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The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE *2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and β-amyloid (Aβ) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aβ or tau PET overall, stratified by racialized group, and with a racialized group interaction. We included 358 older adults (42% African American) with Aβ PET, 134 (29% African American) of whom had tau PET. APOE*4 was associated with higher Aβ in non-Hispanic white (P < 0.0001), but not African American (P = 0.64) participants; racialized group modified the association between APOE*4 and Aβ (P < 0.0001). There were no other racialized group differences. These results suggest that the association of APOE*4 and Aβ differs between African American and non-Hispanic white populations. Other drivers of AD pathology in African American populations should be identified as potential therapeutic targets. • APOE*4 is associated with Aβ in non-Hispanic white, but not African American, participants • There were no racialized group differences in associations of APOE*4 with tau • There were no racialized group differences in associations of APOE*2 with Aβ and tau [ABSTRACT FROM AUTHOR]

• What is the primary question addressed by this study? We investigated whether the presence of small vessel disease (SVD) (measured as significant WMH burden) altered the associations between brain amyloid-beta (Aβ) and hippocampal functional connectivity during associative encoding in cognitively normal older adults. • What is the main finding of this study? In older adults with significant WMH burden (WMH+), greater Aβ burden was associated with a more localized pattern of hippocampal-medial temporal lobe (MTL) hyperconnectivity, but not in individuals with minimum WMH burden (WMH-). This local hippocampal-MTL hyperconnectivity is associated with local MTL atrophy. • What is the meaning of the finding? These observations support a hippocampal excitotoxicity model linking SVD to neurodegeneration in pre-clinical AD. This may explain how SVD may accelerate the progression from Aβ positivity to neurodegeneration, and subsequent AD. Small Vessel Disease (SVD) is known to be associated with higher AD risk, but its relationship to amyloidosis in the progression of AD is unclear. In this cross-sectional study of cognitively normal older adults, we explored the interactive effects of SVD and amyloid-beta (Aβ) pathology on hippocampal functional connectivity during an associative encoding task and on hippocampal volume. This study included 61 cognitively normal older adults (age range: 65–93 years, age mean ± standard deviation: 75.8 ± 6.4, 41 [67.2%] female). PiB PET, T2-weighted FLAIR, T1-weighted and face-name fMRI images were acquired on each participant to evaluate brain Aβ, white matter hyperintensities (WMH+/- status), gray matter density, and hippocampal functional connectivity. We found that, in WMH (+) older adults greater Aβ burden was associated with greater hippocampal local connectivity (i.e., hippocampal-parahippocampal connectivity) and lower gray matter density in medial temporal lobe (MTL), whereas in WMH (-) older adults greater Aβ burden was associated with greater hippocampal distal connectivity (i.e., hippocampal-prefrontal connectivity) and no changes in MTL gray matter density. Moreover, greater hippocampal local connectivity was associated with MTL atrophy. These observations support a hippocampal excitotoxicity model linking SVD to neurodegeneration in preclinical AD. This may explain how SVD may accelerate the progression from Aβ positivity to neurodegeneration, and subsequent AD. [ABSTRACT FROM AUTHOR]

Background: Social cognition indicates the cognitive processes involved in perceiving, interpreting, and processing social information. Although it is one of the six core DSM-5 cognitive domains for diagnosing neurocognitive disorders, it is not routinely assessed in older adults. The Reading the Mind in the Eyes Test assesses Theory of Mind, the social cognition mechanism which forms the root of empathy.Objectives: To describe the distribution of, and factors associated with, scores on a 10-item version of Reading the Mind in the Eyes Test (RMET-10) in older adults.Design: Population-based cross-sectional study.Setting: Small-town communities in Pennsylvania.Participants: Adults aged 66-105 years (N = 902, mean age = 76.6).Measurements: The assessment included RMET-10, demographics, cognitive screening, literacy, depression symptoms, anxiety symptoms, cognitive composites derived from a neuropsychological test battery, Social Norms Questionnaire, and Clinical Dementia Rating (CDR).Results: RMET-10 score was normally distributed in our overall study sample. Normative RMET-10 scores among those rated as CDR = 0 were calculated by age, sex, and education. RMET-10 score was significantly higher with younger age, higher education, white race, higher cognitive screening scores, literacy, social norms scores, higher scores in all five domains in cognitive composites, and lower CDR. RMET-10 score was also significantly higher with fewer depression and anxiety symptoms after adjusting for demographics.Conclusions: The RMET is a potentially useful measure of social cognition for use in the research assessment of older adults. With appropriate calibration it should also have utility in the clinical setting. [ABSTRACT FROM AUTHOR]

Introduction: In cognitively healthy older adults, amyloid-beta (Aβ) burden is associated with greater activity on task-based functional magnetic resonance imaging. Higher levels of functional activation are associated with other factors along with amyloid and the authors investigated these relationships as well as how they relate to Aβ in cognitively healthy older adults.Methods: The authors recruited cognitive healthy older adults (N = 50) from the Pittsburgh community that underwent extensive cognitive batteries, activation during a working memory (digit symbol substitution task, DSST), positron emission tomography scan for Pittsburgh Compound B (PiB, measuring amyloid), and other demographic measures. The authors tested the association between DSST activation and global PiB, neurocognitive batteries, and education.Results: The authors found that the DSST robustly activated expected structures involved in working memory. The authors found that greater global Aβ deposition was associated with greater DSST activation in the right calcarine, precuneus, middle temporal as well as the left insula and inferior frontal gyrus. The authors also found that greater education was associated with lower DSST activation - however this was not significant after adjusting for Aβ.Discussion: Greater amyloid was associated with greater activation, which may represent compensatory activation. Greater education was associated with lower activation, which may represent more efficient activation (i.e., less activation for the same task). After adjusting for amyloid, education was not significantly associated with activation suggesting that during the preclinical stage amyloid is the primary determinant of activation. Further, activation was not associated with cognitive function. Compensatory activation in the preclinical stage may help maintain cognitive function. [ABSTRACT FROM AUTHOR]

Several studies have investigated how lifetime cognitive engagement affects levels of amyloid-beta (Aβ) deposition in the brain. However, there has been some disagreement, leaving the relationship of cognitive activity (CA) to Aβ a largely open question. The present study investigated the relationship between CA, Aβ deposition, and glucose metabolism. One hundred nine cognitively normal participants underwent Pittsburgh Compound-B (PiB) and [18F]fluorodeoxyglucose-positron emission tomography and completed a questionnaire designed to measure current CA. Statistical analyses revealed significant differences in PiB retention between those in the high and low CA groups. Linear regression models revealed a significant negative relationship between PiB retention and CA and a significant positive relationship between glucose metabolism and CA. These data suggest that CA may have a direct beneficial effect on the pathophysiology of AD or reflect another underlying process that results in both higher CA and lower AD pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Much is unknown about changes that occur in the brain in the years preceding the cognitive and functional impairment associated with Alzheimer disease (AD). This period before mild cognitive impairment is present has been referred to as preclinical AD, and is thought to begin with amyloid-beta deposition and then progress to neurodegeneration and functional brain circuit alterations. Prior studies have shown that there is increased medial temporal lobe activation on functional magnetic resonance imaging (fMRI) early in the course of mild cognitive impairment. It is unknown, however, whether this altered fMRI activity precedes cognitive impairment. The purpose of this study is to address this question using Pittsburgh Compound-B (PiB) imaging and fMRI in a sample of cognitively normal older adults.Methods: Forty-four cognitively normal older adults underwent both PiB imaging and fMRI with a face-name memory task: 21 were classified as PiB(+) and 23 were PiB(-). Additionally, thorough cognitive and neuropsychological test batteries were administered outside the scanner. The main outcome measure in this study is fMRI activation in the medial temporal lobe during a face-name memory-encoding task.Results: PiB(+) subjects showed higher fMRI activation during the memory task in the hippocampus relative to PiB(-) participants.Conclusions: The increased medial temporal lobe activation in preclinical AD, observed in this study, may serve as an early biomarker of neurodegeneration. Future studies are needed to clarify whether this functional biomarker can stratify AD risk among PiB(+) older adults. [ABSTRACT FROM AUTHOR]

Objective: To examine the relationships over time between dual trajectories of depressive symptoms and several cognitive domains.Methods: In a 5-year longitudinal study, 1,978 randomly selected individuals aged 65+ years at recruitment were assessed annually. Repeated measures were of depressive symptoms on the modified Center for Epidemiologic Studies Depression Scale and composite scores in the cognitive domains of attention, executive function, memory, language, and visuospatial function. Latent class trajectories were identified for depression and for each cognitive domain and their associations investigated using dual trajectory modeling. Cognitive trajectories with z scores below -1 were designated as persistently low.Results: Five depressive symptom trajectories were observed: rarely depressed (60.5%); low-grade, decreasing symptoms (18.5%); low-grade, increasing symptoms (9.6%); moderate-grade symptoms (7.4%); and consistent higher-grade symptoms (4.0%). For each cognitive domain six trajectories were observed. The rarely depressed and low-grade decreasing symptom groups were the least likely to have persistently low cognition. The symptom trajectory most strongly associated with persistently low functioning in each domain was not the higher-grade group but rather the low-grade increasing group in the case of attention and the moderate-grade trajectory in the other four domains.Conclusion: Consistently higher-grade depressive symptoms are less strongly associated with poor cognitive functioning than with either moderate- or low-grade increasing depressive symptom trajectories, over time and across different domains. Examining both depression and cognition longitudinally allows heterogeneity of both to be addressed, revealing latent groups with potential diagnostic and prognostic implications. [ABSTRACT FROM AUTHOR]

Social cognition is the cognitive domain that processes social information, the means by which we make sense of ourselves in relation to others and our environments. Impaired social cognition is associated with functional dependence on others and can have dire social consequences leading to social isolation, increasing the risk for morbidity and mortality. Social cognition is be impaired in neurodegenerative disorders including Alzheimer's disease (AD). The most recent edition of the American Psychiatric Association's Diagnostic and Statistical Manual for Mental Disorders (DSM-5) include social cognition as one of six core domains of neurocognitive function, alongside memory, executive control, complex attention, language, and visuospatial/perceptuomotor function, that can be impaired in the neurocognitive disorders. We have previously reported population-based norms from older adults on two social cognition measures, the Social Norms Questionnaire [SNQ-22], assessing social perception, and the 10-question version of the Reading the Mind in the Eyes Test [RMET-10], measuring Theory of Mind (ToM). Here, we report on the utility of a social cognition composite measure comprising the SNQ-22 and the RMET-10. Participants are 902 adults from a population-based cohort in Pennsylvania. The mean age is 76.6 years (SD 8.06). We created a social cognition composite comprising standardized z-scores on the Social Norms Questionnaire and the 10-item Reading the Mind in the Eyes Test. We described its distribution in the population-based sample of older adults, its association with demographic factors, other cognitive and behavioral measures, the Clinical Dementia Rating (CDR®). We compared sensitivity, specificity, and the area under the curve of social cognition to those of other cognitive domains for mild cognitive impairment (MCI). We calculated the impact of including social cognition as a sixth cognitive domain on the estimated prevalence of (cohort proportion classified as) neuropsychologically defined MCI. Better social cognition was associated with younger age, female sex, higher education, better general cognition (MMSE), fewer depressive symptoms, and lower Clinical Dementia Rating (CDR). Adjusting for demographics, associations with higher MMSE and fewer depressive symptoms, anxiety symptoms, and subjective cognitive complaints remained significant. The sensitivity and specificity of social cognition for CDR = 0.5 were comparable to those of the traditional five cognitive domains. Including social cognition as the sixth domain of cognition resulted in a 5% increase in the estimated prevalence of MCI. Better social cognition was associated with younger age, female sex, higher education, better general cognition (MMSE), fewer depressive symptoms, and lower Clinical Dementia Rating (CDR). Adjusting for demographics, associations with higher MMSE and fewer depressive symptoms, anxiety symptoms, and subjective cognitive complaints remained significant. We found that social cognition had sensitivity, specificity for CDR that was comparable to those of the five conventional cognitive domains of attention, executive functions, language, memory, and visuospatial function. The AUC values in the 0.6 – 0.7 range, which were comparable to the reported values in the literature. Considering neuropsychologically defined MCI, the inclusion of social cognition as the sixth domain of cognition resulted in about 5% of the sample becoming newly classified as MCI. These individuals differed from those already classified as MCI only in having higher MMSE scores; but they differed from those still classified as normal in having more anxiety symptoms, lower reading levels, and impairment in the CDR domain of home and hobbies. It appears a worthwhile consideration for standard cognitive assessments in older adults to routinely include brief objective assessments of the social cognition domain. The word reported here was supported in part by research grant # R37AG023657 from the National Institute on Aging, National Institutes of Health, US Department of Health and Human Services. [ABSTRACT FROM AUTHOR]

The article discusses a study on the relationship between subjective cognitive complaints (SCC) and amyloid-beta deposition relative to the personality traits of older individuals with normal cognition. Topics covered include the use of the Memory Functioning Questionnaire General Frequency of Forgetting factor as a predictor for Alzheimer's Disease, the link between neuroticism and conscientiousness in SCC and risk for dementia, and education as not associated in any variable.

Highlights: [•] Molecular and anatomical data imply high dimensionality in olfactory perception. [•] Psychophysics uncover low dimensionality in olfactory perception. [•] Physicochemical odor metrics derived from perception predict olfactory neural activity. [•] Physicochemical odor metrics derived from perception predict perceptual odor similarity. [•] The low dimensionality of perception implies non-olfactory functions for olfactory receptors. [ABSTRACT FROM AUTHOR]

Abstract: Substantial individual differences exist in the magnitude of the cognitive decline associated with normal aging. Potential contributors to this intersubject variability include white matter hyperintensities (WMH) and preclinical Alzheimer′s disease, evident as increased brain amyloid. This study examined whether older individuals with minimal evidence of WMH and/or brain amyloid-beta (seen on positron emission tomography with the Pittsburgh compound B radiotracer—PiB) still showed significant cognitive decrements compared to the young. Older individuals, conservatively screened for normal range performance on an extensive neuropsychological battery, underwent structural magnetic resonance imaging (MRI) and PiB scans and performed tests of information processing speed, working memory and inhibitory function. The elderly were divided into PiB(+) and PiB(−) groups based on radiotracer retention. There were no significant differences in cognitive performance between PiB(+) and PiB(−) elderly. However, both PiB groups performed significantly worse than did the young on cognitive testing. WMH burden in the same individuals was quantified by consensus ratings using a 10 point scale with a median split defining two groups, WMH(+) and WMH(−). There were no differences in cognitive performance between WMH(+) and WMH(−) individuals, but both WMH groups performed significantly worse than did the young. Older participants who were both PiB(−) and WMH(−) also performed significantly worse than did the young in all three cognitive domains. The present results suggest that normal-elderly individuals whose brain scans show minimal evidence of amyloid deposition or WMH, still demonstrate a major decrement in comparison to younger persons on measures of processing resources and inhibitory efficiency. [Copyright &y& Elsevier]

Objective: A key component of successful aging is the ability to independently perform instrumental activities of daily living (IADL). We examined the ability to perform multiple IADL tasks in relation to mild cognitive impairment (MCI) defined on purely neuropsychological grounds. Design: Cross-sectional study. Setting: Population-based cohort in southwestern Pennsylvania. Participants: One thousand seven hundred thirty-seven community-dwelling adults age 65 years and older. Measurements: Classification of MCI based on performance with reference to norms in the cognitive domains of memory, language, attention, executive, and visuospatial functions. The ability to perform seven IADL tasks (traveling, shopping, preparing meals, doing housework, taking medications, handling personal finances, and using the telephone) as assessed by the Older Americans Resources and Services scale. Results: Those with cognitively defined MCI were more likely to be dependent in at least one IADL task, as well as in each individual IADL task, than cognitively normal participants. Better memory and executive functioning were associated with lower odds of IADL dependence in MCL Across the subtypes of MCL those with the multiple-domain amnestic subtype were most likely to be dependent in all IADL tasks, with better executive functioning associated with lower risk of dependence in select IADL tasks in this group. Conclusions: Mild impairment in cognition is associated with difficulty performing IADL tasks at the population level. Understanding these associations may help improve prediction of the outcomes of MCI. It may also allow appropriate targeting of cognitive interventions in MCI to potentially help preserve functional independence. [ABSTRACT FROM AUTHOR]

Objectives: To estimate and compare the frequency and prevalence of mild cognitive impairment (MCI) and related entities using different classification approaches at the population level. Design: Cross-sectional epidemiologic study of population-based cohort recruited by age-stratified random sampling from electoral rolls. Setting: Small-town communities in western Pennsylvania. Participants: Of 2,036 individuals aged 65 years and older, 1,982 participants with normal or mildly impaired cognition (age-education-corrected Mini-Mental State scores ≥21). Measurements: Demographics, neuropsychological assessment expressed as cognitive domains, funcional ability, and subjective reports of cognitive difficulties; based on these measurements, operational criteria for the Clinical Dementia Rating (CDR) scale, the 1999 criteria for amnestic MCI, the 2004 Expanded criteria for MCI, and new, purely cognitive criteria for MCI. Results: A CDR rating of 0.5 (uncertain/very mild dementia) was obtained by 27.6% of participants, whereas 1.2% had CDR <1 (mild or moderate dementia). Among those with CDR <1, 2.27% had amnestic MCI and 17.66% had expanded MCI, whereas 35-17% had MCI by purely cognitive classification. Isolated executive function impairment was the least common, whereas impairment in multiple domains including executive function was the most common. Prevalence estimates weighted against the U.S. Census are also provided. Conclusions: The manner in which criteria for MCI are operationalized determines the proportion of individuals who are thus classified and the degree of overlap with other criteria. Prospective follow-up is needed to determine progression from MCI to dementia and thus empirically develop improved MCI criteria with good predictive value. [ABSTRACT FROM AUTHOR]

Objectives: Late-life depression (LLD) is associated with persistent cognitive impairment in a subset of individuals. The purpose of this study was to 1) examine the frequency and characteristics of cognitive diagnoses (Mild Cognitive Impairment [MCI], dementia) among remitted elderly depressed subjects and 2) to compare the prevalence rate and correlates of cognitive diagnoses with those of comparison subjects. Design: Cross sectional. Setting: Outpatient geriatric mental health clinic. Participants: The authors examined cognitive diagnoses among 109 subjects age 65 and older, after depression treatment response and 65 never-depressed, age- and education-equated comparison subjects. Measurements: Cognitive diagnoses were independently established by the University of Pittsburgh's Alzheimer's Disease Research Center. Bivariate and multivariate analyses were conducted to examine the role of specific risk factors for cognitive diagnosis among depressed subjects. Results: Relative to comparison subjects, nearly twice as many depressed subjects were diagnosed with MCI or dementia (48% versus 28%). Of the 109 depressed subjects, 38% were diagnosed with MCI (63% amnestic, 37% nonamnestic). The majority of amnestic MCI subjects (85%) had the multiple domain subtype. Age, but not age of onset or lifetime depression duration, predicted cognitive diagnosis. Conclusions: Despite adequate depression treatment response, 48% of remitted depressed subjects had a cognitive diagnosis. Of the 38% diagnosed with MCI, there was high representation among both the amnestic and the nonamnestic subtypes, suggesting heterogeneity in cognitive course and outcomes in LLD. [ABSTRACT FROM AUTHOR]

Driving is a key and complex instrumental activity of daily living that requires integration of multiple domains including cognitive, motor, visual and sensory functions in order to perform adequately. Older drivers comprise 19 percent of licensed drivers in the US and 70-80 % of drivers over 75 were considered at fault in two vehicle crashes.Although there are many studies in the literature reporting on driving habits and difficulties in samples of older adults in clinical settings, there are relatively few reports from population-based samples. Here we describe the driving history, social habits and self-reported driving difficulties of older adults in a large population based survey. Our study cohort comprised1982 individuals aged 65+ years. Participants were assessed on their ability to perform Instrumental activities of daily living, cognitive functions, self-reported health, social supports, physical limitations, depressive symptoms and driving status. We built multivariate logistic regression models to identify factors associated with (a) never having driven, (b) driving cessation, and (c) self-reported driving difficulties In multivariable models, "never drivers" were more likely than "ever drivers" to be older, female, less educated and to leave home less frequently. Those who had ceased driving, i.e. former drivers, were significantly older, more likely to be women, to have lower test performance in the cognitive domain of attention, have more IADL difficulties, leave home less frequently and have visual field deficits than current drivers. Current drivers who reported difficulties while driving were more likely than those without difficulties to have test performance that was lower in attention but higher in memory, were more likely to report depressive symptoms and to have both vision and hearing loss. In this population-based study of older adults in a small-town, post-industrial, economically disadvantaged region of southwestern Pennsylvania, we identified factors associated with never having driven a motor vehicle, with having given up driving, and with current drivers' self-reported difficulties while driving. There were some similarities and some differences among the three groups of factors. In the fully adjusted models, both never-drivers and former drivers were significantly more likely to be female, older, and to leave home less frequently. Both former drivers and current drivers with difficulties were more likely to have lower cognitive test performance, with former drivers testing worse on attention, and current drivers with difficulties testing worse on attention but better on memory, compared to their respective reference groups. In addition, never-drivers had lesser education, former drivers were more likely to report difficulty with IADLs, and current drivers with difficulties were more likely to report depressive symptoms. Our findings can help health care providers identify their patients whose driving histories and abilities warrant more careful attention. The snapshot we have provided of driving-related issues in a low-SES community may be useful to planners and policy makers in addressing the transportation and safety needs of older adults. The work reported here was supported in part by grant # R01AG023651 from the National Institute on Aging, NIH, US DHHS. [ABSTRACT FROM AUTHOR]

Abstract Amyloid-β (Aβ) accumulation is a hallmark of Alzheimer's disease, although Aβ alone may be insufficient to cause impairments. Modifiable health factors, including sleep, may mitigate functional symptoms of neurodegeneration. We assessed whether sleep moderated the relationship between Aβ and cognitive performance in 41 older adults, mean age 83 years. Sleep measures included actigraphy-assessed wake after sleep onset and total sleep time. Cognitive performance was assessed with memory recall, cognitive flexibility, and verbal fluency. Memory recall was assessed with the Rey-Osterrieth Complex Figure task, cognitive flexibility with the Trail Making test, and verbal fluency with FAS word generation. Aβ was assessed with a global measure of Pittsburgh Compound B. Wake after sleep onset moderated the relationship between Aβ and memory, with a stronger positive association for Aβ and forgetting in those with poorer sleep. These results suggest a possible protective role of sleep in preclinical Alzheimer's disease. [ABSTRACT FROM AUTHOR]

• A rare missense APOE (L28P) has been reported to be a risk factor for late-onset Alzheimer's disease (LOAD). • However, due to the complete linkage disequilibrium of L28P with APOE*4 , its independent genetic association is uncertain. • we have re-evaluated the L28P association in 15,762 White U.S. case-control subjects and in 4139 APOE 3/4 subjects, since APOE 3/4 is the most common genotype containing the APOE*4 allele • Our data suggesting that L28P has an independent genetic effect on LOAD. A rare missense APOE variant (L28P; APOE*4Pittsburgh), which is present only in populations with European ancestry, has been reported to be a risk factor for late-onset Alzheimer's disease (LOAD). However, due to the complete linkage disequilibrium of L28P with APOE*4 (C112R), its independent genetic association is uncertain. The original association study implicating L28P with LOAD risk was carried out in a relatively small sample size. In the current study, we have re-evaluated this association in a large case-control sample of 15,762 White U.S. subjects and investigated its independent effect in APOE 3/4 subjects, as L28P has been observed only in the heterozygous state of APOE*4 carriers and 3/4 is the most common genotype containing the APOE*4 allele. The heterozygous carrier frequency of L28P, all with APOE*4 , was about 3-fold higher in AD cases than in cognitively intact controls (0.845% vs. 0.277%). The age- and sex-adjusted meta-analysis odds ratio (OR) was 2.87 (95% CI: 1.34 – 6.13; = 0.0066). Among APOE 3/4 subjects, age- and sex-adjusted meta-analysis OR was 1.53 (95% CI: 0.70 – 3.36; p = 0.28), indicating its effect was independent of APOE*4. The lack of statistical significance appears mainly due to the low power of 4138 subjects with the 3/4 genotype (12% power at α= 0.05) compared to the required sample of 139,088 subjects with the 3/4 genotype to detect an OR of 1.5 at α= 0.05 and 80% power. Our data suggesting that L28P has an independent genetic effect on AD risk is reinforced by earlier experimental findings showing that this mutation leads to significant structural and conformational changes in the ApoE4 molecule and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. Additional functional studies in cell-based systems and animal models will help to delineate its functional significance in the etiology of AD. [ABSTRACT FROM AUTHOR]

Highlights: [•] APOE*4 allele is associated with increased risk of dementia in Pakistani population. [•] Stressful life events are also associated with dementia risk in Pakistani population. [•] No significant interaction was observed between APOE*4 and stress in Pakistani population. [ABSTRACT FROM AUTHOR]

Abstract: Structural MRI studies of schizophrenia have yielded a diversity of findings. To help characterize regional gray matter changes in schizophrenia, we used an automated region of interest (ROI)-based approach that targeted frontal and temporal regions in schizophrenia patients. The sample compromised 43 schizophrenia patients (21 chronic patients, 22 unmedicated first episode patients), 20 first episode non-schizophrenia psychosis patients and 47 comparison subjects. Automated regional volume measurement was performed in 22 ROIs, including frontal and temporal cortical subregions and hippocampus. Correlations between volume measures, duration of illness and clinical scores were evaluated. Chronic schizophrenia patients showed gray matter volume differences in left dorsolateral prefrontal cortex (DLPFC) and right supplementary motor area (SMA). First episode psychosis patients presented smaller right anterior cingulate cortex (ACC) and left DLPFC than comparison subjects. Disorganization scores and duration of illness correlated negatively with gray matter volume of DLPFC and SMA in chronic schizophrenia patients. Using an automated ROI-based method, we found volume reductions in lateral and medial frontal regions in both first episode and chronic schizophrenia. The automated ROI-based method can be used as a valid and efficient tool for quantification of regional gray matter volume in schizophrenia in multiple ROIs across the brains of large numbers of subjects. [Copyright &y& Elsevier]

To characterize the influence of apolipoprotein-E (APOE) genotype on cerebral Aβ load and longitudinal Aβ trajectories, 11C]Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging was used to assess amyloid load in a clinically heterogeneous cohort of 428 elderly participants with known APOE genotype. Serial 11C]PiB data and a repeated measures model were used to model amyloid trajectories in a subset of 235 participants classified on the basis of APOE genotype. We found that APOE-ε4 was associated with increased Aβ burden and an earlier age of onset of Aβ positivity, whereas APOE-ε2 appeared to have modest protective effects against Aβ. APOE class did not predict rates of Aβ accumulation. The present study suggests that APOE modifies Alzheimer's disease risk through a direct influence on amyloidogenic processes, which manifests as an earlier age of onset of Aβ positivity, although it is likely that other genetic, environmental, and lifestyle factors are important. • APOE-ε4 is associated with increased Aβ burden compared with other APOE genotypes. • Age of onset of Aβ positivity in APOE-ε4+ antecedes other genotypes by > 15 years. • APOE-ε2+ is associated with reduced Aβ burden and a delayed age of onset. • Within-genotype variability suggests additional factors influence Aβ trajectories. [ABSTRACT FROM AUTHOR]

Abstract Compared to men, women are disproportionally affected by Alzheimer's disease (AD) and have an accelerated trajectory of cognitive decline and disease progression. Neurobiological factors underlying gender differences in AD remain unclear. This study investigated brain beta-amyloid (Aβ)-related neural system differences in cognitively normal older men and women (N = 61; 41 females, 65–93 years old). We found that men and women showed different associations between Aβ load and hippocampal functional connectivity. During associative memory encoding, in men greater Aβ burden was accompanied by greater hippocampus-prefrontal connectivity (i.e., more synchronized activities), whereas in women hippocampal connectivity did not vary by Aβ burden. For resting-state data, the interaction of gender × Aβ on hippocampal connectivity did not survive multiple comparison in the whole-brain analyses. In the region of interest–based analyses, resting-state hippocampal-prefrontal connectivity was positively correlated with Aβ load in men and was negatively correlated with Aβ load in women. The observed Aβ-related neural differences may explain the accelerated trajectory of cognitive decline and AD progression in women. Highlights 1. The effects of brain amyloid on functional connectivity in preclinical AD differ by sex. 2. In men, greater amyloid burden was associated with greater hippocampal-prefrontal connectivity. 3. In women, hippocampal-prefrontal connectivity did not vary by amyloid burden. [ABSTRACT FROM AUTHOR]

Abstract Down syndrome (DS) predisposes individuals to early Alzheimer's disease (AD). Using Pittsburgh Compound B ([11C]PiB), a pattern of striatal amyloid beta (Aβ) that is elevated relative to neocortical binding has been reported, similar to that of nondemented autosomal dominant AD mutation carriers. However, it is not known whether changes in striatal and neocortical [11C]PiB retention differ over time in a nondemented DS population when compared to changes in a nondemented elderly (NDE) population. The purpose of this work was to assess longitudinal changes in trajectories of Aβ in a nondemented DS compared to an NDE cohort. The regional trajectories for anterior ventral striatum (AVS), frontal cortex, and precuneus [11C]PiB retention were explored over time using linear mixed effects models with fixed effects of time, cohort, and time-by-cohort interactions and subject as random effects. Significant differences between DS and NDE cohort trajectories for all 3 region of interests were observed (p < 0.05), with the DS cohort showing a faster accumulation in the AVS and slower accumulation in the frontal cortex and precuneus compared to the NDE cohort. These data add to the previously reported distinct pattern of early striatal deposition not commonly seen in sporadic AD by demonstrating that individuals with DS may also accumulate Aβ at a rate faster in the AVS when compared to NDE subjects. [ABSTRACT FROM AUTHOR]

Background: The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed.Methods: For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimer's Disease Research Center every 1-2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using (11)C-Pittsburgh Compound-B PET, posterior cortical metabolism with (18)F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimer's Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65-89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls).Findings: 16 people with mutations in PSEN1, PSEN2, or APP, aged 28-56 years, completed between two and eight assessments (a total of 83 assessments) over 2-11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6-11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline.Interpretation: Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease-active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline-indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease.Funding: National Institutes of Health and Howard Hughes Medical Institute. [ABSTRACT FROM AUTHOR]

Abstract: Cholesterol is implicated in the development of late-onset Alzheimer's disease (AD). We sought to determine the associations between beta amyloid (Aβ) plaque deposition in vivo using Pittsburgh compound B (PiB) and several indices of cholesterol homeostasis (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein E (ApoE), clusterin, oxysterol metabolites of cholesterol, and previously reported genes associated with late-onset AD) in 175 nondemented elderly subjects. High Aβ deposition was associated significantly with a lower Mini-Mental State Examination score (<27 points, p = 0.04), high systolic blood pressure (p = 0.04), carrying the apolipoprotein E epsilon 4 allele (p < 0.01), and lower plasma ApoE levels (p = 0.02), and variation in the ABCA7 (p = 0.02) and EPHA1 genes (p = 0.02). Cholesterol measures were not related to Aβ deposition in this cohort of nondemented elderly adults. However, plasma and genetic factors relating to cholesterol transport were associated with Aβ deposition in the brain. A better understanding of cholesterol transport mechanisms may lead to the design of potential targets for the prevention of Aβ deposition in the brain. [Copyright &y& Elsevier]

Mobility is important for independence in older age. While brain health correlates of objectively measured mobility-related features like gait and balance have been reported, we aimed to test neuroimaging and cognitive correlates of subjective measures of mobility-related confidence. We carried out a cross-sectional observational study comprised of N = 29 cognitively unimpaired older adult participants, mean age 75.8 ± 5.8, 52% female, 24% non-white. We measured cognition, hippocampal volume, white matter hyperintensities, cerebral amyloid-β (Aβ), and gait and balance confidence. We tested associations using unadjusted Spearman correlations and correlations partialling out covariates of interest one at a time. Greater gait confidence was associated with better attention (unadjusted ρ = 0.37, p = 0.05; partially attenuated by adjustment for age, APOE4 , anxiety, motivation, gait speed, or Aβ); executive performance (unadjusted ρ = 0.35, p = 0.06; partially attenuated by adjustment for age, APOE4 , gait speed, or Aβ); and lower Aβ levels (unadjusted ρ = −0.40, p = 0.04; partially attenuated by adjustment for age, depressive symptoms, motivation, or gait speed). Greater balance confidence was associated with better global cognition (unadjusted ρ = 0.41, p = 0.03; partially attenuated by adjustment for APOE4 , gait speed, or Aβ); attention (unadjusted ρ = 0.46, p = 0.01; robust to adjustment); and lower Aβ levels (unadjusted ρ = −0.35, p = 0.07; partially attenuated by adjustment for age, education, APOE4 , depressive symptoms, anxiety, motivation, or gait speed). Self-reported mobility-related confidence is associated with neuroimaging and cognitive measures and would be easy for providers to use in clinical evaluations. These associations should be further evaluated in larger samples, and longitudinal studies can help determine temporality of declines. • Subjective measures of mobility and neuroimaging/cognition assessed in older adults • Greater gait confidence associated with better attention and executive function • Greater balance confidence associated with better global cognition and attention • Greater gait and balance confidence associated with lower brain amyloid levels [ABSTRACT FROM AUTHOR]

To identify novel loci that affect cognitive decline in older adults free of dementia, we conducted genome-wide and gene-based meta-analyses on longitudinal slopes of 5 cognitive domains (memory, executive function, language, attention/processing speed, and visuospatial ability) derived from 2 population-based cohorts. For decline over time in each cognitive domain, we normalized intraindividual slopes within each cohort, accounting for baseline age, sex, and years of education. Normalized slope for each domain was used in cohort-specific genome-wide analyses after including top principal components as covariates followed by genome-wide and gene-based meta-analyses. Both analyses revealed a novel WDFY2 locus at genome-wide (p = 3.37E-08) and gene-wide (p = 7.10E-07) significance levels for the attention/processing speed domain. In the GTEx eQTL analysis, genome-wide significant single-nucleotide polymorphism was associated with RNA expression levels of WDFY2 in several brain regions: cerebellar hemisphere (p = 1.07E-04), cerebellum (p = 6.92E-04), hippocampus (p = 2.18E-03) and cortex (p = 2.29E-02), and in whole blood (p = 4.41E-05). Our results suggest that WDFY2 genetic variation may affect individual differences in decline over time on tests of attention/processing speed. • We followed 2 longitudinal cohorts free of dementia at baseline and calculated intraindividual slopes of linear decline over time in 5 cognitive domains. • We performed genome-wide and gene-based meta-analyses to capture genetic variation associated with decline in each individual domain. • Both analyses revealed a novel WDFY2 locus at genome-wide and gene-wide significance levels for the attention/processing speed domain. [ABSTRACT FROM AUTHOR]

Over 20 risk loci have been identified for late-onset Alzheimer's disease (LOAD), most of which display relatively small effect sizes. Recently, a rare missense (R47H) variant, rs75932628 in TREM2, has been shown to mediate LOAD risk substantially in Icelandic and Caucasian populations. Here, we present more evidence for the association of the R47H with LOAD risk in a Caucasian population comprising 4567 LOAD cases and controls. Our results show that carriers of the R47H variant have a significantly increased risk for LOAD (odds ratio = 7.40, p = 3.66E-06). In addition to Alzheimer's disease risk, we also examined the association of R47H with Alzheimer's disease–related phenotypes, including age-at-onset, psychosis, and amyloid deposition but found no significant association. Our results corroborate those of other studies implicating TREM2 as an LOAD risk locus and indicate the need to determine its biological role in the context of neurodegeneration. [ABSTRACT FROM AUTHOR]

Abstract: A rare amyloid precursor protein gene variant, A673T (rs63750847) was recently reported to protect against Alzheimer's disease and age-related cognitive decline among Icelanders and the same rare variant was observed also in Finnish, Norwegian, and Swedish populations. We investigated this variant in 1674 late-onset Alzheimer's disease cases and 2644 elderly control subjects, all North American Whites (US Whites). We did not observe any example of the A673T variant in our large sample. Our findings suggest that this rare variant could be specific to the individuals of the origin from the Nordic countries. [Copyright &y& Elsevier]