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Cognition or genetics? Predicting Alzheimer's disease with practice effects, APOE genotype, and brain metabolism.

ABSTRACT: As practice effects are common in neuropsychological assessment, this study analyzed their utility to identify individuals with amnestic mild cognitive impairment (aMCI) at the greatest risk for Alzheimer's disease (AD-risk) and compared practice effects with APOE and brain metabolism biomarkers. We regressed Auditory Verbal Learning Test delayed recall (AVLT-DR) at 6 months on baseline AVLT-DR scores in 394 individuals with normal cognition from the Alzheimer's Disease Neuroimaging Initiative database and dichotomized 816 individuals with aMCI as showing practice effect or not showing practice effects (PE-) when the discrepancy between observed and predicted scores was found in less than 10%, 7%, and 5% of normal cognition. Cox regressions analyzed the AD-risk at 6 years. More than 60% of aMCI were showing practice effects. Controlling for age, sex, education, and baseline Mini-Mental State Examination and AVLT-DR scores, the AD-risk was associated with PE- [hazard ratio (HR) = 1.93], lower brain metabolism (HR = 0.95), and APOE genotype (HR = 1.92), with narrower risk estimates for PE-. The lack of practice effects during a 6-month period might be as precise as biomarkers for predicting the 6-year AD-risk.

SUBMITTER: Oltra-Cucarella J

PROVIDER: S-EPMC6162103 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Cognition or genetics? Predicting Alzheimer's disease with practice effects, APOE genotype, and brain metabolism.

Oltra-Cucarella Javier J Sánchez-SanSegundo Miriam M Ferrer-Cascales Rosario R

Neurobiology of aging 20180810

As practice effects are common in neuropsychological assessment, this study analyzed their utility to identify individuals with amnestic mild cognitive impairment (aMCI) at the greatest risk for Alzheimer's disease (AD-risk) and compared practice effects with APOE and brain metabolism biomarkers. We regressed Auditory Verbal Learning Test delayed recall (AVLT-DR) at 6 months on baseline AVLT-DR scores in 394 individuals with normal cognition from the Alzheimer's Disease Neuroimaging Initiative d ...[more]

PMID: 30172222

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Project description:BackgroundA Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer's disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose-positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points.MethodsThis was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model.ResultsFifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P < 0.025), anterior cingulate (P < 0.041), and striatal (P < 0.023) regions. Clinical measures showed benefit in quality of life (P < 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group.DiscussionThese outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response.

Project description:BackgroundThe 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.MethodsWe 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.ResultsThere 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 nondisclosure group and a disclosure subgroup of subjects carrying the APOE epsilon4 allele (which is associated with increased risk) also revealed no significant differences. However, the epsilon4-negative subgroup had a significantly lower level of test-related distress than did the epsilon4-positive subgroup (P=0.01). Subjects with clinically meaningful changes in psychological outcomes were distributed evenly among the nondisclosure group and the epsilon4-positive and epsilon4-negative subgroups. Baseline scores for anxiety and depression were strongly associated with post-disclosure scores of these measures (P<0.001 for both comparisons).ConclusionsThe 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 epsilon4-negative. Persons with high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure. (ClinicalTrials.gov number, NCT00571025.)

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Cognition or genetics? Predicting Alzheimer's disease with practice effects, APOE genotype, and brain metabolism.

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Cognition or genetics? Predicting Alzheimer's disease with practice effects, APOE genotype, and brain metabolism.

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