Background
We classified non‐demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and ...imaging profiles.
Materials and methods
From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut‐offs of 1000 pg/mL for amyloid beta (Aß)1‐42 and 27 pg/mL for p‐tau181 were validated using Gaussian mixture models. Given strong correlation of p‐tau and t‐tau (R2 = 0.98, P < 0.001), neurodegeneration was defined by age‐adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages.
Results
Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A–T–N–, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non‐Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T–N– compared to A–T–N– (P < 0.001).
Discussion
In non‐demented individuals along the AD continuum, p‐tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.
Apolipoprotein-E (APOE) genetic testing for Alzheimer's disease is becoming more important as clinical trials are increasingly targeting individuals carrying APOE-ε4 alleles. Little is known about ...the interest in finding out one's genetic risk for Alzheimer's disease in the general population. Our objective was to examine this in a sample of cognitively normal (CN) adults within a population-based online research registry with the goal to implement APOE-ε4 status for trial recruitment.
An online survey was completed by 442 CN participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia and knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOE-ε4/ε4 genotypes). Cochran's Q and post hoc McNemar tests were used to analyse differences in frequencies across scenarios.
Most participants were interested in participating in research into and disclosure of their genetic risk (81%). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, whilst lower-educated participants were more often undecided. When provided with different risk scenarios, interest in knowing their risk was somewhat higher in the scenarios with higher risk, i.e. in the 50% (79%) compared to the 10% scenario (73%;χ
(2) = 7.98; p = .005). Most individuals expected they would share their genetic risk with close relatives (77-89%), would participate in medication trials (79-88%), and would make long-term arrangements, e.g. retirement, health care, will (69-82%), with larger proportions for scenarios with higher hypothetical genetic risk.
Our findings indicate that the vast majority of CN adults participating in a research registry expresses interest in AD genetic risk research and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOE-ε4 genotype. This suggests APOE-ε4 screening within an online research registry is potentially a well-received method to accelerate inclusion for trials.
Background
Apolipoprotein‐E (APOE) genetic susceptiblity testing for Alzheimer’s disease (AD) dementia is becoming more important as clinical trials are increasingly targeting individuals carrying ...APOE4‐genotypes. As little is known about about the interest in knowing genetic risk for AD dementia in the general population. Our objective was to examine this in a sample of cognitively normal adults within a population‐based online research registry with the goal to implement APOEε4 status for trial recruitment.
Method
An online survey was completed by 442 cognitively normal participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia, and the knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOEε4/ε4 genotypes). All hypothetical scenarios were randomly presented to all participants. Cochran’s Q‐tests was used to analyse differences in frequencies across scenarios.
Result
The vast majority of participants was interested in participating in research and disclosure of their genetic risk (81%; Figure 1). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, while lower‐educated participants more often reported to be unsure. When provided with different risk scenario’s, interest in knowing their risk was somewhat higher in the scenario’s with higher risk (50% scenario (79%) and 30% scenario (77%)) than in the 10% scenario (73%; χ2(2) = 19.91;p<.001). Most individuals expected they would share their genetic risk with close relatives (77‐89%), would participate in medication trials (79‐88%), and would make long‐term arrangements, e.g. retirement, health care, will (69‐82%), with larger proportions for scenarios with higher hypothetical genetic risk.
Conclusion
Our findings indicate that the vast majority of cognitively normal adults participating in a research registry is interested in AD genetic risk research participation and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOEε4 genotypes. This suggests APOEε4 screening within an online research registry is potentially a well‐received method to accelerate inclusion for preclinical trials ultimately disclosing genetic risk.
Background
Interest in Apolipoprotein E (ApoE) genetic testing for Alzheimer’s disease dementia (AD) is increasing. Even though ApoE‐status is more often being disclosed to cognitively normal adults ...in clinical trials and services like 23andMe are growing, disclosure in the context of individualized risk profiling is not yet common practice. Our objective was to examine attitudes towards genetic susceptibility testing for AD in a sample of Dutch cognitively normal adults.
Method
An online survey was completed by 428 cognitively normal respondents (response rate 29%) between the age of 50 and 75 years from the Dutch Brain Research Registry (Hersenonderzoek.nl). The survey assessed interest in participating in research studies about genetic testing and disclosure, perceptions of its reasons and possible impact and degree of control respondents want in deciding to test their genetic risk (Control Preferences Scale). Furthermore, we randomly presented three fictional scenarios to assess interest in genetic risk disclosure for different risks of AD (10, 30 and 50%).
Result
The majority of respondents was interested in genetic risk disclosure (80%) and preferred to decide themselves whether to receive their genetic risk (73%) rather than leaving this decision to a health care professional. The most commonly endorsed reason for testing was contributing to scientific research (94%). When presented with specific scenarios, most respondents were still interested in their genetic risk, regardless of the presented risk (73‐79%). The three most important consequences indicated were: 1) sharing their genetic risk with their close environment (77‐89%), 2) participating in a medication trial (79‐87%) and 3) making long‐term arrangements, e.g. for retirement and health care (69‐82%). More than half of the respondents (50‐67%) would probably adjust their lifestyle, e.g. exercise more or eat healthier.
Conclusion
Our findings indicate that the majority of respondents wants to be informed about their genetic risk for AD and wants to make this decision themselves. The main reason for interest in testing is contributing to scientific research. Future studies should examine the best way to disclose genetic risk for AD by informing participants carefully and closely looking at the possible impact, especially in the context of future individualized risk profiling.
Abstract
Background
Interest in Apolipoprotein E (ApoE) genetic testing for Alzheimer’s disease dementia (AD) is increasing. Even though ApoE‐status is more often being disclosed to cognitively ...normal adults in clinical trials and services like 23andMe are growing, disclosure in the context of individualized risk profiling is not yet common practice. Our objective was to examine attitudes towards genetic susceptibility testing for AD in a sample of Dutch cognitively normal adults.
Method
An online survey was completed by 428 cognitively normal respondents (response rate 29%) between the age of 50 and 75 years from the Dutch Brain Research Registry (Hersenonderzoek.nl). The survey assessed interest in participating in research studies about genetic testing and disclosure, perceptions of its reasons and possible impact and degree of control respondents want in deciding to test their genetic risk (Control Preferences Scale). Furthermore, we randomly presented three fictional scenarios to assess interest in genetic risk disclosure for different risks of AD (10, 30 and 50%).
Result
The majority of respondents was interested in genetic risk disclosure (80%) and preferred to decide themselves whether to receive their genetic risk (73%) rather than leaving this decision to a health care professional. The most commonly endorsed reason for testing was contributing to scientific research (94%). When presented with specific scenarios, most respondents were still interested in their genetic risk, regardless of the presented risk (73‐79%). The three most important consequences indicated were: 1) sharing their genetic risk with their close environment (77‐89%), 2) participating in a medication trial (79‐87%) and 3) making long‐term arrangements, e.g. for retirement and health care (69‐82%). More than half of the respondents (50‐67%) would probably adjust their lifestyle, e.g. exercise more or eat healthier.
Conclusion
Our findings indicate that the majority of respondents wants to be informed about their genetic risk for AD and wants to make this decision themselves. The main reason for interest in testing is contributing to scientific research. Future studies should examine the best way to disclose genetic risk for AD by informing participants carefully and closely looking at the possible impact, especially in the context of future individualized risk profiling.
Abstract
Background
The goal of this study is to assess neuropsychological and radiological characteristics according to the ATN scheme in the EPAD Longitudinal Cohort Study (EPAD‐LCS) after ...establishing data‐driven cut‐offs for classification.
Method
ATN cut‐off values were determined in a deeply phenotyped cohort of 500 nondemented elderly individuals. Amyloid and p‐tau in the cerebrospinal fluid were quantified with Roche Elecsys assays. Hippocampal volume was calculated using LEAP pipeline. The intersection poin of two‐component Gaussian mixture models was used to establish cut‐off values for CSF amyloid ß42 (A) and p‐tau (T). Age‐adjusted w‐scores were used to establish a cut‐off value for neurodegeneration (N). Only subjects classified as healthy controls (A‐T‐N‐) or in the Alzheimer spectrum (A+T‐N‐, A+T+N, A+T+N+) were included. Multinomial regression was performed to test whether significant differences among the ATN groups could be detected with the EPAD Neuropsychological Examination (ENE) after correcting for age, sex, years of education, and site of data collection.
Result
Out of the initial sample of 500 study participants, n=38 did not fulfil EPAD inclusion criteria, n=34 did not have CSF or MRI biomarkers, and n=49 were not either healthy controls or in the Alzheimer spectrum and were thus excluded. Cut‐offs were 1025 pg/mL for CSF amyloid ß1,42 (A), 24 pg/mL for CSF p‐tau (T), and age‐adjusted hippocampal volume w‐score below ‐2 standard deviations for neurodegeneration (N). Out of the n=376 sample, 229 individuals were classified as healthy controls (A‐T‐N‐), 102 as showing only amyloid pathology (A+T‐N‐), 45 showing amyloid and tau pathologies (A+T+N‐), and 3 A+T+N+ were eliminated Table 1. The ENE battery distinguished healthy controls (A‐T‐N‐) from individuals with preclinical AD (A+T+N‐), and individuals with Alzheimer pathological changes (A+T‐N‐) from individuals with preclinical AD (A+T+N‐).
Conclusion
We proposed a data‐driven framework of cut‐offs for classifying preclinical AD patients in the ATN scheme. The ENE battery scores were in line with the expected cognitive decline in the AD spectrum and increasing vascular burden was shown with progression along the AD spectrum. Potential applications include the selection of patients for secondary prevention trials, preclinical disease modelling and monitoring responses to disease‐modifying therapies.
Background
The goal of this study is to assess neuropsychological and radiological characteristics according to the ATN scheme in the EPAD Longitudinal Cohort Study (EPAD‐LCS) after establishing ...data‐driven cut‐offs for classification.
Method
ATN cut‐off values were determined in a deeply phenotyped cohort of 500 nondemented elderly individuals. Amyloid and p‐tau in the cerebrospinal fluid were quantified with Roche Elecsys assays. Hippocampal volume was calculated using LEAP pipeline. The intersection poin of two‐component Gaussian mixture models was used to establish cut‐off values for CSF amyloid ß42 (A) and p‐tau (T). Age‐adjusted w‐scores were used to establish a cut‐off value for neurodegeneration (N). Only subjects classified as healthy controls (A‐T‐N‐) or in the Alzheimer spectrum (A+T‐N‐, A+T+N, A+T+N+) were included. Multinomial regression was performed to test whether significant differences among the ATN groups could be detected with the EPAD Neuropsychological Examination (ENE) after correcting for age, sex, years of education, and site of data collection.
Result
Out of the initial sample of 500 study participants, n=38 did not fulfil EPAD inclusion criteria, n=34 did not have CSF or MRI biomarkers, and n=49 were not either healthy controls or in the Alzheimer spectrum and were thus excluded. Cut‐offs were 1025 pg/mL for CSF amyloid ß1,42 (A), 24 pg/mL for CSF p‐tau (T), and age‐adjusted hippocampal volume w‐score below ‐2 standard deviations for neurodegeneration (N). Out of the n=376 sample, 229 individuals were classified as healthy controls (A‐T‐N‐), 102 as showing only amyloid pathology (A+T‐N‐), 45 showing amyloid and tau pathologies (A+T+N‐), and 3 A+T+N+ were eliminated Table 1. The ENE battery distinguished healthy controls (A‐T‐N‐) from individuals with preclinical AD (A+T+N‐), and individuals with Alzheimer pathological changes (A+T‐N‐) from individuals with preclinical AD (A+T+N‐).
Conclusion
We proposed a data‐driven framework of cut‐offs for classifying preclinical AD patients in the ATN scheme. The ENE battery scores were in line with the expected cognitive decline in the AD spectrum and increasing vascular burden was shown with progression along the AD spectrum. Potential applications include the selection of patients for secondary prevention trials, preclinical disease modelling and monitoring responses to disease‐modifying therapies.
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