To determine the time of acceleration in white matter hyperintensity (WMH) burden, a common indicator of cerebrovascular pathology, in relation to conversion to mild cognitive impairment (MCI) in the elderly.
A total of 181 cognitively intact elderly volunteers from the longitudinal, prospective, Oregon Brain Aging Study underwent yearly evaluations, including brain MRI, and cognitive testing. MRIs were analyzed for imaging markers of neurodegeneration: WMH and ventricular CSF (vCSF) volumes. The time before MCI, when the changes in WMH and vCSF burden accelerate, was assessed using a mixed-effects model with a change point for subjects who developed MCI during follow-up.
During a follow-up duration of up to 19.6 years, 134 subjects converted to MCI. Acceleration in %WMH volume increase occurred 10.6 years before MCI onset. On average, the annual rate of change in %WMH increased an additional 3.3% after the change point. Acceleration in %vCSF volume increase occurred 3.7 years before the onset of MCI. Out of 63 subjects who converted to MCI and had autopsy, only 28.5% had Alzheimer disease (AD) as the sole etiology of their dementia, while almost just as many (24%) had both AD and significant ischemic cerebrovascular disease present.
Acceleration in WMH burden, a common indicator of cerebrovascular disease in the elderly, is a pathologic change that emerges early in the presymptomatic phase leading to MCI. Longitudinal changes in WMH may thus be useful in determining those at risk for cognitive impairment and for planning strategies for introducing disease-modifying therapies prior to dementia onset.
An efficient approach to certain types of biomedical research requires a scale that precludes involvement of all critical contributors in all aspects of experimental design, execution, and as well as writing of most, if not all, derived works. Guarantors of both the integrity of the data and of its subsequent analyses are required. When separate groups are responsible for each of these activities, each should be readily identifiable both in the primary publication and in all subsequent citations. We describe the publication policy of the Alzheimer Disease Neuroimaging Initiative (ADNI), its origins and its acceptance by the editorial and scientific communities.
To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.
CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.
The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.
Alzheimer’s disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid β peptide (Aβ), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5′ and 3′ regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner.
FYN; PPP2R4; MAPT; AD; CSF
Better tools for assessing cognitive impairment in the early stages of Alzheimer’s disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer’s Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.
Older adult participants in the Intelligent Systems for Assessment of Aging Changes study (ISAAC) carried out by the Oregon Center for Aging and Technology (ORCATECH) were surveyed regarding their attitudes about unobtrusive home monitoring and computer use at baseline and after one year (n=119). The survey was part of a longitudinal study using in-home sensor technology to detect cognitive changes and other health problems. Our primary objective was to measure willingness to share health or activity data with one’s doctor or family members and concerns about privacy or security of monitoring over one year of study participation. Differences in attitudes of participants with Mild Cognitive Impairment (MCI) compared to those with normal cognition were also examined. A high proportion (over 72%) of participants reported acceptance of in-home and computer monitoring and willingness to have data shared with their doctor or family members. However, a majority (60%) reported concerns related to privacy or security; these concerns increased after one year of participation. Few differences between participants with MCI and those with normal cognition were identified. Findings suggest that involvement in this unobtrusive in-home monitoring study may have raised awareness about the potential privacy risks of technology. Still, results show high acceptance, stable over time, of sharing information from monitoring systems with family members and doctors. Our findings have important implications for the deployment of technologies among older adults in research studies as well as in the general community.
activity monitoring; technology user receptivity; older adults; mild cognitive impairment
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.