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 ± 17 cm/sec. Characteristic fast walking speed was 96 cm/sec. 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.
Gait; Home-based clinical assessment; Technology
This report describes a pilot study to evaluate feasibility of new home-based assessment technologies applicable to clinical trials for prevention of cognitive loss and Alzheimer disease.
Community-dwelling nondemented individuals ≥ 75 years old were recruited and randomized to 1 of 3 assessment methodologies: (1) mail-in questionnaire/live telephone interviews (MIP); (2) automated telephone with interactive voice recognition (IVR); and (3) internet-based computer Kiosk (KIO). Brief versions of cognitive and noncognitive outcomes were adapted to the different methodologies and administered at baseline and 1-month. An Efficiency measure, consisting of direct staff-to-participant time required to complete assessments, was also compared across arms.
Forty-eight out of 60 screened participants were randomized. The dropout rate across arms from randomization through 1-month was different: 33% for KIO, 25% for IVR, and 0% for MIP (Fisher Exact Test P = 0.04). Nearly all participants who completed baseline also completed 1-month assessment (38 out of 39). The 1-way ANOVA across arms for total staff-to-participant direct contact time (ie, training, baseline, and 1-month) was significant: F (2,33) = 4.588; P = 0.017, with lowest overall direct time in minutes for IVR (Mn = 44.4; SD = 21.5), followed by MIP (Mn = 74.9; SD = 29.9), followed by KIO (Mn = 129.4; SD = 117.0).
In this sample of older individuals, a higher dropout rate occurred in those assigned to the high-technology assessment techniques; however, once participants had completed baseline in all 3 arms, they continued participation through 1 month. High-technology home-based assessment methods, which do not require live testers, began to emerge as more time-efficient over the brief time of this pilot, despite initial time-intensive participant training.
alzheimer disease; prevention trials; home-based assessment
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 interval (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 speed from the FTT and the median IKIs of the non-dominant (r=0.77) and dominant (r=0.70) 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.
Motor speed; Typing; Finger tapping test
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 344 non-demented subjects with autopsy (201 subjects with low and 143 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided genome-wide significant evidence that variants in the RELNgene 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.
There is a paucity of data regarding trends in dementia and its subtype prevalence in Japan. Our aims in the current paper are to: (1) summarize epidemiological studies of dementia in Japan including relevant details of study protocol and diagnostic criteria, (2) compare the age-specific prevalence of all-cause dementia among studies, and (3) assess the trends in Alzheimer's disease (AD) versus vascular dementia (VaD) over time. We reviewed diagnostic criteria, all-cause dementia prevalence, and the AD/VaD ratio from 8 large population studies of dementia in Japan. Compared with the Okinawa 1992 study, studies conducted in 1994, 1998, 2005, and 2008 had a higher prevalence of all-cause dementia using Poisson regression models, after controlling for age and sex. In contrast to the US and some European countries, all-cause dementia prevalence is increasing in Japan. The prevalence of AD as opposed to VaD seems to be increasing over time, but large variability in diagnostic criteria, possible regional variability, and differences in prevalence of subtypes of dementia between men and women make it difficult to draw a conclusion about this trend at the national level. Further studies, for example, comparing the population attributable risk of vascular diseases to the prevalence and incidence of dementia could help to clarify the regional variations in etiological subtypes.
Spoken responses produced by subjects during neuropsychological exams can provide diagnostic markers beyond exam performance. In particular, characteristics of the spoken language itself can discriminate between subject groups. We present results on the utility of such markers in discriminating between healthy elderly subjects and subjects with mild cognitive impairment (MCI). Given the audio and transcript of a spoken narrative recall task, a range of markers are automatically derived. These markers include speech features such as pause frequency and duration, and many linguistic complexity measures. We examine measures calculated from manually annotated time alignments (of the transcript with the audio) and syntactic parse trees, as well as the same measures calculated from automatic (forced) time alignments and automatic parses. We show statistically significant differences between clinical subject groups for a number of measures. These differences are largely preserved with automation. We then present classification results, and demonstrate a statistically significant improvement in the area under the ROC curve (AUC) when using automatic spoken language derived features in addition to the neuropsychological test scores. Our results indicate that using multiple, complementary measures can aid in automatic detection of MCI.
Forced alignment; linguistic complexity; mild cognitive impairment (MCI); parsing; spoken language understanding
Alzheimer’s disease (AD), cerebral vascular brain injury (VBI), and isocortical Lewy body (LB) disease (LBD) are the major contributors to dementia in community- or population-based studies: Adult Changes in Thought (ACT) study, Honolulu-Asia Aging Study (HAAS), Nun Study (NS), and Oregon Brain Aging Study (OBAS). However, the prevalence of clinically silent forms of these diseases in cognitively normal (CN) adults is less clear.
DESIGN and SETTING
We evaluated 1672 brain autopsies from ACT, HAAS, NS, and OBAS of which 424 met criteria for CN.
MAIN OUTCOME MEASURES
Of these, 336 cases had a comprehensive neuropathologic examination of neuritic plaque (NP) density, Braak stage for neurofibrillary tangles (NFTs), Lewy body (LB) distribution, and number of cerebral microinfarcts (CMIs).
47% of CN cases had moderate or frequent NP density; of these 6% also had Braak stage V or VI for NFTs. 15% of CN cases had medullary LBD; 8% also had nigral and 4% isocortical LBD. The presence of any CMIs was identified in 33% and high level CMIs in 10% of CN individuals. Overall burden of lesions in each individual and their co-morbidity varied widely within each study but were similar among studies.
These data show an individually varying complex convergence of subclinical diseases in the brain of older CN adults. Appreciating this ecology should help guide future biomarker or neuroimaging studies as well as clinical trials that focus on community- or population-based cohorts.
Alzheimer’s disease; vascular brain injury; Lewy body disease; cognitive aging
Gait velocity has repeatedly been shown to be an important indicator and predictor of both cognitive and physical function, especially in elderly. However, clinical gait assessments are conducted infrequently and cannot distinguish between abrupt changes in function and changes that occur more slowly over time. Collecting gait measurements continuously in-home has recently been proposed and validated to overcome these clinical limitations. In this paper, we describe the longitudinal analysis of in-home gait velocity collected unobtrusively from passive infrared motion sensors. We first describe a model for the probability density function of the in-home gait velocities. We then describe estimation of the evolution of the density function over time and report empirically determined algorithm parameters that have performed well over a wide variety of different gait velocity data. Finally, we demonstrate how this approach allows detection of significant events (abrupt changes in function) and slower changes over time in gait velocity data collected from a sample of two elderly subjects in the Intelligent Systems for Assessing Aging Changes (ISAAC) study.
Ubiquitous and unobtrusive in-home monitoring has the potential to detect physical and mental decline earlier and with higher precision than current clinical methods. However, given that this field is in its infancy, the specific metrics through which these changes are detected are not well defined. The work presented here offers room-transitions, the act of physically moving from one area of a home to another, as a quantifiable measure for total daily activity that can be inferred from a network of passive infrared sensors. We describe a method to calculate this value from raw sensor data and validate this method on an acute health event: an 18-day quarantine at a retirement community that was initiated in the midst of a norovirus outbreak. The results from this case study show that room-transition values increased significantly as subjects remained in their homes during the quarantine, demonstrating a mean increase of 12 transitions per day. Furthermore, a time-adjusted measure of room-transitions is examined that did not significantly change across the group. Finally, the healthy subjects and those that fell ill were analyzed separately, and significant differences were found between them for both the raw and time-adjusted metrics. As detection algorithms improve, these types of measures may be useful in the early detection of a change in health status.
To describe a longitudinal community cohort study, Intelligent Systems for Assessing Aging Changes, that has deployed an unobtrusive home-based assessment platform in many seniors homes in the existing community.
Several types of sensors have been installed in the homes of 265 elderly persons for an average of 33 months. Metrics assessed by the sensors include total daily activity, time out of home, and walking speed. Participants were given a computer as well as training, and computer usage was monitored. Participants are assessed annually with health and function questionnaires, physical examinations, and neuropsychological testing.
Mean age was 83.3 years, mean years of education was 15.5, and 73% of cohort were women. During a 4-week snapshot, participants left their home twice a day on average for a total of 208 min per day. Mean in-home walking speed was 61.0 cm/s. Participants spent 43% of days on the computer averaging 76 min per day.
These results demonstrate for the first time the feasibility of engaging seniors in a large-scale deployment of in-home activity assessment technology and the successful collection of these activity metrics. We plan to use this platform to determine if continuous unobtrusive monitoring may detect incident cognitive decline.
Cognitive assessment; Dementia; Home-based clinical assessment; Technology
Brain development in the early stages of life has been suggested to be one of the factors that may influence an individual’s risk of Alzheimer disease (AD) later in life. Four microcephaly genes which regulate brain development in utero and have been suggested to play a role in the evolution of the human brain were selected as candidate genes that may modulate risk of AD. We examined the association between single nucleotide polymorphisms (SNPs) tagging common sequence variations in these genes and risk of AD in Caucasian case control samples. We found that the G allele of rs2442607 in microcephalin 1 was associated with an increased risk of AD (under an additive genetic model, p=0.01, OR=3.41, CI=1.77, 6.57). However, this association was not replicated using another Caucasian sample from the Alzheimer Disease Neuroimaging Initiative. We conclude that the common variations we measured in the 4 microcephaly genes do not affect risk of AD, or that their effect size is small.
Alzheimer disease; microcephaly genes; cognitive reserve
The ability to reliably infer the nature of telephone conversations opens up a variety of applications, ranging from designing context-sensitive user interfaces on smartphones, to providing new tools for social psychologists and social scientists to study and understand social life of different subpopulations within different contexts. Using a unique corpus of everyday telephone conversations collected from eight residences over the duration of a year, we investigate the utility of popular features, extracted solely from the content, in classifying business-oriented calls from others. Through feature selection experiments, we find that the discrimination can be performed robustly for a majority of the calls using a small set of features. Remarkably, features learned from unsupervised methods, specifically latent Dirichlet allocation, perform almost as well as with as those from supervised methods. The unsupervised clusters learned in this task shows promise of finer grain inference of social nature of telephone conversations.
The 2000 US census identified 50,454 Americans over the age of 100. Increased longevity is only of benefit if accompanied by maintenance of independence and quality of life. Little is known about the prevalence of dementia and other disabling conditions among rural centenarians although this information is important to clinicians caring for them.
To determine the prevalence of disabling conditions, including cognitive impairment, among the very elderly in a rural setting to guide clinicians in their care.
We performed a population-based cohort study of all residents 97 years and older in the Klamath Basin, a rural region in southern Oregon. The prevalence of disabling conditions was determined by in-person examination.
100% of the target sample was identified. Of the eligible 67 individuals ≥ 97 years old, 31 were evaluated in-person. The prevalence of dementia (probable or possible Alzheimer’s disease or vascular dementia) was 61.3% (95% CI: 43.8, 76.2), mild cognitive impairment was 29.0% (95% CI: 16.1, 46.6), and no dementia was 9.7% (95% CI: 3.4, 25.0). Parkinsonism and the APOEe4 allele were rare. Systemic vascular disease was almost universally present.
While cognitive impairment was nearly universal in this rural population of very elderly persons, almost 40% had not progressed to full dementia. Determining risk factors for dementia in this population can identify strategies to prevent progression to dementia among younger elderly populations.
brain; aging; centenarian; dementia; Alzheimer’s disease; rural
Background. Blood-brain barrier (BBB) dysfunction may have a significant role in the pathogenesis of Alzheimer's disease (AD). Modifiable factors associated with BBB function may have therapeutic implication. This study tested the hypothesis that dyslipidemia is associated with BBB impairment in mild-to-moderate AD. Methods. Thirty-six subjects with AD were followed for 1 year. Fasting CSF and plasma were collected with clinical assessments at baseline and 12 months. BBB impairment was defined as CSF albumin index ≥9. Independent t-tests and linear regression assessed the relationship between plasma lipoproteins and BBB integrity. Results. Dyslipidemia was prevalent in 47% of the population, and in 75% of those with BBB impairment. Subjects with BBB impairment had significantly higher mean plasma triglyceride and lower HDL cholesterol (TG, P = 0.007; HDL, P = 0.043). Plasma triglycerides explained 22% of the variance in BBB integrity and remained significant after controlling for age, gender, ApoE-4 genotype, blood pressure, and statin use. Conclusion. Dyslipidemia is more prevalent in AD subjects with BBB impairment. Plasma triglyceride and HDL cholesterol may have a role in maintaining BBB integrity in mild-to-moderate Alzheimer's disease.
The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.
Preclinical Alzheimer's disease; Biomarker; Amyloid; Neurodegeneration; Prevention
MRI; Cognition; Dementia; Parkinson's Disease
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
Mild cognitive impairment (MCI) is often associated with the preclinical phase of Alzheimer's disease (AD). Special scoring of word-list recall data for serial position has been suggested to improve discrimination of normal aging from dementia. We examined serial position effects in word-list recall for MCI participants compared to Alzheimer patients and controls. Individuals with MCI, like Alzheimer patients, had a diminished primacy effect in recalling words from a list. No alternative scoring system was better than standard scoring of word list recall in distinguishing MCI patients from controls. Retention weighted scoring improved the discrimination of MCI and AD groups.
In the central nervous system (CNS), aging results in a precipitous decline in adult neural stem/progenitor cells (NPCs) and neurogenesis, with concomitant impairments in cognitive functions1. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise1. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age dependent fashion in mice. Accordingly, exposing a young animal to an old systemic environment, or to plasma from old mice, decreased synaptic plasticity and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines - including CCL11/Eotaxin – whose plasma levels correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and whose levels are increased in plasma and cerebral spinal fluid of healthy aging humans. Finally, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis, and cognitive impairments, observed during aging can be in part attributed to changes in blood-borne factors.
We used a Guttman model to represent responses to test items over time as an approximation of what is often referred to as “points lost” in studies of cognitive decline or interventions. To capture this meaning of “point loss”, over four successive assessments, we assumed that once an item is incorrect, it cannot be correct at a later visit. If the loss of a point represents actual decline, then failure of an item to fit the Guttman model over time can be considered measurement error. This representation and definition of measurement error also permits testing the hypotheses that measurement error is constant for items in a test, and that error is independent of “true score”, which are two key consequences of the definition of “measurement error” –and thereby, reliability- under Classical Test Theory. We tested the hypotheses by fitting our model to, and comparing our results from, four consecutive annual evaluations in three groups of elderly persons: a) cognitively normal (NC, N = 149); b) diagnosed with possible or probable AD (N = 78); and c) cognitively normal initially and a later diagnosis of AD (converters, N = 133). Of 16 items that converged, error-free measurement of “cognitive loss” was observed for 10 items in NC, eight in converters, and two in AD. We found that measurement error, as we defined it, was inconsistent over time and across cognitive functioning levels, violating the theory underlying reliability and other psychometric characteristics, and key regression assumptions.
Executive dysfunction has previously been found to be a risk factor for falls. The aim of this study is to investigate the association between executive dysfunction and risk of falling and to determine if this association is independent of balance.
Participants were 188 community-dwelling individuals aged 65 and older. All participants underwent baseline and annual evaluations with review of health history, standardized neurologic examination, neuropsychological testing, and qualitative and quantitative assessment of motor function. Falls were recorded prospectively using weekly online health forms.
During 13 months of follow-up, there were 65 of 188 participants (34.6%) who reported at least one fall. Univariate analysis showed that fallers were more likely to have lower baseline scores in executive function than non-fallers (p = 0.03). Among participants without balance impairment we found that higher executive function z-scores were associated with lower fall counts (p = 0.03) after adjustment for age, sex, health status and prior history of falls using negative binomial regression models. This relationship was not present among participants with poor balance.
Lower scores on executive function tests are a risk factor for falls in participants with minimal balance impairment. However, this effect is attenuated in individuals with poor balance where physical or more direct motor systems factors may play a greater role in fall risk.
The amyloid cascade hypothesis provides an economical mechanistic explanation for Alzheimer's disease (AD) dementia and correlated neuropathology. However, some nonagenarian individuals (high pathology controls, HPC) remain cognitively intact while enduring high amyloid plaque loads for decades. If amyloid accumulation is the prime instigator of neurotoxicity and dementia, specific protective mechanisms must enable these HPC to evade cognitive decline. We evaluated the neuropathological and biochemical differences existing between non-demented (ND)-HPC and an age-matched cohort with AD dementia. The ND-HPC selected for our study were clinically assessed as ND and possessed high amyloid plaque burdens. ELISA and Western blot analyses were used to quantify a group of proteins related to APP/Aβ/tau metabolism and other neurotrophic and inflammation-related molecules that have been found to be altered in neurodegenerative disorders and are pivotal to brain homeostasis and mental health. The molecules assumed to be critical in AD dementia, such as soluble or insoluble Aβ40, Aβ42 and tau were quantified by ELISA. Interestingly, only Aβ42 demonstrated a significant increase in ND-HPC when compared to the AD group. The vascular amyloid load which was not used in the selection of cases, was on the average almost 2-fold greater in AD than the ND-HPC, suggesting that a higher degree of microvascular dysfunction and perfusion compromise was present in the demented cohort. Neurofibrillary tangles were less frequent in the frontal cortices of ND-HPC. Biochemical findings included elevated vascular endothelial growth factor, apolipoprotein E and the neuroprotective factor S100B in ND-HPC, while anti-angiogenic pigment epithelium derived factor levels were lower. The lack of clear Aβ-related pathological/biochemical demarcation between AD and ND-HPC suggests that in addition to amyloid plaques other factors, such as neurofibrillary tangle density and vascular integrity, must play important roles in cognitive failure.
The effect of gender on systemic and brain levels of copper is relatively understudied. We examined gender effects in mice and human subjects. We observed a trend to higher serum copper levels in female compared to male LaFerla “triple transgenic” (1399 ± 233 versus 804 ± 436 ng/mL, P = 0.06) mice, and significantly higher brain copper levels in female- versus male wild-type mice (5.2 ± 0.2 versus 4.18 ± 0.3 ng/mg wet wt, P = 0.03). Plasma copper was significantly correlated with brain copper in mice (R2 = 0.218; P = 0.038). Among human subjects with AD, both plasma copper (1284 ± 118 versus 853 ± 81 ng/mL, P = 0.005) and cerebrospinal fluid copper (12.8 ± 1 versus 10.4 ± 0.7 ng/mL, P = 0.01) were elevated in women compared to men. Among healthy control subjects, plasma copper (1008 ± 51 versus 836 ± 41 ng/mL; P = 0.01) was higher in women than in men, but there was no difference in cerebrospinal fluid copper. We conclude that gender differences in copper status may influence copper-mediated pathological events in the brain.
The ε4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer’s disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21–87 years of age (n = 134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE ε4 and correlation between SNPs (linkage disequilibrium). APOE ε4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.
Apolipoprotein E gene; apolipoprotein E protein; cerebroshinal fluid; enhancer; promoter; SNP
Certain micronutrients are protective against cognitive decline. We examined whether there is any uniform pattern of circulating micronutrients cross–culturally that are associated with successful cognitive aging. For the U.S. sample, we used the stored serum/plasma of 115 participants, collected in Oregon, USA. The Okinawa sample consisted of 49 participants selected using similar inclusion criteria as the Oregon sample, from the Keys to Optimal Cognitive Aging Project. All participants were aged 85 years and older without cognitive impairment. We found that the Okinawan elders used fewer vitamin supplements but had similar levels of vitamin B12 and α-tocopherol, lower folate and γ-tocopherol, compared with Oregonian elders. That is, we did not find a uniform pattern of circulating micronutrients, suggesting that micronutrients other than those examined here or other lifestyle factors than nutrition could play an important role in achieving successful cognitive aging.
Oldest old; Circulating micronutrients; Healthy cognitive aging; Okinawa; Oregon