%0 Journal Article %J J Alzheimers Dis %D 2018 %T Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline. %A Del-Aguila, Jorge L %A Fernández, Maria Victoria %A Schindler, Suzanne %A Ibanez, Laura %A Deming, Yuetiva %A Ma, Shengmei %A Saef, Ben %A Black, Kathleen %A Budde, John %A Norton, Joanne %A Chasse, Rachel %A Harari, Oscar %A Goate, Alison %A Xiong, Chengjie %A Morris, John C %A Cruchaga, Carlos %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Dementia %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heterozygote %K Humans %K Longitudinal Studies %K Male %K Membrane Glycoproteins %K Memory Disorders %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Immunologic %K Risk Assessment %X

Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.

%B J Alzheimers Dis %V 62 %P 745-756 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480181?dopt=Abstract %R 10.3233/JAD-170834 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Tau and Amyloid Positron Emission Tomography Imaging Predict Driving Performance Among Older Adults with and without Preclinical Alzheimer's Disease. %A Roe, Catherine M %A Babulal, Ganesh M %A Mishra, Shruti %A Gordon, Brian A %A Stout, Sarah H %A Ott, Brian R %A Carr, David B %A Ances, Beau M %A Morris, John C %A Benzinger, Tammie L S %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Automobile Driving %K Biomarkers %K Carbolines %K Female %K Humans %K Logistic Models %K Male %K Neuroimaging %K Positron-Emission Tomography %K tau Proteins %X

Abnormal levels of Alzheimer's disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving performance.

%B J Alzheimers Dis %V 61 %P 509-513 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171997?dopt=Abstract %R 10.3233/JAD-170521 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Plasma Phospholipid and Sphingolipid Alterations in Presenilin1 Mutation Carriers: A Pilot Study. %A Chatterjee, Pratishtha %A Lim, Wei L F %A Shui, Guanghou %A Gupta, Veer B %A James, Ian %A Fagan, Anne M %A Xiong, Chengjie %A Sohrabi, Hamid R %A Taddei, Kevin %A Brown, Belinda M %A Benzinger, Tammie %A Masters, Colin %A Snowden, Stuart G %A Wenk, Marcus R %A Bateman, Randall J %A Morris, John C %A Martins, Ralph N %K Adult %K Alzheimer Disease %K Apolipoproteins E %K Female %K Humans %K Linear Models %K Male %K Middle Aged %K Mutation %K Phospholipids %K Pilot Projects %K Presenilin-1 %K Sphingolipids %X

BACKGROUND AND OBJECTIVE: Aberrant lipid metabolism has been implicated in sporadic Alzheimer's disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD).

METHODS: Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman's correlation coefficient.

RESULTS: One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p <  0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p <  0.05).

CONCLUSION: These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort.

%B J Alzheimers Dis %V 50 %P 887-94 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836186?dopt=Abstract %R 10.3233/JAD-150948 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Spatial Navigation in Preclinical Alzheimer's Disease. %A Allison, Samantha L %A Fagan, Anne M %A Morris, John C %A Head, Denise %K Aged %K Alzheimer Disease %K Biomarkers %K Educational Status %K Female %K Humans %K Learning %K Male %K Neuropsychological Tests %K Prodromal Symptoms %K Psychomotor Performance %K ROC Curve %K Spatial Navigation %K tau Proteins %K User-Computer Interface %X

Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD.

%B J Alzheimers Dis %V 52 %P 77-90 %8 2016 02 09 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967209?dopt=Abstract %R 10.3233/JAD-150855 %0 Journal Article %J Arch Neurol %D 2012 %T Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. %A Head, Denise %A Bugg, Julie M %A Goate, Alison M %A Fagan, Anne M %A Mintun, Mark A %A Benzinger, Tammie %A Holtzman, David M %A Morris, John C %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E4 %K Brain %K Cognition %K Cohort Studies %K Exercise %K Female %K Genetic Association Studies %K Genotype %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Positron-Emission Tomography %K Regression Analysis %K Surveys and Questionnaires %K Thiazoles %X

OBJECTIVE: APOE ε4 status has been associated with greater cortical amyloid deposition, whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults.

DESIGN: APOE genotyping data and answers to a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) positron emission tomography. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association.

SETTING: Knight Alzheimer's Disease Research Center at Washington University, St Louis, Missouri.

PARTICIPANTS: A total of 201 cognitively normal adults (135 of whom were women) aged 45 to 88 years were recruited from the Knight Alzheimer's Disease Research Center. Samples of CSF were collected from 165 participants. Amyloid imaging was performed for 163 participants.

RESULTS: APOE ε4 carriers evidenced higher [(11)C]PiB binding (P<.001) and lower CSF Aβ42 levels (P<.001) than did noncarriers. Our previous findings of higher [(11)C]PiB binding (P=.005) and lower CSF Aβ42 levels (P=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for [(11)C]PiB binding (P=.008) such that a more sedentary lifestyle was significantly associated with higher [(11)C]PiB binding for ε4 carriers (P=.013) but not for noncarriers (P=.20). All findings remained significant after controlling for age; sex; educational level; body mass index; the presence or history of hypertension, diabetes mellitus, heart problems, or depression; and the interval between assessments.

CONCLUSION: Collectively, these results suggest that cognitively normal sedentary APOE ε4-positive individuals may be at augmented risk for cerebral amyloid deposition.

%B Arch Neurol %V 69 %P 636-43 %8 2012 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/22232206?dopt=Abstract %R 10.1001/archneurol.2011.845 %0 Journal Article %J Alzheimers Dement %D 2011 %T The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. %A McKhann, Guy M %A Knopman, David S %A Chertkow, Howard %A Hyman, Bradley T %A Jack, Clifford R %A Kawas, Claudia H %A Klunk, William E %A Koroshetz, Walter J %A Manly, Jennifer J %A Mayeux, Richard %A Mohs, Richard C %A Morris, John C %A Rossor, Martin N %A Scheltens, Philip %A Carrillo, Maria C %A Thies, Bill %A Weintraub, Sandra %A Phelps, Creighton H %K Alzheimer Disease %K Biomarkers %K Diagnosis, Differential %K Diagnostic Imaging %K Disease Progression %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K Societies, Medical %K United States %X

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

%B Alzheimers Dement %V 7 %P 263-9 %8 2011 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21514250?dopt=Abstract %R 10.1016/j.jalz.2011.03.005 %0 Journal Article %J Sci Transl Med %D 2011 %T Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. %A Castellano, Joseph M %A Kim, Jungsu %A Stewart, Floy R %A Jiang, Hong %A DeMattos, Ronald B %A Patterson, Bruce W %A Fagan, Anne M %A Morris, John C %A Mawuenyega, Kwasi G %A Cruchaga, Carlos %A Goate, Alison M %A Bales, Kelly R %A Paul, Steven M %A Bateman, Randall J %A Holtzman, David M %K Adult %K Aged %K Alleles %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Apolipoprotein E4 %K Biomarkers %K Brain %K Female %K Genotype %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microdialysis %K Middle Aged %K Protein Isoforms %X

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ(42) peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.

%B Sci Transl Med %V 3 %P 89ra57 %8 2011 Jun 29 %G eng %N 89 %1 http://www.ncbi.nlm.nih.gov/pubmed/21715678?dopt=Abstract %R 10.1126/scitranslmed.3002156 %0 Journal Article %J Ann Neurol %D 2010 %T APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. %A Morris, John C %A Roe, Catherine M %A Xiong, Chengjie %A Fagan, Anne M %A Goate, Alison M %A Holtzman, David M %A Mintun, Mark A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E2 %K Apolipoprotein E4 %K Apolipoproteins E %K Brain %K Female %K Follow-Up Studies %K Genotype %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Peptide Fragments %K Phosphorylation %K Plaque, Amyloid %K tau Proteins %K Thiazoles %X

OBJECTIVE: To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging.

METHODS: Two hundred forty-one cognitively normal individuals, aged 45-88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta(42) (Abeta(42)), tau, and phosphorylated tau (ptau(181)). All individuals were genotyped for APOE.

RESULTS: The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Abeta(42) appeared to begin earlier (18.2% of those aged 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Abeta(42) with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Abeta(42) levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau(181).

INTERPRETATION: Increasing cerebral Abeta deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Abeta deposition may first be lowered CSF Abeta(42), followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.

%B Ann Neurol %V 67 %P 122-31 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20186853?dopt=Abstract %R 10.1002/ana.21843 %0 Journal Article %J PLoS One %D 2010 %T Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. %A Jones, Lesley %A Holmans, Peter A %A Hamshere, Marian L %A Harold, Denise %A Moskvina, Valentina %A Ivanov, Dobril %A Pocklington, Andrew %A Abraham, Richard %A Hollingworth, Paul %A Sims, Rebecca %A Gerrish, Amy %A Pahwa, Jaspreet Singh %A Jones, Nicola %A Stretton, Alexandra %A Morgan, Angharad R %A Lovestone, Simon %A Powell, John %A Proitsi, Petroula %A Lupton, Michelle K %A Brayne, Carol %A Rubinsztein, David C %A Gill, Michael %A Lawlor, Brian %A Lynch, Aoibhinn %A Morgan, Kevin %A Brown, Kristelle S %A Passmore, Peter A %A Craig, David %A McGuinness, Bernadette %A Todd, Stephen %A Holmes, Clive %A Mann, David %A Smith, A David %A Love, Seth %A Kehoe, Patrick G %A Mead, Simon %A Fox, Nick %A Rossor, Martin %A Collinge, John %A Maier, Wolfgang %A Jessen, Frank %A Schürmann, Britta %A Heun, Reinhard %A Kölsch, Heike %A van den Bussche, Hendrik %A Heuser, Isabella %A Peters, Oliver %A Kornhuber, Johannes %A Wiltfang, Jens %A Dichgans, Martin %A Frölich, Lutz %A Hampel, Harald %A Hüll, Michael %A Rujescu, Dan %A Goate, Alison M %A Kauwe, John S K %A Cruchaga, Carlos %A Nowotny, Petra %A Morris, John C %A Mayo, Kevin %A Livingston, Gill %A Bass, Nicholas J %A Gurling, Hugh %A McQuillin, Andrew %A Gwilliam, Rhian %A Deloukas, Panos %A Al-Chalabi, Ammar %A Shaw, Christopher E %A Singleton, Andrew B %A Guerreiro, Rita %A Mühleisen, Thomas W %A Nöthen, Markus M %A Moebus, Susanne %A Jöckel, Karl-Heinz %A Klopp, Norman %A Wichmann, H-Erich %A Rüther, Eckhard %A Carrasquillo, Minerva M %A Pankratz, V Shane %A Younkin, Steven G %A Hardy, John %A O'Donovan, Michael C %A Owen, Michael J %A Williams, Julie %K Alzheimer Disease %K Apolipoproteins E %K Cholesterol %K Chromosome Mapping %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Immune System %K Polymorphism, Single Nucleotide %X

BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.

METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.

PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.

SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

%B PLoS One %V 5 %P e13950 %8 2010 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21085570?dopt=Abstract %R 10.1371/journal.pone.0013950