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1.  Perceptions of Familial Risk in those Seeking a Genetic Risk Assessment for Alzheimer’s Disease 
Journal of genetic counseling  2008;18(2):130-136.
Perceived risk is a complex concept that influences the genetic counseling process and can affect client coping and behavior. Although the association between family history and risk perception is well recognized in the literature, no studies have explored this relationship specifically in those seeking genetic susceptibility testing for a common chronic condition. REVEAL is a randomized trial assessing the impact of APOE disclosure and genetic risk assessment for Alzheimer’s disease (AD). Using baseline REVEAL data, we hypothesized that there would be a significant association between the degree of AD family history and risk perception of AD, and that this relationship would be stronger in those who believed that genetics is a very important AD risk factor. In our sample of 293 participants, we found that a higher self-perceived risk of AD was associated with strength of family history of AD (p<0.001), belief in genetics as an important AD risk factor (p<0.001), being female (p<0.001) and being Caucasian (p=0.02). These results are the first to demonstrate the association between family history and risk perception in persons volunteering for genetic susceptibility testing for a common complex disease.
PMCID: PMC2919070  PMID: 18949541
Risk perception; Alzheimer’s disease; APOE; Genetic susceptibility testing; Risk assessment
2.  Disclosure of APOE Genotype for Risk of Alzheimer's Disease 
The New England journal of medicine  2009;361(3):245-254.
The apolipoprotein E (APOE) genotype provides information on the risk of Alzheimer's disease, but the genotyping of patients and their family members has been discouraged. We examined the effect of genotype disclosure in a prospective, randomized, controlled trial.
We randomly assigned 162 asymptomatic adults who had a parent with Alzheimer's disease to receive the results of their own APOE genotyping (disclosure group) or not to receive such results (nondisclosure group). We measured symptoms of anxiety, depression, and test-related distress 6 weeks, 6 months, and 1 year after disclosure or nondisclosure.
There were no significant differences between the two groups in changes in time-averaged measures of anxiety (4.5 in the disclosure group and 4.4 in the nondisclosure group, P = 0.84), depression (8.8 and 8.7, respectively; P = 0.98), or test-related distress (6.9 and 7.5, respectively; P=0.61). Secondary comparisons between the non-disclosure group and a disclosure subgroup of subjects carrying the APOE ε4 allele (which is associated with increased risk) also revealed no significant differences. However, the ε4-negative subgroup had a significantly lower level of test-related distress than did the ε4-positive subgroup (P=0.01). Subjects with clinically meaningful changes in psychological outcomes were distributed evenly among the nondisclosure group and the ε4-positive and ε4-negative subgroups. Baseline scores for anxiety and depression were strongly associated with post-disclosure scores of these measures (P<0.001 for both comparisons).
The disclosure of APOE genotyping results to adult children of patients with Alzheimer's disease did not result in significant short-term psychological risks. Test-related distress was reduced among those who learned that they were APOE ε4–negative. Persons with high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure. ( number, NCT00571025.)
PMCID: PMC2778270  PMID: 19605829
3.  The role of disease perceptions and results sharing in psychological adaptation after genetic susceptibility testing: the REVEAL Study 
This study evaluates the extent to which psychological adaptation (validated measures of depressive symptoms, anxiety, and test-specific distress) after genetic susceptibility testing is influenced by changes in beliefs about Alzheimer's disease (AD) and sharing of test results with others. Adult children of AD patients (N=269) from a randomized clinical trial involving genetic testing for apolipoprotein E (APOE) provided information before, as well as 6 weeks and 12 months after results disclosure. The levels of adaptation varied highly among participants at 12-month assessment. Participants who learned that they were ε4 negative (lower risk) had a reduction in perceived risk and concern about developing AD compared with those who learned that they were ε4 positive. Those who received results through an extended educational protocol (three in-person visits) had a larger decline in AD concern than those in a condensed protocol (educational brochure and two in-person visits). Increase in AD concern 6 weeks after disclosure was associated with increase in depression scores (b=0.20, P<0.01) and anxiety levels (b=0.20, P<0.01), and higher distress associated with AD genetic testing (b=0.18, P=0.02) 1 year after testing. Increase in perceived risk (b=0.16, P=0.04) was also associated with higher AD genetic testing distress. Sharing the test results with health professionals and friends (but not family) was associated with decrease in depression (b= −0.11, P=0.05) and anxiety levels (b= −0.16, P<0.01), respectively after a year. Enhancing discussion with regard to risks and concerns about AD during pretesting counseling and obtaining support through sharing the results after testing may help facilitate test recipients' long-term psychological adaptation.
PMCID: PMC2988099  PMID: 20664629
susceptibility genetic testing; AD; APOE; results disclosure; communication; risk perceptions
4.  The role of disease perceptions and results sharing in psychological adaptation after genetic susceptibility testing: the REVEAL Study 
European Journal of Human Genetics  2010;18(12):1296-1301.
This study evaluates the extent to which psychological adaptation (validated measures of depressive symptoms, anxiety, and test-specific distress) after genetic susceptibility testing is influenced by changes in beliefs about Alzheimer's disease (AD) and sharing of test results with others. Adult children of AD patients (N=269) from a randomized clinical trial involving genetic testing for apolipoprotein E (APOE) provided information before, as well as 6 weeks and 12 months after results disclosure. The levels of adaptation varied highly among participants at 12-month assessment. Participants who learned that they were ɛ4 negative (lower risk) had a reduction in perceived risk and concern about developing AD compared with those who learned that they were ɛ4 positive. Those who received results through an extended educational protocol (three in-person visits) had a larger decline in AD concern than those in a condensed protocol (educational brochure and two in-person visits). Increase in AD concern 6 weeks after disclosure was associated with increase in depression scores (b=0.20, P<0.01) and anxiety levels (b=0.20, P<0.01), and higher distress associated with AD genetic testing (b=0.18, P=0.02) 1 year after testing. Increase in perceived risk (b=0.16, P=0.04) was also associated with higher AD genetic testing distress. Sharing the test results with health professionals and friends (but not family) was associated with decrease in depression (b = −0.11, P = 0.05) and anxiety levels (b=−0.16, P<0.01), respectively after a year. Enhancing discussion with regard to risks and concerns about AD during pretesting counseling and obtaining support through sharing the results after testing may help facilitate test recipients' long-term psychological adaptation.
PMCID: PMC2988099  PMID: 20664629
susceptibility genetic testing; AD; APOE; results disclosure; communication; risk perceptions
5.  BRCA1/2 Test Results Impact Risk Management Attitudes, Intentions and Uptake 
Women who receive positive or uninformative BRCA1/2 test results face a number of decisions about how to manage their cancer risk. The purpose of this study was to prospectively examine the effect of receiving a positive vs. uninformative BRCA1/2 genetic test result on the perceived pros and cons of risk-reducing mastectomy (RRM) and risk-reducing oophorectomy (RRO) and breast cancer screening. We further examined how perceived pros and cons of surgery predict intention for and uptake of surgery.
308 women (146 positive, 162 uninformative) were included in RRM and breast cancer screening analyses. 276 women were included in RRO analyses. Participants completed questionnaires at pre-disclosure baseline and 1-, 6-and 12-months post-disclosure. We used linear multiple regression to assess whether test result contributed to change in pros and cons and logistic regression to predict intentions and surgery uptake.
Receipt of a positive BRCA1/2 test result predicted stronger pros for RRM and RRO (Ps < .001), but not perceived cons of RRM and RRO. Pros of surgery predicted RRM and RRO intentions in carriers and RRO intentions in uninformatives. Cons predicted RRM intentions in carriers. Pros and cons predicted carriers’ RRO uptake in the year after testing (Ps < .001).
Receipt of BRCA1/2 mutation test results impacts how carriers see the positive aspects of RRO and RRM and their surgical intentions. Both the positive and negative aspects predict uptake of surgery.
PMCID: PMC3039480  PMID: 20383578
breast cancer; BRCA mutation; prophylactic mastectomy; prophylactic oophorectomy; screening; pros; cons
6.  “I know what you told me, but this is what I think:” Perceived risk of Alzheimer disease among individuals who accurately recall their genetics-based risk estimate 
This study evaluates the Alzheimer disease risk perceptions of individuals who accurately recall their genetics-based Alzheimer disease risk assessment.
Two hundred forty-six unaffected first-degree relatives of patients with Alzheimer disease were enrolled in a multisite randomized controlled trial examining the effects of communicating APOE genotype and lifetime Alzheimer disease risk information.
Among the 158 participants who accurately recalled their Alzheimer disease risk assessment 6 weeks after risk disclosure, 75 (47.5%) believed their Alzheimer disease risk was more than 5% points different from the Alzheimer disease risk estimate they were given. Within this subgroup, 69.3% believed that their Alzheimer disease risk was higher than what they were told (discordant high), whereas 30.7% believed that their Alzheimer disease risk was lower (discordant low). Participants with a higher baseline risk perception were more likely to have a discordant-high risk perception (P < 0.05). Participants in the discordant-low group were more likely to be APOE ε4 positive (P < 0.05) and to score higher on an Alzheimer disease controllability scale (P < 0.05).
Our results indicate that even among individuals who accurately recall their Alzheimer disease risk assessment, many people do not take communicated risk estimates at face value. Further exploration of this clinically relevant response to risk information is warranted.
PMCID: PMC2921681  PMID: 20139767
risk recall; risk perception; Alzheimer disease; genetic susceptibility testing
7.  Genetic Testing for Alzheimer’s Disease and its Impact on Insurance Purchasing Behavior 
Health affairs (Project Hope)  2005;24(2):483-490.
New genetic tests for adult-onset diseases raise concerns about possible adverse selection in insurance markets. To test for this behavior, 148 cognitively normal individuals participating in a randomized clinical trial of genetic testing for Alzheimer’s disease (AD) were tracked for one year after risk assessment and APOE genotype disclosure. Although no significant differences were found in health, life, or disability insurance purchases, those who tested positive were 5.76 times more likely to have altered their long-term care insurance than individuals who did not receive APOE genotype disclosure. If genetic testing for AD risk assessment becomes common, it could trigger adverse selection in the long-term care insurance market.
PMCID: PMC1761120  PMID: 15757934
8.  Using Alzheimer’s disease as a model for genetic risk disclosure: Implications for personal genomics 
Clinical Genetics  2011;80(5):407-414.
Susceptibility testing for common, complex adult-onset diseases is projected to become more commonplace as the rapid pace of genomic discoveries continues, and evidence regarding the potential benefits and harms of such testing is needed to inform medical practice and health policy. Apolipoprotein E (APOE) testing for risk of Alzheimer’s disease (AD) provides a paradigm in which to examine the process and impact of disclosing genetic susceptibility for a prevalent, severe and incurable neurological condition. This review summarizes findings from a series of multi-site randomized clinical trials examining psychological and behavioral responses to various methods of genetic risk assessment for AD using APOE disclosure. We discuss challenges involved in disease risk estimation and communication and the extent to which participants comprehend and perceive utility in their genetic risk information. Findings on the psychological impact of test results are presented (e.g., distress), along with data on participants’ health behavior and insurance purchasing responses (e.g., long term care). Finally, we report comparisons of the safety and efficacy of intensive genetic counseling approaches to briefer models that emphasize streamlined processes and educational materials. The implications of these findings for the emerging field of personal genomics are discussed, with directions identified for future research.
PMCID: PMC3191239  PMID: 21696382
9.  Explaining Behavior Change after Genetic Testing: The Problem of Collinearity between Test Results and Risk Estimates 
Genetic testing  2008;12(3):381-386.
This paper explores whether and how the behavioral impact of genotype disclosure can be disentangled from the impact of numerical risk estimates generated by genetic tests. Secondary data analyses are presented from a randomized controlled trial of 162 first-degree relatives of Alzheimer’s disease (AD) patients. Each participant received a lifetime risk estimate of AD. Control group estimates were based on age, gender, family history, and assumed ε4-negative apolipoprotein E (APOE) genotype; intervention group estimates were based upon the first three variables plus true APOE genotype, which was also disclosed. AD-specific self-reported behavior change (diet, exercise, and medication use) was assessed at 12 months. Behavior change was significantly more likely with increasing risk estimates, and also more likely, but not significantly so, in ε4-positive intervention group participants (53% changed behavior) than in control group participants (31%). Intervention group participants receiving ε4-negative genotype feedback (24% changed behavior) and control group participants had similar rates of behavior change and risk estimates, the latter allowing assessment of the independent effects of genotype disclosure. However, collinearity between risk estimates and ε4-positive genotypes, which engender high-risk estimates, prevented assessment of the independent effect of the disclosure of an ε4 genotype. Novel study designs are proposed to determine whether genotype disclosure has an impact upon behavior beyond that of numerical risk estimates.
PMCID: PMC2925186  PMID: 18666860
10.  Health Behavior Changes After Genetic Risk Assessment for Alzheimer Disease: The REVEAL Study 
Risk information for Alzheimer disease (AD) may be communicated through susceptibility gene disclosure, even though this is not currently in clinical use. The REVEAL Study is the first randomized clinical trial of risk assessment for AD with apolipoprotein E (APOE) genotype and numerical risk estimate disclosure. We examined whether APOE genotype and numerical risk disclosure to asymptomatic individuals at high risk for AD alters health behaviors. One hundred sixty-two participants were randomized to either intervention (APOE disclosure) or control (no genotype disclosure) groups. Subjects in both groups received numerical lifetime risk estimates of future AD development based on sex and family history of AD. The intervention group received their APOE genotype. Subjects were informed that no proven preventive measures for AD existed and given an information sheet on preventative therapies under investigation. Participants who learned they were ε4 positive were significantly more likely than ε4 negative participants to report AD-specific health behavior change 1 year after disclosure (adjusted odds ratio: 2.73; 95% confidence interval: 1.14, 6.54; P = 0.02). Post hoc analyses revealed similar significant associations between numerical lifetime risk estimates and self-report of AD-specific health behavior change. Despite lack of preventive measures for AD, knowledge of APOE genotype, numerical lifetime risk, or both, influences health behavior.
PMCID: PMC2483341  PMID: 18317253
Alzheimer; memory; health behavior change; risk assessment
11.  Comparing test-specific distress of susceptibility versus deterministic genetic testing for Alzheimer’s disease 
Genetic risk for Alzheimer’s disease (AD) may be conferred by the susceptibility polymorphism apolipoprotein E (APOE), where the ε4 allele increases the risk of developing late-onset Alzheimer’s disease but is not a definitive predictor of the disease, or by autosomal dominant mutations (e.g., the presenilins), which almost inevitably result in early-onset familial Alzheimer’s disease. The purpose of this study was to compare the psychological impact of using these two different types of genetic information to disclose genetic risk for AD to family members of affected patients.
Data were compared from two separate protocols. The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) Study is a randomized, multi-site clinical trial that evaluated the impact of susceptibility testing for Alzheimer’s disease with APOE in 101 adult children of Alzheimer’s disease patients. A separate study, conducted at the University of Washington, assessed the impact of deterministic genetic testing by disclosing presenilin-1, presenilin-2, or TAU genotype to 22 individuals at risk for familial Alzheimer’s disease or frontotemporal dementia. In both protocols, participants received genetic counseling and completed the Impact of Event Scale (IES), a measure of test-specific distress. Scores were analyzed at the time point closest to one year post-disclosure at which IES data were available. The role of genetic test result (positive vs. negative) and type of genetic testing (deterministic vs. susceptibility) in predicting log-transformed IES scores was assessed with linear regression, controlling for age, gender, and time from disclosure.
Subjects from the REVEAL Study who learned that they were positive for the susceptibility gene APOE ε4+ experienced similar, low levels of test-specific distress compared to those who received positive results of deterministic testing in the University of Washington study (p= 0.78). APOE ε4+ individuals in the susceptibility protocol experienced more test-specific distress than those who tested ε4− in the same study (p= 0.04); however, among those receiving deterministic test disclosure, the subjects who received positive results did not experience significantly higher levels of distress when compared to those who received negative results (p= 0.88).
The findings of this preliminary study, with limited sample size, suggest that the test-related distress experienced by those receiving positive results for a deterministic mutation is similar to the distress experienced by those receiving positive results from genetic susceptibility testing, and that the majority of participants receiving genotype disclosure do not experience clinically significant distress as indicated by IES scores one year after learning of their test results.
PMCID: PMC2610442  PMID: 19012865
genetic susceptibility testing; deterministic testing; Alzheimer’s disease; APOE; genetic counseling
12.  Disclosing the disclosure: Factors associated with communicating the results of genetic susceptibility testing for Alzheimer’s disease 
Journal of health communication  2009;14(8):768-784.
This study explored the extent to which recipients of genetic susceptibility testing for Alzheimer’s disease (AD) communicated their results to others. It also examined demographic characteristics, along with beliefs about AD, associated with such communication. Participants (N = 271) in a randomized clinical trial involving genetic testing for Apolipoprotein E (APOE) gene variants among first-degree relatives of AD patients reported their communication behaviors 6 weeks after the results disclosure. Information on beliefs about AD and genetic testing was collected at baseline. Eighty-two percent of participants receiving APOE genotype information shared their results with someone. Specifically, 64% shared with family members, 51% with spouse or significant others, 35% with friends, and 12% with health care professionals. Greater AD treatment optimism was associated with communicating results to family (OR=1.43), spouse (OR=1.62), friends (OR =1.81), and health care professionals (OR=2.20). Lower perceived risk (OR=0.98) and higher perceived importance of genetics in the development of AD (OR=1.93) were associated with results communication in general. Lower perceived drawbacks of AD genetic testing was associated with results communication to friends (OR=0.65). Beliefs about AD risks and causes, genetic testing, and development of treatments may partly determine the interpersonal communication patterns of genetic susceptibility test results.
PMCID: PMC2801901  PMID: 20029710
Susceptibility genetic testing; Alzheimer’s disease; APOE communication; disclosure
13.  Distress among Women Receiving Uninformative BRCA1/2 Results: 12-month Outcomes 
Psycho-oncology  2009;18(10):1088-1096.
Few data are available regarding the long-term psychological impact of uninformative BRCA1/2 test results. This study examines change in distress from pretesting to 12-months post-disclosure, with medical, family history, and psychological variables, such as pretesting perceived risk of carrying a deleterious mutation prior to testing and primary and secondary appraisals, as predictors.
209 women with uninformative BRCA1/2 test results completed questionnaires at pretesting and 1-, 6-, and 12-months post-disclosure, including measures of anxiety and depression, cancer-specific and genetic testing distress. We used a mixed models approach to predict change in post-disclosure distress.
Distress declined from pretesting to 1-month post-disclosure, but remained stable thereafter. Primary appraisals predicted all types of distress at 1-month post-disclosure. Primary and secondary appraisals predicted genetic testing distress at 1-month as well as change over time. Receiving a variant of uncertain clinical significance (VUCS) and entering testing with a high expectation for carrying a deleterious mutation predicted genetic testing distress that persisted through the year after testing.
As a whole, women receiving uninformative BRCA1/2 test results are a resilient group. For some women, distress experienced in the month after testing does not dissipate. Variables, such as heightened pretesting perceived risk and cognitive appraisals, predict greater likelihood for sustained distress in this group and could be amenable to intervention.
PMCID: PMC3503506  PMID: 19214961
14.  Behaviour change in clients of health centre‐based voluntary HIV counselling and testing services in Kenya 
Sexually Transmitted Infections  2007;83(7):541-546.
To explore behaviour change, baseline risk behaviour, perception of risk, HIV disclosure and life events in health centre‐based voluntary counselling and testing (VCT) clients.
Design and setting
Single‐arm prospective cohort with before–after design at three (one urban and two rural) government health centres in Kenya; study duration 2 years, 1999–2001.
Consecutive eligible adult clients.
Main outcome measures
Numbers of sexual partners, partner type, condom use, reported symptoms of sexually transmitted infection, HIV disclosure and life events.
High rates of enrolment and follow‐up provided a demographically representative sample of 401 clients with mean time to follow‐up of 7.5 months. Baseline indicators showed that clients were at higher risk than the general population, but reported a poor perception of risk. Clients with multiple partners showed a significant reduction of sexual partners at follow‐up (16% to 6%; p<0.001), and numbers reporting symptoms of sexually transmitted infection decreased significantly also (from 40% to 15%; p<0.001). Condom use improved from a low baseline. Low rates of disclosure (55%) were reported by HIV‐positive clients. Overall, no changes in rates of life events were seen.
This study suggests that significant prevention gains can be recorded in clients receiving health centre‐based VCT services in Africa. Prevention issues should be considered when refining counselling and testing policies for expanding treatment programmes.
PMCID: PMC2598642  PMID: 17991688
15.  Willingness to Pay for Genetic Testing for Alzheimer's Disease: A Measure of Personal Utility 
Background: The increased availability of genetic tests for common, complex diseases, such as Alzheimer's disease (AD), raises questions about what people are willing to pay for these services. Methods: We studied willingness-to-pay for genetic testing in a study of AD risk assessment that included APOE genotype disclosure among 276 first-degree relatives of persons with AD. Results: Seventy-one percent reported that they would ask for such testing from their doctor if it were covered by health insurance, and 60% would ask for it even if it required self-pay. Forty-one percent were willing to pay more than $100 for testing, and more than half would have been willing to pay for the test out of pocket. Participants who learned that they were APOE ɛ4 positive and those who had higher education were less likely to want testing if covered by insurance, possibly to avoid discrimination. Conclusion: This is the first report to examine willingness to pay for susceptibility genetic testing in a sample of participants who had actually undergone such testing. These findings reveal that some participants find valuable personal utility in genetic risk information even when such information does not have proven clinical utility.
PMCID: PMC3241735  PMID: 21749214
16.  APOE ε2 and ε4 influence the susceptibility for Alzheimer's disease but not other dementias 
Apolipoprotein E (APOE) genotype was determined in a population of patients with dementia, including 735 patients with Alzheimer's disease (AD), 75 with Frontotemporal Lobar Degeneration (FTLD), 97 with Vascular Dementia (VaD) and 40 with Lewy Body Dementia (LBD), as well as in 506 age- and gender-matched controls (CON). APOE ε2 allele frequency was lower in patients with AD (2.8%) than in CON (6.4%, P≤0.001, OR: 0.41). Similar results were obtained comparing AD with FTLD (6.7%, P≤0.01, OR: 0.37), at difference from VaD (5.6%, P>0.05) or LBD (5.0%, P>0.05). The frequency of the APOE ε4 allele was increased in patients with AD (25.1%) as compared with CON (8.2%, P≤0.001, OR: 4.24), FTLD (11.3%, P≤0.001, OR: 2.67), VaD (11.8%, P≤0.001, OR: 3.02), or LBD (13.8%, P=0.048, OR: 2.07). The frequency of the ε4/ε4 genotype was increased in AD patients compared with controls (6.3 versus 0.8%, P≤0.001, OR: 8.38). The presence of the ε2 allele is a protective factor for AD, whereas the ε4 allele acts as a risk factor for the disease. Both alleles do not influence the susceptibility to FTLD, LBD and VaD.
PMCID: PMC3076771  PMID: 21537391
Apolipoprotein E (APOE); Alzheimer's disease (AD); Frontotemporal Lobar Degeneraton (FTLD); Vascular dementia (VaD); Lewy body dementia (LBD); risk factor
17.  A behavioral task predicts conversion to mild cognitive impairment and Alzheimer’s disease 
Currently, we cannot reliably differentiate individuals at risk of cognitive decline, e.g., Mild Cognitive Impairment (MCI), Alzheimer’s disease (AD) from those individuals who are not at risk.
Thirty-two subjects with MCI and 60 control (CON) subjects were tested on an innovative, sensitive behavioral assay, the Visual Paired Comparison (VPC) task using infrared eyetracking. Subjects were followed for three years after testing.
Scores on the VPC task predicted, up to three years prior to a change in clinical diagnosis, those MCI patients who would and those who would not progress to AD, and CON subjects who would and would not progress to MCI.
The present findings show that the VPC task can predict impending cognitive decline. To our knowledge, this is the first behavioral task that can identify CON subjects who will develop MCI or MCI subjects who will develop AD within the next few years.
PMCID: PMC3670591  PMID: 23271330
memory; mild cognitive impairment; Alzheimer’s disease; prognosis; memory impairment; cognitive impairment
18.  In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS 
PLoS ONE  2012;7(6):e38013.
Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer’s disease and has been implicated in the risk for other neurological disorders. The three common ApoE isoforms (ApoE2, E3, and E4) each differ by a single amino acid, with ApoE4 increasing and ApoE2 decreasing the risk of Alzheimer’s disease (AD). Both the isoform and amount of ApoE in the brain modulate AD pathology by altering the extent of amyloid beta (Aβ) peptide deposition. Therefore, quantifying ApoE isoform production and clearance rates may advance our understanding of the role of ApoE in health and disease. To measure the kinetics of ApoE in the central nervous system (CNS), we applied in vivo stable isotope labeling to quantify the fractional turnover rates of ApoE isoforms in 18 cognitively-normal adults and in ApoE3 and ApoE4 targeted-replacement mice. No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain. However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery. We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis.
PMCID: PMC3366983  PMID: 22675504
19.  Longitudinal changes in medial temporal cortical thickness in normal subjects with the APOE-4 polymorphism 
NeuroImage  2010;53(1):37-43.
People with the apolipoprotein-Eε4 (APOE-4) genetic risk for Alzheimer’s disease show morphologic differences in medial temporal lobe regions when compared to non-carriers of the allele. Using a high-resolution MRI and cortical unfolding approach, our aim was to determine the rate of cortical thinning among medial temporal lobe subregions over the course of 2 years. We hypothesized that APOE-4 genetic risk would contribute to longitudinal cortical thickness change in the subiculum and entorhinal cortex, regions preferentially susceptible to Alzheimer’s disease related pathology. Thirty-two cognitively intact subjects, mean age 61 years, 16 APOE-4 carriers, 16 non-carriers, underwent baseline and follow-up MRI scans. Over this relatively brief interval, we found significantly greater cortical thinning in the subiculum and entorhinal cortex of APOE-4 carriers when compared to non-carriers of the allele. Average cortical thinning across all medial temporal lobe subregions combined was also significantly greater for APOE-4 carriers. This finding is consistent with the hypothesis that carrying the APOE-4 allele renders subjects at a higher risk for developing Alzheimer’s disease.
PMCID: PMC3118546  PMID: 20541611
Alzheimer’s disease; APOE genotype; High-resolution MRI; Medial temporal lobe; Cortical unfolding; Cortical thickness
20.  Cognitive and Emotional Factors Predicting Decisional Conflict among High-Risk Breast Cancer Survivors Who Receive Uninformative BRCA1/2 Results 
To investigate high-risk breast cancer survivors’ risk reduction decision making and decisional conflict after an uninformative BRCA1/2 test.
Prospective, longitudinal study of 182 probands undergoing BRCA1/2 testing, with assessments 1-, 6-, and 12-months post-disclosure.
Primary predictors were health beliefs and emotional responses to testing assessed 1-month post-disclosure. Main outcomes included women’s perception of whether they had made a final risk management decision (decision status) and decisional conflict related to this issue.
There were four patterns of decision making, depending on how long it took women to make a final decision and the stability of their decision status across assessments. Late decision makers and non-decision makers reported the highest decisional conflict; however, substantial numbers of women—even early and intermediate decision makers—reported elevated decisional conflict. Analyses predicting decisional conflict 1- and 12-months post-disclosure found that, after accounting for controls and decision status, health beliefs and emotional factors predicted decisional conflict at different timepoints, with health beliefs more important one month after test disclosure and health beliefs more important one year later.
Many of these women may benefit from decision making assistance.
PMCID: PMC3510002  PMID: 19751083
breast cancer; genetic testing; decisional conflict; decision making; BRCA
21.  BRCA mutation-negative women from hereditary breast and ovarian cancer families: a qualitative study of the BRCA-negative experience 
When women from families with a known BRCA1 or BRCA2 mutation test negative for the family mutation, it is assumed that they will transition their personal cancer risk perception from high to average risk. However, there are scant data regarding the experience of mutation-negative women after genetic testing disclosure, particularly related to the shift of risk perception from assumed mutation-positive to actual mutation-negative. This study was designed to explore cancer risk perception and the experience of being a mutation-negative woman within a known BRCA1 / 2 mutation-positive family.
We employed a qualitative descriptive design and convened a sample of 13 women who contributed in-depth, semi-structured telephone interviews (audio-recorded and transcribed verbatim) and performed qualitative content analysis with NVivo 2.0 software.
Six major content areas emerged from interview data: (i) rationale for initial involvement in the breast imaging study, (ii) rationale for continued participation, (iii) experience of living in a multiple-case family, (iv) risk perception: the personal meaning of mutation-negative status, (v) opinions regarding cancer aetiology and (vi) communication patterns between mutation-negative and mutation-positive family members.
Living in a hereditary breast and ovarian cancer family is a complex experience that affects cognitive, emotional and social functioning. Our findings indicate that mutation-negative women may have unmet psychosocial needs that must be addressed by health-care professionals, particularly in the primary-care setting following genetic disclosure of a potentially reassuring result regarding their lack of the very high cancer risks associated with BRCA1 / 2 mutations.
PMCID: PMC2803025  PMID: 18816319
cancer; genetics; hereditary breast/ovarian cancer; mutation-negative; psychosocial aspects
22.  Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis 
The Journal of Experimental Medicine  2012;209(12):2149-2156.
Anti-ApoE antibody reduces amyloid deposition and enhances the microglial response to Aβ plaques in an Alzheimer’s disease mouse model.
The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid β (Aβ) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with Aβ and facilitates Aβ fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-Aβ antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1ΔE9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble Aβ40 and Aβ42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around Aβ plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in Aβ binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases.
PMCID: PMC3501350  PMID: 23129750
23.  Multilocus genetic profiling to empower drug trials and predict brain atrophy☆ 
NeuroImage : Clinical  2013;2:827-835.
Designers of clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) are actively considering structural and functional neuroimaging, cerebrospinal fluid and genetic biomarkers to reduce the sample sizes needed to detect therapeutic effects. Genetic pre-selection, however, has been limited to Apolipoprotein E (ApoE). Recently discovered polymorphisms in the CLU, CR1 and PICALM genes are also moderate risk factors for AD; each affects lifetime AD risk by ~ 10–20%. Here, we tested the hypothesis that pre-selecting subjects based on these variants along with ApoE genotype would further boost clinical trial power, relative to considering ApoE alone, using an MRI-derived 2-year atrophy rate as our outcome measure. We ranked subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on their cumulative risk from these four genes. We obtained sample size estimates in cohorts enriched in subjects with greater aggregate genetic risk. Enriching for additional genetic biomarkers reduced the required sample sizes by up to 50%, for MCI trials. Thus, AD drug trial enrichment with multiple genotypes may have potential implications for the timeliness, cost, and power of trials.
•ApoE genotype status helps enrich MCI trials, using a structural MRI outcome measure.•CLU, PICALM and CR1 risk genes boost potential MCI trial power beyond ApoE alone.•CLU, PICALM and CR1 show significant, aggregate effects on TBM maps of brain atrophy.
PMCID: PMC3777716  PMID: 24179834
Alzheimer's disease; Neuroimaging; Brain atrophy; Genetics; Genetic risk score; Clinical trial enrichment
24.  Obtaining insurance after DNA diagnostics: a survey among hypertrophic cardiomyopathy mutation carriers 
Hypertrophic cardiomyopathy (HCM) is a common hereditary heart disease associated with increased mortality. Disclosure of DNA test results may have social implications such as low access to insurance. In the Netherlands, insurance companies are restricted in the use of genetic information of their clients by the Medical Examination Act. A cross-sectional survey was used to assess the frequency and type of problems encountered by HCM mutation carriers applying for insurance, and associations with carriers' characteristics. The response rate was 86% (228/264). A total of 66 carriers (29%) applied for insurance of whom 39 reported problems (59%) during an average follow-up of 3 years since the DNA test result. More problems were encountered by carriers with manifest disease (P<0.001) and carriers with symptoms of HCM (P=0.049). Carriers identified after predictive DNA testing less frequently experienced problems (P=0.002). Three carriers without manifest HCM reported problems (5% of applicants). Frequently reported problems were higher premium (72%), grant access to medical records (62%), and complete rejection (33%). In conclusion, HCM mutation carriers frequently encounter problems when applying for insurances, often in the case of manifest disease, but the risk assessment of insurance companies is largely justified. Still, 5% of carriers encounter potentially unjustified problems, indicating the necessity to monitor the application of the existing laws and regulations by insurance companies and to educate counselees on the implications of these laws and regulations.
PMCID: PMC2987186  PMID: 19672285
hypertrophic cardiomyopathy; insurance; genetic testing
25.  Lack of Effect for Decisional Balance as a Brief Motivational Intervention for At-Risk College Drinkers 
Addictive behaviors  2005;30(7):1425-1430.
This study examined the effects of written and in-person decisional balance exercises on measures of risky drinking. College students determined to be at-risk for alcohol-related problems (N = 131) were randomly assigned to an in-person decisional balance (IDB), a written decisional balance (WDB), or an assessment-only control (C) group. IDB participants met with an interventionist for individual 30-minute discussions of the pros and cons of maintaining versus changing their drinking behavior, whereas WDB participants completed written decisional balance exercises. All participants completed alcohol-use assessments at baseline, 2-week posttest, and 6-month follow-up. Process analyses indicated that IDB participants generated more cons of current drinking and more pros of cutting down than WDB participants. Further, the proportion of pros to cons for cutting down predicted IDB but not WDB group drinking change. On the other hand, analyses of covariance indicated no significant differences among the groups on 2-week alcohol consumption, heavy-drinking episodes, alcohol consumption during peak drinking occasions, and alcohol-related problems. This study did not provide support for decisional balance as a stand-alone brief motivational intervention for at-risk college drinkers.
PMCID: PMC2430386  PMID: 16022936
alcohol drinking patterns; alcohol rehabilitation; at-risk populations; college students; alcohol abuse; brief psychotherapy

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