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1.  White matter disease in midlife is heritable, related to hypertension, and shares some genetic influence with systolic blood pressure 
NeuroImage : Clinical  2016;12:737-745.
White matter disease in the brain increases with age and cardiovascular disease, emerging in midlife, and these associations may be influenced by both genetic and environmental factors. We examined the frequency, distribution, and heritability of abnormal white matter and its association with hypertension in 395 middle-aged male twins (61.9 ± 2.6 years) from the Vietnam Era Twin Study of Aging, 67% of whom were hypertensive. A multi-channel segmentation approach estimated abnormal regions within the white matter. Using multivariable regression models, we characterized the frequency distribution of abnormal white matter in midlife and investigated associations with hypertension and Apolipoprotein E-ε4 status and the impact of duration and control of hypertension. Then, using the classical twin design, we estimated abnormal white matter heritability and the extent of shared genetic overlap with blood pressure. Abnormal white matter was predominantly located in periventricular and deep parietal and frontal regions; associated with age (t = 1.9, p = 0.05) and hypertension (t = 2.9, p = 0.004), but not Apolipoprotein ε4 status; and was greater in those with uncontrolled hypertension relative to controlled (t = 3.0, p = 0.003) and normotensive (t = 4.0, p = 0.0001) groups, suggesting that abnormal white matter may reflect currently active cerebrovascular effects. Abnormal white matter was highly heritable (a2 = 0.81) and shared some genetic influences with systolic blood pressure (rA = 0.26), although there was evidence for distinct genetic contributions and unique environmental influences. Future longitudinal research will shed light on factors impacting white matter disease presentation, progression, and potential recovery.
Highlights
•White matter abnormalities were highly heritable and associated with hypertension.•Only some genetic influences were shared with systolic blood pressure.•There is evidence for unique environmental influences unrelated to hypertension.•Poorly controlled hypertension was associated with more abnormal white matter.•Abnormal white matter may reflect currently active cerebrovascular effects.
doi:10.1016/j.nicl.2016.10.001
PMCID: PMC5071546  PMID: 27790395
White matter; MRI; Brain; Hypertension; Blood pressure; Heritability; AWM, abnormal white matter; ApoE, apolipoprotein E; SBP, systolic blood pressure; DBP, diastolic blood pressure; HTN, hypertension; BMI, body mass index; LDL, Low; HDL, high-density lipoprotein; CRP, C-Reactive protein; ICV, intracranial vault
2.  HYPERTENSION-RELATED ALTERATIONS IN WHITE MATTER MICROSTRUCTURE DETECTABLE IN MIDDLE AGE 
Hypertension  2015;66(2):317-323.
Most studies examining associations between hypertension and brain white matter microstructure have focused on older adults or on cohorts with a large age range. Since hypertension effects on the brain may vary with age it is important to focus on middle age, when hypertension becomes more prevalent. We used linear mixed effect models to examine differences in white matter diffusion metrics as a function of hypertension in a well-characterized cohort of middle-aged men (N=316, mean 61.8 years; range 56.7–65.6). Diffusion metrics were examined in nine tracts reported to be sensitive to hypertension in older adults. Relative to normotensive individuals, individuals with longstanding hypertension (> 5.6 years) showed reduced fractional anisotropy or increased diffusivity in most tracts. Effects were stronger among carriers than non-carriers of the apolipoprotein E ε4 allele for two tracts connecting frontal regions with other brain areas. Significant differences were observed even after adjustment for potentially-related lifestyle and cardiovascular risk factors. Shorter duration of hypertension or better blood pressure control among hypertensive individuals did not lessen the adverse effects. These findings suggest that microstructural white matter alterations appear early in the course of hypertension and may persist despite adequate treatment. Although longitudinal studies are needed to confirm these findings, the results suggest that prevention—rather than management—of hypertension may be vital to preserving brain health in aging.
doi:10.1161/HYPERTENSIONAHA.115.05336
PMCID: PMC4499000  PMID: 26056337
diffusion-weighted imaging; APOE; fractional anisotropy; mean diffusivity; aging
3.  Changes in Alcohol Intake and their Relation to Health Status over a 24 Year Follow-up Period in Community-Dwelling Older Adults 
Journal of the American Geriatrics Society  2013;61(8):10.1111/jgs.12366.
OBJECTIVES
To determine whether alcohol use changes over time in older adults, and whether alcohol intake is associated with common chronic diseases.
DESIGN
Longitudinal study spanning 24 years.
SETTING
Southern California community
PARTICIPANTS
1076 members of the Rancho Bernardo cohort, aged 50–89 years at baseline.
MEASUREMENTS
Participants completed two to six research visits at approximate four year intervals between 1984 and 2009. At each visit, participants completed standard questionnaires on alcohol use, chronic diseases, and behaviors. Mixed-effects linear models were used to examine changes in average weekly alcohol intake over time and in relation to health status.
RESULTS
Prevalence and frequency of alcohol use was high throughout the study with more than 60% of participants reporting weekly alcohol intake. The average amount consumed declined over time with advancing age, irrespective of the presence of any of the eight most common chronic diseases. Prevalence of drinking in excess of age and sex-specific low risk guidelines was high across all visits and did not vary by disease burden. At the final visit, 29% of participants drank in excess of low risk drinking guidelines; including 28% of those with hypertension and 31% of those with diabetes.
CONCLUSION
Prevalence and frequency of alcohol intake remained stable over a 24 year follow-up in this cohort of White, educated middle class older adults, although average amount consumed decreased over time with advanced age. Despite this decrease, a high proportion of older adults, including those with common chronic health conditions, drank in excess of current guidelines. Clinicians should provide more education on the importance of moderating alcohol intake in older patients.
doi:10.1111/jgs.12366
PMCID: PMC3819601  PMID: 23865905
aging; alcohol trajectories; drinking; hypertension; diabetes
4.  Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease 
JAMA neurology  2016;73(6):691-697.
IMPORTANCE
Late-onset Alzheimer disease (AD), the most common form of dementia, places a large burden on families and society. Although epidemiological and clinical evidence suggests a relationship between inflammation and AD, their relationship is not well understood and could have implications for treatment and prevention strategies.
OBJECTIVE
To determine whether a subset of genes involved with increased risk of inflammation are also associated with increased risk for AD.
DESIGN, SETTING, AND PARTICIPANTS
In a genetic epidemiology study conducted in July 2015, we systematically investigated genetic overlap between AD (International Genomics of Alzheimer’s Project stage 1) and Crohn disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, and psoriasis using summary data from genome-wide association studies at multiple academic clinical research centers. P values and odds ratios from genome-wide association studies of more than 100 000 individuals were from previous comparisons of patients vs respective control cohorts. Diagnosis for each disorder was previously established for the parent study using consensus criteria.
MAIN OUTCOMES AND MEASURES
The primary outcome was the pleiotropic (conjunction) false discovery rate P value. Follow-up for candidate variants included neuritic plaque and neurofibrillary tangle pathology; longitudinal Alzheimer’s Disease Assessment Scale cognitive subscale scores as a measure of cognitive dysfunction (Alzheimer’s Disease Neuroimaging Initiative); and gene expression in AD vs control brains (Gene Expression Omnibus data).
RESULTS
Eight single-nucleotide polymorphisms (false discovery rate P < .05) were associated with both AD and immune-mediated diseases. Of these, rs2516049 (closest gene HLA-DRB5; conjunction false discovery rate P = .04 for AD and psoriasis, 5.37 × 10−5 for AD, and 6.03 × 10−15 for psoriasis) and rs12570088 (closest gene IPMK; conjunction false discovery rate P = .009 for AD and Crohn disease, P = 5.73 × 10−6 for AD, and 6.57 × 10−5 for Crohn disease) demonstrated the same direction of allelic effect between AD and the immune-mediated diseases. Both rs2516049 and rs12570088 were significantly associated with neurofibrillary tangle pathology (P = .01352 and .03151, respectively); rs2516049 additionally correlated with longitudinal decline on Alzheimer’s Disease Assessment Scale cognitive subscale scores (β [SE], 0.405 [0.190]; P = .03). Regarding gene expression, HLA-DRA and IPMK transcript expression was significantly altered in AD brains compared with control brains (HLA-DRA: β [SE], 0.155 [0.024]; P = 1.97 × 10−10; IPMK: β [SE], −0.096 [0.013]; P = 7.57 × 10−13).
CONCLUSIONS AND RELEVANCE
Our findings demonstrate genetic overlap between AD and immune-mediated diseases and suggest that immune system processes influence AD pathogenesis and progression.
doi:10.1001/jamaneurol.2016.0150
PMCID: PMC4905783  PMID: 27088644
5.  Polygenic Overlap Between C-Reactive Protein, Plasma Lipids and Alzheimer's Disease 
Circulation  2015;131(23):2061-2069.
Background
Epidemiological findings suggest a relationship between Alzheimer's disease (AD), inflammation and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis.
Methods and Results
Using summary statistics (p-values and odds ratios) from genome-wide association studies of over 200,000 individuals, we investigated overlap in single nucleotide polymorphisms (SNPs) associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides (TG), high- (HDL) and low-density lipoprotein (LDL) levels. We found up to 50-fold enrichment of AD SNPs for different levels of association with CRP, LDL, HDL and TG SNPs using an FDR threshold < 0.05. By conditioning on polymorphisms associated with the four phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across four independent AD cohorts (total n = 29,054 AD cases and 114,824 healthy controls) and discovered two genome-wide significant variants on chromosome 4 (rs13113697, closest gene HS3ST1, odds ratio (OR) = 1.07, 95% confidence interval (CI) = 1.05-1.11, p = 2.86 × 10−8) and chromosome 10 (rs7920721, closest gene ECHDC3, OR = 1.07, 95% CI = 1.04-1.11, p = 3.38 × 10−8). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains.
Conclusions
We demonstrate genetic overlap between AD, CRP, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci including two genome-wide significant variants conferring increased risk for Alzheimer's disease.
doi:10.1161/CIRCULATIONAHA.115.015489
PMCID: PMC4677995  PMID: 25862742
Alzheimer's disease; inflammation; plasma lipids; GWAS
6.  Genetic overlap between Alzheimer’s disease and Parkinson’s disease at the MAPT locus 
Molecular psychiatry  2015;20(12):1588-1595.
We investigated genetic overlap between Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using summary statistics (p-values) from large recent genomewide association studies (GWAS) (total n = 89,904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis p-value across 5 independent AD cohorts = 1.65 × 10−7). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD and extending prior work, we show that the MAPT region increases risk of Alzheimer’s neurodegeneration.
doi:10.1038/mp.2015.6
PMCID: PMC4539304  PMID: 25687773
7.  The role of clusterin in amyloid-β associated neurodegeneration 
JAMA neurology  2014;71(2):180-187.
Importance
Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer's disease (AD) neurodegeneration. However, the precise role of clusterin in AD pathogenesis is still not well understood.
Objective
To elucidate the relationship between clusterin, amyloid-β (Aβ), p-tau, and rate of brain atrophy over time among non-demented older individuals.
Design
A longitudinal cohort of cognitively normal older participants (HC) and individuals with mild cognitive impairment (MCI) assessed with baseline lumbar puncture and longitudinal structural MRI.
Setting
Research centers across the United States and Canada.
Participants
We examined 241 non-demented older individuals (91 participants with a Clinical Dementia Rating (CDR) of 0 and 150 individuals with a CDR of 0.5).
Main Outcome Measures
Using linear mixed effects models, we investigated interactions between CSF clusterin, CSF Aβ1-42 and CSF p-tau181p on atrophy rate of the entorhinal cortex and hippocampus.
Results
Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on entorhinal cortex atrophy rate, but not on hippocampal atrophy rate. CSF clusterin was associated with entorhinal cortex atrophy rate among CSF Aβ1-42 positive individuals, but not among CSF Aβ1-42 negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin and CSF Aβ1-42 and CSF p-tau181p on entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the MCI and HC cohorts.
Conclusions and Relevance
In non-demented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the AD neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss.
doi:10.1001/jamaneurol.2013.4560
PMCID: PMC4118752  PMID: 24378367
8.  APOE ε4 does not modulate amyloid-β associated neurodegeneration in preclinical Alzheimer’s disease 
Background and Purpose
Among cognitively normal older individuals, the relationship between the two hallmark proteins of Alzheimer’s disease (AD), amyloid-β (Aβ) and tau, the ε4 allele of apolipoprotein E (APOE ε4), and neurodegeneration is not well understood.
Materials and Methods
We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed effects model, we concurrently investigated main and interactive effects between APOE ε4 genotype and CSF Aβ1-42, CSF phospo-tau (p-tau181p) and CSF Aβ1-42, and APOE ε4 genotype and CSF p-tau181p on entorhinal cortex atrophy rate. We also examined the relationship between APOE ε4, CSF p-tau181p, and CSF Aβ1-42 on atrophy rate of other AD-vulnerable neuroanatomic regions.
Results
The full model with main and interactive effects demonstrated a significant interaction only between CSF p-tau181p and CSF Aβ1-42 on entorhinal cortex atrophy rate indicating elevated atrophy over time in individuals with increased CSF p-tau181p and decreased CSF Aβ1-42. APOE ε4 genotype was significantly and specifically associated with CSF Aβ1-42. However, the interaction between APOE ε4 genotype and either CSF Aβ1-42 or CSF p-tau181p on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.
Conclusions
Based upon our findings and building upon prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD where APOE ε4 primarily influences Alzheimer’s pathology via Aβ-related mechanisms and in turn, Aβ-associated neurodegeneration occurs only in the presence of phospho-tau.
doi:10.3174/ajnr.A3267
PMCID: PMC4041629  PMID: 22976236
preclinical AD; neurodegeneration; p-tau; amyloid-β; APOE
9.  Plasma leptin levels are not predictive of dementia in patients with mild cognitive impairment 
Age and Ageing  2014;44(1):53-58.
Background: animal studies suggest a neuroprotective role for leptin, but human studies have shown mixed results. We examined whether plasma leptin levels in individuals with mild cognitive impairment (MCI) were related to cognitive function at baseline and whether higher leptin levels were associated with reduced risk of dementia.
Methods: we categorised 352 MCI participants into sex-specific tertiles based on log-transformed fasting plasma leptin levels. In sex-stratified analyses, we investigated whether cognitive ability differed by leptin tertile. We also examined whether the risk of dementia over a 3-year follow-up period differed by leptin level. Analyses controlled for numerous potential confounding variables, including body mass index, hypertension and levels of blood insulin and C-reactive protein.
Results: baseline cognitive ability did not differ as a function of leptin level, nor were higher leptin levels associated with reduced hazard of developing dementia. Controlling for related co-variates did not reveal any significant associations between leptin and dementia risk.
Conclusion: in this cohort of older adults with MCI, plasma leptin level was not associated with cognitive function at baseline, nor did it predict risk of dementia. Other biological measures, such as volumetric MRI and cerebrospinal fluid protein levels, have demonstrated robust dementia prediction in this cohort. Thus, the current negative findings suggest that plasma leptin, on its own, is unlikely to become a useful clinical biomarker for Alzheimer's disease. Efforts to develop other blood-based biomarkers are needed.
doi:10.1093/ageing/afu160
PMCID: PMC4255616  PMID: 25349150
Alzheimer's disease; blood biomarker; MCI; dementia prediction; older people
10.  Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci 
PLoS ONE  2015;10(12):e0144531.
Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.
doi:10.1371/journal.pone.0144531
PMCID: PMC4687843  PMID: 26695485
11.  Enrichment and Stratification for Predementia Alzheimer Disease Clinical Trials 
PLoS ONE  2012;7(10):e47739.
The tau and amyloid pathobiological processes underlying Alzheimer disease (AD) progresses slowly over periods of decades before clinical manifestation as mild cognitive impairment (MCI), then more rapidly to dementia, and eventually to end-stage organ failure. The failure of clinical trials of candidate disease modifying therapies to slow disease progression in patients already diagnosed with early AD has led to increased interest in exploring the possibility of early intervention and prevention trials, targeting MCI and cognitively healthy (HC) populations. Here, we stratify MCI individuals based on cerebrospinal fluid (CSF) biomarkers and structural atrophy risk factors for the disease. We also stratify HC individuals into risk groups on the basis of CSF biomarkers for the two hallmark AD pathologies. Results show that the broad category of MCI can be decomposed into subsets of individuals with significantly different average regional atrophy rates. By thus selectively identifying individuals, combinations of these biomarkers and risk factors could enable significant reductions in sample size requirements for clinical trials of investigational AD-modifying therapies, and provide stratification mechanisms to more finely assess response to therapy. Power is sufficiently high that detecting efficacy in MCI cohorts should not be a limiting factor in AD therapeutics research. In contrast, we show that sample size estimates for clinical trials aimed at the preclinical stage of the disorder (HCs with evidence of AD pathology) are prohibitively large. Longer natural history studies are needed to inform design of trials aimed at the presymptomatic stage.
doi:10.1371/journal.pone.0047739
PMCID: PMC3474753  PMID: 23082203
12.  Amyloid-β associated volume loss occurs only in the presence of phospho-tau 
Annals of Neurology  2011;70(4):657-661.
The relationship between neurodegeneration and the two hallmark proteins of Alzheimer's disease, amyloid-β (Aβ) and tau, is still unclear. Here, we examined 286 non-demented participants (107 cognitively normal older adults and 179 memory impaired individuals) who underwent longitudinal MR imaging and lumbar puncture. Using mixed effects models, we investigated the relationship between longitudinal entorhinal cortex atrophy, CSF p-tau181p and CSF Aβ1-42. We found a significant relationship between elevated entorhinal cortex atrophy and decreased CSF Aβ1-42 only with elevated CSF p-tau181p. Our findings indicate that Aβ-associated volume loss occurs only in the presence of phospho-tauin humans at risk for dementia.
doi:10.1002/ana.22509
PMCID: PMC3368003  PMID: 22002658
13.  Amyloid-β associated clinical decline occurs only in the presence of elevated p-tau 
Archives of neurology  2012;69(6):709-713.
Objective
To elucidate the relationship between the two hallmark proteins of Alzheimer's disease (AD), amyloid-β (Aβ) and tau, and clinical decline over time among cognitively normal older individuals.
Design
A longitudinal cohort of clinically and cognitively normal older individuals assessed with baseline lumbar puncture and longitudinal clinical assessments.
Setting
Research centers across the United States and Canada.
Patients
We examined one hundred seven participants with a Clinical Dementia Rating (CDR) of 0 at baseline examination.
Main Outcome Measures
Using linear mixed effects models, we investigated the relationship between CSF p-tau181p, CSF Aβ1-42 and clinical decline as assessed using longitudinal change in global CDR, CDR-Sum of Boxes (CDR-SB), and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog).
Results
We found a significant relationship between decreased CSF Aβ1-42 and longitudinal change in global CDR, CDR-SB, and ADAS-cog in individuals with elevated CSF p-tau181p. In the absence of CSF p-tau181p, the effect of CSF Aβ1-42 on longitudinal clinical decline was not significantly different from zero.
Conclusions
In cognitively normal older individuals, Aβ-associated clinical decline over a mean of three years may occur only in the presence of ongoing, “downstream” neurodegeneration.
doi:10.1001/archneurol.2011.3354
PMCID: PMC3423526  PMID: 22529247
14.  Rates of Decline in Alzheimer Disease Decrease with Age 
PLoS ONE  2012;7(8):e42325.
Age is the strongest risk factor for sporadic Alzheimer disease (AD), yet the effects of age on rates of clinical decline and brain atrophy in AD have been largely unexplored. Here, we examined longitudinal rates of change as a function of baseline age for measures of clinical decline and structural MRI-based regional brain atrophy, in cohorts of AD, mild cognitive impairment (MCI), and cognitively healthy (HC) individuals aged 65 to 90 years (total n = 723). The effect of age was modeled using mixed effects linear regression. There was pronounced reduction in rates of clinical decline and atrophy with age for AD and MCI individuals, whereas HCs showed increased rates of clinical decline and atrophy with age. This resulted in convergence in rates of change for HCs and patients with advancing age for several measures. Baseline cerebrospinal fluid densities of AD-relevant proteins, Aβ1–42, tau, and phospho-tau181p (ptau), showed a similar pattern of convergence with advanced age across cohorts, particularly for ptau. In contrast, baseline clinical measures did not differ by age, indicating uniformity of clinical severity at baseline. These results imply that the phenotypic expression of AD is relatively mild in individuals older than approximately 85 years, and this may affect the ability to distinguish AD from normal aging in the very old. Our findings show that inclusion of older individuals in clinical trials will substantially reduce the power to detect disease-modifying therapeutic effects, leading to dramatic increases in required clinical trial sample sizes with age of study sample.
doi:10.1371/journal.pone.0042325
PMCID: PMC3410919  PMID: 22876315
15.  Fetuin-A, a New Vascular Biomarker of Cognitive Decline in Older Adults 
Clinical endocrinology  2014;81(1):134-140.
Objectives
Fetuin-A is an abundant plasma protein known to predict vascular disease. Fetuin-A levels are lower in patients with Alzheimer’s disease in proportion to the severity of cognitive impairment, but their association with normal cognitive aging is unknown. We evaluated the association of serum fetuin-A levels with cognitive function in community-dwelling older adults.
Design/Patients/Measurements
A population-based study of 1382 older adults (median age 75) who had plasma fetuin-A levels and cognitive function evaluated in 1992–96; 855 had repeat cognitive function assessment a median of 4 years later.
Results
Adjusting for age, sex, education, and depression, higher levels of fetuin-A were associated with better baseline performance on the Mini-Mental Status Exam (MMSE) (P=0.012) and a tendency for better Trails Making B scores (P=0.066). In longitudinal analyses, the likelihood of a major decline (highest decile of change) in Trails B was 29% lower (P=0.010) for each SD higher baseline fetuin-A level; odds of major decline in MMSE was 42% lower (P=0.005) per SD higher fetuin-A for individuals with no known CVD, but were not related to fetuin-A in those with CVD (P=0.33). Fetuin-A was not related to Category Fluency performance. Results were independent of multiple vascular risk factors and comorbid conditions.
Conclusions
Higher plasma fetuin-A concentrations are associated with better performance on tests of global cognitive function and executive function and with less likelihood of major decline in these cognitive abilities over a 4-year period. Fetuin-A may serve as a biological link between vascular disease and normal age-related cognitive decline.
doi:10.1111/cen.12382
PMCID: PMC4053483  PMID: 24325554
fetuin-A; cognitive function; vascular disease; inflammation; aging; epidemiology
17.  APOE interacts with age to modify rate of decline in cognitive and brain changes in Alzheimer’s disease 
Background
To determine (1) whether age-standardized cognitive declines and brain morphometric change differ between Young-Old (YOAD) and Very-Old (VOAD) patients with Alzheimer’s disease (AD) and (2) whether apolipoprotein E (APOE) genotype modifies these neuropsychological and morphometric changes.
Methods
Baseline and 12-month follow up neuropsychological and morphometric measures were examined for healthy control and AD individuals. The two AD groups were further divided into subgroups on the basis of the presence of at least one APOE ε4 allele.
Results
The YOAD showed more severe deficits andsteeper declines in cognition than the VOAD. Moreover, the presence of an APOE ε4 allele had a more deleterious effect on the YOAD than the VOAD on cognition and brain structure both cross-sectionally and longitudinally.
Conclusions
Results underscore the importance of integrating an individual’s age and genetic susceptibility—and their interaction—when examining neuropsychological and neuroimaging changes in the early stages of Alzheimer’s disease.
doi:10.1016/j.jalz.2013.05.1763
PMCID: PMC3815680  PMID: 23896613
Alzheimer’s disease; APOE genotype; cognition; morphometry; MRI; longitudinal
18.  Abundant Genetic Overlap between Blood Lipids and Immune-Mediated Diseases Indicates Shared Molecular Genetic Mechanisms 
PLoS ONE  2015;10(4):e0123057.
Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn’s disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.
doi:10.1371/journal.pone.0123057
PMCID: PMC4390360  PMID: 25853426
19.  White Matter Tracts Associated with Set-Shifting in Healthy Aging 
Neuropsychologia  2009;47(13):2835-2842.
Attentional set-shifting ability, commonly assessed with the Trail Making Test (TMT), decreases with increasing age in adults. Since set-shifting performance relies on activity in widespread brain regions, deterioration of the white matter tracts that connect these regions may underlie the age-related decrease in performance. We used an automated fiber tracking method to investigate the relationship between white matter integrity in several cortical association tracts and TMT performance in a sample of 24 healthy adults, 21 – 80 years. Diffusion tensor images were used to compute average fractional anisotropy (FA) for five cortical association tracts, the corpus callosum (CC), and the corticospinal tract (CST), which served as a control. Results showed that advancing age was associated with declines in set-shifting performance and with decreased FA in the CC and in association tracts that connect frontal cortex to more posterior brain regions, including the inferior fronto-occipital fasciculus (IFOF), uncinate fasciculus (UF), and superior longitudinal fasciculus (SLF). Declines in average FA in these tracts, and in average FA of the right inferior longitudinal fasciculus (ILF), were associated with increased time to completion on the set-shifting subtask of the TMT but not with the simple sequencing subtask. FA values in these tracts were strong mediators of the effect of age on set-shifting performance. Automated tractography methods can enhance our understanding of the fiber systems involved in performance of specific cognitive tasks and of the functional consequences of age-related changes in those systems.
doi:10.1016/j.neuropsychologia.2009.06.008
PMCID: PMC2749901  PMID: 19540862
20.  Identifying common genetic variants in blood pressure due to polygenic pleiotropy with associated phenotypes 
Hypertension  2014;63(4):819-826.
Blood pressure is a critical determinant of cardiovascular morbidity and mortality. It is affected by environmental factors, but has a strong heritable component. Despite recent large genome-wide association studies, few genetic risk factors for blood pressure have been identified. Epidemiological studies suggest associations between blood pressure and several diseases and traits, which may partly arise from a shared genetic basis (genetic pleiotropy). Using genome-wide association studies summary statistics and a genetic pleiotropy-informed conditional False Discovery Rate method, we systematically investigated genetic overlap between systolic blood pressure and 12 co-morbid traits and diseases. We found significant ‘enrichment’ of single nucleotide polymorphisms associated with systolic blood pressure as a function of their association with body mass index, low density lipoprotein, waist hip ratio, schizophrenia, bone mineral density, type 1 diabetes and celiac disease. In contrast, the magnitude of enrichment due to shared polygenic effects was smaller with the other phenotypes (triglycerides, high density lipoproteins, type 2 diabetes, rheumatoid arthritis, and height). Applying the conditional False Discovery Rate method to the enriched phenotypes, we identified 62 loci associated with systolic blood pressure (False Discovery Rate < 0.01), including 42 novel loci. The observed polygenic overlap between systolic blood pressure and several related disorders indicates that the epidemiological associations are not mediated solely via lifestyle factors, but also reflect an etiological relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to lipid biology and the immune system in systolic blood pressure.
doi:10.1161/HYPERTENSIONAHA.113.02077
PMCID: PMC3984909  PMID: 24396023
Genome-wide association study; genetic pleiotropy; systolic blood pressure; comorbid disorders
21.  CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer’s disease risk in an APOE-dependent manner 
Brain imaging and behavior  2012;6(1):16-26.
Two alleles in cholesteryl ester transfer protein (CETP) gene polymorphisms have been disputably linked to enhanced cognition and decreased risk of Alzheimer’s disease (AD): the V and A alleles of I405V and C-629A. This study investigates whether these polymorphisms affect brain structure in 188 elderly controls and 318 AD or mild cognitive impairment (MCI) subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort. Nominally signficant associations were dependent on APOE ε4 carrier status. In APOE ε4 carriers, the V and A alleles, both of which decrease CETP and increase HDL, associated with greater baseline cortical thickness and less 12-month atrophy in the medial temporal lobe. Conversely, in APOE ε4 non-carriers, the I allele, which increases CETP and decreases HDL, associated with greater baseline thickness, less atrophy and lower risk of dementia. These results suggest CETP may contribute to the genetic variability of brain structure and dementia susceptibility in an APOE-dependent manner.
doi:10.1007/s11682-011-9137-0
PMCID: PMC4305449  PMID: 21892657
Imaging genetics; Quantitative neuroimaging; CETP; Alzheimer’s disease; Dementia; APOE
22.  Genetic network properties of the human cortex based on regional thickness and surface area measures 
We examined network properties of genetic covariance between average cortical thickness (CT) and surface area (SA) within genetically-identified cortical parcellations that we previously derived from human cortical genetic maps using vertex-wise fuzzy clustering analysis with high spatial resolution. There were 24 hierarchical parcellations based on vertex-wise CT and 24 based on vertex-wise SA expansion/contraction; in both cases the 12 parcellations per hemisphere were largely symmetrical. We utilized three techniques—biometrical genetic modeling, cluster analysis, and graph theory—to examine genetic relationships and network properties within and between the 48 parcellation measures. Biometrical modeling indicated significant shared genetic covariance between size of several of the genetic parcellations. Cluster analysis suggested small distinct groupings of genetic covariance; networks highlighted several significant negative and positive genetic correlations between bilateral parcellations. Graph theoretical analysis suggested that small world, but not rich club, network properties may characterize the genetic relationships between these regional size measures. These findings suggest that cortical genetic parcellations exhibit short characteristic path lengths across a broad network of connections. This property may be protective against network failure. In contrast, previous research with structural data has observed strong rich club properties with tightly interconnected hub networks. Future studies of these genetic networks might provide powerful phenotypes for genetic studies of normal and pathological brain development, aging, and function.
doi:10.3389/fnhum.2015.00440
PMCID: PMC4542323  PMID: 26347632
imaging; genetic; twin; cortical thickness; surface area; network; small world; structural
23.  Higher Rates of Decline for Women and APOE ε4 Carriers 
Background and Purpose
Age and the ε4 allele of apolipoprotein E (APOE ε4) are well-known risk factors for Alzheimer disease (AD), but whether female sex is also a risk factor remains controversial. It is also unclear how these risk factors affect rates of structural brain and clinical decline across the spectrum of preclinical to clinical AD. Our objective is to estimate the effects of APOE ε4 and sex on age-specific rates of morphometric and clinical decline in late onset sporadic AD.
Materials and Methods
Using linear mixed effects models, we examined the effect of age, APOE ε4, and sex on longitudinal brain atrophy and clinical decline among cognitively normal older individuals, and individuals with mild cognitive impairment and AD (total = 688). We also evaluated the relationship between these effects and cerebrospinal fluid (CSF) biomarkers of AD pathology.
Results
APOE ε4 significantly accelerated rates of decline, and women in all cohorts experienced higher rates of decline than men. The magnitude of the sex effect on rates of decline were as large as those of ε4, yet their relationship to measures of CSF biomarkers were weaker.
Conclusion
These results indicate that in addition to APOE ε4 status, diagnostic and therapeutic strategies should take into account the effect of female sex on the Alzheimer disease process.
doi:10.3174/ajnr.A3601
PMCID: PMC3894062  PMID: 23828104
24.  Higher Education is Not Associated with Greater Cortical Thickness in Brain Areas Related to Literacy or Intelligence in Normal Aging or Mild Cognitive Impairment 
Education may reduce risk of dementia through passive reserve, by increasing neural substrate. We tested the hypotheses that education is associated with thicker cortex and reduced rates of atrophy in brain regions related to literacy and intellectual ability. Healthy older adults and those with mild cognitive impairment were categorized into High (≥18 yrs) and Low (≤13 yrs) education groups. Higher education was associated with thinner cortices in several areas, but one-year atrophy rates in these areas did not differ by education group. These results do not support a passive reserve model in which early life education protects against dementia by increasing cortical thickness. Connectivity and synaptic efficiency, or other lifestyle factors may more directly reflect cognitive reserve.
doi:10.1080/13803395.2012.702733
PMCID: PMC3488147  PMID: 22905705
Brain reserve; cortical thickness; education; hippocampal volume; literacy; Mild Cognitive Impairment (MCI); aging
25.  Heart fatty acid binding protein and Aβ-associated Alzheimer’s neurodegeneration 
Background
Epidemiological and molecular findings suggest a relationship between Alzheimer’s disease (AD) and dyslipidemia, although the nature of this association is not well understood.
Results
Using linear mixed effects models, we investigated the relationship between CSF levels of heart fatty acid binding protein (HFABP), a lipid binding protein involved with fatty acid metabolism and lipid transport, amyloid-β (Aβ), phospho-tau, and longitudinal MRI-based measures of brain atrophy among 295 non-demented and demented older individuals. Across all participants, we found a significant association of CSF HFABP with longitudinal atrophy of the entorhinal cortex and other AD-vulnerable neuroanatomic regions. However, we found that the relationship between CSF HABP and brain atrophy was significant only among those with low CSF Aβ1–42 and occurred irrespective of phospho-tau181p status.
Conclusions
Our findings indicate that Aβ-associated volume loss occurs in the presence of elevated HFABP irrespective of phospho-tau. This implicates a potentially important role for fatty acid binding proteins in Alzheimer’s disease neurodegeneration.
doi:10.1186/1750-1326-8-39
PMCID: PMC3850652  PMID: 24088526
Alzheimer’s disease; Fatty acids; Lipids; Amyloid; Tau; Brain atrophy

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