Preclinical Cognitive Decline Research Articles

HYPERTENSION DOES NOT CONTRIBUTE TO MICROBLEEDS ONSET IN FEMALE EFAD MICE

Cerebral microbleeds (MBs) contribute to pre-clinical cognitive decline and are an additional clinical burden in Alzheimer Disease (AD). Hypertension is associated with MBs, with nearly 2-fold higher likelihood for MBs per SD increment in blood pressure (BP). We investigated the possible role of age-related hypertension in the EFAD mouse model (transgenic for carrying familial AD mutations and targeted replacement of human APO-E3 or -E4). MBs were detected by Prussian Blue histochemistry. We extended prior findings with observations that MBs arise early in life, by 2 months, and confirmed female excess for ApoE3 and-E4 carriers. Wildtype C57BL/6J mice also accumulated MBs, and a 10-fold lower level and more slowly up to 21mo of age. BP was measured by the tail-cuff method. All mice had BP in the normotensive range, <150 mm Hg, systolic. Longitudinal measurements of blood pressure at ages 2, 4, and 6 months showed few age changes, except for E3FAD females at 6 months (systolic, +20%, p<0.05; diastolic, +33%, p<0.05). A possible decrease in blood pressure was observed in EFAD mice (-33%, p<0.01) compared to C57BL/6J mice. A not statistical trend of increase was observed in older C57BL/6J mice up to 18 mo of age, consistent with previous reports. Older ages are required for complete negation of role of hypertension in the MB model. Ongoing studies will examine mice older than 6 months for potential relations of blood pressure and MB, and in relation to brain amyloid deposits which surrounded MBs in our prior study.

A promising structural magnetic resonance imaging assessment in patients with preclinical cognitive decline and diabetes mellitus.

Subjective cognitive decline (SCD) is frequently reported in diabetic patients. Diabetes mellitus (DM) is associated with changes in the microstructure of the brain arise in diabetic patients, including changes in gray matter volume (GMV). However, the underlying mechanisms of changes in GMV in DM patients with cognitive impairment remain uncertain. Here, we present an overview of amyloid-β-dependent cognitive impairment in DM patients with SCD. Moreover, we review the evolving insights from studies on the GMV changes in GMV and cognitive dysfunction to which provide the mechanisms of cognitive impairment in T2DM. Ultimately, the novel structural magnetic resonance imaging (MRI) protocol was used for detecting neuroimaging biomarkers that can predict the clinical outcomes in diabetic patients with SCD. A reliable MRI protocol would be helpful to detect neurobiomarkers, and to understand the pathological mechanisms of preclinical cognitive impairment in diabetic patients.

A Three-Factor Structure of Cognitive Functioning Among Unimpaired Carriers and Non-Carriers of Autosomal-Dominant Alzheimer's Disease.

There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline. We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset. The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

Device-Embedded Cameras for Eye Tracking-Based Cognitive Assessment: Validation With Paper-Pencil and Computerized Cognitive Composites.

BackgroundAs eye tracking-based assessment of cognition becomes more widely used in older adults, particularly those at risk for dementia, reliable and scalable methods to collect high-quality data are required. Eye tracking-based cognitive tests that utilize device-embedded cameras have the potential to reach large numbers of people as a screening tool for preclinical cognitive decline. However, to fully validate this approach, more empirical evidence about the comparability of eyetracking-based paradigms to existing cognitive batteries is needed.ObjectiveUsing a population of clinically normal older adults, we examined the relationship between a 30-minute Visual Paired Comparison (VPC) recognition memory task and cognitive composite indices sensitive to a subtle decline in domains associated with Alzheimer disease. Additionally, the scoring accuracy between software used with a commercial grade eye tracking camera at 60 frames per second (FPS) and a manually scored procedure used with a laptop-embedded web camera (3 FPS) on the VPC task was compared, as well as the relationship between VPC task performance and domain-specific cognitive function.MethodsA group of 49 clinically normal older adults completed a 30-min VPC recognition memory task with simultaneous recording of eye movements by a commercial-grade eye-tracking camera and a laptop-embedded camera. Relationships between webcam VPC performance and the Preclinical Alzheimer Cognitive Composite (PACC) and National Institutes of Health Toolbox Cognitive Battery (NIHTB-CB) were examined. Inter-rater reliability for manually scored tests was analyzed using Krippendorff’s kappa formula, and we used Spearman’s Rho correlations to investigate the relationship between VPC performance scores with both cameras. We also examined the relationship between VPC performance with the device-embedded camera and domain-specific cognitive performance.ResultsModest relationships were seen between mean VPC novelty preference and the PACC (r=.39, P=.007) and NIHTB-CB (r=.35, P=.03) composite scores, and additional individual neurocognitive task scores including letter fluency (r=.33, P=.02), category fluency (r=.36, P=.01), and Trail Making Test A (–.40, P=.006). Robust relationships were observed between the 60 FPS eye tracker and 3 FPS webcam on both trial-level VPC novelty preference (r=.82, P<.001) and overall mean VPC novelty preference (r=.92 P<.001). Inter-rater agreement of manually scored web camera data was high (kappa=.84).ConclusionsIn a sample of clinically normal older adults, performance on a 30-minute VPC task correlated modestly with computerized and paper-pencil based cognitive composites that serve as preclinical Alzheimer disease cognitive indices. The strength of these relationships did not differ between camera devices. We suggest that using a device-embedded camera is a reliable and valid way to assess performance on VPC tasks accurately and that these tasks correlate with existing cognitive composites.

Smoking, APOE Genotype, and Cognitive Decline: The Rotterdam Study.

The association of smoking with preclinical cognitive decline remains unclear and may be modified by the APOEɛ4 genotype. In 5,705 participants (mean age: 63.9±9.1 years; 57.4% women) from the population-based Rotterdam Study, we investigated the relationship between smoking and cognitive decline over a 5.5-year period and examined potential effect modification by APOEɛ4 genotype. We found that current smoking was related to decline in global cognition [difference compared to never smoking: -0.06 (95% C.I.-0.10;-0.01)], as well as decline on specific cognitive tests including the Letter Digit Substitution Task, the 15-Word Learning Test, and the Purdue Pegboard. We found no evidence for effect modification by APOEɛ4 genotype on this relation.

Peripheral inflammation related to lower fMRI activation during a working memory task and resting functional connectivity among older adults: a preliminary study.

Peripheral inflammation has been associated with adverse effects on cognition and brain structure in late life, a process called 'inflammaging.' Identifying biomarkers of preclinical cognitive decline is critical in the development of preventative therapies, and peripheral inflammation may be able to serve as an indicator of cognitive decline. However, little is known regarding the relationship between peripheral inflammation and brain structure and function among older adults. Twenty-four older adults (mean age = 78) underwent a functional magnetic resonance imaging (fMRI) resting state functional connectivity scan, and a subset (n = 14) completed the n-Back working memory task in the scanner. All participants completed a blood draw, and inflammation was measured with interleukin 6 (IL-6) and C-Reactive Protein (CRP). Surprisingly, age was unrelated to measures of inflammation (IL-6, CRP) or brain function (default mode network (DMN) connectivity; working memory performance; blood oxygenation level dependent (BOLD) activation with higher working memory load). However, lower functional connectivity between the left parietal seed and all other DMN regions was associated with higher levels of IL-6 and CRP. Additionally, greater plasma concentration of IL-6 was associated with lower BOLD activation in the left middle frontal gyrus in response to increased working memory load. These preliminary findings support the importance of IL-6 and CRP in brain function among older adults. Frontal and parietal regions may be particularly sensitive to the effects of inflammation. Additionally, these findings provide preliminary evidence of inflammatory contributions to level of neural activity, even after accounting for vascular risk factors.

Cognitive Decline in a Colombian Kindred With Autosomal Dominant Alzheimer Disease: A Retrospective Cohort Study.

Data from an autosomal dominant Alzheimer disease (ADAD) kindred were used to track the longitudinal trajectory of cognitive decline associated with preclinical ADAD and explore factors that may modify the rate of cognitive decline. To evaluate the onset and rate of cognitive decline during preclinical ADAD and the effect of socioeconomic, vascular, and genetic factors on the cognitive decline. We performed a retrospective cohort study from January 1, 1995, through June 31, 2012, of individuals from Antioquia, Colombia, who tested positive for the ADAD-associated PSEN1 E280A mutation. Data analysis was performed from August 20, 2014, through November 30, 2015. A mixed-effects model was used to estimate annual rates of change in cognitive test scores and to mark the onset of cognitive decline. Memory, language, praxis, and total scores from the Consortium to Establish a Registry for Alzheimer Disease test battery. Chronologic age was used as a time scale in the models. We explore the effects of sex; educational level; socioeconomic status; residence area; occupation type; marital status; history of hypertension, diabetes mellitus, and dyslipidemia; tobacco and alcohol use; and APOE ε4 on the rates of cognitive decline. A total of 493 carriers met the inclusion criteria and were analyzed. A total of 256 carriers had 2 or more assessments. At the time of the initial assessment, participants had a mean (SD) age of 33.4 (11.7) years and a mean (SD) educational level of 7.2 (4.2) years. They were predominantly female (270 [54.8%]), married (293 [59.4%]), and of low socioeconomic status (322 [65.3%]). Word list recall scores provided the earliest indicator of preclinical cognitive decline at 32 years of age, 12 and 17 years before the kindred's respective median ages at mild cognitive impairment and dementia onset. After the change point, carriers had a statistically significant cognitive decline with a loss of 0.24 (95% CI, -0.26 to -0.22) points per year for the word list recall test and 2.13 (95% CI, -2.29 to -1.96) points per year for total scores. Carriers with high educational levels had an increase of approximately 36% in the rate of cognitive decline after the change point when compared with those with low educational levels (-2.89 vs -2.13 points per year, respectively). Onset of cognitive decline was delayed by 3 years in individuals with higher educational levels compared with those with lower educational levels. Those with higher educational level, middle/high socioeconomic status, history of diabetes and hypertension, and tobacco and alcohol use had a steeper cognitive decline after onset. Preclinical cognitive decline was evident in PSEN1 E280A mutation carriers 12 years before the onset of clinical impairment. Educational level may be a protective factor against the onset of cognitive impairment.

Association of Occlusal Force with Cognition in Independent Older Japanese People.

Recent longitudinal studies have shown the influence of multiple tooth loss on cognitive impairment, and earlier studies suggested that periodontal disease was related to cognitive decline. Tooth loss is associated with reduced masticatory function, which may affect stimulation of the central nervous system and dietary intake. Although some studies have reported a relationship between chewing ability and cognitive function, no studies have examined this area in terms of objective oral function. The aim of this study was to examine the association of occlusal force with cognitive decline in the preclinical stage among older people with higher-level functional capacity. This cross-sectional study for community-dwelling older people living in urban and rural areas in Japan examined 994 persons in the 70-y group (age range, 69-71 y) and 968 persons in the 80-y group (age range, 79-81 y). Retention of higher-level competence was defined according to the Tokyo Metropolitan Institute of Gerontology Index of Competence. Cognitive function was measured with the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Oral status and function were assessed by the number of remaining teeth, periodontal pocket depth, and maximal occlusal force. Associations between the MoCA-J score and occlusal force were examined by bivariate and multivariate analysis. Approximately one-half of the participants retained higher-level functional capacity and were included in the analysis. Multiple regression analysis showed that occlusal force was significantly related to cognitive function after controlling for possible predictors including age, sex, socioeconomic status, medical condition, and handgrip strength. The number of remaining teeth and periodontal pocket depth were not significantly associated with cognitive function. Among community-dwelling older people with retained competence, maximal occlusal force was positively associated with their cognitive function. These results suggest that oral function might be a predictor for preclinical cognitive decline. Knowledge Transfer Statement: Multiple regression analysis showed that occlusal force was significantly related to cognition after controlling for possible predictors including handgrip strength as an indicator of general muscle strength, suggesting the independence of oral function. The number of remaining teeth did not have this association. The majority of older people have lost teeth and have received prosthodontic treatment, and their occlusal force is determined not only by the number of remaining teeth but also by prosthetic rehabilitation. These results can be used by clinicians focusing on prevention of tooth loss among the entire population, as well as to encourage partially edentulous and fully edentulous patients to restore their oral function with prostheses in order to eliminate a possible risk factor for cognitive impairment.

Trajectories of decline in cognition and daily functioning in preclinical dementia

IntroductionAlthough preclinical dementia is characterized by decline in cognition and daily functioning, little is known on their temporal sequence. We investigated trajectories of cognition and daily functioning in preclinical dementia, during 18 years of follow-up. MethodsIn 856 dementia cases and 1712 controls, we repetitively assessed cognition and daily functioning with memory complaints, mini-mental state examination (MMSE), instrumental activities of daily living (IADL), and basic activities of daily living (BADL). ResultsDementia cases first reported memory complaints 16 years before diagnosis, followed by decline in MMSE, IADL, and finally BADL. Vascular dementia related to earlier decline in daily functioning but later in cognition, compared with Alzheimer's disease. Higher education related to larger preclinical cognitive decline, whereas apolipoprotein E (APOE) ε4 carriers declined less in daily functioning. DiscussionThese results emphasize the long hierarchical preclinical trajectory of functional decline in dementia. Furthermore, they show that various pathologic, environmental, and genetic factors may influence these trajectories of decline.

Refined sugar intake is associated with lower cognitive performance across the cognitive continuum but is not associated with preclinical cognitive decline in intact elderly subjects (P7.111)

Refined sugar intake is associated with lower cognitive performance across the cognitive continuum but is not associated with preclinical cognitive decline in intact elderly subjects (P7.111)

Establishing Composite Cognitive Endpoints for Use in Preclinical Alzheimer's Disease Trials.

Establishing Composite Cognitive Endpoints for Use in Preclinical Alzheimer's Disease Trials.

Exaggerated reaction to novelty as a subclinical consequence of mild traumatic brain injury

Objectives: To evaluate exaggerated reaction to novelty as a behavioural marker of sub-clinical cognitive dysfunction in individuals with a history of mild traumatic brain injury (mTBI).Background and hypothesis: A sub-set of individuals who sustain mTBIs report persistent cognitive difficulties despite normal performance on traditional neuropsychological measures. Evidence of subtle neuroimaging abnormalities following mTBI lends support to such subjective complaints. However, behavioural evidence is limited. This study examined whether behavioural response to task novelty (‘novelty effect’ or NE) is exaggerated in mTBI (NE has previously successfully identified pre-clinical cognitive decline among older adults). It was hypothesized that individuals with a history of mTBI would exhibit increased NE relative to controls, despite normal performance on traditional neuropsychological measures.Methods: Thirty-eight male criminal offenders completed semi-structured interviews of their mTBI and other history, conventional neuropsychological testing and a computerized motor planning task that quantified NE.Results: As expected, participants with a history of mTBI exhibited significantly greater NE, despite no group differences in traditional neuropsychological test performance. A greater number of injuries was positively related to NE magnitude and unrelated to traditional measures.Conclusions: Increased NE indexes sub-clinical sequelae of mTBI and may represent a general marker of mild neurological dysfunction.

Preliminary evidence for low openness to experience as a pre-clinical marker of incipient cognitive decline in older adults

The current study examined self-reported Openness to Experience as a marker of incipient cognitive decline among older adults. Seventy five cognitively-intact, community-dwelling adults ages 58–87 were assessed with the NEO Personality Inventory-Revised (NEO PI-R; (Costa & McCrae, 1992) and the Mattis Dementia Rating Scale 2nd edition (DRS-2; (Mattis, Jurica, & Leitten, 1988) to examine association with incipient decline over approximately 1year. Low Openness to Experience was associated with decline, controlling for baseline screening scores, age, education, and the other four personality factors. Examination of facet-level associations indicated that lower scores on the Values and Aesthetics facets of Openness primarily explained the association. Current findings build on prior research suggesting that exaggerated reaction to novelty may signal pre-clinical cognitive decline.

Fibrillar amyloid correlates of preclinical cognitive decline

BackgroundIt is not known whether preclinical cognitive decline is associated with fibrillar β-amyloid (Aβ) deposition irrespective of apolipoprotein E (APOE) ε4 status. MethodsFrom a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ε4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral-to-cerebellar PiB distribution volume ratios (DVRs), reflecting fibrillar Aβ burden. ResultsAt P < .005 (uncorrected), decliners had significantly greater DVRs in comparison to nondecliners. ConclusionsAsymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ε4 genotype.

The effect of amyloid β on cognitive decline is modulated by neural integrity in cognitively normal elderly

ObjectiveAlzheimer's disease (AD) pathology of amyloid β (Aβ) accumulation and neurodegeneration may be relevant to preclinical cognitive decline. The objective of this study was to relate AD-sensitive biomarkers of Aβ and neurodegeneration and their interaction to longitudinal cognitive change in cognitively normal elderly. MethodsThirty-eight older people completed at least three consecutive neuropsychological examinations. Using positron emission tomography (PET), Aβ plaque burden was measured with [11C]Pittsburgh compound B (PiB). PiB retention was dichotomized into a positive (n = 13) and negative (n = 25) PiB status. Neurodegenerative biomarkers were extracted within AD-vulnerable regions of interest (ROIs)—namely, the hippocampus and temporoparietal cortical areas. Within each ROI, metabolism was quantified with [18F] fluorodeoxyglucose (FDG) PET, and the gray matter structure was evaluated using volume (hippocampus) or thickness (cortical regions). ROI-specific functional and structural biomarkers were combined further into cross-modality neurodegenerative composite measures. Using hierarchical regression models, PiB and the neurodegenerative biomarkers were related to cognitive trajectories. ResultsPiB positivity was associated with memory and nonmemory worsening. The neurodegenerative biomarkers modified these relationships. Longitudinal cognitive decline was accelerated in those individuals who exhibited both PiB positivity and lower neurodegenerative biomarker scores, although the two measures appeared to be independent. PiB retention interacted predominantly with the cortical neurodegenerative composite for nonmemory change. Memory decline was best explained by the interaction between PiB and the hippocampal neurodegenerative composite, suggesting regional specificity of the neurodegenerative modulations. ConclusionsOur findings indicate that cognitive trajectories deteriorate at a faster rate in cognitively normal individuals expressing Aβ burden and neurodegeneration within specific AD-sensitive regions.

Prevalence and Clinical Correlates of Restless Legs Syndrome in an Elderly French Population: The Synapse Study

The occurrence of restless legs syndrome (RLS) in elderly individuals is well known but the incidence and the clinical correlates in these subjects are still unclear. The present study explores the prevalence of and assesses symptoms associated with RLS in an older French population. The study sample for this study comprised 318 subjects (219 women and 99 men), aged 68.6 +/- 0.8 years. All subjects underwent clinical assessment, nocturnal polygraphy, and cognitive and mood disorders evaluation. RLS was assessed with the standard validated criteria and severity was evaluated by the use of International Restless Legs Syndrome Study Group (IRLS) questionnaire. RLS was present in 24.2% of the sample, prevalence being greater in women (29.7%) than in men (12.1%). The mean IRLS score was 16.6 +/- 4.8, 67% of cases having mild to moderate range. Participants with RLS reported greater hypnotic (p < .001) and antidepressant medication intake (p < .001) and had higher anxiety (p < .001) and depression (p < .001) scores. Participants with RLS had lower cognitive performances at Stroop and Verbal fluency tests than participants without RLS (p < .05 and p = .002, respectively). These associations remained significant after multivariate adjustment for medication, depression, and subjective sleep. Presence of undiagnosed RLS is higher in healthy elderly participants without previously diagnosed sleep disorders, affecting women more often than men. The presence of RLS increased the risk of anxiety and mood disorders and predispose to preclinical cognitive decline independently of anxiety, mood disorders, duration and quality of sleep, and medication.

Preclinical cognitive decline and subsequent sleep disturbance in older women

To determine whether longitudinal cognitive decline is associated with increased risk of sleep disturbance in older, nondemented, community-dwelling women. We studied 2,474 women (mean age 68.9 years) who were part of a prospective study started in 1986; women with baseline or follow-up evidence of possible dementia were excluded. Cognitive data were gathered over 15 years for modified Mini-Mental State Examination (mMMSE) and 13 years for Trails B; cognitive decline was defined as declining >1.5 SDs on the mMMSE (> or =3 points) or Trails B (>92 seconds). Sleep disturbance was measured objectively using actigraphy (Sleepwatch-O, Ambulatory Monitoring) at the 15-year follow-up visit; measures included total sleep hours, sleep efficiency, sleep latency, napping, and time awake after sleep onset (WASO). During follow-up, 11% of women declined on mMMSE and 15% on Trails B. Cognitive decliners were more likely than non-decliners to experience sleep disturbance at follow-up on most measures. For women who declined on mMMSE, adjusted ORs (aOR) (95% CI) were 1.71 (1.24, 2.37) for sleep efficiency <70%, 1.57 (1.12, 2.21) for sleep latency > or =1 hour, and 1.43 (1.07, 1.92) for WASO > or =90 minutes. Results were similar for women who declined on Trails B; in addition, these women were more likely to nap >2 hours per day (aOR: 1.73; 95% CI: 1.28, 2.33). Cognitive decline on either test was not associated with total sleep time. Cognitive decline is associated with sleep disturbance in nondemented community-dwelling elderly women.

S1-01-04: Estrogens / endogeneous & exogeneous

Cognitive impairment affects at least 10% of elders aged 65 years and older, increasing in prevalence to 50% of elders 85 years of age and older. In hopes of identifying agents that may prevent cognitive impairment, there has been tremendous interest in the role of both exogenous and endogenous hormones and risk of Alzheimer's disease (AD) and pre–clinical cognitive decline, especially in women. Indeed, estogen receptors (ER) (both ER α and ER β) are located throughout the brain, especially in regions involved in learning and memory such as the hippocampus and amygdala. However, studies in women involving estrogens have been conflicting with the predonderance of observational studies suggesting benefit and the randomized trials suggesting no benefit and possible harm. We will review the current evidence of the effect of exogenous estrogen and the risk of developing dementia. In addition, we will discuss results from studies of selective estrogen receptor modulators (SERMs) and highlight areas of future research with these and other novel estrogenic compounds. We will also review the literature on endogenous estrogens and cognitive function and risk of AD and suggest future directions for research.

Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein E-e4/4 homozygotes: a replication study

In a previous cross-sectional study of 100 asymptomatic individuals aged 49–69, we reported age-related decline in immediate and delayed memory that was steeper in apolipoprotein E (apoE)-e4/4 homozygotes than in members of other genetic subgroups. These findings were preliminarily based upon the statistical problem of multiple comparisons. We therefore sought to replicate these findings in a new cohort. From 1998 to 2000, 80 asymptomatic residents of Maricopa County, AZ were recruited through newspaper ads. 20 apoE-e4/4 homozygotes, 20 e3/4 heterozygotes, and 40 e4 noncarriers were matched (1:1:2) by age, gender, and years of education. All had normal neurologic and psychiatric examinations, including Folstein minimental status exam (MMSE) and Hamilton depression scale, and underwent a battery of neuropsychological tests identical to those in our previous study. The groups were well-matched for age (55.9±5.9 years), gender (60% women), and education (15.9±2.2 years), and were demographically similar to our previous cohort. Complex figure test recall was lower in e3/4 heterozygotes than noncarriers, but there was no significant difference between e4/4 homozygotes and noncarriers. There were no other significant differences in mean test scores between groups, but Wechsler adult intelligence scale-revised (WAIS-R) digit span showed a significant negative correlation with age in the e4/4 homozygote group relative to e4 noncarriers ( p=0.008) as we had found in our previous study. In conclusion, we found a significant negative correlation of WAIS-R digit span with age in apoE-e4/4 homozygotes relative to e4 noncarriers in two separate cohorts, possibly reflecting an age-related effect on frontal lobe function in this genetic subgroup.