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1.
APOE and MS4A6A interact with GnRH signaling in Alzheimer's disease: Enrichment of epistatic effects
Introduction
It is unknown if risk loci, identified by genome-wide association studies of late-onset Alzheimer's disease (LOAD), are linked to common molecular mechanisms through epistatic effects.Methods
We performed genome-wide interaction studies of five risk variants for LOAD followed by enrichment analyses to find if there are pathways that simultaneously interact with more than one variant. This novel approach was applied to four independent cohorts (5393 cases and 3746 controls).Results
We found enrichment of epistasis in gonadotropin-releasing hormone signaling with risk single-nucleotide polymorphisms in APOE and MS4A6A (P value = 3.7 × 10?5, P value = 5.6 × 10?6); vascular smooth muscle contraction pathway was also enriched in epistasis with these loci (P value = 9.6 × 10?5, P value = 2.4 × 10?7). MS4A6A risk variant also interacted with dilated cardiomyopathy pathway (P value = 3.1 × 10?7).Discussion
In addition to APOE, MS4A6A polymorphisms should be considered in hormone trials targeting gonadotropins. Interactions of risk variants with neurovascular pathways may also be important in LOAD pathology. 相似文献2.
Gyungah R. Jun Jaeyoon Chung Jesse Mez Robert Barber Gary W. Beecham David A. Bennett Joseph D. Buxbaum Goldie S. Byrd Minerva M. Carrasquillo Paul K. Crane Carlos Cruchaga Philip De Jager Nilufer Ertekin-Taner Denis Evans M. Danielle Fallin Tatiana M. Foroud Robert P. Friedland Alison M. Goate Lindsay A. Farrer 《Alzheimer's & dementia》2017,13(7):727-738
Introduction
Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.Methods
We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.Results
Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests (P < 5 × 10?8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10?6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10?6).Discussion
Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci. 相似文献3.
Alex C. Bender Andrea M. Austin Francine Grodstein Julie P.W. Bynum 《Alzheimer's & dementia》2017,13(7):792-800
Introduction
We examined the relationship between health care expenditures and cognition, focusing on differences across cognitive systems defined by global cognition, executive function, or episodic memory.Methods
We used linear regression models to compare annual health expenditures by cognitive status in 8125 Nurses' Health Study participants who completed a cognitive battery and were enrolled in Medicare parts A and B.Results
Adjusting for demographics and comorbidity, executive impairment was associated with higher total annual expenditures of $1488 per person (P < .01) compared with those without impairment. No association for episodic memory impairment was found. Expenditures exhibited a linear relationship with executive function, but not episodic memory ($584 higher for every 1 standard deviation decrement in executive function; P < .01).Discussion
Impairment in executive function is specifically and linearly associated with higher health care expenditures. Focusing on management strategies that address early losses in executive function may be effective in reducing costly services. 相似文献4.
Shubhabrata Mukherjee Joshua C. Russell Daniel T. Carr Jeremy D. Burgess Mariet Allen Daniel J. Serie Kevin L. Boehme John S.K. Kauwe Adam C. Naj David W. Fardo Dennis W. Dickson Thomas J. Montine Nilufer Ertekin-Taner Matt R. Kaeberlein Paul K. Crane 《Alzheimer's & dementia》2017,13(10):1133-1142
Introduction
We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci.Methods
We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.Results
We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex.Discussion
Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex. 相似文献5.
Hugh C. Hendrie Mengjie Zheng Wei Li Kathleen Lane Roberta Ambuehl Christianna Purnell Frederick W. Unverzagt Alexia Torke Ashok Balasubramanyam Chris M. Callahan Sujuan Gao 《Alzheimer's & dementia》2017,13(2):111-118
Introduction
High blood glucose levels may be responsible for the increased risk for dementia in diabetic patients.Methods
A secondary data analysis merging electronic medical records (EMRs) with data collected from the Indianapolis–Ibadan Dementia project (IIDP). Of the enrolled 4105 African Americans, 3778 were identified in the EMR. Study endpoints were dementia, mild cognitive impairment (MCI), or normal cognition. Repeated serum glucose measurements were used as the outcome variables.Results
Diabetic participants who developed incident dementia had a significant decrease in serum glucose levels in the years preceding the diagnosis compared to the participants with normal cognition (P = .0002). They also had significantly higher glucose levels up to 9 years before the dementia diagnosis (P = .0367).Discussion
High glucose levels followed by a decline occurring years before diagnosis in African American participants with diabetes may represent a powerful presymptomatic metabolic indicator of dementia. 相似文献6.
David R. Roalf Tyler M. Moore Dawn Mechanic-Hamilton David A. Wolk Steven E. Arnold Daniel A. Weintraub Paul J. Moberg 《Alzheimer's & dementia》2017,13(8):947-952
Introduction
To provide a crosswalk between the recently proposed short Montreal Cognitive Assessment (s-MoCA) and Mini-Mental State Examination (MMSE) within a clinical cohort.Methods
A total of 791 participants, with and without neurologic conditions, received both the MMSE and the MoCA at the same visit. s-MoCA scores were calculated and equipercentile equating was used to create a crosswalk between the s-MoCA and MMSE.Results
As expected, s-MoCA scores were highly correlated (Pearson r = 0.82, P < .001) with MMSE scores. s-MoCA scores correctly classified 85% of healthy older adults and 91% of individuals with neurologic conditions that impair cognition. In addition, we provide an easy to use table that enables the conversion of s-MoCA score to MMSE score.Discussion
The s-MoCA is quick to administer, provides high sensitivity and specificity for cognitive impairment, and now can be compared directly with the MMSE. 相似文献7.
Thanh G.N. Ton Thomas DeLeire Suepattra G. May Ningqi Hou Mahlet G. Tebeka Er Chen Joshua Chodosh 《Alzheimer's & dementia》2017,13(3):217-224
Introduction
Individuals with amnestic mild cognitive impairment (aMCI) are at elevated risk of developing Alzheimer's disease (AD) dementia.Methods
With data from the Aging, Demographics, and Memory Study, we used the Clinical Dementia Rating Sum of Boxes classifications to conduct a cross-sectional analysis assessing the relationship between cognitive state and various direct and indirect costs and health care utilization patterns.Results
Patients with aMCI had less medical expenditures than patients with moderate and severe AD dementia (P < .001) and were also significantly less likely to have been hospitalized (P = .04) and admitted to nursing home (P < .001). Compared to individuals with normal cognition, patients with aMCI had significantly less household income (P = .018).Discussion
Patients with aMCI had lower medical expenditures than patients with AD dementia. Poor cognitive status was linearly associated with lower household income, higher medical expenditures, higher likelihood of nursing and home care services, and lower likelihood of outpatient visits. 相似文献8.
María M. Corrada Kathleen M. Hayden Annlia Paganini-Hill Szofia S. Bullain Jaime DeMoss Colette Aguirre Ron Brookmeyer Claudia H. Kawas 《Alzheimer's & dementia》2017,13(2):103-110
Introduction
We investigated the association between age of onset of hypertension and dementia risk in an oldest-old cohort.Methods
Participants are from The 90+ Study, a population-based longitudinal study of people aged 90+ who are survivors from the Leisure World Cohort Study. We estimated hypertension onset age using self-reported information from The 90+ Study and Leisure World Cohort Study, collected about 20 years earlier. A total of 559 participants without dementia were followed every 6 months for up to 10 years.Results
A total of 224 participants developed dementia during follow-up (mean = 2.8 years). Compared with those without hypertension, participants whose hypertension onset age was 80 to 89 years had a lower dementia risk (hazard ratio = 0.58, P = .04) and participants with an onset age of 90+ years had the lowest risk (hazard ratio = 0.37, P = .004).Discussion
Developing hypertension at older ages may protect against dementia. Understanding the mechanisms for this lower risk is important for determining ways to prevent dementia in the very elderly. 相似文献9.
Karen Ritchie Isabelle Carrière Li Su John T. O&#x;Brien Simon Lovestone Katie Wells Craig W. Ritchie 《Alzheimer's & dementia》2017,13(10):1089-1097
Introduction
Although biomarker studies of late-onset Alzheimer's disease suggest pathology to be present decades before diagnosis, little is known about cognitive performance at this stage.Methods
A sample of 210 adults (aged 40–59) of whom 103 have a parent diagnosed with dementia (family history subgroup) underwent computerized cognitive testing. Apolipoprotein E (apoE) status was determined, and 193 subjects had magnetic resonance imaging. Distance from dementia onset was estimated in relation to age of parental diagnosis, and Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Scores were calculated.Results
Lower hippocampal volumes (P = .04) were associated with poorer spatial location recall and higher Dementia Risk Scores with poorer visual recognition (P = .0005), and lower brain and hippocampal volume (P < .0001, P = .04, respectively). Family history subgroup participants closer to dementia onset had lower scores on visual working memory (P = .05), whereas those with an APOE ε4 allele performed better on form perception (P = .005).Discussion
Middle-aged adults at risk of dementia show evidence of poorer cognitive performance, principally in visuospatial functions. 相似文献10.
Franc Llorens Niels Kruse Matthias Schmitz Nadine Gotzmann Ewa Golanska Katrin Thüne Orgeta Zejneli Eirini Kanata Tobias Knipper Maria Cramm Peter Lange Saima Zafar Beata Sikorska Pawel P. Liberski Eva Mitrova Daniela Varges Christian Schmidt Theodoros Sklaviadis Inga Zerr 《Alzheimer's & dementia》2017,13(6):710-719
Introduction
Accurate diagnosis of prion diseases and discrimination from alternative dementias gain importance in the clinical routine, but partial overlap in cerebrospinal fluid (CSF) biomarkers impedes absolute discrimination in the differential diagnostic context.Methods
We established the clinical parameters for prion disease diagnosis for the quantification of CSF α-synuclein in patients with sporadic (n = 234) and genetic (n = 56) prion diseases, in cases with cognitive impairment/dementia or neurodegenerative disease (n = 278), and in the neurologic control group (n = 111).Results
An optimal cutoff value of 680 pg/mL α-synuclein results in 94% sensitivity and 96% specificity when diagnosing sporadic Creutzfeldt-Jakob disease (CJD). Genetic CJD cases showed increased CSF α-synuclein values. No increased α-synuclein levels were detected in non-CJD cases with rapid progression course.Discussion
Detection of α-synuclein in the CSF of patients with suspected CJD is a valuable diagnostic test reaching almost full discrimination from non-prion disease cases. These data highlight the utility of CSF α-synuclein quantification in front of classical CSF biomarkers in clinical routine. 相似文献11.
Catherine Feart Catherine Helmer Bénédicte Merle François R. Herrmann Cédric Annweiler Jean-François Dartigues Cécile Delcourt Cécilia Samieri 《Alzheimer's & dementia》2017,13(11):1207-1216
Introduction
Hypovitaminosis D has been associated with several chronic conditions; yet, its association with cognitive decline and the risk of dementia and Alzheimer's disease (AD) has been inconsistent.Methods
The study population consisted of 916 participants from the Three-City Bordeaux cohort aged 65+, nondemented at baseline, with assessment of vitamin D status and who were followed for up to 12 years.Results
In multivariate analysis, compared with individuals with 25(OH)D sufficiency (n = 151), participants with 25(OH)D deficiency (n = 218) exhibited a faster cognitive decline. A total of 177 dementia cases (124 AD) occurred: 25(OH)D deficiency was associated with a nearly three-fold increased risk of AD (hazard ratio = 2.85, 95% confidence interval 1.37–5.97).Discussion
This large prospective study of French older adults suggests that maintaining adequate vitamin D status in older age could contribute to slow down cognitive decline and to delay or prevent the onset of dementia, especially of AD etiology. 相似文献12.
Joanna M. Wardlaw Stephen J. Makin Maria C. Valdés Hernández Paul A. Armitage Anna K. Heye Francesca M. Chappell Susana Muñoz-Maniega Eleni Sakka Kirsten Shuler Martin S. Dennis Michael J. Thrippleton 《Alzheimer's & dementia》2017,13(6):634-643
Introduction
Small vessel disease (SVD) is a common contributor to dementia. Subtle blood-brain barrier (BBB) leakage may be important in SVD-induced brain damage.Methods
We assessed imaging, clinical variables, and cognition in patients with mild (i.e., nondisabling) ischemic lacunar or cortical stroke. We analyzed BBB leakage, interstitial fluid, and white matter integrity using multimodal tissue-specific spatial analysis around white matter hyperintensities (WMH). We assessed predictors of 1 year cognition, recurrent stroke, and dependency.Results
In 201 patients, median age 67 (range 34–97), BBB leakage, and interstitial fluid were higher in WMH than normal-appearing white matter; leakage in normal-appearing white matter increased with proximity to WMH (P < .0001), with WMH severity (P = .033), age (P = .03), and hypertension (P < .0001). BBB leakage in WMH predicted declining cognition at 1 year.Discussion
BBB leakage increases in normal-appearing white matter with WMH and predicts worsening cognition. Interventions to reduce BBB leakage may prevent SVD-associated dementia. 相似文献13.
Ester Cerin Stephanie R. Rainey-Smith David Ames Nicola T. Lautenschlager S. Lance Macaulay Christopher Fowler Joanne S. Robertson Christopher C. Rowe Paul Maruff Ralph N. Martins Colin L. Masters Kathryn A. Ellis 《Alzheimer's & dementia》2017,13(4):388-398
Introduction
“Walkable” neighborhoods offer older adults opportunities for activities that may benefit cognition-related biological mechanisms. These have not previously been examined in this context.Methods
We objectively assessed neighborhood walkability for participants (n = 146) from the Australian Imaging, Biomarkers and Lifestyle study with apolipoprotein E (APOE) genotype and two 18-month-apart brain volumetric and/or amyloid β burden assessments. Linear mixed models estimated associations of neighborhood walkability with levels and changes in brain imaging outcomes, the moderating effect of APOE ε4 status, and the extent to which associations were explained by physical activity.Results
Cross-sectionally, neighborhood walkability was predictive of better neuroimaging outcomes except for left hippocampal volume. These associations were to a small extent explained by physical activity. APOE ε4 carriers showed slower worsening of outcomes if living in walkable neighborhoods.Discussion
These findings indicate associations between neighborhood walkability and brain imaging measures (especially in APOE ε4 carriers) minimally attributable to physical activity. 相似文献14.
Willa D. Brenowitz Rebecca A. Hubbard C. Dirk Keene Stephen E. Hawes W.T. Longstreth Randy L. Woltjer Walter A. Kukull 《Alzheimer's & dementia》2017,13(6):654-662
Introduction
Whether co-occurring neuropathologies interact or independently affect clinical disease progression is uncertain. We estimated rates of clinical progression and tested whether associations between clinical progression and Alzheimer's disease neuropathology (ADNP) were modified by co-occurring Lewy body disease (LBD) or vascular brain injury (VBI).Methods
Linear mixed effects models evaluated longitudinal trends in the Clinical Dementia Rating Scale Sum of Boxes on 2046 autopsied participants seen at a U.S. Alzheimer's Disease Center.Results
Annual clinical progression was slightly faster for ADNP + LBD compared with ADNP only (P = .06) and slightly slower for ADNP + VBI (P = .003). Differences in progression were less than expected if each neuropathology independently contributed to progression; ADNP interacted with LBD (P = .002) and VBI (P = .003). In secondary models, the effect of additional pathologies on clinical progression was greater in those with intermediate compared with high levels of ADNP.Discussion
The impact of co-occurring pathologies on progression may depend on severity of ADNP. 相似文献15.
Daniel Jaraj Carsten Wikkelsø Katrin Rabiei Thomas Marlow Christer Jensen Svante Östling Ingmar Skoog 《Alzheimer's & dementia》2017,13(8):850-857
Introduction
We examined mortality, dementia, and progression of hydrocephalic symptoms among untreated individuals with idiopathic normal-pressure hydrocephalus (iNPH) in a population-based sample.Methods
A total of 1235 persons were examined between 1986 and 2012. Shunted individuals were excluded. We examined 53 persons with hydrocephalic ventricular enlargement (probable iNPH: n = 24, asymptomatic or possible iNPH: n = 29). Comparisons were made with individuals without hydrocephalic ventricular enlargement.Results
The 5-year mortality was 87.5% among those with probable iNPH. The hazard ratio (HR) for death was 3.8 (95% confidence interval [CI]: 2.5–6.0) for probable iNPH. Those with possible iNPH and asymptomatic hydrocephalic ventricular enlargement had increased risk of developing dementia, HR 2.8 (95% CI: 1.5–5.2). Only two individuals with hydrocephalic ventricular enlargement remained asymptomatic.Discussion
In the present sample, persons with clinical and imaging signs of iNPH had excess mortality and an increased risk of dementia. The data also suggest that radiological signs of iNPH might be more important than previously supposed. 相似文献16.
Camille Amadieu Sophie Lefèvre-Arbogast Cécile Delcourt Jean-François Dartigues Catherine Helmer Catherine Féart Cécilia Samieri 《Alzheimer's & dementia》2017,13(10):1125-1132
Introduction
Several nutrients may predict dementia risk. We characterized nutrient biomarker patterns, which integrate the complexity of nutrient exposure and biodisponibility associated with long-term risk of dementia in a large cohort of older persons, the Three-City study.Methods
We included 666 nondemented participants with plasma measurements of 22 fat-soluble nutrients at baseline, who were followed up for 12 years for dementia.Results
A “deleterious” pattern combining lower blood status in vitamin D, carotenoids, and polyunsaturated fats and higher saturated fats was strongly associated with a higher risk of dementia. Compared with individuals in the first quintile of the pattern score, participants in the highest quintile of score had an approximately fourfold increased risk of dementia (hazard ratio = 4.53 [95% confidence interval 1.99, 10.32], P for trend <.001) in multivariate models.Discussion
A blood pattern reflecting lower status in several nutrients among nondemented individuals appeared strongly associated with the long-term risk of dementia in this cohort. 相似文献17.
Stephanie Kielb Emily Rogalski Sandra Weintraub Alfred Rademaker 《Alzheimer's & dementia》2017,13(12):1337-1344
Introduction
Functional and cognitive features of subjective cognitive decline (SCD) were identified in a longitudinal database from the National Alzheimer's Coordinating Center.Methods
Cognitively normal older adults with (SCD+) and without (SCD?) self-reported memory complaints (N = 3915) were compared on (1) baseline Functional Assessment Questionnaire ratings, (2) baseline scores and longitudinal rate of change estimates from nine neuropsychological tests, and (3) final clinical diagnoses.Results
SCD+ had higher baseline ratings of functional impairment, reduced episodic memory practice effects and poorer performance on neuropsychological tests of psychomotor speed and language, and higher frequencies of mild cognitive impairment and dementia diagnoses at the end of follow-up compared with the SCD-group.Discussion
Subtle clinical features of SCD identified in this large cohort are difficult to detect at the individual level. More sensitive tests are needed to identify those with SCD who are vulnerable to cognitive decline and dementia. 相似文献18.
Kieu T.T. Phung Monique Chaaya Martin Prince Samir Atweh Khalil El Asmar Georges Karam Rose Mary Khoury Lilian Ghandour Husam Ghusn T. Rune Nielsen Gunhild Waldemar 《Alzheimer's & dementia》2017,13(12):1317-1326
Introduction
In North Africa and the Middle East, studies about dementia prevalence are scarce. A pilot study was conducted in Lebanon to assess dementia prevalence, using the Arabic-validated 10/66 Dementia Research Group (DRG) diagnostic assessment for case ascertainment. The study also examined care arrangement and access to care.Methods
A random sample of 502 persons older than 65 years and their informant were recruited from Beirut and Mount Lebanon governorates through multistage cluster sampling.Results
The crude and age-standardized dementia prevalences were 7.4% and 9.0%, respectively. People with dementia were mainly cared for by relatives at home. Access to formal care was very limited.Discussion
Dementia prevalence in Lebanon ranks high within the global range of estimates. These first evidence-based data about disease burden and barriers to care serve to raise awareness and call for social and health care reform to tackle the dementia epidemic in Lebanon and in North Africa and the Middle East. 相似文献19.
Kenneth Rockwood Susan E. Howlett Deborah Hoffman Rachel Schindler Arnold Mitnitski 《Alzheimer's & dementia》2017,13(10):1098-1106
Introduction
The clinical meaningfulness of Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog) subscale change is disputed. We compared 2- to 4-point ADAS-Cog changes with changes in Goal Attainment Scaling (GAS) and everyday function across initial ADAS-Cog scores and treatment responses.Methods
This exploratory analysis evaluated mild-moderate Alzheimer's disease patients treated with donepezil (12 months) or galantamine (8 months). Clinical meaningfulness was defined as concomitant ADAS-Cog and GAS changes of ±3 points and/or functional improvement.Results
Patients with ≥3-point ADAS-Cog improvement significantly improved on GAS but not on standard tests of everyday function. ADAS-Cog “no change” (≤±3 points) was seen with mean GAS improvement. Initial ADAS-Cog improvement made endpoint improvement (ADAS-Cog 3 points and GAS 1 point) more likely (odds ratio = 6.9; 95% confidence interval = 2.5–19.5). In contrast, initial deterioration made endpoint improvement unlikely (0.33; 0.14–0.64).Discussion
ADAS-Cog improvement and no change were each associated with GAS improvement. Initial ADAS-Cog worsening was unlikely to result in later improvement.Clinical trial registration number
ISRCTN26167328. 相似文献20.
Jinying Zhao Yun Zhu Jingyun Yang Lin Li Hao Wu Philip L. De Jager Peng Jin David A. Bennett 《Alzheimer's & dementia》2017,13(6):674-688