Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline

Associations between postmenopausal hormone therapy (HT) and cognitive decline may depend on apolipoprotein E (APOE) status or timing of initiation. We included 16,514 Nurses' Health Study participants aged 70-81 years who were followed since 1976 and completed up to 3 telephone cognitive assessments (2 years apart), between 1995 and 2006. The tests assessed general cognition (Telephone Interview of Cognitive Status; TICS), verbal memory, and category fluency. We used longitudinal analyses to estimate differences in cognitive decline across hormone groups. APOE genotype was available in 3697 participants. Compared with never users, past or current HT users showed modest but statistically significant worse rates of decline in the TICS: the multivariable-adjusted difference in annual rate of decline in the TICS among current estrogen only users versus never users was -0.04 (95% confidence interval, -0.07 to -0.004); for current estrogen + progestin users, the mean difference was -0.05 (95% confidence interval, -0.10 to -0.002). These differences were equivalent to those observed in women who are 1-2 years apart in age. We observed no protective associations with early timing of hormone initiation. We found suggestive interactions with APOE e4 status (e.g., on TICS, p interaction, 0.10), where the fastest rate of decline was observed among APOE e4 carriers who were current HT users. Regardless of timing of initiation, HT may be associated with worse rates of decline in general cognition, especially among those with an APOE e4 allele.     

APOE ε4 differentially influences change in memory performance depending on age. The SMART-MR study

The apolipoprotein E (APOE) gene may act differently in young and old persons, known as antagonistic pleiotropy. We therefore examined the prospective associations between the APOE ε4 allele and cognitive functioning, and the modifying effect of age, in 375 nondemented adults (mean age 57 ± 10 years; follow-up period 3.8 ± 0.2 years) with available data on APOE genotype and cognitive functioning, within the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) cohort study. Neuropsychological tests assessing memory performance and executive functioning were performed at baseline and follow-up, and composite z-scores were calculated. Age significantly modified the association of APOE ε4 with change in memory performance (p interaction = 0.02). In persons ≤ 57 years (median split), an APOE ε4 allele was associated with an increase in immediate recall (B = 0.42; 95% confidence interval [CI], 0.17 to 0.66) and delayed recall (B = 0.37; 95% CI, 0.09 to 0.64), while in persons > 57 years, an APOE ε4 allele was associated with decline in immediate recall (B = -0.25; 95% CI, -0.52 to 0.01). Our findings suggest that the APOE ε4 allele has a differential effect on change in verbal memory performance depending on age, consistent with the hypothesis of antagonistic pleiotropy.     

Patterns of brain activation in people at risk for Alzheimer's disease

BACKGROUND: The epsilon4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimer's disease, the most common cause of dementia late in life. To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer's disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition. METHODS: We studied 30 subjects (age, 47 to 82 years) who were neurologically normal, of whom 16 were carriers of the APOE epsilon4 allele and 14 were homozygous for the APOE epsilon3 allele. The mean age and level of education were similar in the two groups. Patterns of brain activation during functional MRI scanning were determined while subjects memorized and recalled unrelated pairs of words and while subjects rested between such periods. Memory was reassessed in 14 subjects two years later. RESULTS: Both the magnitude and the extent of brain activation during memory-activation tasks in regions affected by Alzheimer's disease, including the left hippocampal, parietal, and prefrontal regions, were greater among the carriers of the APOE epsilon4 allele than among the carriers of the APOE epsilon3 allele. During periods of recall, the carriers of the APOE epsilon4 allele had a greater average increase in signal intensity in the hippocampal region (1.03 percent vs. 0.62 percent, P<0.001) and a greater mean (+/-SD) number of activated regions throughout the brain (15.9+/-6.2 vs. 9.4+/-5.5, P=0.005) than did carriers of the APOE epsilon3 allele. Longitudinal assessment after two years indicated that the degree of base-line brain activation correlated with degree of decline in memory. CONCLUSIONS: Patterns of brain activation during tasks requiring memory differ depending on the genetic risk of Alzheimer's disease and may predict a subsequent decline in memory.     

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 epsilon4-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 epsilon4 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 epsilon4 alleles failed more profoundly in acquiring and recollecting episodic information than carriers of 1 epsilon4 allele, who in turn failed more than carriers of non-epsilon4 alleles. The pattern of findings observed for older epsilon4 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.     

Common variation in GRB-associated Binding Protein 2 (GAB2) and increased risk for Alzheimer dementia

GRB-associated binding protein 2 (GAB2) was recently reported to be a modifier of late-onset Alzheimer dementia (AD) risk in carriers of the APOE epsilon4 allele in a genome-wide association analysis. We aimed to investigate this association in a well-characterized Belgian late-onset AD patient/control group: 528 Belgian AD patients (mean onset age 79.0+/-5.2 years, 70.2% females) and 601 ethnically matched control individuals (mean age 61.9+/-15.3 years, 57.1% females) were genotyped for 10 SNPs across the GAB2 locus. For 2 SNPs the most common genotype was associated with risk for AD, with the most significant result for rs4945261 [OR 1.49 (95%CI 1.04-2.15)]. After stratification by presence or absence of APOE epsilon4 these associations were present in APOE epsilon4 carriers only. When assessing the effect of APOE and rs4945261 in one model, rs4945261 did not show a main effect, but the joint risk effect of rs4945261-GG and APOE epsilon4 on AD was significant (OR 3.87, 95%CI 2.66-5.63; p=1.0E-12), with a deviation of 1.87 from the multiplicative model of interaction. Haplotype analyses showed evidence of association in the total (global p(sim) 0.04) and APOE epsilon4+ (global p(sim) 0.02) but not in the APOE epsilon4 - group (global p(sim) 0.6). The association was driven by a higher frequency of the major haplotype in patients. Our data independently replicate an association between GAB2 and late-onset AD, which appears to be limited to APOE epsilon4 carriers.     

Cognitive and neural signatures of the APOE E4 allele in mid-aged adults

The apolipoprotein E (APOE) e4 allele is strongly associated with increased risk of cognitive impairments in older adulthood. There is also a possible link to enhanced cognitive performance in younger adults, and the APOE e4 allele may constitute an example of antagonistic pleiotropy. The aim of this work was to investigate the cognitive and neural (functional) effects of the APOE e4 allele during mid-age (45–55 years), where a transition toward cognitive deficit might be expected. APOE e4 carriers (e4+) were compared with non-e4 carriers (e4−) on tasks of sustained and covert attention and prospective memory, and functional magnetic resonance imaging data acquired. Performance by e4+ was equivalent or better than e4− on all 3 tasks, although performance benefits were less pronounced than in youth. Neurally, e4+ showed less task-related recruitment of extrastriate and parietal areas. This became more evident when neural activation data were compared with that of young adults acquired in a parallel study. As expected, mid-age participants showed more diffuse neural activation. Notable was the fact that e4+ showed a relative inability to recruit parietal regions as they aged. This was coupled with a tendency to show greater recruitment of frontal regions, and underactivation of extrastriate visual regions. Thus, mid-age e4+ show a pattern of neural recruitment usually seen later in life, possibly reflecting the source of an accelerated aging profile that describes the e4 genotype.     

Apolipoprotein E and prospective memory in normally aging adults

The epsilon4 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 epsilon4 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 epsilon4 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.     

Substantial effects of apolipoprotein E ε4 on memory decline in very old age: longitudinal findings from a population-based sample

We examined associations between the apolipoprotein E (APOE) ε4 allele and levels of performance and rates of change in cognition in late life taking incident dementia into account. The sample consisted of 482 nondemented individuals, aged 80 years and older at baseline, drawn from the OCTO twin study. A battery of 10 cognitive tests was administered at 5 occasions with measurements intervals of 2 years. We fitted hierarchical linear models with time specified as time to death and controlled for baseline age, sex, education, stroke, cardiovascular disease, hypertension, diabetes, and incident dementia. The ε4 allele was significantly associated with lower levels of performance or steeper rate of decline in all 7 memory tests. Largest effect sizes were found in tests of delayed recall and recognition memory. The effects of the APOE ε4 allele were, however, reduced to a nonsignificant level in all tests except 1 after accounting for incident dementia. The findings support the notion that the APOE ε4 allele is associated with substantial memory decline in very old age, but as expected, the effect is largely related to incident dementia.     

Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults

The apolipoprotein E genotype (APOE) is an established risk factor for Alzheimer disease, with the age-at-onset occurring earlier in individuals having at least one APOE epsilon 4 allele, relative to the APOE epsilon 3 or APOE epsilon 2 isoforms. Moreover, nondemented older adults with the APOE epsilon 4 allele also show diminished cognitive performance, particularly on tests of learning and memory, and an accelerated decline in memory performance with increasing age. The current investigation extends the study of the APOE epsilon 4 allele and cognitive performance to healthy, middle-aged adults. A community sample of 220 non-Hispanic Caucasian men and women, aged 24-60 (average age = 46), were genotyped for the APOE polymorphism and completed a battery of neuropsychological tests. Multivariate analyses were conducted on measures of verbal learning and memory (e. g., learning a list of words and recalling them 30 min later), visual memory (e.g., reproducing a previously copied figure from memory), and attention span (e.g., repeating long lists of digits), after adjustments for age, and estimated IQ. Results indicated that performance on learning and memory tasks was significantly poorer in adults having any APOE epsilon 4 allele, relative to adults with APOE epsilon 2 and epsilon 3 genotypes (P <.01). Attention span did not differ by genotype. These findings, the first in a sample of middle-aged adults, suggest that the APOE polymorphism is a marker for age-related decline in memory (detectable prior to overt, clinical manifestations of memory loss), and/or a marker for individual differences in memory ability across the life span. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:707-711, 2000.     

ESR1 and APOE gene polymorphisms, serum lipids, and hormonal replacement therapy

OBJECTIVES: The risks and benefits of hormone replacement therapy (HRT) are, at least in part, mediated by the metabolic individuality of women. Therefore, we investigated the association between polymorphisms at the estrogen receptor 1 gene (ESR1) and at the apolipoprotein E gene (APOE) with lipid and lipoprotein levels in order to verify whether these concentrations are modulated by these gene variants in women with different hormonal status. METHODS: One hundred and eighteen postmenopausal women using oral HRT with estrogen or estrogen plus progestagen (HRT+, mean age=56+/-6.7 years, 39-75 years) and 167 postmenopausal women that were not on HRT (HRT-, mean age=58+/-9.8 years, 38-85 years) participated in the study. The polymorphisms were genotyped by PCR-RFLP methods. RESULTS: No significant effect of ESR1 genotypes or haplotypes and ESR1*HRT interactions were detected on lipid levels in two-way analysis of variance. Postmenopausal women HRT nonusers carriers of the APOE*4 allele had higher T-chol and LDL-C levels than postmenopausal women HRT nonusers carriers of the APOE*3 and APOE*2 allele. T-chol and LDL-C concentrations in postmenopausal users of HRT that were APOE*4 carriers were similar to those in postmenopausal women nonusers of HRT homozygotes for APOE*3 and APOE*2 carriers. A significant APOE*4/HRT interaction was detected on T-chol and LDL-C levels by multiple regression analysis. CONCLUSION: The results from this study suggest that the HRT influence on T-chol and LDL-C levels is modulated by APOE isoforms but not by ESR1 polymorphisms.     

Interaction of herpesviridae, APOE gene, and education in cognitive impairment

While high age, low level of education and APOE epsilon4 allele are known to predict dementia, there is recent data suggesting that certain viruses and subtypes of APOE epsilon3 could be involved, too. We investigated these relationships in a home-dwelling cohort of 357 elderly people with various cardiovascular diseases (DEBATE study). MMSE score below 24 was used to define cognitive impairment (n = 58). When adjusted for age and the presence of diabetes, multivariate analysis demonstrated maximally increased risk of cognitive impairment in association with a combination of three factors: seropositivity for herpesviridae, presence of APOE epsilon4, and low education (risk ratio 6.1, 95% CI 2.4-15.2). In the subcohort of APOE3/3 individuals (n = 216) homozygosity for the -219G epsilon3 haplotype showed a similar association (risk ratio 8.8, 95% CI 2.6-29.8). These results demonstrate an interaction of specific genetic (APOE) and environmental (education and herpesviridae) risk factors in the development of cognitive impairment and indicate that not only the epsilon4 allele of APOE but also the epsilon3 haplotype is a risk factor for dementia.     

Gene dose of apolipoprotein E and age-related hearing loss

Next to outer hair cell dysfunction, age-related hearing loss may be explained by apolipoprotein E (APOE) genotype. In the Leiden 85-plus Study, a population-based study, the participants were 85 years old. We measured hearing loss by pure-tone audiometry in 435 participants in relation to APOE. Results demonstrated that those with the APOE-ε4/ε4 genotype had the highest levels of hearing loss (n = 6; 56.1 dB), those with the APOE-ε3/ε4 or ε2/ε4 genotype (n = 89) had intermediate levels of hearing loss (51.0 dB), and those without the APOE-ε4 allele (n = 340) had the lowest levels of hearing loss (48.9 dB), p for trend = 0.02. Eighty percent of participants had hearing loss of 35 dB and more, that is, hearing impairment. The APOE-ε4 allele was associated with a 2.0-fold increased risk of hearing impairment (confidence interval [CI 95%], 1.0-4.0), compared with those without the APOE-ε4 allele. The risk for hearing impairment in subjects with the APOE-ε4 allele remained similar after adjustment for cardiovascular disease, stroke, and cognitive impairment. Our results suggest that the APOE-ε4 allele contributes to age-related hearing loss.     

Functional connectivity of the hippocampus in elderly with mild memory dysfunction carrying the APOE epsilon4 allele

The purpose of the present study was to evaluate functional connectivity of the hippocampus during a fMRI face-name learning task in a group of elders with mild memory impairment on the basis of the presence or absence of the APOE epsilon4 allele. Twelve epsilon4 carriers and 20 non-carriers with mild memory dysfunction and exhibiting equivalent performance in clinical evaluations of global cognitive function and memory were studied. Subjects underwent a fMRI session consisting of a face-name encoding memory task. Following scanning, subjects were asked to pair faces with their corresponding proper name. Functional connectivity of the hippocampus was measured by using coherence analysis to evaluate the activity of brain circuits related to memory encoding processes. In contrast to non-APOE epsilon4 allele bearers, APOE epsilon4 carriers showed enhanced connectivity with the anterior cingulate, inferior parietal/postcentral gyrus region and the caudate nucleus. Enhanced hippocampal connectivity with additional brain regions in APOE epsilon4 allele carriers during the performance of an associative memory task may reveal the existence of additional activity in the cortico-subcortical network engaged during memory encoding in subjects carrying this genetic variant.     

No evidence of a longitudinal association between diurnal cortisol patterns and cognition

We examined the effect of salivary cortisol on cognitive performance and decline in 3229 adults (79% men), mean age 61 years. Six saliva samples over the day along with a cognition test battery were administered twice in 5 years. In fully-adjusted cross-sectional analyses from 2002 to 2004, higher waking cortisol was associated with higher reasoning score (β = 0.08, 95% confidence interval: 0.01, 0.15) but this finding was not replicated using data from 2007 to 2009. Over the mean 5 years follow-up there was decline in all cognitive tests but this decline did not vary as a function of cortisol levels; the exception was among APOE e4 carriers where a flatter diurnal slope and higher bedtime cortisol were associated with faster decline in verbal fluency. Changes in cortisol measures between 2002/2004 and 2007/2009 or chronically elevated levels were not associated with cognitive performance in 2007/2009. These results, based on a large sample of community-dwelling adults suggest that variability in hypothalamic-pituitary-adrenal function is not a strong contributor to cognitive aging.     

Effect of the angiotensin I-converting enzyme I/D polymorphism on cognitive decline. The EVA Study Group

Several clinical, epidemiological, and pathological observations suggest that vascular risk factors are associated with cognitive performances. The renin-angiotensin system components, major determinants of the cardiovascular system, are expressed in the brain. To estimate their potential impact on cognitive performances, we studied the association between cognitive functioning and an insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene. In a sample of 1168 highly performing subjects (59-71 years), DD homozygotes had the lowest cognitive scores as evaluated by the Mini-Mental State Examination. Cognitive decline at 4-year follow-up (defined as the loss of at least 3 points in Mini-Mental State Examination score) was more prevalent in these subjects, the odds ratio being equal to 1.53 (95% CI: 1.04-2.24) with subjects ID as reference class. Moreover, the combined effect of the presence of at least one APOE epsilon4 allele and ACE DD homozygosity was a risk factor for cognitive decline. This report reinforces the hypothesis of an influence of cardiovascular risk factors on cognitive performances.     

A distinctive interaction between memory and chronic daytime somnolence in asymptomatic APOE e4 homozygotes

STUDY OBJECTIVES: To correlate memory measures with a trait measure of chronic daytime somnolence in cognitively normal individuals with different gene doses of the apolipoprotein E (APOE) e4 allele, a common Alzheimer's disease susceptibility gene. DESIGN: Cross-sectional, exploratory study of cognitive abilities in APOE e4 homozygotes (HMZ) (n=42), heterozygotes (HTZ), (n=42) and noncarriers (NC) (n=42) who are matched for age, gender, educational level, and family history of dementia. SETTING: Tertiary care academic medical center. PARTICIPANTS: Cognitively normal residents of Maricopa County, Arizona who are 30-70 years of age, genotyped for APOE, and have no history of a sleep disorder INTERVENTIONS: N/A. MEASUREMENTS: Epworth Sleepiness Scale (ESS) and a battery of neuropsychological tests RESULTS: Age, education, gender, and insomnia complaints did not significantly differ among groups. Despite normal baseline memory scores, memory declined with increasing ESS on all eight memory measures in the HMZ, two of eight in the HTZ, and one of eight in the NC. Differences between HMZ and NC on the slope of memory decline with increasing ESS reached statistical significance on two verbal memory measures, AVLT Long-Term Memory (p=0.048) and Percent Delayed Recall (p=0.035). CONCLUSIONS: Chronic daytime somnolence is associated with a distinctive decline in verbal memory in cognitively normal APOE e4 HMZ, a group at particularly high risk of Alzheimer's disease. Additional studies are needed to confirm these exploratory findings and to determine the effects of acute somnolence on cognition in these genetic subgroups.     

The CDC2 I-G-T haplotype associated with the APOE epsilon4 allele increases the risk of sporadic Alzheimer's disease in Sicily

The cell division cycle 2 (CDC2) gene is a candidate susceptibility gene for Alzheimer's disease (AD). We investigated the CDC2 genotype, and allele and haplotype frequencies in AD patients and matched controls, distinguishing between apolipoprotein E (APOE) epsilon4 allele carriers and non-carriers. APOE epsilon4 is an established predictor of AD risk. APOE and CDC2 genotypes were examined in 109 sporadic AD patients and in 110 healthy age- and sex-matched controls from Sicily. The epsilon4 allele of APOE was predictive of AD risk in our study group (odds ratio: 5.37, 95% CI 2.77-10.41; P<0.0001). Genotype and allele frequencies of the three tested CDC2 polymorphisms (Ex6+7I/D, Ex7-15 G>A, Ex7-14 T>A) were not significantly different between AD patients and controls. However, a significant different distribution of a specific CDC2 haplotype (I-G-T) was found between AD patients and controls when analyzing APOE epsilon4-positive subjects (P=0.0288). Moreover, the combined presence of the I-G-T haplotype and the epsilon4 allele almost doubled the risk of AD (odds ratio: 10.09, 95% CI 3.88-26.25; P<0.0001) compared to carriers of epsilon4 alone. This study suggests that the I-G-T haplotype of the CDC2 gene increases the risk of AD in APOE epsilon4 carriers.     

Apolipoprotein E epsilon 4 affects new learning in cognitively normal individuals at risk for Alzheimer's disease

The Apolipoprotein E (APOE) epsilon 4 allele is an important risk factor for Alzheimer's disease (AD). Given the interest in early identification of at-risk individuals, we examined memory decline as a function of APOE status and age in cognitively intact participants aged 48-77 years old (yo). Participants were grouped by age (<60 versus > or =60) and APOE (epsilon4+/-). Longitudinal analysis of several components of memory over a 2-year interval showed a significant Age-by-APOE interaction reflecting a decline in new learning for the > or =60 epsilon4+ group only. Among epsilon4+, 76% of the > or =60 participants showed a decline versus 32% of the <60, but the amount of decline in new learning over the 2-year interval within the > or =60 group was not further influenced by age. That is, the size of the 2-year change was the same for 60 and 70 year old participants. This suggests that longitudinal study of new learning is a sensitive measure for detecting early cognitive changes in at-risk individuals that precede the symptomatic onset of mild cognitive impairment and AD.     

The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades

Neuroimaging shows brain-functional differences due to apolipoprotein E (APOE) polymorphisms may exist decades before the increased risk period for Alzheimer's disease, but little is known about their effect on cognition and brain function in children and young adults. This study assessed 415 healthy epsilon2 and epsilon4 carriers and matched epsilon3/epsilon3 controls, spanning ages 6-65, on a range of cognitive tests. Subjects were also compared on a new dynamical measure of EEG activity during a visual working memory task using alphabetical stimuli. epsilon4 subjects had better verbal fluency compared to epsilon3, an effect that was strongest in 51-65 year-olds. No epsilon4 deficits in cognition were found. In 6-15 year-olds, there were differences in total spatio-temporal wave activity between epsilon3 and epsilon4 subjects in the theta band, approximately 200ms post-stimulus. Differences in brain function in younger epsilon4 subjects and superior verbal fluency across the entire age range suggest that the APOE epsilon4 allele is an example of antagonistic pleiotropy.     

Apolipoprotein ɛ4 and neuropsychological performance in Alzheimer's disease and vascular dementia

The apolipoprotein (APOE) ?4 allele is a genetic risk factor for the development of Alzheimer's disease (AD). It has also been associated with vascular dementia (VaD) in some but not all studies. Previous studies have examined the role of APOE in predicting performance on cognitive tests in both demented and non-demented populations. In cognitively intact individuals, statistically significant group differences between APOE ?4 carriers and non-carriers have been demonstrated for several cognitive domains. In AD studies of the impact of APOE ?4 on cognition have been conflicting while no previous study has assessed cognition and impact of APOE ?4 in VaD. In this study we investigated the impact of APOE ?4 on performance in neuropsychological tests including information processing speed in patients with mild-moderate AD and VaD. We incorporated both computerized and pen and paper tests to ensure a sensitive method of assessing cognition. 109 patients participated in the study (VaD = 41, AD = 68). Neurocognitive performance of 44 ?4 present AD patients was compared to 24 ?4absent patients and performance of 23 ?4 present VaD patients was compared to 18 ?4 absent patients. There was evidence that APOE ?4 conferred a risk of poorer cognitive functioning in both patient groups. In the AD group presence of ?4 conferred a negative impact on some measures of speed of information processing and immediate recall while in the VaD group ?4 present patients had evidence of poorer accuracy on tasks such as choice reaction time and spatial working memory. In AD and VaD groups ?4 present patients showed impairment in selective attention. These findings provide further support of the negative impact of the ?4 allele in cognition.