data, blood samples and CSF. DNA samples were sent overnight to Columbia university (CU) for processing. CSF, Paxgene tubes, serum and plasma samples were processed in the DR and stored at ‐80F for batch shipping to CU. APOE genotyping was conducted in the US. Biomarkers, metabolomics, and proteomics data was generated at Columbia University. Methylation assays from Paxgene was conducted at Uniformed Services University (USUHS).
Result
We have databased a total of 1899 individuals with plasma samples, 1707 with Paxgene, 1731 with serum and 203 with CSF. Blood samples from 1079 participants have genome wide arra, whole genome sequencing and APOE genotyping. 192 CSF samples have proteomics completed, 153 CSF samples have metabolomics data and 742 have plasma biomarkers (Ab40, Ab42, T‐tau, P‐tau181, NFL and GFAP)).
Conclusion
Sample collection for genetic studies in developing countries present important logistical challenges. Despite these challenges, sample quality is comparable to those collected in New York. Biomarkers from CSF, serum and plasma can give us a closer look into underrepresented populations such as Caribbean Hispanics. Results suggest that similar protocols can be successful in Latin America. Future work will augment the biosample collection of the cohort by collecting samples from additional subjects.
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