APOE genotype and cognitive functioning in a large age-stratified population sample.

There is evidence that the cognitive effects of Alzheimer's disease can be seen decades before disease diagnosis. If this is the case, then the apolipoprotein E (APOE) *E4 allele might be expected to have effects on cognitive functioning earlier in the life span. To assess such effects, the authors examined data on the *E4 allele and cognitive functioning from a population sample of 6,560 Caucasians covering the age groups of 20-24, 40-44, and 60-64 years. Participants were assessed on tests of episodic memory, working memory, mental speed, reaction time, and reading vocabulary. Although performance on all tests except reading vocabulary declined across age groups, there was no effect of the APOE *E4 allele at any age. These results indicate that APOE *E4 does not have preclinical effects early in the life span on these cognitive functions. Cognitive aging effects between the ages of 20 and 64 years must not be due to preclinical Alzheimer's disease. (PsycINFO Database Record (c) 2010 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)     

Are processing speed tasks biomarkers of cognitive aging?

We examined the association between 5 processing speed measures and general cognitive ability in a large (>900) sample of relatively healthy men and women at age 70. The processing speed tests were the Wechsler Digit Symbol-Coding and Symbol Search, simple reaction time, 4-choice reaction time, and inspection time. To inquire whether the processing speed tasks might be biomarkers of cognitive aging, we examined the attenuations in their associations with general cognitive ability after adjusting for cognitive ability measured almost 60 years earlier. With the exception of inspection time, the attenuations were substantial. Inspection time was the only processing speed measure—all of which were measured at age 70—whose correlation with cognitive ability at age 70 was significantly greater than the correlation with cognitive ability at age 11. In old age, individual differences in most commonly used measures of processing speed are largely dependent on childhood cognitive ability. For all processing speed tasks, a little variance is left that appears to be related to aging differences. Inspection time, the marker that was least dependent on childhood intelligence, should be considered further as one biomarker of cognitive aging. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Is body mass index in old age related to cognitive abilities? The Lothian Birth Cohort 1936 Study.

We tested the hypothesis that the previously reported association between a higher body mass index (BMI) and poorer cognition in later adulthood is an artifact of confounding by previous cognitive ability and socioeconomic status. Participants were 1,079 adults aged about 70 years in the Lothian Birth Cohort 1936 Study, on whom there are IQ data from age 11. Cognitive outcome measures included: IQ at age 70 using the same test that was administered at age 11; composite measures of general cognitive ability (g factor), speed of information processing, and memory; and two tests of verbal ability. People classified as overweight or obese in later adulthood had significantly lower scores on tests of childhood IQ, age 70 IQ, g factor, and verbal ability. There was no significant association with processing speed or memory performance. After adjusting for childhood IQ and social class in general linear models, associations with age 70 IQ and g factor were nonsignificant or attenuated. However, throughout the models, there was a persistent (inverse) relationship between BMI and performance on the National Adult Reading Test (NART) and Wechsler Test of Adult Reading (WTAR), which remained significant after full adjustment for all sociodemographic and health covariates (for the NART, p = .025; for the WTAR, p = .011). The findings suggest that the previously reported BMI–cognition associations in later adulthood could be largely accounted for by prior ability and socioeconomic status, and by the possible influence of these factors on the adoption of health behaviors in adulthood. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Apolipoprotein E Gene Variability and Cognitive Functions at Age 79: A Follow-Up of the Scottish Mental Survey of 1932.

Apolipoprotein E (APOE) genotype is a possible influence on nonpathological cognitive aging. The authors studied 462 community-dwelling, 79-year-old people born in 1921, whose childhood IQ had been assessed in the Scottish Mental Survey of 1932 (Scottish Council for Research in Education, 1933). Adjusting for sex, childhood IQ, and self-reported illnesses, the authors found that those with an APOE e4 allele had significantly lower Wechsler Logical Memory (D. Wechsler, 1987) scores than those without an e4 allele. Those people with APOE s2/e3 genotypes had significantly higher Wechsler Logical Memory scores than e3/s3, who were significantly higher than e3/e4. Neither nonverbal reasoning nor verbal fluency were affected. In this sample, APOE genotype contributed to verbal memory in old age. (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)     

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)     

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)     

Personality and risk of cancer in men with coronary heart disease

BACKGROUND: Virtually all individuals with Down syndrome (DS) have neuropathologic changes characteristic of Alzheimer's disease (AD) beginning at 40 years of age. Few studies have examined factors that influence age at onset of AD in DS. We investigated whether sex differences in age at onset and risk of AD among adults with DS are similar to those observed in the general population and whether the effect of sex on risk of AD is modified by apolipoprotein E (APOE) genotype. METHODS: A community-based sample of 111 adults with cytogenetically confirmed DS (34 to 71 years of age) was ascertained through the New York State Developmental Disabilities system. A semistructured interview with caregivers and review of medical records was used to ascertain the presence or absence of AD. APOE genotyping was carried out without knowledge of the subject's medical history or clinical diagnosis. RESULTS AND CONCLUSIONS: Both male gender and the presence of an APOE epsilon4 allele were associated with an earlier onset of AD. Compared with women, men with DS were three times as likely to develop AD. Compared with those with the APOE 3/3 genotype, adults with DS with the 3/4 or 4/4 genotypes were four times as likely to develop AD. No individual with an APOE epsilon2 allele developed AD. No evidence of interaction of sex and APOE genotype was found in risk of AD. The higher risk of AD in men may be related to differences in hormonal function between men and women with DS that are distinct from those in the general population.     

Cognitive engagement and cognitive aging: Is openness protective?

The purpose of this study was to examine whether openness to experience is related to longitudinal change in cognitive performance across advancing age. Participants were 857 individuals from the Swedish Adoption/Twin Study of Aging (SATSA). Factors for 5 cognitive domains were created, including verbal ability, spatial ability, memory, processing speed, and a global score, g. Latent growth curve models were used to assess level and longitudinal trajectories of cognitive performance. It was hypothesized that individuals who endorsed higher levels of openness would have higher cognitive test scores and lesser rates of cognitive decline. As predicted, higher openness to experience was associated with significantly higher performance across all cognitive tests for both men and women even after adjusting for education, cardiovascular disease, and activities of daily living. Openness, however, was not predictive of differences in the trajectories of cognitive performance over age. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interdisciplinary forum: from Genetic Diagnosis to Gene Therapy in Oncology. 26 September-1 October, 1996, Madrid, Spain

Alzheimer's disease (AD) represents a heterogeneous disorder, and several factors have been associated with its development. The presence of the apolipoprotein E type (APOE) epsilon 4 allele has been proposed as a risk factor for AD, but how it influences the development of the characteristic hallmarks of the disease remains unknown. In the present study, the neuropathological changes and levels of both core PHF-tau and normal tau protein in 4 neocortical areas, cerebellum and medial temporal cortex were determined in 18 AD cases. The extent of these changes was compared between 10 cases possessing an epsilon 4 allele and 8 cases without. These two groups were indistinguishable in terms of neurofibrillary pathology, whereas cases with an epsilon 4 allele had more diffuse plaques, particularly in the temporal neocortex. Biochemically, there was no difference in the levels of PHF-tau protein between the two groups. These data indicate that APOE epsilon 4 allele may influence deposition of diffuse amyloid, but altered tau protein processing, which underlies the development of the neurofibrillary pathology in AD, is not influenced by this allele.     

The influence of apolipoprotein e genotype on visuospatial attention dissipates after age 80.

Although it is established that apolipoprotein E (APOE) e4 allele increases the risk of Alzheimer's disease (AD), epidemiological studies indicate that genetic risk decreases late in life. This raises the question of whether the effects of APOE on cognition that are seen in midlife arise from a cognitive phenotype of APOE or from the presence of early AD in some APOE-e4 carriers. The authors addressed this question by comparing the cognitive consequences of variation in the APOE gene between individuals over the age of 80 (old-old) and middle-aged and young-old individuals. A spatially cued discrimination paradigm--previously shown to be sensitive to AD and to APOE genotype--required a speeded categorization of a target letter following cues that were valid, invalid, or neutral in predicting target location. Results revealed greater costs of invalid cues in the APOE-e4 carriers of middle-aged and young-old, but not old-old, groups. The dissipation of the APOE effect in old-old individuals at lower risk of AD suggests that visuospatial attention impairments seen as early as midlife in APOE-e4 carriers may be a preclinical marker of AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism

Genetic studies on Alzheimer's disease (AD), a devastating neurodegenerative disorder, have identified the apolipoprotein E (APOE) gene as a strong susceptibility marker for AD. The E*4 allele of APOE is a major risk factor for AD regardless of age of onset or family history. However, the observation that the APOE*4 allele is neither necessary nor sufficient for the expression of AD emphasizes the involvement of other environmental or genetic elements that, either in conjunction with APOE*4 or alone, increase an individual's risk of developing AD. Among the candidate genes that may affect the risk of this multifactorial disease is the gene coding for alpha 1-antichymotrypsin (ACT). Like APOE protein, ACT binds to beta-amyloid peptide (A beta P) with high affinity in the filamentous deposits found in the AD brain and serves as a strong stimulatory factor in the polymerization of A beta P into amyloid filaments. In AD brains, ACT expression is enhanced, particularly in areas that develop amyloid plaques, suggesting that ACT may play an important role in the pathogenesis of AD. Here we show that a common polymorphism in the signal peptide of ACT confers a significant risk for AD. Furthermore, the APOE*4 gene dosage effect associated with AD risk is significantly modified by the ACT polymorphism. We have also identified a unique combination of the ACT/AA and APOE 4/4 genotypes as a potential susceptibility marker for AD, as its frequency was 1/17 in the AD group compared to 1/313 in the general population control. Our data show that ACT behaves as a modifier gene that alters the AD risk conventionally associated with the APOE*4 allele.     

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)     

Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease

BACKGROUND: The epsilon4 allele of the gene encoding apolipoprotein E (APOE) is strongly associated with Alzheimer's disease, but its value in the diagnosis remains uncertain. METHODS: We reviewed clinical diagnoses and diagnoses obtained at autopsy in 2188 patients referred to 1 of 26 Alzheimer's disease centers for evaluation of dementia. The sensitivity and specificity of the clinical diagnosis or the presence of an APOE epsilon4 allele were calculated, with pathologically confirmed Alzheimer's disease used as the standard. The added value of the APOE genotype was estimated with pretest and post-test probabilities from multivariate analyses to generate receiver-operating-characteristic curves plotting sensitivity against the false positive rate. RESULTS: Of the 2188 patients, 1833 were given a clinical diagnosis of Alzheimer's disease, and the diagnosis was confirmed pathologically in 1770 patients at autopsy. Sixty-two percent of patients with clinically diagnosed Alzheimer's disease, as compared with 65 percent of those with pathologically confirmed Alzheimer's disease, had at least one APOE epsilon4 allele. The sensitivity of the clinical diagnosis was 93 percent, and the specificity was 55 percent, whereas the sensitivity and specificity of the APOE epsilon4 allele were 65 and 68 percent, respectively. The addition of information about the APOE genotype increased the overall specificity to 84 percent in patients who met the clinical criteria for Alzheimer's disease, although the sensitivity decreased. The improvement in specificity remained statistically significant in the multivariate analysis after adjustment for differences in age, clinical diagnosis, sex, and center. CONCLUSIONS: APOE genotyping does not provide sufficient sensitivity or specificity to be used alone as a diagnostic test for Alzheimer's disease, but when used in combination with clinical criteria, it improves the specificity of the diagnosis.     

Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females

Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles (epsilon2, epsilon3, and epsilon4). Compared with APOE epsilon2 and epsilon3, APOE epsilon4 increases the risk of cognitive impairments, lowers the age of onset of Alzheimer's disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE epsilon4 allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE epsilon4 might affect cognition and increase AD risk. To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE. Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE epsilon4 carriers. NSE-apoE mice and similar models may facilitate the preclinical assessment of treatments for apoE-related cognitive deficits.     

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)     

How shared are age-related influences on cognitive and noncognitive variables?

Several theories have suggested that age-related declines in cognitive processing are due to a pervasive unitary mechanism, such as a decline in processing speed. Structural equation model tests have shown some support for such common factor explanations. These results, however, may not be as conclusive as previously claimed. A further analysis of 4 cross-sectional data sets described in T. Salthouse, D. Hambrick, and K. McGuthry (1998) and T. Salthouse and S. Czaja (2000) found that although the best fitting model included a common factor in 3 of the data sets, additional direct age paths were significant, indicating the presence of specific age effects. For the remaining data set, a factor-specific model fit at least as well as the best fitting common factor model. Three simulated data sets with known structure were then tested with a sequence of structural equation models. Common factor models could not always be falsified-even when they were false. In contrast, factor-specific models were more easily falsified when the true model included a unitary common factor. These results suggest that it is premature to conclude that all age-related cognitive declines are due to a single mechanism. Common factor models may be particularly difficult to falsify with current analytic procedures. (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.