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Objective The Survey for Memory, Attention, and Reaction Time (SMART) was recently introduced as a brief (<5 min), self-administered, web-based measure of cognitive performance in older adults. The purpose of this study was threefold: (1) to develop preliminary norms on the SMART; (2) to examine the relationship between demographic variables (i.e. age, sex, education), device type used, and SMART performance; and (3) to assess user attitudes of the SMART. Method A sample of 1,050 community-dwelling adults ( M age =59.5 (15.2), M education = 16.5 (2.1), 67.1% female, 96% white) was recruited from an ongoing web-based research cohort. Participants completed the SMART, which consists of four face-valid cognitive tasks assessing visual memory, attention/processing speed, and executive functioning. SMART performance outcome metrics were subtest completion time (CT), click count, and total CT. Participants provided demographic information and completed a survey of user attitudes toward the SMART (i.e. usability, acceptability). Results Older age was the only demographic variable associated with slower SMART total CT ( r = .60, p <.001). Education was not associated with SMART CT or click counts overall ( p > .05). Male sex was generally associated with longer SMART CT ( p < .001, partial eta squared = .14) on all sub-tests. Regarding acceptability, 97.3% indicated willingness to take the SMART again, with more than half willing to complete it on a weekly basis. Conclusion The preliminary normative data on the SMART indicates that it is a feasible and well-accepted web-based cognitive assessment tool that can be administered on multiple device platforms.

Objective: Handgrip strength, an indicator of overall muscle strength, has been found to be associated with slower rate of cognitive decline and decreased risk for cognitive impairment and dementia. However, evaluating the replicability of associations between aging-related changes in physical and cognitive functioning is challenging due to differences in study designs and analytical models. A multiple-study coordinated analysis approach was used to generate new longitudinal results based on comparable construct-level measurements and identical statistical models and to facilitate replication and research synthesis., Methods: We performed coordinated analysis on 9 cohort studies affiliated with the Integrative Analysis of Longitudinal Studies of Aging and Dementia (IALSA) research network. Bivariate linear mixed models were used to examine associations among individual differences in baseline level, rate of change, and occasion-specific variation across grip strength and indicators of cognitive function, including mental status, processing speed, attention and working memory, perceptual reasoning, verbal ability, and learning and memory. Results were summarized using meta-analysis., Results: After adjustment for covariates, we found an overall moderate association between change in grip strength and change in each cognitive domain for both males and females: Average correlation coefficient was 0.55 (95% CI = 0.44-0.56). We also found a high level of heterogeneity in this association across studies., Discussion: Meta-analytic results from nine longitudinal studies showed consistently positive associations between linear rates of change in grip strength and changes in cognitive functioning. Future work will benefit from the examination of individual patterns of change to understand the heterogeneity in rates of aging and health-related changes across physical and cognitive biomarkers., (Published by Oxford University Press on behalf of The Gerontological Society of America 2019.)

Background: Computer use is a cognitively complex instrumental activity of daily living (IADL) that has been linked to cognitive functioning in older adulthood, yet little work has explored its capacity to detect incident mild cognitive impairment (MCI)., Objective: To examine whether routine home computer use (general computer use as well as use of specific applications) could effectively discriminate between older adults with and without MCI, as well as explore associations between use of common computer applications and cognitive domains known to be important for IADL performance., Methods: A total of 60 community-dwelling older adults (39 cognitively healthy, 21 with MCI) completed a neuropsychological evaluation at study baseline and subsequently had their routine home computer use behaviors passively recorded for three months., Results: Compared to those with MCI, cognitively healthy participants spent more time using the computer, had a greater number of computer sessions, and had an earlier mean time of first daily computer session. They also spent more time using email and word processing applications, and used email, search, and word processing applications on a greater number of days. Better performance in several cognitive domains, but in particular memory and language, was associated with greater frequency of browser, word processing, search, and game application use., Conclusion: Computer and application use are useful in identifying older adults with MCI. Longitudinal studies are needed to determine whether decreases in overall computer use and specific computer application use are predictors of incident cognitive decline.

Introduction: Brief, Web-based, and self-administered cognitive assessments hold promise for early detection of cognitive decline in individuals at risk for dementia. The current study describes the design, implementation, and convergent validity of a fWeb-based cognitive assessment tool, the Survey for Memory, Attention, and Reaction Time (SMART), for older adults., Methods: A community-dwelling sample of older adults (n = 69) was included, classified as cognitively intact (n = 44) or diagnosed with mild cognitive impairment (MCI, n = 25). Participants completed the SMART at home using their computer, tablet, or other Internet-connected device. The SMART consists of 4 face-valid cognitive tasks available in the public domain assessing visual memory, attention/processing speed, and executive functioning. Participants also completed a battery of standardized neuropsychological tests, a cognitive screener, and a daily function questionnaire. Primary SMART outcome measures consisted of subtest completion time (CT); secondary meta-metrics included outcomes indirectly assessed or calculated within the SMART (e.g., click count, total CT, time to complete practice items, and time of day the test was completed)., Results: Regarding validity, total SMART CT, which includes time to complete test items, practice items, and directions, had the strongest relationship with global cognition (β = -0.47, p < 0.01). Test item CT was significantly greater for the MCI group (F = 5.20, p = 0.026). Of the SMART tasks, the executive functioning subtests had the strongest relationship with cognitive status as compared to the attention/processing speed and visual memory subtests. The primary outcome measures demonstrated fair to excellent test-retest reliability (intraclass correlation coefficient = 0.50-0.76)., Conclusions: This study provides preliminary evidence for the use of the SMART protocol as a feasible, reliable, and valid assessment method to monitor cognitive performance in cognitively intact and MCI older adults., (© 2021 S. Karger AG, Basel.)

Background: Cerebrovascular disease is a common cause of dementia in older adults, and potentially preventable with early intervention. Oxylipins are produced from the oxidation of long-chain polyunsaturated fatty acids (PUFA) possessing potent vascular effects. Oxylipins generated from the cytochrome P450 pathway are enzymatically converted to diols by soluble epoxide hydrolase (sEH); sEH products have been associated with small vessel ischemic disease. Little is known about oxylipins' impact on markers of dementia risk., Objective: An exploratory examination of the association between omega-6 and omega-3 derived oxylipins, brain MRI, and cognition., Methods: Thirty-seven non-demented participants with controlled hypertension (mean age 65.6 years) were enrolled in a dementia prevention study investigating fish oil and lipoic acid on preserving cognitive function. Baseline associations between plasma oxylipins, white matter hyperintensity (WMH), and Trails-B were examined using linear regression. P450-derived diol/epoxide ratio was an indirect measure of sEH activity., Results: Omega-6 derived 9-HODE was associated with increased WMH (p = 0.017) and reduced grey matter volume (p = 0.02). Omega-6 P450-derived diol/epoxide ratio 9,10-DiHOME/9,10-EpOME was associated with increased WMH (p = 0.035) and poorer performance on Trails-B (p = 0.05); ratio14,15-DHET/14,15-EET was associated with increased WMH (p = 0.045). Omega-3 P450-derived diol/epoxide ratio 19,20-DiHDPE/19,20-EpDPE was associated with increased WMH (p = 0.04) and poorer performance on Trails-B (p = 0.04). Arachidonic acid was associated with better performance on Trails-B (p = 0.012); Omega-3 derived 16,17-EpDPE was associated with decreased WMH (p = 0.005)., Conclusions: With the exception of arachidonic acid, it was specific oxylipin products, not their parent PUFAs, that were associated with unfavorable and favorable MRI and cognitive markers of dementia risk.

Background: Alzheimer disease (AD) is a very challenging experience for all those affected. Unfortunately, detection of Alzheimer disease in its early stages when clinical treatments may be most effective is challenging, as the clinical evaluations are time-consuming and costly. Recent studies have demonstrated a close relationship between cognitive function and everyday behavior, an avenue of research that holds great promise for the early detection of cognitive decline. One area of behavior that changes with cognitive decline is language use. Multiple groups have demonstrated a close relationship between cognitive function and vocabulary size, verbal fluency, and semantic ability, using conventional in-person cognitive testing. An alternative to this approach which is inherently ecologically valid may be to take advantage of automated computer monitoring software to continually capture and analyze language use while on the computer., Objective: The aim of this study was to understand the relationship between Internet searches as a measure of language and cognitive function in older adults. We hypothesize that individuals with poorer cognitive function will search using fewer unique terms, employ shorter words, and use less obscure words in their searches., Methods: Computer monitoring software (WorkTime, Nestersoft Inc) was used to continuously track the terms people entered while conducting searches in Google, Yahoo, Bing, and Ask.com. For all searches, punctuation, accents, and non-ASCII characters were removed, and the resulting search terms were spell-checked before any analysis. Cognitive function was evaluated as a z-normalized summary score capturing five unique cognitive domains. Linear regression was used to determine the relationship between cognitive function and Internet searches by controlling for variables such as age, sex, and education., Results: Over a 6-month monitoring period, 42 participants (mean age 81 years [SD 10.5], 83% [35/42] female) conducted 2915 searches using these top search engines. Participants averaged 3.08 words per search (SD 1.6) and 5.77 letters per word (SD 2.2). Individuals with higher cognitive function used more unique terms per search (beta=.39, P=.002) and employed less common terms in their searches (beta=1.39, P=.02). Cognitive function was not significantly associated with the length of the words used in the searches., Conclusions: These results suggest that early decline in cognitive function may be detected from the terms people search for when they use the Internet. By continuously tracking basic aspects of Internet search terms, it may be possible to detect cognitive decline earlier than currently possible, thereby enabling proactive treatment and intervention., (©Johanna Austin, Kristy Hollingshead, Jeffrey Kaye. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 06.09.2017.)

Significant progress has been made in characterizing the biological changes occurring in preclinical Alzheimer's disease (AD). Cognitive dysfunction has been viewed, however, as a late-stage phenomenon, despite increasing evidence that changes may be detected in the decades preceding dementia. In the absence of comprehensive evidence-based guidelines for preclinical cognitive assessment, longitudinal cohort and neuroimaging studies have been reviewed to determine the temporal order and brain biomarker correlates of specific cognitive functions. Episodic memory decline was observed to be the most salient cognitive function, correlating with high levels of amyloid deposition and hypoconnectivity across large-scale brain networks. Prospective studies point to early decline in both episodic and semantic memory processing as well as executive functions in the predementia period. The cognitive tests have, however, been principally those used to diagnose dementia. New procedures are required which target more finely the medial temporal lobe subregions first affected by clinically silent AD pathology., (Copyright © 2016 the Alzheimer's Association. All rights reserved.)

The Horizon 2020/IMI European Prevention of Alzheimer's Dementia (EPAD) project will undertake large-scale proof-of-concept trials in predementia Alzheimer's disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross-cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimer's disease., (Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Importance: Cognitive impairment and dementia, including Alzheimer disease (AD), are common within the aging population, yet the factors that render the aging brain vulnerable to these processes are unknown. Perivascular localization of aquaporin-4 (AQP4) facilitates the clearance of interstitial solutes, including amyloid-β, through the brainwide network of perivascular pathways termed the glymphatic system, which may be compromised in the aging brain., Objectives: To determine whether alterations in AQP4 expression or loss of perivascular AQP4 localization are features of the aging human brain and to define their association with AD pathology., Design, Setting, and Participants: Expression of AQP4 was analyzed in postmortem frontal cortex of cognitively healthy and histopathologically confirmed individuals with AD by Western blot or immunofluorescence for AQP4, amyloid-β 1-42, and glial fibrillary acidic protein. Postmortem tissue and clinical data were provided by the Oregon Health and Science University Layton Aging and Alzheimer Disease Center and Oregon Brain Bank. Postmortem tissue from 79 individuals was evaluated, including cognitively intact "young" individuals aged younger than 60 years (range, 33-57 years), cognitively intact "aged" individuals aged older than 60 years (range, 61-96 years) with no known neurological disease, and individuals older than 60 years (range, 61-105 years) of age with a clinical history of AD confirmed by histopathological evaluation. Forty-eight patient samples (10 young, 20 aged, and 18 with AD) underwent histological analysis. Sixty patient samples underwent Western blot analysis (15 young, 24 aged, and 21 with AD)., Main Outcomes and Measures: Expression of AQP4 protein, AQP4 immunoreactivity, and perivascular AQP4 localization in the frontal cortex were evaluated., Results: Expression of AQP4 was associated with advancing age among all individuals (R2 = 0.17; P = .003). Perivascular AQP4 localization was significantly associated with AD status independent of age (OR, 11.7 per 10% increase in localization; z = -2.89; P = .004) and was preserved among eldest individuals older than 85 years of age who remained cognitively intact. When controlling for age, loss of perivascular AQP4 localization was associated with increased amyloid-β burden (R2 = 0.15; P = .003) and increasing Braak stage (R2 = 0.14; P = .006)., Conclusions and Relevance: In this study, altered AQP4 expression was associated with aging brains. Loss of perivascular AQP4 localization may be a factor that renders the aging brain vulnerable to the misaggregation of proteins, such as amyloid-β, in neurodegenerative conditions such as AD.

Background: Difficulty turning is a major contributor to mobility disability, falls, and reduced quality of life in older people because it requires dynamic balance control that worsens with age. However, no study has quantified the quality and quantity of turning during normal daily activities in older people. The objective of this pilot study was to determine if quality of turning during daily activities is associated with falls and/or cognitive function., Methods: Thirty-five elderly participants (85 ± 8 years) wore three Opal inertial sensors. Turning and activity rate were measured. Based on retrospective falls, participants were grouped into nonfallers (N = 16), single fallers (N = 12), and recurrent fallers (N = 7). We also determined which turning characteristic predicted falls in the 6 months following the week of monitoring., Results: Quality of turning was significantly compromised in recurrent fallers compared with nonfallers (p < .05). In contrast, activity rate and mean number of turns per hour were similar across the three groups. Also, quality of turning during a prescribed test was similar across the three groups. Visuospatial and memory functions and the Tinetti Balance Scores were associated with quality of turning. Future falls were related to an increased variability of number of steps to turn., Conclusions: Continuous monitoring of turning characteristics, while walking during daily activities, is feasible in older people. Turning characteristics during daily life appear to be more sensitive to fall risk than prescribed turning tasks. These findings suggest a slower, less variable, cautious turning strategy in elderly volunteers with a history of falls., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Time out-of-home has been linked with numerous health outcomes, including cognitive decline, poor physical ability and low emotional state. Comprehensive characterization of this important health metric would potentially enable objective monitoring of key health outcomes. The objective of this study is to determine the relationship between time out-of-home and cognitive status, physical ability and emotional state., Methods and Findings: Participants included 85 independent older adults, age 65-96 years (M = 86.36; SD = 6.79) who lived alone, from the Intelligent Systems for Assessing Aging Changes (ISAAC) and the ORCATECH Life Laboratory cohorts. Factors hypothesized to affect time out-of-home were assessed on three different temporal levels: yearly (cognitive status, loneliness, clinical walking speed), weekly (pain and mood) or daily (time out-of-home, in-home walking speed, weather, and season). Subject characteristics including age, race, and gender were assessed at baseline. Total daily time out-of-home in hours was assessed objectively and unobtrusively for up to one year using an in-home activity sensor platform. A longitudinal tobit mixed effects regression model was used to relate daily time out-of-home to cognitive status, physical ability and emotional state. More hours spend outside the home was associated with better cognitive function as assessed using the Clinical Dementia Rating (CDR) Scale, where higher scores indicate lower cognitive function (βCDR = -1.69, p<0.001). More hours outside the home was also associated with superior physical ability (βPain = -0.123, p<0.001) and improved emotional state (βLonely = -0.046, p<0.001; βLow mood = -0.520, p<0.001). Weather, season, and weekday also affected the daily time out-of-home., Conclusions: These results suggest that objective longitudinal monitoring of time out-of-home may enable unobtrusive assessment of cognitive, physical and emotional state. In addition, these results indicate that the factors affecting out-of-home behavior are complex, with factors such as living environment, weather and season significantly affecting time out-of-home. Studies investigating the relationship between time out-of-home and health outcomes may be optimized by taking into account the environment and life factors presented here.

The relationship between recent episodes of poor sleep and cognitive testing performance in healthy cognitively intact older adults is not well understood. In this exploratory study we examined the impact of recent sleep disturbance, sleep duration, and sleep variability on cognitive performance in 63 cognitively intact older adults using a novel unobtrusive in-home sensor-based sleep assessment methodology. Specifically, we examined the impact of sleep the night prior, the week prior, and the month prior to a neuropsychological evaluation on cognitive performance. Results showed that mildly disturbed sleep the week prior and month prior to cognitive testing was associated with reduced working memory on cognitive evaluation. One night of mild sleep disturbance was not associated with decreased cognitive performance the next day. Sleep duration was unrelated to cognition. In-home, unobtrusive, sensor monitoring technologies provide a novel method for objective, long-term, and continuous assessment of sleep behavior and other everyday activities that might contribute to decreased or variable cognitive performance in healthy older adults.

To evaluate the efficacy of cognitive rehabilitation therapies (CRTs) for mild cognitive impairment (MCI). Our review revealed a need for evidence-based treatments for MCI and a lack of a theoretical rehabilitation model to guide the development and evaluation of these interventions. We have thus proposed a theoretical rehabilitation model of MCI that yields key intervention targets-cognitive compromise, functional compromise, neuropsychiatric symptoms, and modifiable risk and protective factors known to be associated with MCI and dementia. Our model additionally defines specific cognitive rehabilitation approaches that may directly or indirectly target key outcomes-restorative cognitive training, compensatory cognitive training, lifestyle interventions, and psychotherapeutic techniques. Fourteen randomized controlled trials met inclusion criteria and were reviewed. Studies markedly varied in terms of intervention approaches and selected outcome measures and were frequently hampered by design limitations. The bulk of the evidence suggested that CRTs can change targeted behaviors in individuals with MCI and that CRTs are associated with improvements in objective cognitive performance, but the pattern of effects on specific cognitive domains was inconsistent across studies. Other important outcomes (i.e., daily functioning, quality of life, neuropsychiatric symptom severity) were infrequently assessed across studies. Few studies evaluated long-term outcomes or the impact of CRTs on conversion rates from MCI to dementia or normal cognition. Overall, results from trials are promising but inconclusive. Additional well-designed and adequately powered trials are warranted and required before CRTs for MCI can be considered evidence-based.

Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The demand for rapidly administered, sensitive, and reliable cognitive assessments that are specifically designed for identifying individuals in the earliest stages of cognitive decline (and to measure subtle change over time) has escalated as the emphasis in Alzheimer's disease clinical research has shifted from clinical diagnosis and treatment toward the goal of developing presymptomatic neuroprotective therapies. To meet these changing clinical requirements, cognitive measures or tailored batteries of tests must be validated and determined to be fit-for-use for the discrimination between cognitively healthy individuals and persons who are experiencing very subtle cognitive changes that likely signal the emergence of early mild cognitive impairment. We sought to collect and review data systematically from a wide variety of (mostly computer-administered) cognitive measures, all of which are currently marketed or distributed with the claims that these instruments are sensitive and reliable for the early identification of disease or, if untested for this purpose, are promising tools based on other variables. The survey responses for 16 measures/batteries are presented in brief in this review; full survey responses and summary tables are archived and publicly available on the Campaign to Prevent Alzheimer's Disease by 2020 Web site (http://pad2020.org). A decision tree diagram highlighting critical decision points for selecting measures to meet varying clinical trials requirements has also been provided. Ultimately, the survey questionnaire, framework, and decision guidelines provided in this review should remain as useful aids for the evaluation of any new or updated sets of instruments in the years to come., (Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: This was a cross-sectional study of the ability of independently living healthy elders to follow a medication regimen. Participants were divided into a group with High Cognitive Function (HCF) or Low Cognitive Function (LCF) based on their scores on the ADAS-Cog., Method: Thirty-eight participants aged 65 or older and living independently in the community followed a twice-daily vitamin C regimen for 5 weeks. Adherence was measured using an electronic 7-day pillbox., Results: The LCF group had significantly poorer total adherence than the HCF group (LCF: 63.9 +/- 11.2%, HCF: 86.8 +/- 4.3%, t( 36) = 2.57, p = .007), and there was a 4.1 relative risk of non-adherence in the LCF group as compared to the HCF group., Discussion: This study has important implications for the conduct of clinical drug trials, as it provides strong evidence that even very mild cognitive impairment in healthy elderly has a detrimental impact on medication adherence.

Background: Decreased cerebrospinal fluid (CSF) beta-amyloid 42 (A beta 42) concentration, but not A beta 40 concentration, is a biomarker for Alzheimer disease. This A beta 42 concentration decrease in CSF likely reflects precipitation of A beta 42 in amyloid plaques in brain parenchyma. This pathogenic plaque deposition begins years before the clinical expression of dementia in Alzheimer disease. Normal aging and the presence of the apolipoprotein E (APOE*4) allele are the most important known risk factors for Alzheimer disease., Objective: To estimate the interactive effects of normal aging and presence of the APOE*4 allele on CSF A beta 42 concentration in adults with normal cognition across the life span., Design: The CSF was collected in the morning after an overnight fast using Sprotte 24-g atraumatic spinal needles. The CSF A beta 42 and A beta 40 concentrations were measured in the 10th milliliter of CSF collected by sandwich enzyme-linked immunosorbent assay. The APOE genotype was determined by a restriction digest method. Subjects One hundred eighty-four community volunteers with normal cognition aged 21 to 88 years., Results: The CSF A beta 42, but not the A beta 40, concentration decreased significantly with age. There was a sharp decrease in CSF A beta 42 concentration beginning in the sixth decade in subjects with the APOE*4 allele. This age-associated decrease in CSF A beta 42 concentration was significantly and substantially greater in subjects with the APOE*4 allele compared with those without the APOE*4 allele., Conclusion: These CSF A beta 42 findings are consistent with acceleration by the APOE*4 allele of pathogenic A beta 42 brain deposition starting in later middle age in persons with normal cognition.

Widespread cognitive test screening as part of tele-public health initiatives necessitates a test that is self-administered online and automatically scored, with no clinician effort. The feasibility of unsupervised cognitive screening is unclear. We adapted the Self-Administered Tasks Uncovering Risk of Neurodegeneration (SATURN) to make it suitable for self-administration and automatic scoring. A sample of 364 healthy older adults completed SATURN via a web browser, in a fully independent manner. SATURNs overall score was not modulated by gender, education, reading speed, the time of day at which the test was taken, or an individuals familiarity with technology. SATURN proved extremely portable across operating systems. Importantly, comments from participants reported satisfaction with the experience and the clarity of the instructions. SATURN represents a fast and easy screening tool that can be used for a first assessment, during a routine test or clinical evaluation, or during periodic health monitoring, in person or remotely.

BackgroundConsiderable variability exists in international prevalence and incidence estimates of dementia. The accuracy of estimates of dementia in the oldest-old and the controversial question of whether dementia incidence and prevalence decline at very old age will be crucial for better understanding the dynamics between survival to extreme old age and the occurrence and risk for various types of dementia and comorbidities. International Centenarian Consortium - Dementia (ICC-Dementia) seeks to harmonise centenarian and near-centenarian studies internationally to describe the cognitive and functional profiles of exceptionally old individuals, and ascertain the trajectories of decline and thereby the age-standardised prevalence and incidence of dementia in this population. The primary goal of the ICC-Dementia is to establish a large and thorough heterogeneous sample that has the power to answer epidemiological questions that small, separate studies cannot. A secondary aim is to examine cohort-specific effects and differential survivorship into very old age. We hope to lay the foundation for further investigation into risk and protective factors for dementia and healthy exceptional brain ageing in centenarians across diverse ethnoracial and sociocultural groups.MethodsStudies focusing on individuals aged ≥95 years (approximately the oldest 1 percentile for men, oldest 5th percentile for women), with a minimum sample of 80 individuals, including assessment of cognition and functional status, are invited to participate. There are currently seventeen member or potential member studies from Asia, Europe, the Americas, and Oceania. Initial attempts at harmonising key variables are in progress.DiscussionGeneral challenges facing large, international consortia like ICC-Dementia include timely and effective communication among member studies, ethical and practical issues relating to human subject studies and data sharing, and the challenges related to data harmonisation. A specific challenge for ICC-Dementia relates to the concept and definition of'abnormal' in this exceptional group of individuals who are rarely free of physical, sensory and/or cognitive impairments.

Background and Objectives Social isolation is a risk factor for cognitive decline and dementia. We conducted a randomized controlled clinical trial (RCT) of enhanced social interactions, hypothesizing that conversational interactions can stimulate brain functions among socially isolated older adults without dementia. We report topline results of this multisite RCT (Internet-based conversational engagement clinical trial [I-CONECT]; NCT02871921). Research Design and Methods The experimental group received cognitively stimulating semistructured conversations with trained interviewers via internet/webcam 4 times per week for 6 months (induction) and twice per week for an additional 6 months (maintenance). The experimental and control groups both received weekly 10 minutes telephone check-ins. Protocol modifications were required due to the coronavirus disease 2019 pandemic. Results A total of 186 participants were randomized. After the induction period, the experimental group had higher global cognitive test scores (Montreal Cognitive Assessment [primary outcome]; 1.75 points [ p  = .03]) compared with the control group. After induction, experimental group participants with normal cognition had higher language-based executive function (semantic fluency test [secondary outcome]; 2.56 points [ p  = .03]). At the end of the maintenance period, the experimental group of mild cognitive impairment subjects had higher encoding function (Craft Story immediate recall test [secondary outcome]; 2.19 points [ p  = .04]). Measure of emotional well-being improved in both control and experimental groups. Resting-state functional magnetic resonance imaging showed that the experimental group had increased connectivity within the dorsal attention network relative to the control group (p  = .02), but the sample size was limited. Discussion and Implications Providing frequent stimulating conversational interactions via the internet could be an effective home-based dementia risk-reduction strategy against social isolation and cognitive decline. Clinical Trials Registration Number NCT02871921 [ABSTRACT FROM AUTHOR]

ObjectiveTo estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate.MethodsIn 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression.ResultsRates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline.ConclusionsA considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline.

BackgroundThe goal of this study was to identify a clinical biomarker signature of brain amyloidosis in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) mild cognitive impairment (MCI) cohort.MethodsWe developed a multimodal biomarker classifier for predicting brain amyloidosis using cognitive, imaging, and peripheral blood protein ADNI1 MCI data. We used CSF β-amyloid 1-42 (Aβ42) ≤ 192 pg/mL as proxy measure for Pittsburgh compound B (PiB)-PET standard uptake value ratio ≥ 1.5. We trained our classifier in the subcohort with CSF Aβ42 but no PiB-PET data and tested its performance in the subcohort with PiB-PET but no CSF Aβ42 data. We also examined the utility of our biomarker signature for predicting disease progression from MCI to Alzheimer dementia.ResultsThe CSF training classifier selected Mini-Mental State Examination, Trails B, Auditory Verbal Learning Test delayed recall, education, APOE genotype, interleukin 6 receptor, clusterin, and ApoE protein, and achieved leave-one-out accuracy of 85% (area under the curve [AUC] = 0.8). The PiB testing classifier achieved an AUC of 0.72, and when classifier self-tuning was allowed, AUC = 0.74. The 36-month disease-progression classifier achieved AUC = 0.75 and accuracy = 71%.ConclusionsAutomated classifiers based on cognitive and peripheral blood protein variables can identify the presence of brain amyloidosis with a modest level of accuracy. Such methods could have implications for clinical trial design and enrollment in the near future.Classification of evidenceThis study provides Class II evidence that a classification algorithm based on cognitive, imaging, and peripheral blood protein measures identifies patients with brain amyloid on PiB-PET with moderate accuracy (sensitivity 68%, specificity 78%).

In-home assessment of everyday activities over many months to years may be useful in predicting cognitive decline in older adulthood. This study examined whether a comparatively brief data collection period (3 months) may yield similar diagnostic information. A total of 91 community-dwelling older adults without dementia underwent baseline neuropsychological testing and completed weekly computer-based surveys assessing health-related events/activities. A subset of participants wore fitness tracker watches assessing daily sleep and physical activity patterns, used a sensor-instrumented pillbox, and had their computer use frequency recorded on a daily basis. Similar patterns in computer use, sleep and medication use were noted in comparison to prior literature with more extensive data collection periods. Greater computer use and sleep, as well as self-reported pain and independence, were also linked to better cognition. These activities and symptoms may be useful correlates of cognitive function even when assessed over a relatively brief monitoring period. [ABSTRACT FROM AUTHOR]

Introduction: Impairment in financial capacity places older adults at risk of fraud or abuse and can be a harbinger of loss of independence. Online automated monitoring of financial transactions offers an objective, unobtrusive, and continuous data collection strategy to minimize risk and to detect early changes in an important complex activity of daily living. Methods: Ninety‐three participants used an online financial activity monitoring platform that extracted metrics related to use and potential departures from established patterns of financial behavior. Standard neuropsychological assessments and a performance‐based measure of financial capacity at baseline were compared using continuous monitoring metrics. Results: Participants demonstrated a willingness to engage with an online financial activity monitoring system. Online metrics were not associated with performance in specific cognitive domains. Performance on an established test of financial capacity was negatively correlated with a ratio of alerts to transactions, that is, a higher likelihood of errors or deviations from previous activity. Discussion: To our knowledge, this is the first reported study using secure online technology to link ongoing unobtrusively collected financial activity monitoring data with other objective measures of function and cognition in a cohort of independent living older adults. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to examine the unique contributions of age to objectively measure driving frequency and dangerous driving behaviors in healthy older adults after adjusting for executive function (EF). Method: A total of 28 community-dwelling older adults (mean age = 82.0 years, standard deviation [SD] = 7.5) without dementia who were in good physical health and enrolled in a longitudinal aging study completed several EF and clinical self-report measures at baseline. Participants subsequently had a sensor installed in their vehicle for a mean of 208 (SD = 38, range = 127–257) days. Results: Participants drove for an average of 54 min per day. Mixed-effects models indicated that after controlling for EF, older age was associated with less time driving per day, decreased number of trips, and less nighttime driving. Age was not associated with hard brakes or hard accelerations. Discussion: After accounting for EF, greater age is associated with higher driving self-regulation but not dangerous driving behaviors in healthy older adults. Future studies should recruit larger samples and collect sensor-measured driving data over a more extended time frame to better determine how and why these self-regulation changes take place. [ABSTRACT FROM AUTHOR]

Background: Inter-relationships between multimorbidity and geriatric syndromes are poorly understood. This study assesses heterogeneity in joint trajectories of somatic disease, functional status, cognitive performance, and depressive symptomatology. Methods: We analyzed 16 years of longitudinal data from the Health and Retirement Study (HRS, 1998-2016) for n = 11,565 older adults (≥65 years) in the United States. Group-based mixture modeling identified latent clusters of older adults following similar joint trajectories across domains. Results: We identified four distinct multidimensional trajectory groups: (1) Minimal Impairment with Low Multimorbidity (32.7% of the sample; mean = 0.60 conditions at age 65, 2.1 conditions at age 90) had limited deterioration; (2) Minimal Impairment with High Multimorbidity (32.9%; mean = 2.3 conditions at age 65, 4.0 at age 90) had minimal deterioration; (3) Multidomain Impairment with Intermediate Multimorbidity (19.9%; mean = 1.3 conditions at age 65, 2.7 at age 90) had moderate depressive symptomatology and functional impariments with worsening cognitive performance; (4) Multidomain Impairment with High Multimorbidity (14.1%; mean = 3.3 conditions at age 65; 4.7 at age 90) had substantial functional limitation and high depressive symptomatology with worsening cognitive performance. Black and Hispanic race/ethnicity, lower wealth, lower education, male sex, and smoking history were significantly associated with membership in the two Multidomain Impairment classes. Conclusions: There is substantial heterogeneity in combined trajectories of interrelated health domains in late life. Membership in the two most impaired classes was more likely for minoritized older adults. [ABSTRACT FROM AUTHOR]

Background and Objectives Greater everyday decision-making involvement by persons living with dementia (PLWD) and congruent appraisal between PLWDs and their caregivers have been associated with a better quality of life (QOL) for both members of the dyad. However, no study has examined the association between the appraisals of everyday decision-making involvement of PLWDs and their QOL among African Americans. Research Design and Methods A secondary analysis of cross-sectional data from 62 African American dementia dyads was conducted. Multilevel and latent class mixture modeling was used to characterize dyadic appraisal of the decision-making involvement of African American PLWDs and identify distinct patterns thereof. Results Three distinct patterns were observed. "Incongruent, PLWD Low Involvement" labeled 19.4% of the sample, 53.2% were labeled "Incongruent, PLWD Moderate Involvement," and 27.4% were labeled "Congruent, PLWD High Involvement." The Congruent, PLWD High Involvement pattern consisted of PLWDs who were significantly younger and had significantly less cognitive impairment than PLWDs in the other patterns. In the Incongruent, PLWD Moderate Involvement pattern, PLWDs had significantly better QOL than PLWDs in the Incongruent, PLWD Low Involvement pattern, but QOL did not significantly differ from PLWDs in the Congruent, PLWD High Involvement pattern. Discussion and Implications There is a need to tailor strategies to optimize QOL in African American dementia dyads. While increasing everyday decision-making involvement for PLWDs in the Incongruent, PLWD Low Involvement pattern is an important goal, other strategies may be needed to improve the QOL of PLWDs in the remaining patterns. [ABSTRACT FROM AUTHOR]

Background: Substantial research is dedicated to understanding the aging-related dynamics among individual differences in level, change, and variation across physical and cognitive abilities. Evaluating replicability and synthesizing these findings has been limited by differences in measurements and samples, and by study design and statistical analyses confounding between-person differences with within-person changes. In this article, we conducted a coordinated analysis and summary meta-analysis of new results on the aging-related dynamics linking pulmonary function and cognitive performance.Methods: We performed coordinated analysis of bivariate growth models in data from 20,586 participants across eight longitudinal studies to examine individual differences in baseline level, rate of change, and occasion-specific variability in pulmonary and cognitive functioning. Results were summarized using meta-analysis.Results: We found consistent but weak baseline and longitudinal associations in levels of pulmonary and cognitive functioning, but no associations in occasion-specific variability.Conclusions: Results provide limited evidence for a consistent link between simultaneous changes in pulmonary and cognitive function in a normal aging population. Further research is required to understand patterns of onset of decline and differences in rates of change within and across physical and cognitive functioning domains, both within-individuals and across countries and birth cohorts. Coordinated analysis provides an efficient and rigorous approach for replicating and comparing results across independent longitudinal studies. [ABSTRACT FROM AUTHOR]

Background: Understanding contributions of different brain pathologies to domain-specific cognitive trajectories in the oldest old is crucial to guide future intervention studies.Methods: Two-hundred-twenty Oregon Alzheimer's Disease Center research participants who were cognitively intact at entry were followed on average for 7.3 years with annual neuropsychological testing until death (mean age, 93.7 y) and autopsy. Mixed effects models examined the relationship between trajectories in memory, verbal fluency, and mini-mental state examination (MMSE) and pathology (neurofibrillary tangles, neuritic plaques, gross infarcts, hippocampal sclerosis, Lewy bodies, APOE genotype, age at death, and years of education). The association between the MMSE trajectory and pathologic variables were examined using a Poisson model with MMSE errors as outcomes given the nonlinear distribution of MMSE scores.Results: Memory trajectory was associated with the APOε4 allele (P=0.006). Verbal fluency trajectory was associated with gross infarcts (P=0.008). MMSE trajectory was associated with high Braak scores (P=0.03), gross infarcts (P<0.0001), hippocampal sclerosis (P=0.003), moderate neuritic plaques (P=0.04), and the APOε4 allele (P=0.02).Conclusions: The association between trajectory of decline in global cognitive scores and multiple brain pathologies highlights the importance of accounting for comorbid pathologies in therapeutic trials aimed at one specific pathology in the oldest old. Only the APOε4 allele showed an association with memory decline, despite accounting for Alzheimer's disease pathology, suggesting that APOE may be involved in mechanisms beyond amyloid metabolism in its role in memory. Further studies are needed to examine the role of APOE in brain aging. [ABSTRACT FROM AUTHOR]

Background: Driving is a key functional activity for many older adults, and changes in routine driving may be associated with emerging cognitive decline due to early neurodegenerative disease. Current methods for assessing driving such as self-report are inadequate for identifying and monitoring subtle changes in driving patterns that may be the earliest signals of functional change in developing mild cognitive impairment (MCI).Objective: This proof of concept study aimed to establish the feasibility of continuous driving monitoring in a sample of cognitively normal and MCI older adults for an average of 206 days using an unobtrusive driving sensor and demonstrate that derived sensor-based driving metrics could effectively discriminate between MCI and cognitively intact groups.Methods: Novel objective driving measures derived from 6 months of routine driving monitoring were examined in older adults with intact cognition (n = 21) and MCI (n = 7) who were enrolled in the Oregon Center for Aging and Technology (ORCATECH) longitudinal assessment program.Results: Unobtrusive continuous monitoring of older adults' routine driving using a driving sensor was feasible and well accepted. MCI participants drove fewer miles and spent less time on the highway per day than cognitively intact participants. MCI drivers showed less day-to-day fluctuations in their driving habits than cognitively intact drivers.Conclusion: Sensor-based driving measures are objective, unobtrusive, and can be assessed every time a person drives his or her vehicle to identify clinically meaningful changes in daily driving. This novel methodology has the potential to be useful for the early detection and monitoring of changes in daily functioning within individuals. [ABSTRACT FROM AUTHOR]

Significant progress has been made in characterizing the biological changes occurring in preclinical Alzheimer's disease (AD). Cognitive dysfunction has been viewed, however, as a late-stage phenomenon, despite increasing evidence that changes may be detected in the decades preceding dementia. In the absence of comprehensive evidence-based guidelines for preclinical cognitive assessment, longitudinal cohort and neuroimaging studies have been reviewed to determine the temporal order and brain biomarker correlates of specific cognitive functions. Episodic memory decline was observed to be the most salient cognitive function, correlating with high levels of amyloid deposition and hypoconnectivity across large-scale brain networks. Prospective studies point to early decline in both episodic and semantic memory processing as well as executive functions in the predementia period. The cognitive tests have, however, been principally those used to diagnose dementia. New procedures are required which target more finely the medial temporal lobe subregions first affected by clinically silent AD pathology. [ABSTRACT FROM AUTHOR]

The Horizon 2020/IMI European Prevention of Alzheimer's Dementia (EPAD) project will undertake large-scale proof-of-concept trials in predementia Alzheimer's disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross-cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Assessment of the earlier stages of Alzheimer's disease requires different strategies than those previously developed for fully syndromal Alzheimer's disease. This challenge is further magnified in very early stages, where symptomatology may be minimal and functional deficits very subtle to absent. This paper reviews strategies for performance-based assessment of the early stages of Alzheimer's disease, including assessments of cognition, functional capacity, and social cognition. Meetings with an International Society for CNS Clinical Trials and Methodology working group served as the basis for this paper and its companion. The current state of the art of detection and staging-oriented assessments is presented, and information is provided regarding the practicality and validity of these approaches, with a special focus on their usefulness in clinical trials for new medication development. [ABSTRACT FROM AUTHOR]

Objectives: Loneliness and social isolation are two important health outcomes among older adults. Current assessment of these outcomes relies on self-report which is susceptible to bias. This paper reports on the relationship between loneliness and objective measures of isolation using a phone monitoring device. Method: Phone monitors were installed in the homes of 26 independent elderly individuals from the ORCATECH Life Laboratory cohort (age 86 ± 4.5, 88% female) and used to monitor the daily phone usage for an average of 174 days. Loneliness was assessed using the 20-item University of California Los Angeles (UCLA) Loneliness scale. A mixed effects negative binomial regression was used to model the relationship between loneliness and social isolation, as assessed using the total number of calls, controlling for cognitive function, pain, age, gender, and weekday. A secondary analysis examined the differential effect of loneliness on incoming and outgoing calls. Results: The average UCLA Loneliness score was 35.3 ± 7.6, and the median daily number of calls was 4. Loneliness was negatively associated with telephone use (IRR = 0.99, p < 0.05). Daily phone use was also associated with gender (IRR = 2.03, p < 0.001) and cognitive status (IRR = 1.51, p < 0.001). The secondary analysis revealed that loneliness was significantly related to incoming (IRR = 0.98, p < 0.01) but not outgoing calls. Conclusions: These results demonstrate the close relationship between loneliness and social isolation, showing that phone behaviour is associated with emotional state and cognitive function. Because phone behaviour can be monitored unobtrusively, it may be possible to sense loneliness levels in older adults using objective assessments of key aspects of behaviour. [ABSTRACT FROM AUTHOR]

Abstract: Physical performance measures predict health and function in older populations. Walking speed in particular has consistently predicted morbidity and mortality. However, single brief walking measures may not reflect a person''s typical ability. Using a system that unobtrusively and continuously measures walking activity in a person''s home we examined walking speed metrics and their relation to function. In 76 persons living independently (mean age, 86) we measured every instance of walking past a line of passive infra-red motion sensors placed strategically in their home during a four-week period surrounding their annual clinical evaluation. Walking speeds and the variance in these measures were calculated and compared to conventional measures of gait, motor function and cognition. Median number of walks per day was 18±15. Overall mean walking speed was 61±17cm/s. Characteristic fast walking speed was 96cm/s. Men walked as frequently and fast as women. Those using a walking aid walked significantly slower and with greater variability. Morning speeds were significantly faster than afternoon/evening speeds. In-home walking speeds were significantly associated with several neuropsychological tests as well as tests of motor performance. Unobtrusive home walking assessments are ecologically valid measures of walking function. They provide previously unattainable metrics (periodicity, variability, range of minimum and maximum speeds) of everyday motor function. [Copyright &y& Elsevier]

Motor speed is an important indicator and predictor of both cognitive and physical function. One common assessment of motor speed is the finger-tapping test (FTT), which is typically administered as part of a neurological or neuropsychological assessment. However, the FTT suffers from several limitations, including infrequent in-person administration, the need for a trained assessor and dedicated equipment, and potential short-term sensory-motor fatigue. In this article, we propose an alternative method of measuring motor speed, with face validity to the FTT, that addresses these limitations by measuring the interkeystroke intervals (IKI) of familiar and repeated login data collected in the home during a subject's regular computer use. We show significant correlations between the mean tapping speeds from the FTT and the median IKIs of the nondominant ( r = .77) and dominant ( r = .70) hands, respectively, in an elderly cohort of subjects living independently. Finally, we discuss how the proposed method for measuring motor speed fits well into the framework of unobtrusive and continuous in-home assessment. [ABSTRACT FROM AUTHOR]

Abstract: The demand for rapidly administered, sensitive, and reliable cognitive assessments that are specifically designed for identifying individuals in the earliest stages of cognitive decline (and to measure subtle change over time) has escalated as the emphasis in Alzheimer’s disease clinical research has shifted from clinical diagnosis and treatment toward the goal of developing presymptomatic neuroprotective therapies. To meet these changing clinical requirements, cognitive measures or tailored batteries of tests must be validated and determined to be fit-for-use for the discrimination between cognitively healthy individuals and persons who are experiencing very subtle cognitive changes that likely signal the emergence of early mild cognitive impairment. We sought to collect and review data systematically from a wide variety of (mostly computer-administered) cognitive measures, all of which are currently marketed or distributed with the claims that these instruments are sensitive and reliable for the early identification of disease or, if untested for this purpose, are promising tools based on other variables. The survey responses for 16 measures/batteries are presented in brief in this review; full survey responses and summary tables are archived and publicly available on the Campaign to Prevent Alzheimer’s Disease by 2020 Web site (http://pad2020.org). A decision tree diagram highlighting critical decision points for selecting measures to meet varying clinical trials requirements has also been provided. Ultimately, the survey questionnaire, framework, and decision guidelines provided in this review should remain as useful aids for the evaluation of any new or updated sets of instruments in the years to come. [Copyright &y& Elsevier]

The prevalence of cognitive impairment and dementia in Parkinson's disease (PD) is high and can potentially occur as the result of multiple differing pathologies. Neuroimaging has provided evidence of decreased cortical volume, increased white matter diffusion changes, and decreased resting metabolic activity that appears to begin prior to the onset of dementia in PD patients. Cognitive impairment has been found to be associated with multiple neurotransmitter transmission deficiencies, including dopamine and acetylcholine, indicating a widespread neurotransmitter dysfunction in PD-related dementia. Findings of increased Pittsburgh Compound B (PiB) binding in subjects with Lewy Body Disease (LBD) compared with Parkinson's disease and dementia (PDD) may explain phenotype differences in the spectrum of Dementia with Lewy Bodies (DLB), and show promise in guiding future therapeutic trials aimed at this disease. Advances in neuroimaging now allow for the detection of volumetric, pharmacologic, and pathological changes that may assist in the diagnosis and prediction of cognitive impairment in Parkinson's patients so that better evaluation of disease progression and treatment can be obtained. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To explore the performance of a test of temporal orientation (TTO) comprising four items derived from the Mini-Mental State Examination over 4 years. Methods: Responses were obtained from two large cohorts participating in longitudinal studies of aging in the United States (352 normal elderly, 98 persons with very mild probable or possible Alzheimer’s disease). Sensitivity, specificity, and predictive value (positive, PV+, negative, PV−) of the TTO were estimated for each of four annual visits. Results: When four correct answers were treated as “oriented to time” and 0 to 3 correct answers were treated as “not oriented to time,” sensitivity (to the presence of AD) ranged from 46.0% to 69.2% and PV+ ranged from 32.1% to 49.5%. Specificity (for normal cognition) decreased from 93.2% at the first visit to 81.3% at the fourth visit; TTO performed most reliably in terms of PV−, the probability of normal cognitive function given orientation to time (TTO = 4), which ranged from 92.8% to 95.4%. Conclusion: Given the stability and strength of the predictive negative value of a dichotomized TTO over time, a TTO could contribute to monitoring normal cognitive functioning in longitudinal studies in which cognitive status is not the primary focus. Prospective validation of the TTO is warranted. [Copyright &y& Elsevier]

Abstract: Low cerebrospinal fluid (CSF) Aβ42 levels correlate with increased brain Aβ deposition in Alzheimer's disease (AD), which suggests a disruption in the degradation and clearance of Aβ from the brain. In addition, APOE ε4 carriers have lower CSF Aβ42 levels than non-carriers. The hypothesis of this investigation was that CSF Aβ42 levels would correlate with regulatory region variation in genes that are biologically associated with degradation or clearance of Aβ from the brain. CSF Aβ42 levels were tested for associations with Aβ degradation and clearance genes and APOE ε4. Twenty-four SNPs located within the 5′ and 3′ regions of 12 genes were analyzed. The study sample consisted of 99 AD patients and 168 cognitively normal control subjects. CSF Aβ42 levels were associated with APOE ε4 status in controls but not in AD patients; A2M regulatory region SNPs were also associated with CSF Aβ42 levels in controls but not in AD patients, even after adjusting for APOE ε4. These results suggest that genetic variation within the A2M gene influences CSF Aβ42 levels. [Copyright &y& Elsevier]