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1.  Arguing Against the Proposed Definition Changes of PD 
As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article entitled, "Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease." In particular, we suggest that the one-year rule distinguishing Parkinson’s disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice, in clinical and basic science research, and in helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, “PD (dementia with Lewy bodies subtype)”, will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions.
doi:10.1002/mds.26721
PMCID: PMC5168716  PMID: 27492190
2.  Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis 
The Lancet. Neurology  2017;16(1):55-65.
Background
There exists great heterogeneity in patient survival and the time interval between motor symptom and dementia onset (MDI) across Lewy body spectrum disorders (LBSD). The goal of this study is to identify genetic and pathological findings that have the strongest association with these features of clinical heterogeneity in LBSD.
Methods
In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of LBSD patients with autopsy-confirmed α-synucleinopathy (as of Oct 1, 2015) recruited from 5 clinical research centres in 5 cities in the USA. Using histopathology techniques and markers, we assessed the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathologic changes in cortical regions using averaged ordinal scores and genotyped cases for variants associated with LBSD. We evaluated the time interval from onset of motor symptoms to dementia (MDI) and overall survival in groups with varying levels of co-morbid Alzheimer’s disease pathology (AD) according to current National Institute on Aging–Alzheimer’s Association neuropathological criteria and used multivariate regression to control for age at death and gender.
Findings
This study included 213 patients who had been followed to autopsy and met inclusion criteria of clinical LBSD with autopsy-confirmed α-synculeinopathy. Patient groups were characterized by no (n=49,23%), low-level (n=56,26%), intermediate-level (n=45,21%) or high-level (n=63,30%) AD neuropathology. Across groups of increasing levels of AD neuropathology, there were higher cerebral α-synuclein scores, shorter MDI, and shorter disease duration (p<0·0001 all). Multivariate regression found independent negative associations of cerebral tau score with MDI (β= −4·0, 95% CI −5·5 to −2·6; p<0·0001) (R2=0·22, p<0·0001) and with survival (β=−2·0, 95% CI −3·2 to −0·8; p<0·0001) (R2=0·15, p<0·0001) in models including age at death, gender, cerebral neuritic plaque scores, cerebral α-synuclein, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates.
Interpretation
AD neuropathology is common in LBSD and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tau tangle burden, α-synuclein pathology, and amyloid plaque pathology are the strongest pathological predictors of a shorter MDI and survival in LBSD. In the future, clinical diagnostic criteria which use reliable biomarkers for AD neuropathology in LBSD should help identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-beta or α-synuclein, and stratify them by level of AD neuropathology.
Funding
NIH (NIA/NINDS).
doi:10.1016/S1474-4422(16)30291-5
PMCID: PMC5181646  PMID: 27979356
3.  Fetuin-A and risk of coronary heart disease: a Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies 
Atherosclerosis  2015;243(1):44-52.
Background and aims
Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima- media thickness, ankle-arm index, and coronary artery calcification).
Methods
Genetic variation and fetuin-A levels were assessed in 3,299 community-living individuals (2,733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992– 1993.
Results
Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele (P<0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95% CI: 1.00– 1.26) for rs2248690 and 1.02 (0.91- 1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70– 1.00) for rs2248690 and 0.97 (95% CI: 0.82– 1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3,295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93– 1.34) and 1.06 (0.93– 1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048).
Conclusion
Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.
doi:10.1016/j.atherosclerosis.2015.08.031
PMCID: PMC4609621  PMID: 26343871
Fetuin-A; single nucleotide polymorphisms; coronary heart disease; Mendelian randomization; meta-analysis
4.  Trajectories of peripheral interleukin-6, structure of the hippocampus, and cognitive impairment over 14 years in older adults 
Neurobiology of aging  2015;36(11):3038-3044.
We aimed to investigate if trajectory components (baseline level, slope and variability) of peripheral IL-6 over time were related to cognitive impairment and smaller hippocampal volume, and if hippocampal volume explained the associations between IL-6 and cognitive impairment. Multivariable regression models were used to test the association between IL-6 trajectory components with change in neuroimaging measures of the hippocampus, and with cognitive impairment among 135 older adults (70–79 years at baseline) from the Healthy Brain Project over 14 years. IL-6 variability was positively associated with cognitive impairment (OR = 5.86, 95% CI:1.24, 27.61) and with greater decrease per year of gray matter volume of the hippocampus (β=−0.008, SE=0.004, p=0.03). After adjustment for hippocampal volume, the odds ratio of cognitive impairment decreased for each unit of IL-6 variability, and confidence intervals widened (OR=4.36, 95% CI: 0.67, 28.29). Neither baseline levels nor slopes of IL-6 were related to cognitive impairment or hippocampal volume. We believe this has potential clinical and public health implications by suggesting adults with stable levels of peripheral IL-6 may be better targets for intervention studies for slowing or preventing cognitive decline.
doi:10.1016/j.neurobiolaging.2015.07.025
PMCID: PMC4718400  PMID: 26279115
cognitive impairment; interleukin-6; hippocampal morphology; aging; epidemiology
5.  Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease 
PLoS Genetics  2016;12(10):e1006327.
We performed an exome-wide association analysis in 1393 late-onset Alzheimer’s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5–15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.
Author Summary
Alzheimer’s disease (AD) is the most common cause of dementia in the older adult population. There is substantial evidence for an important genetic contribution to AD risk. While prior work has comprehensively evaluated the contribution of common genetic variants in large population-based cohorts, the role of rare variants remains to be defined. Here, we have used a newer genotyping array to characterize less common variants, including those likely to impact the function of encoded proteins, in a combined cohort of 1393 AD cases and 8141 control subjects without AD. Our results implicate a novel, amino acid-changing variant, P155L, in the TM2D3 gene. This variant was discovered to be more common in the Icelandic population, where it was significantly associated with both increased risk and earlier age of onset of AD. Lastly, in order to examine the potential functional impact of the implicated variant, we performed additional studies in the fruit fly. Our results suggest that P155L causes a loss-of-function in TM2D3, in the context of Notch-Presenilin signal transduction. In sum, we identify a novel, rare TM2D3 variant in association with AD risk and highlight functional connections with AD-relevant biology.
doi:10.1371/journal.pgen.1006327
PMCID: PMC5072721  PMID: 27764101
6.  Subjective cognitive complaints, personality and brain amyloid-beta in cognitively normal older adults 
Objectives
Subjective cognitive complaints in otherwise normal aging are common but may be associated with preclinical Alzheimer Disease in some individuals. Little is known about who is mostly likely to show associations between cognitive complaints and preclinical Alzheimer pathology. We sought to 1) demonstrate associations between subjective complaints and brain amyloid-β in cognitively normal older adults; 2) to explore personality factors as potential moderators of this association.
Design
Cross-sectional observational study.
Setting
Clinical neuroimaging research center.
Participants
Community volunteer sample of 92 healthy older adults, screened for normal cognition with comprehensive neuropsychological evaluation.
Measurements
Subjective cognitive self-report measures included the Memory Functioning Questionnaire, Cognitive Failures Questionnaire, and the Subjective Cognitive Complaint Scale. Personality was measured with the NEO Five Factor Inventory. Brain amyloid-β deposition was assessed with Pittsburgh compound B (PiB)-PET imaging.
Results
One of three cognitive complaint measures, the Memory Functioning Questionnaire, was associated with global PiB retention (standardized beta =−.230, p=.046, adjusting for age, sex and depressive symptoms). Neuroticism moderated this association such that only high neuroticism individuals showed the predicted pattern of high complaint – high amyloid-β association.
Conclusions
Evidence for association between subjective cognition and brain amyloid-β deposition in healthy older adults is demonstrable but measure-specific. Neuroticism may moderate the MFQ – amyloid-β association such that it is observed in the context of higher trait neuroticism. Subjective cognitive complaints and neuroticism may reflect a common susceptibility toward psychological distress and negative affect, which are in turn risk factors for cognitive decline in aging and incident Alzheimer Disease.
doi:10.1016/j.jagp.2015.01.008
PMCID: PMC4532656  PMID: 25746485
amyloid imaging; cognition; personality; subjective memory
7.  Effect of a 24-month physical activity intervention compared to health education on cognitive outcomes in sedentary older adults: the LIFE Randomized Trial 
JAMA  2015;314(8):781-790.
Importance
Epidemiologic evidence suggests that physical activity benefits cognition, but results from randomized trials are limited and mixed.
Objective
To determine whether a 24-month physical activity program results in better cognitive function and/or lower risk of mild cognitive impairment (MCI) or dementia compared to a health education program.
Design, Setting, and Participants
The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized clinical trial that enrolled 1635 community-living participants at 8 centers in the U.S. from February 2010 until December 2011. Participants were sedentary adults aged 70–89 years at risk for mobility disability, but able to walk 400m.
Intervention
Participants were randomized to a structured, moderate-intensity physical activity program (n=818) that included walking, resistance training, and flexibility exercises or to a health education program (n=817) of educational workshops and upper extremity stretching.
Outcomes and Measures
Pre-specified secondary outcomes of the LIFE study included cognitive function measured by the Digit Symbol Coding task (0–133 scale, higher=better) and Hopkins Verbal Learning Test-Revised (12-word list recall) assessed in 1,476 (90.3%) participants. Tertiary outcomes included global and executive cognitive function and incident MCI or dementia at 24 months. Pre-specified subgroups analyses were performed based on age, sex, baseline physical performance, and baseline Modified Mini-Mental State Examination score.
Results
At 24 months, DSC and HVLT-R scores (adjusted for clinic site, gender, and baseline values) were not different between groups. Mean DSC scores were 46.26 points for physical activity vs. 46.28 for health education; mean difference −0.014 points, 95% CI −0.80 to 0.77, p= 0.97. Mean HVLT-R delayed recall scores were 7.22 for physical activity vs. 7.25 for health education; mean difference −0.03 words, 95% CI −0.29 to 0.24, p= 0.84.
No differences for any other cognitive or composite measures were observed. Participants randomized to physical activity who were ≥80 years (n=307) and those with poorer baseline physical performance (n=328) had better changes in executive function composite scores vs. those randomized to health education (interaction p=0.01, respectively). Incident MCI or dementia occurred in 98 (13.2%) participants randomized to physical activity and 91 (12.1%) participants randomized to health education (OR 1.08, 95% CI 0.80 to 1.46).
Conclusions and Relevance
Among sedentary older adults, a 24-month moderate intensity physical activity program, compared to a health education program, did not result in improvements in global or domain-specific cognitive function.
doi:10.1001/jama.2015.9617
PMCID: PMC4698980  PMID: 26305648
8.  Empirically Derived Trajectories to Dementia Over 15 Years of Follow-up Identified by Using Mixed Membership Models 
American Journal of Epidemiology  2015;182(4):366-374.
Alzheimer disease is the most common form of dementia in the elderly, and the complex relationships among risk factors produce highly variable natural histories from normal cognition through the prodromal stage of mild cognitive impairment (MCI) to clinical dementia. We used a novel statistical approach, mixed membership trajectory models, to capture the variety of such pathways in 652 participants in the Cardiovascular Health Study Cognition Study over 22 years of follow-up (1992–2014). We identified 3 trajectories: a “healthy” profile with a peak probability of MCI between 95 and 100 years of age and only a 50% probability of dementia by age 100; an “intermediate” profile with a peak probability of MCI between 85 and 90 years of age and progression to dementia between 90 and 95 years; and an “unhealthy” profile with a peak probability of progressing to MCI between ages 75 and 80 years and to dementia between the ages of 80 and 85 years. Hypertension, education, race, and the ϵ4 allele of the apolipoprotein E gene all affected the closeness of an individual to 1 or more of the canonical trajectories. These results provide new insights into the natural history of Alzheimer disease and evidence for a potential difference in the pathophysiology of the development of dementia.
doi:10.1093/aje/kwv051
PMCID: PMC4528953  PMID: 26209524
dementia; mild cognitive impairment; mixed membership; trajectory models
9.  More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer’s disease risk 
Neurobiology of aging  2015;36(8):2443.e21-2443.e26.
Over twenty risk loci have been identified for late onset Alzheimer’s disease (LOAD), most of which display relatively small effect sizes. Recently, a rare missense (R47H) variant, rs75932628 in TREM2, has been shown to mediate LOAD risk substantially in Icelandic and Caucasian populations. Here we present more evidence for the association of the R47H with LOAD risk in a Caucasian population comprising 4,567 LOAD cases and controls. Our results show that carriers of the R47H variant have a significantly increased risk for LOAD (OR=7.40, P=3.66E-06). In addition to AD risk, we also examined the association of R47H with AD-related phenotypes, including age-at-onset, psychosis, and amyloid deposition, but found no significant association. Our results corroborate those of other studies implicating TREM2 as a LOAD risk locus and indicate the need to determine its biological role in the context of neurodegeneration.
doi:10.1016/j.neurobiolaging.2015.04.012
PMCID: PMC4465085  PMID: 26058841
TREM2; rare variants; LOAD
10.  Longitudinal change of neuroimaging and clinical markers in autosomal dominant Alzheimer’s disease: a prospective cohort study 
The Lancet. Neurology  2015;14(8):804-813.
Background
The biomarker model of Alzheimer’s disease (AD) hypothesizes a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline, as an individual progresses from preclinical AD to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed.
Methods
Autosomal dominant AD (ADAD) mutation carriers, aged 21 years or older (no cognitive restrictions), were recruited from across the United States via referral by colleagues or ADAD families themselves. Sixteen individuals with mutations in PSEN1, PSEN2 or APP, aged 28 to 56, were assessed longitudinally every one to two years, between March 23, 2003 and August 1, 2014. Participants completed two to eight assessments (total=83), over a period of two to eleven years. We measured global amyloid-beta load with Pittsburgh Compound-B PET, posterior cortical metabolism with [18F]fluorodeoxyglucose PET, hippocampal volume (age-, and gender-corrected) with T1 MRI, verbal memory with 10-item delayed word recall, and general cognition with Mini Mental State Exam. We estimated overall biomarker trajectories across estimated years from symptom onset (EYO) using linear mixed models, and compared ADAD estimates to cross-sectional data from cognitively normal, older controls selected to be negative for amyloidosis, hypometabolism, and hippocampal atrophy. In seven individuals with the longest follow-up (seven/eight assessments spanning six to eleven years), we further examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition, to identify progressive within-individual change in these markers (increase/decrease of greater than two Z-scores standardized to controls).
Findings
Significant differences in ADAD compared to controls (p<0·01) were detected in the following order: increased amyloidosis (−7.5 EYO), decreased metabolism (0 EYO), decreased hippocampal volume and verbal memory (+7.5 EYO), decreased general cognition (+10 EYO). Within-individual examination of AD markers found three individuals demonstrating active amyloidosis, without progressive neurodegeneration or cognitive decline. Two amyloid-positive individuals showed neither active amyloidosis, nor progressive neurodegeneration or cognitive decline. The two remaining amyloid-positive individuals showed progressive neurodegeneration and cognitive decline, without further progressive amyloidosis.
Interpretation
Our results strongly support amyloidosis as the earliest progressive component of the biomarker model in ADAD. Our within-individual examination further suggests three sequential phases across ADAD development: 1) active amyloidosis, 2) stable amyloid-positive and, 3) progressive neurodegeneration and cognitive decline, indicating that amyloid-beta accumulation is largely complete before progressive neurodegeneration and cognitive decline in our ADAD cohort, supporting efforts to target early amyloid-beta deposition as a means of secondary prevention in this population.
doi:10.1016/S1474-4422(15)00135-0
PMCID: PMC4519011  PMID: 26139022
11.  Convergent genetic and expression data implicate immunity in Alzheimer's disease 
Jones, Lesley | Lambert, Jean-Charles | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Vedernikov, Alexey | Escott-Price, Valentina | Stone, Timothy | Richards, Alexander | Bellenguez, Céline | Ibrahim-Verbaas, Carla A | Naj, Adam C | Sims, Rebecca | Gerrish, Amy | Jun, Gyungah | DeStefano, Anita L | Bis, Joshua C | Beecham, Gary W | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A | Jones, Nicola | Smith, Albert V | Chouraki, Vincent | Thomas, Charlene | Ikram, M Arfan | Zelenika, Diana | Vardarajan, Badri N | Kamatani, Yoichiro | Lin, Chiao-Feng | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L | De Jager, Philip L | Deramecourt, Vincent | Johnston, Janet A | Evans, Denis | Lovestone, Simon | Letteneur, Luc | Kornhuber, Johanes | Tárraga, Lluís | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Emilsson, Valur | Brown, Kristelle | Kamboh, M Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B | Myers, Amanda J | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Kehoe, Pat | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleὀ, Alberti | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick | Hardy, John | Naranjo, Maria Candida Deniz | Razquin, Cristina | Bosco, Paola | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Moebus, Susanne | Mecocci, Patrizia | del Zompo, Maria | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Jessen, Frank | Dichgans, Martin | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alavarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | Mateo, Ignacio | Owen, Michael J | Faber, Kelley M | Jonsson, Palmi V | Combarros, Onofre | O'Donovan, Michael C | Cantwell, Laura B | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H | Bennett, David A | Harris, Tamara B | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee FAG | Passmore, Peter | Montine, Thomas J | Bettens, Karolien | Rotter, Jerome I | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M | Kukull, Walter A | Hannequin, Didier | Powell, John F | Nalls, Michael A | Ritchie, Karen | Lunetta, Kathryn L | Kauwe, John SK | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Pastor, Pau | Schmidt, Reinhold | Rujescu, Dan | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M | Graff, Caroline | Psaty, Bruce M | Haines, Jonathan L | Lathrop, Mark | Pericak-Vance, Margaret A | Launer, Lenore J | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broekhoven, Christine | Ramirez, Alfredo | Schellenberg, Gerard D | Seshadri, Sudha | Amouyel, Philippe | Williams, Julie | Holmans, Peter A
Background
Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis.
Methods
The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.
Results
ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05).
Conclusions
The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics.
doi:10.1016/j.jalz.2014.05.1757
PMCID: PMC4672734  PMID: 25533204
Alzheimer's disease; dementia; neurodegeneration; immune response; endocytosis; cholesterol metabolism; uniquitination; pathway analysis; ALIGATOR; Weighted gene coexpression network analysis
12.  A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN 
Jun, Gyungah | Ibrahim-Verbaas, Carla A. | Vronskaya, Maria | Lambert, Jean-Charles | Chung, Jaeyoon | Naj, Adam C. | Kunkle, Brian W. | Wang, Li-San | Bis, Joshua C. | Bellenguez, Céline | Harold, Denise | Lunetta, Kathryn L. | Destefano, Anita L. | Grenier-Boley, Benjamin | Sims, Rebecca | Beecham, Gary W. | Smith, Albert V. | Chouraki, Vincent | Hamilton-Nelson, Kara L. | Ikram, M. Arfan | Fievet, Nathalie | Denning, Nicola | Martin, Eden R. | Schmidt, Helena | Kamatani, Yochiro | Dunstan, Melanie L | Valladares, Otto | Laza, Agustin Ruiz | Zelenika, Diana | Ramirez, Alfredo | Foroud, Tatiana M. | Choi, Seung-Hoan | Boland, Anne | Becker, Tim | Kukull, Walter A. | van der Lee, Sven J. | Pasquier, Florence | Cruchaga, Carlos | Beekly, Duane | Fitzpatrick, Annette L. | Hanon, Oliver | Gill, Michael | Barber, Robert | Gudnason, Vilmundur | Campion, Dominique | Love, Seth | Bennett, David A. | Amin, Najaf | Berr, Claudine | Tsolaki, Magda | Buxbaum, Joseph D. | Lopez, Oscar L. | Deramecourt, Vincent | Fox, Nick C | Cantwell, Laura B. | Tárraga, Lluis | Dufouil, Carole | Hardy, John | Crane, Paul K. | Eiriksdottir, Gudny | Hannequin, Didier | Clarke, Robert | Evans, Denis | Mosley, Thomas H. | Letenneur, Luc | Brayne, Carol | Maier, Wolfgang | De Jager, Philip | Emilsson, Valur | Dartigues, Jean-François | Hampel, Harald | Kamboh, M. Ilyas | de Bruijn, Renee F.A.G. | Tzourio, Christophe | Pastor, Pau | Larson, Eric B. | Rotter, Jerome I. | O’Donovan, Michael C | Montine, Thomas J. | Nalls, Michael A. | Mead, Simon | Reiman, Eric M. | Jonsson, Palmi V. | Holmes, Clive | St George-Hyslop, Peter H. | Boada, Mercè | Passmore, Peter | Wendland, Jens R. | Schmidt, Reinhold | Morgan, Kevin | Winslow, Ashley R. | Powell, John F | Carasquillo, Minerva | Younkin, Steven G. | Jakobsdóttir, Jóhanna | Kauwe, John SK | Wilhelmsen, Kirk C. | Rujescu, Dan | Nöthen, Markus M | Hofman, Albert | Jones, Lesley | Haines, Jonathan L. | Psaty, Bruce M. | Van Broeckhoven, Christine | Holmans, Peter | Launer, Lenore J. | Mayeux, Richard | Lathrop, Mark | Goate, Alison M. | Escott-Price, Valentina | Seshadri, Sudha | Pericak-Vance, Margaret A. | Amouyel, Philippe | Williams, Julie | van Duijn, Cornelia M. | Schellenberg, Gerard D. | Farrer, Lindsay A.
Molecular psychiatry  2015;21(1):108-117.
APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ε4+ (10,352 cases and 9,207 controls) and APOE ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10−4) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10−9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4− subjects (MS4A6A/MS4A4A/ MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6x10−7) is noteworthy because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3x10−8), frontal cortex (P≤1.3x10−9), and temporal cortex (P≤1.2x10−11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10−6) and temporal cortex (P=2.6x10−6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared to persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
doi:10.1038/mp.2015.23
PMCID: PMC4573764  PMID: 25778476
13.  Shared genetic contribution to ischemic stroke and Alzheimer's disease 
Traylor, Matthew | Adib‐Samii, Poneh | Harold, Denise | Dichgans, Martin | Williams, Julie | Lewis, Cathryn M. | Markus, Hugh S. | Fornage, Myriam | Holliday, Elizabeth G | Sharma, Pankaj | Bis, Joshua C | Psaty, Bruce M | Seshadri, Sudha | Nalls, Mike A | Devan, William J | Boncoraglio, Giorgio | Malik, Rainer | Mitchell, Braxton D | Kittner, Steven J | Ikram, M Arfan | Clarke, Robert | Rosand, Jonathan | Meschia, James F | Sudlow, Cathie | Rothwell, Peter M | Levi, Christopher | Bevan, Steve | Kilarski, Laura L | Walters, Matthew | Thijs, Vincent | Slowik, Agnieszka | Lindgren, Arne | de Bakker, Paul I W | Lambert, Jean‐Charles | Ibrahim‐Verbaas, Carla A | Harold, Denise | Naj, Adam C | Sims, Rebecca | Bellenguez, Céline | Jun, Gyungah | DeStefano, Anita L | Bis, Joshua C | Beecham, Gary W | Grenier‐Boley, Benjamin | Russo, Giancarlo | Thornton‐Wells, Tricia A | Jones, Nicola | Smith, Albert V | Chouraki, Vincent | Thomas, Charlene | Ikram, M Arfan | Zelenika, Diana | Vardarajan, Badri N | Kamatani, Yoichiro | Lin, Chiao‐Feng | Gerrish, Amy | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie‐Thçrèse | Choi, Seung‐Hoan | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Ramirez, Alfredo | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L | De Jager, Philip L | Deramecourt, Vincent | Johnston, Janet A | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Morón, Francisco J | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiçvet, Nathalie | Huentelman, Matthew J | Gill, Michael | Brown, Kristelle | Kamboh, M Ilyas | Keller, Lina | Barberger‐Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B | Green, Robert | Myers, Amanda J | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | St George‐Hyslop, Peter | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petroula | Collinge, John | Sorbi, Sandro | Sanchez‐Garcia, Florentino | Fox, Nick C | Hardy, John | Deniz Naranjo, Maria Candida | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Matthews, Fiona | Moebus, Susanne | Mecocci, Patrizia | Del Zompo, Maria | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton‐Nelson, Kara L | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J | Faber, Kelley M | Jonsson, Palmi V | Combarros, Onofre | O'Donovan, Michael C | Cantwell, Laura B | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H | Bennett, David A | Harris, Tamara B | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F A G | Passmore, Peter | Montine, Thomas J | Bettens, Karolien | Rotter, Jerome I | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M | Kukull, Walter A | Hannequin, Didier | Powell, John F | Nalls, Michael A | Ritchie, Karen | Lunetta, Kathryn L | Kauwe, John S K | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Schmidt, Reinhold | Rujescu, Dan | Wang, Li‐San | Dartigues, Jean‐François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M | Graff, Caroline | Psaty, Bruce M | Jones, Lesley | Haines, Jonathan L | Holmans, Peter A | Lathrop, Mark | Pericak‐Vance, Margaret A | Launer, Lenore J | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broeckhoven, Christine | Moskvina, Valentina | Seshadri, Sudha | Williams, Julie | Schellenberg, Gerard D | Amouyel, Philippe
Annals of Neurology  2016;79(5):739-747.
Objective
Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases.
Methods
Using genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred.
Results
We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response.
Interpretation
Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–747
doi:10.1002/ana.24621
PMCID: PMC4864940  PMID: 26913989
14.  Vitamin D and Risk of Neuroimaging Abnormalities 
PLoS ONE  2016;11(5):e0154896.
Vitamin D deficiency has been linked with an increased risk of incident all-cause dementia and Alzheimer’s disease. The aim of the current study was to explore the potential mechanisms underlying these associations by determining whether low vitamin D concentrations are associated with the development of incident cerebrovascular and neurodegenerative neuroimaging abnormalities. The population consisted of 1,658 participants aged ≥65 years from the US-based Cardiovascular Health Study who were free from prevalent cardiovascular disease, stroke and dementia at baseline in 1992–93. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected at baseline. The first MRI scan was conducted between 1991–1994 and the second MRI scan was conducted between 1997–1999. Change in white matter grade, ventricular grade and presence of infarcts between MRI scan one and two were used to define neuroimaging abnormalities. During a mean follow-up of 5.0 years, serum 25(OH)D status was not significantly associated with the development of any neuroimaging abnormalities. Using logistic regression models, the multivariate adjusted odds ratios (95% confidence interval) for worsening white matter grade in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25–50 nmol/L) were 0.76 (0.35–1.66) and 1.09 (0.76–1.55) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted odds ratios for ventricular grade in participants who were severely 25(OH)D deficient and deficient were 0.49 (0.20–1.19) and 1.12 (0.79–1.59) compared to those sufficient. The multivariate adjusted odds ratios for incident infarcts in participants who were severely 25(OH)D deficient and deficient were 1.95 (0.84–4.54) and 0.73 (0.47–1.95) compared to those sufficient. Overall, serum vitamin D concentrations could not be shown to be associated with the development of cerebrovascular or neurodegenerative neuroimaging abnormalities in Cardiovascular Health Study participants.
doi:10.1371/journal.pone.0154896
PMCID: PMC4864237  PMID: 27166613
15.  Voxel Level Survival Analysis of Grey Matter Volume and Incident Mild Cognitive Impairment or Alzheimer’s Disease 
The purpose of this study was to identify, at the voxel level, brain regions associated with the time to develop mild cognitive impairment (MCI) or Alzheimer’s disease (AD) from normal cognition. We analyzed incident MCI (n = 58) or AD (n = 151) in 292 cognitively normal participants in the Cardiovascular Health Study–Cognition Study (mean age = 79.2±3.6 years). We used segmented, modulated grey matter maps from 3D (spoiled gradient echo) MRI scans obtained in 1998/99 (with clinical follow-up through 2012) that were smoothed with a 3-D 4 mm Gaussian filter. We fit approximately 1.92 million voxel-level Cox proportional hazard models to examine the grey matter volume effect on time to event, adjusting for age, sex, and diabetes. We used the significance threshold of p < 0.005 with contiguity threshold of at least 68 voxels (false detection probability <2.5 × 10−8). Areas within the mesial temporal lobe (MTL), anterior temporal lobe, hippocampus, and posterior cingulate gyrus were associated with time to MCI or AD. The presence of white matter lesions (a marker of small vessel disease in the brain) was associated with the volumes of the MTL and precuneus; MRI-identified infarcts also predicted MTL volume. These findings are important because we identified critical brain regions that predict a person’s increased likelihood of developing MCI or AD over a decade prior to the onset of clinical symptoms; these critical brain regions were themselves affected by the presence of vascular disease.
doi:10.3233/JAD-150047
PMCID: PMC4550581  PMID: 25720412
Alzheimer’s disease; Cox survival model; incidence; mild cognitive impairment; MRI
16.  Objective Measures of Physical Activity, White Matter Integrity and Cognitive Status in Adults Over Age 80 
Behavioural brain research  2015;284:51-57.
The neuroprotective effects of physical activity (PA) are consistently shown in older adults, but the neural substrates, particularly in white matter (WM), are understudied, especially in very old adults with the fastest growth rate and the highest risk of dementia. This study quantified the association between PA and WM integrity in adults over 80. The moderating effects of cardiometabolic conditions, physical functional limitations and WM hyperintensities were also examined, as they can affect PA and brain integrity. Fractional anisotropy (FA) from normal-appearing WM via diffusion tensor imaging and WM hyperintensities were obtained in 90 participants (mean age=87.4, 51.1% female, 55.6% white) with concurrent objective measures of steps, active energy expenditure (AEE in kcal), duration (minutes), and intensity (Metabolic equivalents, METs) via SenseWear Armband. Clinical adjudication of cognitive status, prevalence of stroke and diabetes, systolic blood pressure, and gait speed were assessed at time of neuroimaging. Participants were on average sedentary (mean±SD/day: 1766±1345 steps, 202±311 kcal, 211±39 minutes, 1.8±1.1 METs). Higher steps, AEE and duration, but not intensity, were significantly associated with higher FA. Associations were localized in frontal and temporal areas. Moderating effects of cardiometabolic conditions, physical functional limitations, and WM hyperintensities were not significant. Neither FA nor PA was related to cognitive status. Older adults with a sedentary lifestyle and a wide range of cardiometabolic conditions and physical functional limitations, displayed higher WM integrity in relation to higher PA. Studies of very old adults to quantify the role of PA in reducing dementia burden via WM integrity are warranted.
doi:10.1016/j.bbr.2015.01.045
PMCID: PMC4369426  PMID: 25655514
White matter integrity; diffusion tensor imaging; SenseWear Armband; very old adults
17.  Longer lithium exposure is associated with better white matter integrity in older adults with bipolar disorder 
Bipolar disorders  2014;17(3):248-256.
Background
Bipolar Disorder (BD) is associated with cognitive dysfunction and structural brain abnormalities. In human and non-human studies, lithium has been related to neuroprotective and neurotrophic effects. We explored whether lithium treatment is related to better brain integrity and cognitive function in older adults with BD.
Methods
We examined cognitive and neuroimaging data in 58 individuals with BD mean (SD) age 64.5 (9.8) years and 21 mentally healthy comparators (“controls”) of similar age and education. Subjects received comprehensive neurocognitive assessment and structural brain imaging, examining total gray matter volume, overall white matter integrity (fractional anisotropy), and total white matter hyperintensity (WMH) burden.
Results
In comparison to controls, subjects with BD had worse overall cognitive performance, lower total gray matter volume, and lower white matter integrity. Among BD subjects, longer duration of lithium treatment was related to higher white matter integrity after controlling for age and vascular disease burden, but not with better cognitive performance.
Conclusions
Lithium treatment appears to be related to better brain integrity in older individuals with BD, in particular in those who take it long-term. While intriguing, these findings need to be confirmed in a larger sample.
doi:10.1111/bdi.12260
PMCID: PMC4374042  PMID: 25257942
Lithium; Bipolar Disorder; Neuroprotection
18.  Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium 
Debette, Stéphanie | Ibrahim Verbaas, Carla A. | Bressler, Jan | Schuur, Maaike | Smith, Albert | Bis, Joshua C. | Davies, Gail | Wolf, Christiane | Gudnason, Vilmundur | Chibnik, Lori B. | Yang, Qiong | deStefano, Anita L. | de Quervain, Dominique J.F. | Srikanth, Velandai | Lahti, Jari | Grabe, Hans J. | Smith, Jennifer A. | Priebe, Lutz | Yu, Lei | Karbalai, Nazanin | Hayward, Caroline | Wilson, James F. | Campbell, Harry | Petrovic, Katja | Fornage, Myriam | Chauhan, Ganesh | Yeo, Robin | Boxall, Ruth | Becker, James | Stegle, Oliver | Mather, Karen A. | Chouraki, Vincent | Sun, Qi | Rose, Lynda M. | Resnick, Susan | Oldmeadow, Christopher | Kirin, Mirna | Wright, Alan F. | Jonsdottir, Maria K. | Au, Rhoda | Becker, Albert | Amin, Najaf | Nalls, Mike A. | Turner, Stephen T. | Kardia, Sharon L.R. | Oostra, Ben | Windham, Gwen | Coker, Laura H. | Zhao, Wei | Knopman, David S. | Heiss, Gerardo | Griswold, Michael E. | Gottesman, Rebecca F. | Vitart, Veronique | Hastie, Nicholas D. | Zgaga, Lina | Rudan, Igor | Polasek, Ozren | Holliday, Elizabeth G. | Schofield, Peter | Choi, Seung Hoan | Tanaka, Toshiko | An, Yang | Perry, Rodney T. | Kennedy, Richard E. | Sale, Michèle M. | Wang, Jing | Wadley, Virginia G. | Liewald, David C. | Ridker, Paul M. | Gow, Alan J. | Pattie, Alison | Starr, John M. | Porteous, David | Liu, Xuan | Thomson, Russell | Armstrong, Nicola J. | Eiriksdottir, Gudny | Assareh, Arezoo A. | Kochan, Nicole A. | Widen, Elisabeth | Palotie, Aarno | Hsieh, Yi-Chen | Eriksson, Johan G. | Vogler, Christian | van Swieten, John C. | Shulman, Joshua M. | Beiser, Alexa | Rotter, Jerome | Schmidt, Carsten O. | Hoffmann, Wolfgang | Nöthen, Markus M. | Ferrucci, Luigi | Attia, John | Uitterlinden, Andre G. | Amouyel, Philippe | Dartigues, Jean-François | Amieva, Hélène | Räikkönen, Katri | Garcia, Melissa | Wolf, Philip A. | Hofman, Albert | Longstreth, W.T. | Psaty, Bruce M. | Boerwinkle, Eric | DeJager, Philip L. | Sachdev, Perminder S. | Schmidt, Reinhold | Breteler, Monique M.B. | Teumer, Alexander | Lopez, Oscar L. | Cichon, Sven | Chasman, Daniel I. | Grodstein, Francine | Müller-Myhsok, Bertram | Tzourio, Christophe | Papassotiropoulos, Andreas | Bennett, David A. | Ikram, Arfan M. | Deary, Ian J. | van Duijn, Cornelia M. | Launer, Lenore | Fitzpatrick, Annette L. | Seshadri, Sudha | Mosley, Thomas H.
Biological psychiatry  2014;77(8):749-763.
BACKGROUND
Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
METHODS
We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia-and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
RESULTS
rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
CONCLUSIONS
This largest study to date exploring the genetics of memory function in ~ 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
doi:10.1016/j.biopsych.2014.08.027
PMCID: PMC4513651  PMID: 25648963
Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory
19.  Mild Cognitive Impairment 
Continuum : Lifelong Learning in Neurology  2013;19(2 Dementia):411-424.
Purpose of Review: The term mild cognitive impairment (MCI) is used to describe older subjects with demonstrable cognitive impairment who have not crossed the threshold for dementia. Because patients with MCI have an increased risk of developing dementia, especially Alzheimer disease (AD), there is significant interest in the clinical characterization of these subjects and in understanding the pathophysiology of the transition from MCI to AD.
Recent Findings: The MCI syndrome, as an expression of an incipient disorder that may lead to dementia, is extremely heterogeneous and may coexist with systemic, neurologic, or psychiatric disorders that can cause cognitive deficits. Recent clinical criteria were designed to take into account the different forms of clinical presentation of the syndrome, and introduced the possible contribution of biomarkers to the clinical diagnosis. Bedside diagnosis of MCI can be difficult, since patients who report having cognitive problems may have normal scores in global cognitive scales or in brief neuropsychological instruments.
Summary: This article presents the evolution of the clinical concept of MCI, the operationalization of its current definitions, the development of biomarkers that can help to identify an underlying neurodegenerative process as the etiology of the syndrome, and its proposed treatments.
doi:10.1212/01.CON.0000429175.29601.97
PMCID: PMC3915547  PMID: 23558486
20.  Association of Alzheimer disease GWAS loci with MRI-markers of brain aging 
Neurobiology of aging  2015;36(4):1765.e7-1765.e16.
Whether novel risk variants of Alzheimer’s disease (AD) identified through genome-wide association studies (GWAS) also influence MRI-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume (ICV), total brain volume (TBV), hippocampal volume (HV), white matter hyperintensity (WMH) burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N=8,175–11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p=0.0054) and CD33 (rs3865444) with smaller ICV (p=0.0058) In gene-based tests, there was associations of HLA-DRB1 with TBV (p=0.0006) and BIN1 with HV (p=0.00089). A weighted AD genetic risk score was associated with smaller HV (beta±SE=−0.047±0.013, p=0.00041), even after excluding the APOE locus (p=0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in non-demented older community persons.
doi:10.1016/j.neurobiolaging.2014.12.028
PMCID: PMC4391343  PMID: 25670335
Alzheimer; MRI-markers; genetic risk score; GWAS; hippocampal volume
21.  Patterns of Compensation and Vulnerability in Normal Subjects at Risk of Alzheimer’s Disease 
Journal of Alzheimer's disease : JAD  2013;33(0 1):S427-S438.
Alzheimer’s disease (AD) is the most frequent form of dementia in elderly individuals and its incidence and prevalence increases with age. This risk of AD is increased in the presence of genetic and demographic factors including apolipoprotein E 4 allele, lower education, and family history of AD. There are medical risk modifiers including systemic hypertension, diabetes mellitus, cardiovascular disease, and cerebrovascular disease that increase the vulnerability for AD. By contrast, there are lifestyle risk modifiers that reduce the effects of AD risk factors include diet and physical and cognitive activity. Our research has consistently shown that it is the interactions among these risk factors with the pathobiological cascade of AD that determine the likelihood of a clinical expression of AD—either as dementia or mild cognitive impairment. However, the association between “vulnerability” and “protective” factors varies with age, since the effects of these factors on the risk for AD may differ in younger (age < 80) versus older (age > 80) individuals. The understanding of the dynamic of these factors at different age periods will be essential for the implementation of primary prevention treatments for AD.
doi:10.3233/JAD-2012-129015
PMCID: PMC3951098  PMID: 22669014
Alzheimer’s disease; cardiovascular disease; cerebrovascular disease; mild cognitive impairment
22.  Relative 11C-PiB Delivery as a Proxy of Relative CBF: Quantitative Evaluation Using Single-Session 15O-Water and 11C-PiB PET 
The primary goal of this study was to assess the suitability of 11C-Pittsburgh compound B (11C-PiB) blood–brain barrier delivery (K1) and relative delivery (R1) parameters as surrogate indices of cerebral blood flow (CBF), with a secondary goal of directly examining the extent to which simplified uptake measures of 11C-PiB retention (amyloid-β load) may be influenced by CBF, in a cohort of controls and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD).
Methods
Nineteen participants (6 controls, 5 AD, 8 MCI) underwent MR imaging, 15O-water PET, and 11C-PiB PET in a single session. Fourteen regions of interest (including cerebellar reference region) were defined on MR imaging and applied to dynamic coregistered PET to generate time–activity curves. Multiple analysis approaches provided regional 15O-water and 11C-PiB measures of delivery and 11C-PiB retention that included compartmental modeling distribution volume ratio (DVR), arterial- and reference-based Logan DVR, simplified reference tissue modeling 2 (SRTM2) DVR, and standardized uptake value ratios. Spearman correlation was performed among delivery measures (i.e., 15O-water K1 and 11C-PiB K1, relative K1 normalized to cerebellum [Rel-K1-Water and Rel-K1-PiB], and 11C-PiB SRTM2-R1) and between delivery measures and 11C-PiB retention, using the Bonferroni method for multiple-comparison correction.
Results
Primary analysis showed positive correlations (ρ ≈0.2–0.5) between 15O-water K1 and 11C-PiB K1 that did not survive Bonferroni adjustment. Significant positive correlations were found between Rel-K1-Water and Rel-K1-PiB and between Rel-K1-Water and 11C-PiB SRTM2-R1 (ρ ≈0.5–0.8, P < 0.0036) across primary cortical regions. Secondary analysis showed few significant correlations between 11C-PiB retention and relative 11C-PiB delivery measures (but not 15O-water delivery measures) in primary cortical areas that arose only after accounting for cerebrospinal fluid dilution.
Conclusion
11C-PiB SRTM2-R1 is highly correlated with regional relative CBF, as measured by 15O-water K1 normalized to cerebellum, and cross-sectional 11C-PiB retention did not strongly depend on CBF across primary cortical regions. These results provide further support for potential dual-imaging assessments of regional brain status (i.e., amyloid-β load and relative CBF) through dynamic 11C-PiB imaging.
doi:10.2967/jnumed.114.152405
PMCID: PMC4730871  PMID: 26045309
amyloid; blood flow; PiB PET; Alzheimer’s disease; kinetic modeling
23.  Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals 
JAMA neurology  2015;72(9):1021-1028.
IMPORTANCE
Cerebral microbleeds (CMBs) are collections of blood breakdown products that are a common incidental finding in magnetic resonance imaging of elderly individuals. Cerebral microbleeds are associated with cognitive deficits, but the mechanism is unclear. Studies show that individuals with CMBs related to symptomatic cerebral amyloid angiopathy have abnormal vascular reactivity and cerebral blood flow (CBF), but, to our knowledge, abnormalities in cerebral blood flow have not been reported for healthy individuals with incidental CMBs.
OBJECTIVE
To evaluate the association of incidental CMBs with resting-state CBF, cerebral metabolism, cerebrovascular disease, β-amyloid (Aβ), and cognition.
DESIGN, SETTING, AND PARTICIPANTS
A cross-sectional study of 55 cognitively normal individuals with a mean (SD) age of 86.8 (2.7) years was conducted from May 1, 2010, to May 1, 2013, in an academic medical center in Pittsburgh; data analysis was performed between June 10, 2013, and April 9, 2015.
INTERVENTIONS
3-Tesla magnetic resonance imaging was performed with susceptibility-weighted imaging or gradient-recalled echo to assess CMBs, arterial spin labeling for CBF, and T1- and T2-weighted imaging for atrophy, white matter hyperintensities, and infarcts. Positron emission tomography was conducted with fluorodeoxyglucose to measure cerebral metabolism and Pittsburgh compound B for fibrillar Aβ. Neuropsychological evaluation, including the Clinical Dementia Rating scale, was performed.
MAIN OUTCOMES AND MEASURES
Magnetic resonance images were rated for the presence and location of CMBs. Lobar CMBs were subclassified as cortical or subcortical. Measurements of CBF, metabolism, and Aβ were compared with the presence and number of CMBs with voxelwise and region-of-interest analyses.
RESULTS
The presence of cortical CMBs was associated with significantly reduced CBF in multiple regions on voxelwise and region-of-interest analyses (percentage difference in global CBF, −25.3%; P = .0003), with the largest reductions in the parietal cortex (−37.6%; P < .0001) and precuneus (−31.8%; P = .0006). Participants with any CMBs showed a nonsignificant trend toward reduced CBF. Participants with cortical CMBs had a significant association with greater prevalence of infarcts (24% vs 6%; P = .047) and demonstrated a trend to greater prevalence of deficits demonstrated on the Clinical Dementia Rating scale (45% vs 19%; P = .12). There was no difference in cortical amyloid (measured by Pittsburgh compound B positron emission tomography) between participants with and without CMBs (P = .60).
CONCLUSIONS AND RELEVANCE
In cognitively normal elderly individuals, incidental CMBs in cortical locations are associated with widespread reductions in resting-state CBF. Chronic hypoperfusion may put these people at risk for neuronal injury and neurodegeneration. Our results suggest that resting-state CBF is a marker of CMB-related small-vessel disease.
doi:10.1001/jamaneurol.2015.1359
PMCID: PMC4724412  PMID: 26167811
24.  Physical Activity, Body Mass Index, and Brain Atrophy in Alzheimer's Disease 
Neurobiology of aging  2014;36(0 1):S194-S202.
The purpose of this study was to utilize a novel imaging biomarker to assess the associations between physical activity (PA), body mass index (BMI), and brain structure in normal aging, mild cognitive impairment (MCI) and Alzheimer's dementia (AD). We studied 963 participants (mean age: 74.1 ± 4.4) from the multi-site Cardiovascular Health Study including healthy controls (n=724), AD (n=104), and MCI (n=135). Volumetric brain images were processed using tensor-based morphometry for analyzing regional brain volumes. We regressed the local brain tissue volume on reported PA and computed BMI, and performed conjunction analyses using both variables. Covariates included age, sex and study site. PA was independently associated with greater whole brain and regional brain volumes, and reduced ventricular dilation. People with higher BMI had lower whole brain and regional brain volumes. A PA-BMI conjunction analysis showed brain preservation with PA and volume loss with increased BMI in overlapping brain regions. In one of the largest voxel-based cross-sectional studies to date, PA and lower BMI may be beneficial to the brain across the spectrum of aging and neurodegeneration.
doi:10.1016/j.neurobiolaging.2014.05.036
PMCID: PMC4303036  PMID: 25248607
physical activity; body mass index; Alzheimer's; tensor based morphometry
25.  Evolution of the diagnostic criteria for degenerative and cognitive disorders 
Current Opinion in Neurology  2011;24(6):532-541.
Purpose of review
This review describes the evolution of the clinical criteria for Alzheimer’s disease over the past 25 years, with special emphasis on those recently published that have incorporated the use of biomarkers.
Recent findings
One of the most important advances in the knowledge of Alzheimer’s disease was the development of cerebrospinal fluid, PET and MRI biomarkers. These have shown that the Alzheimer’s disease is present in cognitively normal individuals, suggesting that there is a long incubation process that precedes the onset of the symptoms. Although there are diagnostic criteria for Alzheimer’s disease, the National Institute on Aging and the Alzheimer’s Association has proposed a set of diagnostic criteria oriented to provide a unified vision of the pathological process from preclinical, to mild cognitive impairment, and to full-blown dementia. These new criteria take advantage of different biomarkers to support the clinical diagnosis of the different stages of the disease.
Summary
The new guidelines provide a definition of the dementia syndrome and core diagnostic features to be used in research and clinical practice, although they caution about the use of biomarkers, since they still require validation, and the longitudinal interaction and dynamics of these biomarkers in relationship to the manifestation of the symptoms are not fully understood.
doi:10.1097/WCO.0b013e32834cd45b
PMCID: PMC3268228  PMID: 22071334
Alzheimer’s disease; dementia; diagnostic criteria; mild cognitive impairment; preclinical Alzheimer’s disease

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