Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials.

BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.

Measuring the Effect of Carers on Patients' Risk of Adverse Healthcare Outcomes Using the Caregiver Network Score.

BACKGROUND: Although caregivers are important in the management of frail, community-dwelling older adults, the influence of different caregiver network types on the risk of adverse healthcare outcomes is unknown. OBJECTIVE: To examine the association between caregiver type and the caregiver network subtest of The Risk Instrument for Screening in the Community (RISC), a five point Likert scale scored from one ("can manage") to five ("absent/liability"). To measure the association between caregiver network scores and the one-year incidence of institutionalisation, hospitalisation and death. DESIGN: Observational cohort study. SETTING AND PARTICIPANTS: Community-dwelling adults, aged >65, attending health centres in Ireland, (n=779). PROCEDURE AND MEASUREMENTS: The caregiver network subtest of the RISC was scored by public health nurses. Caregivers were grouped dichotomously into low-risk (score of one) or high-risk (scores two-five). RESULTS: The majority of patients had a primary caregiver (582/779; 75%), most often their child (200/582; 34%). Caregiver network scores were highest, indicating greatest risk, when patients had no recognised primary caregiver and lowest when only a spouse or child was available. Despite this, patients with a caregiver were significantly more likely to be institutionalised than those where none was required or identified (11.5% versus 6.5%, p=0.047). The highest one-year incidence of adverse outcomes occurred when state provided care was the sole support; the lowest when private care was the sole support. Significantly more patients whose caregiver networks were scored high-risk required institutionalisation than low-risk networks; this association was strongest for perceived difficulty managing medical domain issues, odds ratio (OR) 3.87:(2.22-6.76). Only perceived difficulty managing ADL was significantly associated with death, OR 1.72:(1.06-2.79). There was no association between caregiver network scores and risk of hospitalisation. CONCLUSION: This study operationalizes a simple method to evaluate caregiver networks. Networks consisting of close family (spouse/children) and those reflecting greater socioeconomic privilege (private supports) were associated with lower incidence of adverse outcomes. Caregiver network scores better predicted institutionalisation than hospitalisation or death.

Components of the Risk Instrument for Screening in the Community (RISC) that Correlate with Public Health Nurses' Perception of Risk.

BACKGROUND: Functional decline and frailty are common in community-dwelling older adults, leading to an increased risk of adverse outcomes. OBJECTIVE: To examine the factors that public health nurses perceive to cause risk of three adverse outcomes: institutionalisation, hospitalisation, and death, in older adults, using the Risk Instrument for Screening in the Community (RISC). DESIGN: A quantitative, correlational, descriptive design was used. SETTING AND PARTICIPANTS: A sample of 803 community-dwellers, aged over 65 years receiving regular follow-up by public health nurses. Procedure and Measurements: Public health nurses (n=15) scored the RISC and the Clinical Frailty Scale (CFS) on patients in their caseload. We examined and compared correlations between the severity of concern and ability of the caregiver network to manage these concerns with public health nurses' perception of risk of the three defined adverse outcomes. RESULTS: In total, 782 RISC scores were available. Concern was higher for the medical state domain (686/782,88%) compared with the mental state (306/782,39%) and activities of daily living (595/782,76%) domains. Concern was rated as severe for only a small percentage of patients. Perceived risk of institutionalisation had the strongest correlation with concern over patients mental state,(r=0.53), while risk of hospitalisation,(r=0.53) and death,(r=0.40) correlated most strongly with concern over the medical state. Weaker correlations were found for the other domains and RISC scores. The CFS most strongly correlated with the ADL domain,(r=0.78). CONCLUSION: Although the prevalence of concern was high, it was mostly rated as mild. Perceived risk of institutionalisation correlated most with concern over the ability of caregiver networks to manage patients' mental state, while risk of hospitalisation and death correlated with patients' medical state. The findings suggest the importance of including an assessment of the caregiver network when examining community-dwelling older adults. Validation of the RISC and public health nurses' ratings are now required.

The Community Assessment of Risk Instrument: Investigation of Inter-Rater Reliability of an Instrument Measuring Risk of Adverse Outcomes.

BACKGROUND: Frailty is increasingly common in community dwelling older adults and increases their risk of adverse outcomes. Risk assessment is implicit in the Aged Care Assessment Teams process, but few studies have considered the factors that influence the assessor's decision making or explored the factors that may contribute to their interpretation of risk. OBJECTIVE: to examine the inter-rater reliability of the Community Assessment of Risk Instrument (CARI), which is a new risk assessment instrument. DESIGN: A cohort study was used. SETTING AND PARTICIPANTS: A sample of 50 community dwelling older adults underwent comprehensive geriatric assessment by two raters: a geriatrician and a registered nurse. Procedure and measurements: Each participant was scored for risk by the two raters using the CARI. This instrument ranks risk of three adverse outcomes, namely i) institutionalisation, ii) hospitalisation and iii) death within the next year from a score of 1, which is minimal risk to 5, which is extreme risk. Inter-rater reliability was assessed with Gamma, Spearman correlation and Kappa statistics. Internal consistency was assessed with Cronbach's alpha. RESULTS: There were 30 female (mean age 82.23 years) and 20 male (mean age 81.75 years) participants. Items within domains showed good-excellent agreement. The gamma statistic was >0.77 on 6/7 Mental State items, 14/15 items in the Activities of Daily Living domain. In the Medical domain, 6/9 items had Gamma scores >0.80. The global domain scores correlated well, 0.88, 0.72 and 0.87. Caregiver network scores were 0.71, 0.73 and 0.51 for the three domains. Inter-rater reliability scores for global risk scales were 0.86 (institutionalisation) and 0.78 (death). The gamma statistic for hospitalisation was 0.29, indicative of lower inter-rater reliability. Cronbach's alpha was 0.86 and 0.83 for the Activities of Daily Living domain, 0.51 and 0.42 for the Mental state domain and 0.23 and 0.10 for the Medical state domain. CONCLUSIONS: Overall, the instrument shows good inter-rater reliability. Poor correlations on some items relate to poor communication of clinical data and variable interpretation based on professional background. Lack of internal consistency in the medical condition domain confirms the discrete nature of these variables.

Vitamins B(12), B(6), and folic acid for cognition in older men.

OBJECTIVE: To investigate whether supplementing older men with vitamins B(12), B(6), and folic acid improves cognitive function. METHODS: The investigators recruited 299 community-representative hypertensive men 75 years and older to a randomized, double-blind controlled clinical trial of folic acid, vitamin B(6), and B(12) supplementation vs placebo over 2 years. The primary outcome of interest was the change in the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog). A secondary aim of the study was to determine if supplementation with vitamins decreased the risk of cognitive impairment and dementia over 8 years. RESULTS: The groups were well-balanced for demographic and biochemical parameters. There was no difference in the ADAS-cog change from baseline to 24 months between the placebo (0.8, SD 4.0) and vitamins group (0.7, SD 3.4). The adjusted scores in the treatment groups did not differ over time (placebo 0.2 lower, z = 0.71, p = 0.478). There was a nonsignificant 28% decrease in the risk of cognitive impairment (odds ratio 0.72, 95% confidence interval 0.25-2.09) and dementia (hazard ratio 0.72, 95% confidence interval 0.29-1.78) over 8 years of follow-up. CONCLUSIONS: The daily supplementation of vitamins B(12), B(6), and folic acid does not benefit cognitive function in older men, nor does it reduce the risk of cognitive impairment or dementia. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that vitamin supplementation with daily doses of 500 µg [DOSAGE ERROR CORRECTED] of B(12), 2 mg of folic acid, and 25 mg of B(6) over 2 years does not improve cognitive function in hypertensive men aged 75 and older.

Severe hypoglycaemia and cognitive impairment in older patients with diabetes: the Fremantle Diabetes Study.

AIMS/HYPOTHESIS: The aim was to investigate the relationship between severe hypoglycaemia and cognitive impairment in older patients with diabetes. METHODS: A sample of 302 diabetic patients aged >/=70 years was assessed for dementia or cognitive impairment without dementia in 2001-2002 and a subsample of non-demented patients (n = 205) was followed to assess cognitive decline. A history of severe hypoglycaemia was determined from self-reports, physician assessments and records of health service use for hypoglycaemia (HSH). Prospective HSH was determined up to 2006. Data analysis, including multiple logistic and Cox regression models, was used to determine whether: (1) there were cross-sectional associations between hypoglycaemia and cognitive status, (2) historical hypoglycaemia predicted cognitive decline, and (3) baseline cognitive status predicted subsequent HSH. RESULTS: There were significant cross-sectional associations between both cognitive impairment and dementia and hypoglycaemia. Independent risk factors for future HSH included dementia (hazard ratio 3.00, 95% CI 1.06-8.48) and inability to self-manage medications (hazard ratio 4.17, 95% CI 1.43-12.13). However, there were no significant associations between historical hypoglycaemia, incident HSH and cognitive decline. CONCLUSIONS/INTERPRETATION: Dementia is an important risk factor for hypoglycaemia requiring health service utilisation. We found no evidence that hypoglycaemia contributes to cognitive impairment in older patients with diabetes.

Predictors of cognitive impairment and dementia in older people with diabetes.

AIMS/HYPOTHESIS: Diabetes is associated with an increased risk of dementia but the reasons for this association are unclear because there are many potential mechanisms. We explored the relative contribution of diabetes-related variables as predictors of dementia in older individuals with diabetes. METHODS: Survivors, aged > or =70 or more, were recruited from an existing observational cohort study 7.6 +/- 1.0 years after baseline, when they underwent a comprehensive assessment of diabetes, complications and cardiovascular risk factors. Dementia, probable Alzheimer's disease and cognitive impairment without dementia were diagnosed clinically. Logistic regression modelling determined independent predictors of cognitive diagnoses. RESULTS: Of 302 participants, aged 75.7 +/- 4.6 years, 28 (9.3%) had dementia (16 with probable Alzheimer's disease) and 60 (19.9%) had cognitive impairment without dementia. The major independent longitudinal predictors of dementia were older age (per decade; odds ratio 4.0, 95% CI 1.59-10.10), diabetes duration (for each 5 years; odds ratio 1.69, 95% CI 1.24-2.32), peripheral arterial disease (odds ratio 5.35, 95% CI 2.08-13.72) and exercise (which was protective; odds ratio 0.26, 95% CI 0.09-0.73). For Alzheimer's disease, diabetes duration was an independent predictor in addition to age and diastolic blood pressure. The results of the cross-sectional analyses were similar with respect to diabetes duration and peripheral arterial disease. CONCLUSIONS/INTERPRETATION: Peripheral arterial disease is a strong independent risk factor for dementia in diabetes. After adjustment for a wide range of potential risk factors, diabetes duration remains independently associated with dementia and probable Alzheimer's disease, indicating that factors not measured in this study may be important in the pathogenesis of dementia in diabetes.

Vascular depression in older people with diabetes.

AIMS/HYPOTHESIS: Cerebrovascular disease may be causal or a vulnerability factor in late-onset depression and may explain the high rate of depression in older adults with diabetes. We explored a wide range of potential explanatory variables of depression in a longitudinal study of older diabetic subjects to investigate the vascular depression hypothesis in these patients. METHODS: We recruited 207 subjects with diabetes selected for potential cognitive deficits from an existing observational cohort study (average age 75.7 +/- 4.6 years, 52.2% men) for an assessment of depression using a standardised diagnostic instrument (Cambridge Examination for Mental Disorders of the Elderly -- Revised). All subjects underwent a detailed clinical assessment at baseline and at follow-up (after 7.5 +/- 1.1 years). RESULTS: Major depression was present in 45 subjects (21.7%) and minor depression in ten (4.8%). A positive history of strokes and the presence of peripheral arterial disease were significantly associated with depression at the time of diagnosis. In a subsample of 93 cases who underwent structural neuroimaging, the presence of cerebral infarcts was also significantly associated with depression. Treatment with glucose-lowering therapy, higher serum cholesterol levels and difficulties with activities of daily living at baseline were significant predictors of depression at follow-up. CONCLUSIONS/INTERPRETATION: A history of cerebrovascular disease was strongly associated with depression and cerebrovascular risk factors were significant predictors of depression in older diabetic patients. Our findings are consistent with the hypothesis that the excess risk of depression in older diabetic patients is related to underlying cerebrovascular disease.

Quantitative MR imaging R2 relaxometry in elderly participants reporting memory loss.

BACKGROUND AND PURPOSE: In Alzheimer disease (AD), elevated brain iron concentrations in gray matter suggest a disruption in iron homeostasis, while demyelination processes in white matter increase the water content. Our aim was to assess whether the transverse proton relaxation rate, or R2, an MR imaging parameter affected by changes in brain iron concentration and water content, was different in elderly participants with mild to severe levels of cognitive impairment compared with healthy controls. METHODS: Twelve elderly participants reporting memory problems and 11 healthy volunteers underwent single-spin-echo MR imaging in a 1.5T scanner, with subsequent neuropsychological testing. R2 data were collected from 14 brain regions in cortical and subcortical gray and white matter. Those with memory complaints were separated into 2 further subgroups: MC1 (no objective cognitive impairment) and MC2 (mild to severe objective cognitive impairment). RESULTS: Mean brain R2 values from the 11 controls correlated strongly (r = 0.94, P < .0001) with reference brain iron concentrations for healthy adults. R2 values in the MC1 and MC2 subgroups were significantly higher in the right temporal cortex and significantly lower in the left internal capsule, compared with healthy controls. R2 values in the MC2 subgroup were significantly lower in the left temporal and frontal white matter, compared with healthy controls. CONCLUSIONS: R2 differences between both subgroups and the healthy controls suggest iron has increased in the temporal cortex, and myelin has been lost from several white matter regions in those with memory complaints, consistent with incipient AD pathogenesis and biochemical data.

Neurological soft signs are associated with APOE genotype, age and cognitive performance.

Neurodegeneration is associated with increased frequency of neurological soft signs (NSS). We designed the present study to investigate the association between NSS and subjective memory complaints, cognitive function and apolipoprotein E genotype in a community-dwelling sample of volunteers participating in an ongoing longitudinal program investigating predictors of cognitive decline. NSS were found to be associated with apolipoprotein E (APOE) epsilon4 genotype (p = 0.015), age (p = 0.012) and poor cognitive performance, as assessed by the Mini Mental State Examination (p = 0.053). There was no significant difference between subjects with and without memory complaints in relation to the frequency of NSS (p = 0.130). The association with age and the APOE epsilon4 genotype suggests that the systematic investigation of NSS may contribute to identify subjects at risk of clinically significant cognitive decline in later life.

Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4.

There is currently intense controversy regarding the use of hormone replacement therapy (HRT) in postmenopausal women, in relation to its therapeutic efficacy in Alzheimer's disease (AD). It has been suggested that the benefits of HRT may be modified by apolipoprotein E (APOE) genotype (the major genetic risk factor for AD). Here we report the findings of the first study designed to systematically explore the interaction of (a) oestrogen replacement therapy (ERT) and (b) possession of an epsilon4 allele of APOE on specific elements of episodic learning and memory that are commonly used indices of age-related cognitive decline. This data represents a cross-sectional analysis of the interaction of ERT and APOE genotype on learning and memory in a cohort of 181 healthy postmenopausal women [ERT users (n = 101, mean age 65.40 +/- 6.34); ERT non-users (n = 80, mean age 67.03 +/- 6.80)] residing in Perth, Western Australia. The highest level of learning (trials 2-5; P < 0.05) and memory (e.g. total number of items recalled; P < 0.05) performance was observed in women taking ERT who were not carriers of the APOE epsilon4 allele. APOEepsilon4 carriers receiving ERT performed no better on episodic memory testing than APOE epsilon4 carriers who were not receiving ERT. These cognitive differences related to genetic profile, were noted on both recall and recognition (P = 0.005) tests of memory. The findings have significance for evaluating whether and when ERT may be clinically indicated. Specifically, ERT may benefit the cognitive functioning of women not carrying the APOE epsilon4 allele.

Relationship between testosterone, sex hormone binding globulin and plasma amyloid beta peptide 40 in older men with subjective memory loss or dementia.

In a group of 28 older men with either subjective memory loss or dementia, serum total testosterone and sex hormone binding globulin (SHBG) correlated inversely with plasma levels of amyloid beta peptide 40 (Abeta40, r=-0.5, P=0.01 and r=-0.4, P=0.04, respectively). Calculated free testosterone was also inversely correlated (r=-0.4, P=0.03), and all three relationships remained statistically significant after allowing for age. A similar but non-significant trend was seen with dehydroepiandrosterone sulphate (DHEAS), and neither luteinising hormone (LH) nor estradiol correlated with Abeta40. These data demonstrate that lower androgen levels are associated with increased plasma Abeta40 in older men with memory loss or dementia, suggesting that subclinical androgen deficiency enhances the expression of Alzheimer's disease-related peptides in vivo. An inverse correlation exists between SHBG and Abeta40, warranting further investigation.

APOE-epsilon4 and APOE -491A polymorphisms in individuals with subjective memory loss.

The accurate clinical diagnosis of Alzheimer's disease can only be made with a high degree of certainty in specialized centres. The identification of predictive or diagnostic genetic factors may improve accuracy of disease prediction or diagnosis. One major genetic risk factor, the epsilon4 allele of the apolipoprotein E gene, is universally recognised. We have recently shown that the A allele of the apolipoprotein E, -491A/T promoter polymorphism is also an important risk factor for Alzheimer's disease in an Australian population. We designed the present study to investigate the association between apolipoprotein E genotype, -491A/T polymorphism, plasma apoE levels and the subjective experience of memory decline among 98 subjects and 49 age, gender and education-matched normal controls. An increased frequency of the epsilon4 allele of apolipoprotein E was significantly associated with the 'memory complainers' group (OR = 2.35, P = 0.02) as was the A allele of the -491A/T polymorphism (OR = 2, P = 0.02). Among all subjects, only seven individuals were homozygous for both of these alleles, and six of these seven individuals belonged to the 'memory complainers' group. This sub-group also had relatively elevated plasma apolipoprotein E levels (P < 0.01) and tended to score lower on the Mini-Mental State Examination (MMSE) and Cambridge Cognition Test. These data suggest that the epsilon4 allele of apolipoprotein E and the -491A allele are over-represented among individuals who complain of memory difficulties. Follow-up studies should clarify whether these genotypes and phenotypes are useful in the prediction and/or diagnosis of Alzheimer's disease.

Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population.

Mutations in the presenilin-1 (PS-1) gene on chromosome 14 account for the majority of early-onset familial Alzheimer's disease (FAD) cases. To date, more than 90 mutations have been identified and, while most of these mutations are completely penetrant, the Glu318Gly mutation has been suggested to be partially penetrant. These findings indicate that it may play a similar role to apolipoprotein E (APOE)-epsilon4 by acting as a genetic risk factor for AD. In the current study, a total of 682 subjects were tested to assess the frequency of the Glu318Gly mutation in AD in the Australian population. The Glu318Gly mutation was identified in six sporadic late-onset AD patients, four FAD patients (unrelated) and in nine control subjects. The frequency of this mutation was highest in the familial AD group (8.7%) and lowest in control subjects (2.2%). When the mutation frequencies were compared, we found a statistically significant difference between the latter two groups (Fisher's exact test, P < 0.05). The genotype frequency of the Glu318Gly mutation in all AD cases and controls in the Australian population was 2.8%. This frequency is comparable to that observed for the Dutch population (3.2%), but not for the Finnish population (6.8% and 6.0%) or the Spanish population (5.3%). These findings show that the frequency of the Glu318Gly mutation is increased in FAD patients, suggesting a potential role as a genetic risk factor contributing to the pathogenesis of familial AD.

Clinical characteristics of individuals with subjective memory loss in Western Australia: results from a cross-sectional survey.

Subjective memory complaint is common in later life. Its relationship to future risk of dementia is unclear, although many reports have found a positive association. We designed the present cross-sectional survey to investigate the clinical features associated with subjective memory impairment. One hundred and eight volunteers and 38 non-complainers acting as age-matched controls were recruited. Eleven subjects with memory complaints were excluded because of prior stroke or low MMSE score. The CAMCOG was used to measure cognition; complainers had significantly lower scores (p<0.001). Univariate analysis showed that complainers had greater prevalence of depression, anxiety, insomnia, psychotic phenomenon, difficulties with ADL and word-finding difficulties. The frequency distribution of the apolipoprotein E epsilon4 allele was similar for both groups (p=0.469). Logistic regression analysis indicated that CAMCOG scores (p=0.002) and word-finding difficulty (p=0.002) were independently associated with memory complaints. These results show that memory complainers have worse cognitive performance than non-complainers and support the findings of other studies that suggest that subjective memory loss may be a reliable indicator of cognitive decline.

An investigation of 2 techniques for optimizing joint surface congruency using multiple cylindrical osteochondral autografts.

PURPOSE: To compare 2 techniques for optimizing joint congruency for miniature osteochondral autografting in the knee: intrinsic postoperative forces acting on overdrilled autografts protruding from the femur versus alignment by a surgeon at the time of grafting. TYPE OF STUDY: Controlled animal model experiment. METHODS: A full-thickness cartilage defect was created on the weight-bearing surface of the medial femoral condyle of 13 mature sheep. Three 4.5 x 10 mm cylindrical autografts were inserted into 14-mm deep recipient holes such that the grafts were held in place by side-wall friction alone. One treatment group received grafts that were delivered flush with the surrounding cartilage and the second group received grafts that were left 2-mm proud of the joint surface. RESULTS: Three months postoperatively, the proud grafts had been repositioned by weight bearing but perigraft fissuring and fibroplasia, and subchondral cavitations were serious complications. It is suspected that these complications were caused by excessive motion between the graft and recipient site in the proud grafts. CONCLUSIONS: Grafts should be delivered flush with the joint surface when performing osteochondral transfers to avoid graft micromotion and the consequent interference with graft integration and function.

The -491AA polymorphism in the APOE gene is associated with increased plasma apoE levels in Alzheimer's disease.

Recent evidence suggests that a polymorphism in the regulatory region of the apolipoprotein E gene (APOE) is associated with an increased risk for developing Alzheimer's disease (AD) independent of that conveyed by the epsilon4 allele of APOE. Previous work by our group indicated that plasma apolipoprotein E (apoE) levels were elevated in AD, raising the possibility that the -491 genotype might modify AD risk by increasing expression of the APOE gene. In a total of 638 individuals the -491AA genotype was significantly associated with AD (P < 0.005) while the TT genotype was associated with controls (P < 0.005). In 138 individuals the AA genotype showed significantly higher plasma apoE levels, independent of epsilon4 and AD status (P < 0.01) as well as within control and AD groups (P < 0.05). Within the AD group the AA genotype showed increased apoE levels when compared to AA controls (P < 0.0001). These results suggest that the -491 AA genotype is associated with increased plasma apoE levels, providing a potential basis for elucidating how that genotype increases the risk for developing AD.