The Relation Between Personality and Biomarkers in Sensitivity and Conversion to Alzheimer-Type Dementia.

OBJECTIVES: The present study explored relationships among personality, Alzheimer's disease (AD) biomarkers, and dementia by addressing the following questions: (1) Does personality discriminate healthy aging and earliest detectable stage of AD? (2) Does personality predict conversion from healthy aging to early-stage AD? (3) Do AD biomarkers mediate any observed relationships between personality and dementia status/conversion? METHODS: Both self- and informant ratings of personality were obtained in a large well-characterized longitudinal sample of cognitively normal older adults (N = 436) and individuals with early-stage dementia (N = 74). Biomarkers included amyloid imaging, hippocampal volume, cerebral spinal fluid (CSF) Aß42, and CSF tau. RESULTS: Higher neuroticism, lower conscientiousness, along with all four biomarkers strongly discriminated cognitively normal controls from early-stage AD individuals. The direct effects of neuroticism and conscientiousness were only mediated by hippocampal volume. Conscientiousness along with all biomarkers predicted conversion from healthy aging to early-stage AD; however, none of the biomarkers mediated the relationship between conscientiousness and conversion. Conscientiousness predicted conversion as strongly as the biomarkers, with the exception of hippocampal volume. CONCLUSIONS: Conscientiousness and to a lesser extent neuroticism serve as important independent behavioral markers for AD risk.

Alzheimer Disease Cerebrospinal Fluid Biomarkers Moderate Baseline Differences and Predict Longitudinal Change in Attentional Control and Episodic Memory Composites in the Adult Children Study.

Cognitive measures that are sensitive to biological markers of Alzheimer disease (AD) pathology are needed to (a) facilitate preclinical staging, (b) identify individuals who are at the highest risk for developing clinical symptoms, and (c) serve as endpoints for evaluating the efficacy of interventions. The present study assesses the utility of two cognitive composite scores of attentional control and episodic memory as markers for preclinical AD pathology in a group of cognitively normal older adults (N = 238), as part of the Adult Children Study. All participants were given a baseline cognitive assessment and follow-up assessments every 3 years over an 8-year period, as well as a lumbar puncture within 2 years of the initial assessment to collect cerebrospinal fluid (CSF) and amyloid tracer Pittsburgh compound-B scan for amyloid imaging. Results indicated that attentional control was correlated with levels of Aß42 at the initial assessment whereas episodic memory was not. Longitudinally, individuals with high CSF tau exhibited a decline in both attention and episodic memory over the course of the study. These results indicate that measures of attentional control and episodic memory can be used to evaluate cognitive decline in preclinical AD and provide support that CSF tau may be a key mechanism driving longitudinal cognitive change.

A Genetic Variant (COMT) Coding Dopaminergic Activity Predicts Personality Traits in Healthy Elderly.

Association studies between the NEO five factor personality inventory and COMT rs4680 have focused on young adults and the results have been inconsistent. However, personality and cortical changes with age may put older adults in a more sensitive range for detecting a relationship. The present study examined associations of COMT rs4680 and personality in older adults. Genetic association analyses were carried out between the NEO and the targeted COMT rs4680 in a large, well-characterized sample of healthy, cognitively normal older adults (N = 616, mean age = 69.26 years). Three significant associations were found: participants with GG genotype showed lower mean scores on Neuroticism (p = 0.039) and higher scores on Agreeableness (p = 0.020) and Conscientiousness (p = 0.006) than participants with AA or AG genotypes. These results suggest that older adults with higher COMT enzymatic activity (GG), therefore lower dopamine level, have lower Neuroticism scores, and higher Agreeableness and Conscientiousness scores. This is consistent with a recent model of phasic and tonic dopamine release suggesting that even though GG genotype is associated with lower tonic dopamine release, the phasic release of dopamine might be optimal for a more adaptive personality profile.

Association between personality and tau-PET binding in cognitively normal older adults.

Personality traits such as Neuroticism and Conscientiousness are associated with Alzheimer disease (AD) pathophysiology in cognitively normal (CN) and impaired individuals, and may represent potential risk or resilience factors, respectively. This study examined the cross-sectional relationship between personality traits and regional tau deposition using positron emission tomography (PET) in cognitively normal older adults. A cohort of CN (Clinical Dementia Rating (CDR) 0, n = 128) older adults completed the NEO Five-Factor Inventory to assess traits of Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness and underwent tau-PET and ß-amyloid (Aß)-PET imaging. We utilized linear regression models, adjusting for age, sex, geriatric depression score, and Aß to evaluate the association between each of the personality traits and regional tau-PET accumulation. Elevated Neuroticism scores were associated with higher tau-PET accumulation in the amygdala (p = .002), entorhinal cortex (p = .012), and inferior temporal cortex (p = .016), as well as with a composite tau-PET measure (p = .002). In contrast, Extroversion, Openness, Agreeableness, and Conscientiousness were not associated with tau deposition in any of these regions (p's > 0.160). Our results indicate that increased Neuroticism is associated with higher tau pathophysiology in regions known to be vulnerable to AD pathophysiology in CN participants. High Neuroticism scores may therefore serve as a potential risk factor for tau accumulation. Alternatively, personality can change with the onset of AD, thus increased tau levels may affect Neuroticism scores. While future longitudinal studies are needed to determine directionality, our findings suggest early associations between Neuroticism and tau accumulation in CN adults.

The power of personality in discriminating between healthy aging and early-stage Alzheimer's disease.

This study examined differences in personality in the earliest stages of dementia of the Alzheimer type (DAT) relative to healthy aging, and the power of personality in discriminating healthy aging from early-stage DAT. Four groups of participants (middle-aged controls, older controls, persons with very mild DAT, and persons with mild DAT) and their families were administered Costa and McCrae's NEO Five-Factor Inventory. On the basis of both self-report and informant report, there was an increase in neuroticism and a decrease in conscientiousness in persons with very mild DAT relative to healthy individuals without it, and in persons with mild DAT relative to those with very mild DAT. Moreover, informant reports of neuroticism and conscientiousness capture substantial unique variance in discriminating healthy aging and very mild DAT, above and beyond standard neuropsychological tests. Discussion focuses on the importance of personality traits as a noncognitive indicator of early-stage DAT.

Process dissociation analyses of memory changes in healthy aging, preclinical, and very mild Alzheimer disease: Evidence for isolated recollection deficits.

OBJECTIVE: Recollection and familiarity are independent processes that contribute to memory performance. Recollection is dependent on attentional control, which has been shown to be disrupted in early stage Alzheimer's disease (AD), whereas familiarity is independent of attention. The present longitudinal study examines the sensitivity of recollection estimates based on Jacoby's (1991) process dissociation procedure to AD-related biomarkers in a large sample of well-characterized cognitively normal middle-aged and older adults (N = 519) and the extent to which recollection discriminates these individuals from individuals with very mild symptomatic AD (N = 64). METHOD: Participants studied word pairs (e.g., knee bone), then completed a primed, explicit, cued fragment-completion memory task (e.g., knee b_n_). Primes were either congruent with the correct response (e.g., bone), incongruent (e.g., bend), or neutral (e.g., &&&). This design allowed for the estimation of independent contributions of recollection and familiarity processes, using the process dissociation procedure. RESULTS: Recollection, but not familiarity, was impaired in healthy aging and in very mild AD. Recollection discriminated cognitively normal individuals from the earliest detectable stage of symptomatic AD above and beyond standard psychometric tests. In cognitively normal individuals, baseline CSF measures indicative of AD pathology were related to lower initial recollection and less practice-related improvement in recollection over time. Finally, presence of amyloid plaques, as imaged by PIB-PET, was also related to less improvement in recollection over time. CONCLUSIONS: These findings suggest that attention-demanding memory processes, such as recollection, may be particularly sensitive to both symptomatic and preclinical AD pathology. (PsycINFO Database Record

Prospective memory and apolipoprotein E in healthy aging and early stage Alzheimer's disease.

The present study examined whether prospective memory performance discriminates healthy aging from very mild dementia of the Alzheimer type (DAT) and individuals at risk for DAT because of the presence of the apolipoprotein E (ApoE) epsilon4 allele. Four groups (young subjects, young-old control subjects, old-old control subjects, and subjects with very mild DAT) engaged in an event-based prospective memory task wherein they responded to a specific word embedded in a general knowledge test. Results indicated that prospective memory performance was clearly impaired in the very mild DAT group relative to the healthy older control groups. Moreover, prospective memory performance appears to capture unique variance in discriminating these 2 groups above and beyond standard retrospective memory tests. However, prospective memory was not affected by ApoE status in the young-old control group and, contrary to predictions, the epsilon4+ old-old control subjects showed better performance than did the epsilon4- subjects. In contrast to the healthy individuals, in the very mild DAT group, epsilon4+ subjects showed deficits in performance relative to the epsilon4- subjects. Discussion focuses on prospective memory as a cognitive indicator of early stage DAT.

Does expanded retrieval produce benefits over equal-interval spacing? Explorations of spacing effects in healthy aging and early stage Alzheimer's disease.

Three experiments explored different schedules of retrieval practice in young adults, older adults, and individuals with dementia of the Alzheimer type. In each experiment, an initial acquisition phase was presented in which participants studied or attempted to retrieve response words to cues, followed by a later cued-recall test. Experiment 1 produced a benefit of expanded retrieval over equal-interval retrieval during acquisition, but this benefit was lost in final cued recall. In Experiments 2 and 3, participants received corrective feedback during acquisition and modified spacing schedules. There was again no evidence of a difference between expanded and equal-interval conditions in final cued recall. Discussion focuses on the potential benefits and costs of expanded retrieval on a theoretical and applied level.

Failure to control prepotent pathways in early stage dementia of the Alzheimer's type: evidence from dichotic listening.

The authors examined the right ear advantage in a dichotic listening task in healthy aging and very mild and mild stages of Alzheimer's disease. Subjects were simultaneously presented 3 pairs of digits to the left and right ears (e.g., left ear: 4, 3, 1; right ear: 9, 2, 5) for immediate ordered recall. Four lists of triads were presented, varying in presentation rate between digit pairs within a triad (0.5, 1.0, 1.5, 2.0 s). Results indicated that the very mild and mild Alzheimer's groups showed a larger right ear advantage in free recall compared with the healthy controls, indicating a tendency to respond to the prepotent left hemisphere pathway for language processing. Also, the right ear advantage and proportion of switches made during recall were correlated with psychometric measures of frontal lobe function in the mild Alzheimer's group but not in the very mild or healthy control groups.

Dissociative global and local task-switching costs across younger adults, middle-aged adults, older adults, and very mild Alzheimer's disease individuals.

A task-switching paradigm was used to examine differences in attentional control across younger adults, middle-aged adults, healthy older adults, and individuals classified in the earliest detectable stage of Alzheimer's disease (AD). A large sample of participants (570) completed a switching task in which participants were cued to classify the letter (consonant/vowel) or number (odd/even) task-set dimension of a bivalent stimulus (e.g., A 14), respectively. A pure block consisting of single-task trials and a switch block consisting of nonswitch and switch trials were completed. Local (switch vs. nonswitch trials) and global (nonswitch vs. pure trials) costs in mean error rates, mean response latencies, underlying reaction time (RT) distributions, along with stimulus-response congruency effects were computed. Local costs in errors were group invariant, but global costs in errors systematically increased as a function of age and AD. Response latencies yielded a strong dissociation: Local costs decreased across groups whereas global costs increased across groups. Vincentile distribution analyses revealed that the dissociation of local and global costs primarily occurred in the slowest response latencies. Stimulus-response congruency effects within the switch block were particularly robust in accuracy in participants in the very mild AD group. We argue that the results are consistent with the notion that the impaired groups show a reduced local cost because the task sets are not as well tuned, and hence produce minimal cost on switch trials. In contrast, global costs increase because of the additional burden on working memory of maintaining 2 task sets.

Longitudinal driving performance in early-stage dementia of the Alzheimer type.

OBJECTIVES: To longitudinally assess on-road driving performance in healthy older adults and those with early-stage dementia of the Alzheimer type (DAT). DESIGN: A prospective longitudinal study. SETTING: Large urban medical center and surrounding area. PARTICIPANTS: A sample of 58 healthy controls, 21 participants with very mild DAT, and 29 participants with mild DAT participated. DAT was diagnosed using validated clinical diagnostic criteria and staged according to the Clinical Dementia Rating (CDR) Scale. MEASUREMENTS: Healthy controls and individuals with very mild DAT and mild DAT were administered a standardized on-road driving assessment over repeated times of testing. RESULTS: Subjects in the CDR=1 group (mild DAT) had a faster rate of receiving a rating of not safe on the driving test than subjects in the CDR=0 group (healthy controls; log rank test, P=.006), and the survival function of the CDR=0.5 group (very mild DAT) fell between those of the CDR=0 and CDR=1 groups. A Cox proportional hazards model indicated a significant difference in survival functions between the CDR=0 and CDR=1 groups after baseline age was controlled for (P<.001). Cox regression analysis also indicated that baseline age was a significant risk factor for a rating of "not safe" (P=.002). CONCLUSION: This study provides longitudinal evidence for a decline in driving performance over time, primarily in early-stage DAT, and supports the need not only for driving assessments, but also for reevaluation of individuals with very mild and mild DAT.

Relationship between Stroop performance and resting state functional connectivity in cognitively normal older adults.

OBJECTIVE: Early biomarkers of Alzheimer's disease (AD) are needed for developing therapeutic interventions. Measures of attentional control in Stroop-type tasks discriminate healthy aging from early stage AD and predict future development of AD in cognitively normal individuals. Disruption in resting state functional connectivity MRI (rs-fcMRI) has been reported in AD and in healthy controls at risk for AD. We explored the relationship among Stroop performance, rs-fcMRI, and CSF Aß42 levels in cognitively normal older adults. METHOD: A computerized Stroop task (along with standard neuropsychological measures), rs-fcMRI, and CSF were obtained in 237 cognitively normal older adults. We compared the relationship between Stroop performance, including measures from reaction distributional analyses, and composite scores from four resting state networks (RSNs; default mode [DMN], salience [SAL], dorsal attention [DAN], and sensory-motor [SMN]), and the modulatory influence of CSF Aß42 levels. RESULTS: A larger Stroop effect in errors was associated with reduced rs-fcMRI within the DMN and SAL. Reaction time (RT) distributional analyses indicated the slow tail of the RT distribution was related to reduced rs-fcMRI functional connectivity within the SAL. Standard psychometric measures were not related to RSN composite scores. A relationship between Stroop performance and DMN (but not SAL) functional connectivity was stronger in CSF Aß42-positive individuals. CONCLUSIONS: A link exists between RSN composite scores and specific attentional performance measures. Both measures may be sensitive biomarkers for AD.

White matter integrity and reaction time intraindividual variability in healthy aging and early-stage Alzheimer disease.

Aging and early-stage Alzheimer disease (AD) have been shown to be associated with increased RT intraindividual variability (IIV, as reflected by the coefficient of variation) and an exaggeration of the slow tail of the reaction time (RT) distribution in attentional control tasks, based on ex-Gaussian analyses. The current study examined associations between white matter volume, IIV, and ex-Gaussian RT distribution parameters in cognitively normal aging and early-stage AD. Three RT attention tasks (Stroop, Simon, and a consonant-vowel odd-even switching task) in conjunction with MRI-based measures of cerebral and regional white matter volume were obtained in 133 cognitively normal and 33 early-stage AD individuals. Larger volumes were associated with less IIV and less slowing in the tail of the RT distribution, and larger cerebral and inferior parietal white matter volumes were associated with faster modal reaction time. Collectively, these results support a role of white matter integrity in IIV and distributional skewing, and are consistent with the hypothesis that IIV and RT distributional skewing are sensitive to breakdowns in executive control processes in normal and pathological aging.

The role of forgetting rate in producing a benefit of expanded over equal spaced retrieval in young and older adults.

The current study examined the effects of two manipulations on equal and expanded spaced retrieval schedules in young and older adults. First, we examined the role that the type of expansion (systematic vs. nonsystematic) has in producing a benefit of expanded retrieval. Second, we examined the influence of an immediate retrieval attempt to minimize forgetting after the original encoding event. It was predicted that including multiple retrieval attempts with minimal intervening spacing (best accomplished in a nonsystematic retrieval schedule) would be necessary to produce a benefit of expanded retrieval over equal spaced retrieval for older adults but not young adults due to age differences in working memory capacity. Results from two experiments revealed that the presence of an expanded over equal spaced retrieval benefit is modulated by the extent to which the spacing conditions minimize forgetting in the early retrieval attempts in the spaced conditions. As predicted, these conditions differ substantially across young and older adults. In particular, in older adults two intervening items between early retrieval attempts produce dramatic rates of forgetting compared to one intervening item, whereas younger adults can maintain performance up to five intervening events in comparable conditions. Discussion focuses on age differences in short term forgetting, working memory capacity, and the relation between forgetting rates and spaced retrieval schedules.

Role of family history for Alzheimer biomarker abnormalities in the adult children study.

OBJECTIVE: To assess whether family history (FH) of Alzheimer disease (AD) alone influences AD biomarker abnormalities. DESIGN: Adult Children Study. SETTING: Washington University's Charles F. and Joanne Knight Alzheimer's Disease Research Center. PARTICIPANTS: A total of 269 cognitively normal middle- to older-aged individuals with and without an FH for AD. MAIN OUTCOME MEASURES: Clinical and cognitive measures, magnetic resonance imaging-based brain volumes, diffusion tensor imaging-based white matter microstructure, cerebrospinal fluid biomarkers, and molecular imaging of cerebral fibrillar amyloid with positron emission tomography using the [(11)C] benzothiazole tracer, Pittsburgh compound B. RESULTS: A positive FH for AD was associated with an age-related decrease of cerebrospinal fluid Aß42; the ε4 allele of apolipoprotein E (APOE4) did not alter this effect. Age-adjusted cerebrospinal fluid Aß42 was decreased for individuals with APOE4 compared with the level for those without, and the decrease was larger for individuals with a positive FH compared with the decrease for those without. The variation of cerebrospinal fluid tau and Pittsburgh compound B mean cortical binding potential increased by age. For individuals younger than 55, an age-related increase in mean cortical binding potential was associated with APOE4 but not FH. For individuals older than 55, a positive FH and a positive APOE4 implied the fastest age-related increase in mean cortical binding potential. A positive FH was associated with decreased fractional anisotropy from diffusion tensor imaging in the genu and splenium of the corpus callosum. CONCLUSION: Independent of APOE4, FH is associated with age-related change of several cerebrospinal fluid, Pittsburgh compound B, and diffusion tensor imaging biomarkers in cognitively normal middle- to older-aged individuals, suggesting that non- APOE susceptibility genes for AD influence AD biomarkers.

The utility of Stroop task switching as a marker for early-stage Alzheimer's disease.

Past studies have suggested attentional control tasks such as the Stroop task and the task-switching paradigm may be sensitive for the early detection of dementia of the Alzheimer's type (DAT). The authors of the current study combined these tasks to create a Stroop switching task. Performance was compared across young adults, older adults, and individuals diagnosed with very mild dementia. Results indicated that this task strongly discriminated individuals with healthy aging from those with early-stage DAT. In a logistic regression analysis, incongruent error rates from the Stroop switching task discriminated healthy aging from DAT better than any of the other 18 cognitive tasks given in a psychometric battery.

Effects of healthy aging and early stage dementia of the Alzheimer's type on components of response time distributions in three attention tasks.

OBJECTIVE: The characteristics of response time (RT) distributions beyond measures of central tendency were explored in 3 attention tasks across groups of young adults, healthy older adults, and individuals with very mild dementia of the Alzheimer's type (DAT). METHOD: Participants were administered computerized Stroop, Simon, and switching tasks, along with psychometric tasks that tap various cognitive abilities and a standard personality inventory (NEO-FFI). Ex-Gaussian (and Vincentile) analyses were used to capture the characteristics of the RT distributions for each participant across the 3 tasks, which afforded 3 components: mu and sigma (mean and standard deviation of the modal portion of the distribution) and tau (the positive tail of the distribution). RESULTS: The results indicated that across all 3 attention tasks, healthy aging produced large changes in the central tendency mu parameter of the distribution along with some change in sigma and tau (mean etap(2) = .17, .08, and .04, respectively). In contrast, early stage DAT primarily produced an increase in the tau component (mean etap(2) = .06). tau was also correlated with the psychometric measures of episodic/semantic memory, working memory, and processing speed, and with the personality traits of neuroticism and conscientiousness. Structural equation modeling indicated a unique relation between a latent tau construct (-.90), as opposed to sigma (-.09) and mu constructs (.24), with working memory measures. CONCLUSIONS: The results suggest a critical role of attentional control systems in discriminating healthy aging from early stage DAT and the utility of RT distribution analyses to better specify the nature of such change.

Predicting conversion to dementia of the Alzheimer's type in a healthy control sample: the power of errors in Stroop color naming.

In the present study, we investigated which cognitive functions in older adults at Time A are predictive of conversion to dementia of the Alzheimer's type (DAT) at Time B. Forty-seven healthy individuals were initially tested in 1992-1994 on a trial-by-trial computerized Stroop task along with a battery of psychometric measures that tap general knowledge, declarative memory, visual-spatial processing, and processing speed. Twelve of these individuals subsequently developed DAT. The errors on the color incongruent trials (along with the difference between congruent and incongruent trials) and changes in the reaction time distributions were the strongest predictors of conversion to DAT, consistent with recent arguments regarding the sensitivity of these measures. Notably in the psychometric measures, there was little evidence of a difference in declarative memory between converters and nonconverters, but there was some evidence of changes in visual-spatial processing. Discussion focuses on the accumulating evidence suggesting a role of attentional control mechanisms as an early marker for the transition from healthy cognitive aging to DAT.

The utility of placing recollection in opposition to familiarity in early discrimination of healthy aging and very mild dementia of the Alzheimer's type.

This study explored the ability to control familiarity-based information in a memory exclusion paradigm in healthy young, older adults, and early stage DAT individuals. We compared the predictive power of memory exclusion performance to standard psychometric performance in discriminating between aging and the earliest stage of DAT and between APOe4-present and APOe4-absent genotype in healthy control individuals. Participants responded "yes" to words that were previously semantically encoded, and "no" to words that were previously read aloud and to new words. The number of targets and distractors on the read "distractor" list was manipulated to investigate the degree to which aging and DAT influence the ability to recollect in the face of distractor familiarity due to repetition. Memory exclusion performance was better for healthy older adults than very mild DAT individuals and better for healthy control individuals with APOe4 allele than those without APOe4 allele even after controlling for standard psychometric performance. Discussion focuses on the importance of attentional control systems in memory retrieval and the utility of the opposition paradigm for discriminating healthy versus pathological aging.

The utility of intraindividual variability in selective attention tasks as an early marker for Alzheimer's disease.

This study explored differences in intraindividual variability in 3 attention tasks across a large sample of healthy older adults and individuals with very mild dementia of the Alzheimer's type (DAT). Three groups of participants (healthy young adults, healthy older adults, very mild DAT) were administered 3 experimental measures of attentional selection and switching (Stroop, Simon, task switching). The results indicated that a measure of intraindividual variability, coefficient of variation (CoV; SD/M), increased across age and early stage DAT. The CoV in Stroop discriminated the performance of epsilon4 carriers from noncarriers in healthy older controls and the CoV in task switching was correlated with cerebrospinal fluid (CSF) biomarkers predictive of DAT.