Effects of Apolipoprotein E Genotype on Spatial Attention, Working Memory, and Their Interaction in Healthy, Middle-Aged Adults: Results From the National Institute of Mental Health's BIOCARD Study.

The cognitive consequences of the apolipoprotein E-ε4 (APOE-ε4) allele were examined in middle age, before likely onset of symptoms of Alzheimer's disease. The authors identified 3 cognitive processes--visuospatial attention, spatial working memory, and the effect of visuospatial attention on working memory--and devised "behavioral assays" of the integrity of components of these processes. Redirecting visuospatial attention, retention of memory for location, and attentional modulation of memory of target location were affected by APOE genotype. Visuospatial attention showed additive effects of ε4 gene dose; each additional ε4 allele inherited further slowed disengagement from invalidly cued space. In contrast, working memory performance was affected only in ε4 homozygotes. Effect sizes for the APOE gene were moderate to large, ranging from 14% to 24%. Effects of APOE genotype on component processes of cognition in healthy, middle-aged adults is consistent with the emergence in adulthood of an APOE-ε4 cognitive phenotype. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Apolipoprotein E and Cognitive Performance: A Meta-Analysis.

The ε4 allele of the apolipoprotein E (APOE) gene is a known risk factor for Alzheimer's disease and may also affect cognitive performance in normal aging. Evidence of the presence and magnitude of ε4-related cognitive deficits was examined with a meta-analysis of the available literature. Thirty-eight studies were included, and cognitive performance was collapsed into 8 domains. Results indicated significant APOE-ε4 group differences for global cognitive functioning, episodic memory, and executive functioning, in favor of non-ε4 carriers. In addition, older age and APOE-ε4 heterozygosity was associated with smaller ε4-related impairments. The meta-analysis results suggest that APOE-ε4 genotype does affect cognitive performance in healthy aging, although the influence is relatively small and specific to certain domains of cognitive performance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influences of APOE ε4 and expertise on performance of older pilots.

Little is known about how APOE ε4-related differences in cognitive performance translate to real-life performance, where training and experience may help to sustain performance. We investigated the influences of APOE ε4 status, expertise (FAA pilot proficiency ratings), and their interaction on longitudinal flight simulator performance. Over a 2-year period, 139 pilots aged 42–69 years were tested annually. APOE ε4 carriers had lower memory performance than noncarriers (p = .019). APOE interacted with Expertise (p = .036), such that the beneficial influence of expertise (p = .013) on longitudinal flight simulator performance was more pronounced for ε4 carriers. Results suggest that relevant training and activity may help sustain middle-aged and older adults' real-world performance, especially among APOE ε4 carriers. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Scaling of visuospatial attention undergoes differential longitudinal change as a function of APOE genotype prior to old age: Results from the NIMH BIOCARD Study.

The effect of apolipoprotein E (APOE) genotype on longitudinal cognitive decline in midlife was investigated with attentional scaling. Healthy individuals (mean age 59.6 years) genotyped for APOE were tested at 3 12-month intervals on a cued visual search task. A random effects model revealed significant interaction in effect of precue size on search speed between APOE-ε4 gene dose and assessment, with longitudinal increases in noncarriers and heterozygotes but longitudinal decreases in homozygotes. Association of APOE-ε4 with cognitive decline in midlife is consistent with an Alzheimer's disease (AD) prodrome, albeit a decade or more before average age of AD diagnosis. However, cognitive decline in midlife associated with a gene modulating neuronal response to insult argues that the concept of an AD prodrome includes factors that allow as well as cause AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Change in cognitive functioning associated with ApoE genotype in a community sample of older adults.

The influence of a genetic risk factor, apolipoprotein E (apoE) ε4 variant, was assessed in older adults aged 70 to 94 on 3 occasions over 7 years. The results of latent growth curve analyses are reported for individuals genotyped for apoE at the 2nd measurement occasion (n = 601) and for a subsample of individuals without probable or definite dementia during the 1st or 2nd occasion (n = 434). ApoE-ε4 status was a significant predictor of level and change in memory performance and change in speed performance in the full sample, and of initial level and change in memory performance in the nondemented subsample. These results support previous findings that apoE-ε4 is associated with accelerated memory deterioration in individuals without clinical dementia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuropsychological function and apolipoprotein E genotype in the preclinical detection of Alzheimer's disease.

Nondemented older adults genotyped for the Apolipoprotein E (ApoE) ε4 allele (n?=?43) were neuropsychologically compared to participants without a copy of the ε4 allele (n?=?90). At baseline, the groups did not differ on age, education, gender, or global cognitive status. ApoE-ε4 participants demonstrated significantly poorer mean performances on delayed recall, but no significant group differences emerged on attention, language, constructional skills, psychomotor speed, or executive function. Significantly more ApoE-ε4 participants developed probable or questionable Alzheimer's disease (AD) compared with non-ε4 participants, suggesting that the group differences resulted from a preponderance of preclinical AD cases within the ε4 group and not from a direct influence of ApoE genotype on cognition. Cox proportional hazards analysis, adjusting for age, years of education, and global cognitive status, revealed that ApoE-ε4 allele status and measures of recall performance were significant and independent predictors of conversion to AD. Results support the importance of specific episodic memory changes and possession of the ApoE-ε4 allele in the preclinical detection of AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Apolipoprotein E and Prospective Memory in Normally Aging Adults.

The ε4 allele of apolipoprotein E (APOE) is an established risk factor for Alzheimer's disease, despite uncertainty as to its effect on cognitive function in normal aging. Some evidence suggests poor episodic memory and executive functioning in ε4 allele carriers. Prospective memory has been overlooked in investigations of the relationship between APOE and cognition. The authors used a laboratory paradigm to examine the relationship between prospective memory and APOE status in healthy elderly adults, and they varied the association (high vs. low) between a target word and a response word. The authors found a significant deficit in prospective memory for ε4 allele carriers but no effect of association in either group. The results suggest the deficit was due to failure of the prospective component of the task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Is the apolipoprotein e genotype a biomarker for mild cognitive impairment? Findings from a nationally representative study.

Objective: Although the ε4 allele of the apolipoprotein E (APOE) genotype is a known risk factor for Alzheimer's dementia (AD), prior findings on whether it is also a risk factor for mild cognitive impairment (MCI) have been inconsistent. We tested two contrasting explanations: (a) an ε4-AD specificity hypothesis, and (b) a measurement insensitivity hypothesis. Method: The frequency of the ε4 allele was investigated in older adults (mean age > 70) with various types of cognitive impairment (including MCI) and various types of dementia (including AD) with the aging, demographics, and memory study (ADAMS) of the National Institute on Aging's Health and Retirement Study (HRS). The ADAMS controls sources of Type I and Type II error that are posited in the ε4-AD specificity hypothesis and the measurement insensitivity hypothesis, and it is the only nationally representative data set on aging and cognitive impairment. Results: ε4 was a reliable predictor of MCI, with a frequency of 32% in MCI subjects versus 20% in healthy control subjects. This link was specific to MCI because ε4 was not a risk factor for other forms of cognitive impairment without dementia. Conclusions: The results support the measurement insensitivity hypothesis rather than the ε4-AD specificity hypothesis and are consistent with recent research showing modest reductions in cognitive performance among normal functioning ε4 carriers. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Cognitive predictors of incident Alzheimer's disease: A prospective longitudinal study.

The present study examined whether cognitive variables measured at baseline could predict incident cases of Alzheimer's disease (AD) after a 3-year follow-up period. Twenty-six incident AD adults and 179 very old (M?=?83.5 years) adults without dementia participated in a population-based study. Cognitive performance was indexed by the Mini-Mental State Examination (MMSE) and multiple indices of memory and visuospatial and verbal performance. A logistic regression analysis that controlled for age, gender, and education indicated that MMSE scores were reliable indicators of who would develop AD. In addition, recall of organizable words, recognition of faces, and letter fluency were reliable predictors of subsequent dementia status after differences in MMSE performance were partialed out. Thus, although the MMSE is useful in predicting dementia, there is an additional advantage of assessing specific indices of cognitive functioning. Further, supportive episodic memory tasks may be more salient predictors of incident AD than tasks that offer less supportive encoding or retrieval conditions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Heterogeneity of cognitive trajectories in diverse older persons.

This study examined trajectories of cognitive change in psychometrically matched measures of episodic memory, semantic memory, and executive function in an ethnically, demographically, and cognitively diverse sample of older persons. Individual rates of change showed considerable heterogeneity in each domain. Baseline clinical diagnosis predicted differential change in semantic memory and executive function, dementia > mild cognitive impairment (MCI) > normal, but average decline in verbal episodic memory was similar across all 3 diagnostic groups. There was substantial overlap of distributions of cognitive change across baseline diagnostic groups for all 3 measures. Cognitive change was strongly related to change in clinical diagnosis. Rapid and similar change was present for all 3 cognitive measures in patients with dementia and in those with normal cognition and those with MCI who progressed clinically. In cognitively normal patients, verbal episodic memory change was greater than change in the other two domains. Global status, measured by the Clinical Dementia Rating scale (Morris, 1993), predicted change in semantic memory and executive function, whereas APOE genotype predicted change in verbal episodic memory, and age had no effect on rates of change in any domain independent of global status and APOE. Results show important limitations in using cross-sectional diagnosis to predict prognosis and suggest that research to identify robust predictors of cognitive change across the full spectrum from normal to dementia is needed for better early identification of diseases that cause progressive decline. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The influence of apoe status on episodic and semantic memory: Data from a population-based study.

In a prospective cohort study, the authors demonstrated a more pronounced ε4-related deficit for participants 70 years of age and older in tasks assessing episodic recall. Apolipoprotein E (APOE) and age interacted for episodic memory tasks, whereas the interaction for semantic memory tasks was between APOE and test wave. Heterozygotes of ε4 between middle-age and young-old participants performed at a higher level than noncarriers of this allele in recall tasks. A dose effect was found such that carriers of 2 ε4 alleles failed more profoundly in acquiring and recollecting episodic information than carriers of 1 ε4 allele, who in turn failed more than carriers of non-ε4 alleles. The pattern of findings observed for older ε4 carriers suggests that these individuals have particular difficulty when the executive task demands are high. Several factors (e.g., smaller hippocampal volumes, less effective neural repair mechanisms) may account for these findings. On the basis of the data obtained, the authors argue that analyses of the effect of specific genes in cognition should be accompanied by assessment of performance at a specific level, with due attention to the individual's age. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Association between apolipoprotein E epsilon4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia

OBJECTIVE: To determine whether the apolipoprotein E epsilon4 allele (apoE epsilon4) is associated with cognitive decline in individuals with and without dementia, we conducted a 4-year longitudinal study of subjects with a range of cognitive function. SETTING: At baseline, respondents (n=511) were randomly selected according to age and Mini-Mental State Examination score from a community-based study of dementia among noninstitutionalized persons aged 65 to 84 years. Respondents were examined at baseline and followed up in 3 annual visits. At baseline, subjects were classified as having normal cognitive function, minimal dementia, or dementia, according to criteria from the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) and the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Of the 511 respondents at baseline, 405 who were examined at least 2 times are included in this analysis. MAIN OUTCOME MEASURES: Cognitive decline was determined by a slope estimating yearly change in score on the neuropsychological test, the CAMCOG (the cognitive section of the CAMDEX), and its sub-scales of memory and nonmemory functions. RESULTS: Among the subjects who had normal cognitive function at baseline, apoE epsilon4 carriers showed a significantly greater decline (P<.001) in score on the CAMCOG compared with noncarriers. Differences in decline on the memory and nonmemory subtests were also significant (P<.001). Rates of cognitive decline were not related to apoE epsilon4 status in the groups with minimal dementia and dementia. CONCLUSIONS: In our community-based sample, apoE epsilon4 was associated with the rate of cognitive decline prior to the clinically symptomatic phase of dementia. Knowing the apoE epsilon4 status of those already symptomatic for dementia may not improve knowledge about a patient's prognosis.     

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) ε4 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 ε4+ old-old control subjects showed better performance than did the ε4- subjects. In contrast to the healthy individuals, in the very mild DAT group, ε4+ subjects showed deficits in performance relative to the ε4- subjects. Discussion focuses on prospective memory as a cognitive indicator of early stage DAT. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetic and vascular modifiers of age-sensitive cognitive skills: Effects of COMT, BDNF, ApoE, and hypertension.

Several single nucleotide polymorphisms have been linked to neural and cognitive variation in healthy adults. We examined contribution of three polymorphisms frequently associated with individual differences in cognition (Catechol-O-Methyl-Transferase Val158Met, Brain-Derived-Neurotrophic-Factor Val66Met, and Apolipoprotein E ?4) and a vascular risk factor (hypertension) in a sample of 189 volunteers (age 18-82). Genotypes were determined from buccal culture samples, and cognitive performance was assessed in 4 age-sensitive domains?fluid intelligence, executive function (inhibition), associative memory, and processing speed. We found that younger age and COMT Met/Met genotype, associated with low COMT activity and higher prefrontal dopamine content, were independently linked to better performance in most of the tested domains. Homozygotes for Val allele of BDNF polymorphism exhibited better associative memory and faster speed of processing than the Met allele carriers, with greater effect for women and persons with hypertension. Carriers of ApoE ε4 allele evidenced steeper age-related increase in costs of Stroop color interference, but showed no negative effects on memory. The findings indicate that age-related cognitive performance is differentially affected by distinct genetic factors and their interactions with vascular health status. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Longitudinal change in cognitive performance among individuals with mild cognitive impairment.

The authors used mixed-effects growth models to examine longitudinal change in neuropsychological performance over a 4-year period among 197 individuals who were either normal or had mild cognitive impairment (MCI) at baseline. At follow-up, the participants were divided into 4 groups: (a) controls: participants who were normal at both baseline and follow-up (n = 33), (b) stables: participants with MCI whose Clinical Dementia Rating-Sum of Boxes (CDR-SB) score did not differ between the first and last evaluations (n = 22), (c) decliners: participants with MCI whose CDR-SB score declined between the first and last evaluations (n = 95), and (d) converters: participants who received a clinical diagnosis of Alzheimer's disease during the follow-up period (n = 47). Only the Episodic Memory factor showed a significantly greater rate of decline over the follow-up period among the converters. Two other factors were significantly lower in converters at baseline in comparison with other groups (the executive function factor and the general knowledge factor), but the rate of decline over time did not differ. Individuals with an APOE ε4 allele scored lower on the episodic memory and executive function factors at baseline. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The apolipoprotein E gene, attention, and brain function.

The ε4 allele of the apolipoprotein E (ApoE) gene is associated with alterations in brain function and is a risk factor for Alzheimer's disease (AD). Changes in components of visuospatial attention with ApoE-ε4, aging, and AD are described. Healthy middle-aged adults without dementia who have the ApoE-ε4 gene show deficits in spatial attention and working memory that are qualitatively similar to those seen in clinically diagnosed AD patients. The findings support an association between ApoE polymorphism and specific components of visuospatial attention. Molecular mechanisms that may mediate the ApoE-attention link by modulating cholinergic neurotransmission to the posterior parietal cortex are discussed. Studies of attention and brain function in ApoE-ε4 carriers without dementia can advance knowledge of the genetics of visual attention, may enhance understanding of the preclinical phase of AD, and may lead to better methods for early AD detection. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Crosslinking of apolipoprotein E by products of lipid peroxidation

Apolipoprotein E (APOE) genotype and advancing aging are interacting ri sk factors in the expression of late onset and sporadic Alzheimer's Disease (AD). We tested the hypothesis that 2 products of lipid peroxidation, malondialdehyde (MDA) and 4 hydroxy-2-nonenal (HNE), covalently modify APOE and alter its metabolism. In vitro, both HNE and MDA crosslinked purified APOE3 and APOE4. HNE was a more potent crosslinker than MDA, and purified APO3 was more susceptible to crosslinking by HNE than was purified APOE4. In P19 neuroglial cultures, oxidative stress with lipid peroxidation led to increased intracellular accumulation of anti-HNE and anti-APOE immunoreactive proteins of approximately 50 kDa. Intercellular accumulation of the 50 kDa APOE-immunoreactive protein (APOE-50) was not prevented by cyclohexamide, suggesting formation by post-translational mechanisms. In CSF, a 50 kDa APOE-immunoreactive protein co-migrated with proteins most immunoreactive for HNE and MDA adducts, containing NaB3H4-reducible bonds. These proteins were in CSF from adult subjects (with or without dementia), and in AD patients homozygous for APOE3 or APOE4 alleles. These data suggest that HNE covalently crosslinks APOE in P19 neuroglial cultures to form a 50 kDa protein, and that similar modifications of APOE appear to occur in vivo.     

Cognitive predictors of medical decision-making capacity in traumatic brain injury.

Objective: To identify cognitive predictors of medical decision-making capacity (MDC) in participants with moderate to severe traumatic brain injury (TBI). Participants: At baseline, participants were 34 adults with TBI and 20 healthy adults. At 6-month follow-up, participants were 24 adults with TBI and 20 healthy adults. Main Outcome Measures: Participants were administered the Capacity to Consent to Treatment Instrument (CCTI) and neuropsychological test measures. Multivariate cognitive predictor models were developed for CCTI consent abilities/standards (S) of understanding (S5); reasoning (S4); and appreciation (S3). Results: At baseline, short-term verbal memory and semantic fluency predicted TBI group performance on understanding (S5); short-term verbal memory and attention predicted performance on reasoning (S4); and working memory predicted performance on appreciation (S3). At 6 month follow-up, executive function, verbal processing speed, and working memory predicted TBI performance on understanding (S5); working memory and short-term memory predicted reasoning (S4); and basic executive functioning predicted appreciation (S3). Conclusions: Multiple cognitive functions are associated with acute impairment and partial recovery of MDC in patients with TBI. Short-term verbal memory predicted consent capacity of TBI participants at the time of acute inpatient hospitalization, while executive functioning and working memory predicted improved capacity at six-month follow-up. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intraindividual variability in cognitive performance in older adults: Comparison of adults with mild dementia, adults with arthritis, and healthy adults.

Intraindividual variability in latency and accuracy of cognitive performance across both trials and occasions was examined in 3 groups of older adults: healthy adults, adults with arthritis, and adults diagnosed with mild dementia. Participants completed 2 reaction-time and 2 episodic-memory tasks on 4 occasions. Results indicated that intraindividual variability in latency was greater in individuals diagnosed with mild dementia than in adults who were neurologically intact, regardless of their health status. Individual differences in variability were stable over time and across cognitive domains. Intraindividual variability was also related to level of performance and was uniquely predictive of neurological status, independent of level of performance. Results suggest that intraindividual variability may be a behavioral indicator of compromised neurological mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Allelic variability in D21S11, but not in APP or APOE, is associated with cognitive decline in Down syndrome

Genetic variation in the APOE gene and variation in chromosome 21 genotypes, including the APP locus, may influence age-associated cognitive decline in adults with Down syndrome. Molecular genetic and longitudinal neuropsychological analysis was performed for 41 unrelated Caucasian individuals (mean age 48.1 +/- 1.1 years (s.c.m.)) with free trisomy 21. Allele frequencies and genotype distributions were compared among subgroups with or without evidence of cognitive decline. Genetic variability at APOE and APP was not significantly associated with evidence of cognitive decline. However, aged individuals with Down syndrome, without evidence of cognitive decline, demonstrated unusual allelic variability at D21S11. These findings are discussed in the context of current hypotheses of Alzheimer-type dementia in Down syndrome and in the general population.