Optimal likelihood-ratio multiple testing with application to Alzheimer’s disease and questionable dementia

Test scores from a comprehensive neuropsychological battery administered to 1602 subjects consisting of 1347 subjects with probable Alzheimer's disease (AD), 100 subjects with questionable dementia (QD) and 155 non-demented elderly control subjects were cross-sectionally analyzed. Subjects with probable AD were categorized as mild (n = 244), moderate (n = 480), severe (n = 376), and very severe (n = 247) according to modified mini mental status exam (mMMSE) scores. Mean scores on individual neuropsychological tests are provided for each group of subjects. Stratified random sampling was performed to select a sample of mild AD subjects who were matched in age and education to non-demented elderly controls, and analyses focused on the performance of QD subjects and mild AD subjects, whose scores were compared to those of the elderly control subjects. Selected scores were organized by cognitive domain and logistic regressions were used to determine the domains and individual tests within each that were most predictive of group status. Results suggested a profile of scores associated with QD and mild AD including impaired recall of verbal information for both groups. Areas of lower functioning in QD subjects as compared to elderly controls included category fluency and visuospatial ability. (JINS, 2003, 9, 720–732.)

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Likelihood ratio statistics for gene set enrichment in Alzheimer's disease pathways

Alzheimer s & Dementia ◽

10.1002/alz.12223 ◽

2021 ◽

Author(s):

Jordan Bryan ◽

Arpita Mandan ◽

Gauri Kamat ◽

W. Kirby Gottschalk ◽

Alexandra Badea ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Likelihood Ratio ◽

Gene Set Enrichment ◽

Gene Set ◽

Likelihood Ratio Statistics ◽

Disease Pathways

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A Two-Study Comparison of Clinical and MRI Markers of Transition from Mild Cognitive Impairment to Alzheimer’s Disease

International Journal of Alzheimer s Disease ◽

10.1155/2012/483469 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

D. P. Devanand ◽

Xinhua Liu ◽

Patrick J. Brown ◽

Edward D. Huey ◽

Yaakov Stern ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cohort Study ◽

Entorhinal Cortex ◽

Verbal Memory ◽

Area Under The Curve ◽

Predictive Utility ◽

Predictor Model ◽

Questionable Dementia ◽

And Function

A published predictor model in a single-site cohort study (questionable dementia, QD) that contained episodic verbal memory (SRT total recall), informant report of function (FAQ), and MRI measures was tested using logistic regression and ROC analyses with comparable measures in a second multisite cohort study (Alzheimer’s Disease Neuroimaging Initiative, ADNI). There were 126 patients in QD and 282 patients in ADNI with MCI followed for 3 years. Within each sample, the differences in AUCs between the statistical models were very similar. Adding hippocampal and entorhinal cortex volumes to the model containing AVLT/SRT, FAQ, age and MMSE increased the area under the curve (AUC) in ADNI but not QD, with sensitivity increasing by 2% in ADNI and 2% in QD for a fixed specificity of 80%. Conversely, adding episodic verbal memory (SRT/AVLT) and FAQ to the model containing age, Mini Mental State Exam (MMSE), hippocampal and entorhinal cortex volumes increased the AUC in ADNI and QD, with sensitivity increasing by 17% in ADNI and 10% in QD for 80% specificity. The predictor models showed similar differences from each other in both studies, supporting independent validation. MRI hippocampal and entorhinal cortex volumes showed limited added predictive utility to memory and function measures.

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Manifestations of genetic risk for Alzheimer’s Disease in the blood: a cross-sectional multi-omic analysis in healthy adults aged 18-90+

10.1101/2021.03.26.437267 ◽

2021 ◽

Author(s):

Laura Heath ◽

John C. Earls ◽

Andrew T. Magis ◽

Sergey A. Kornilov ◽

Jennifer C. Lovejoy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Genetic Variants ◽

Genetic Risk ◽

Multiple Testing ◽

Large Scale ◽

Genome Wide Association Study ◽

Cross Sectional ◽

Risk Variants

AbstractDeeply phenotyped cohort data can elucidate differences associated with genetic risk for common complex diseases across an age spectrum. Previous work has identified genetic variants associated with Alzheimer’s disease (AD) risk from large-scale genome-wide association study meta-analyses. To explore effects of known AD-risk variants, we performed a phenome-wide association study on ~2000 clinical, proteomic, and metabolic blood-based analytes obtained from 2,831 cognitively normal adult clients of a consumer-based scientific wellness company. Results uncovered statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE). These effects were detectable from early adulthood. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. Sex-stratified GWAS results from an independent AD case-control meta-analysis supported sexspecific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. These analyses support evidence from previous functional genomics studies in the identification of a causal variant within the PILRA gene. Taken together, this study highlights clues to the earliest effects of AD genetic risk variants in individuals where disease symptoms have not (yet) arisen.

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Large-scale proteome analysis of CSF implicates altered glucose metabolism in Alzheimer's disease

10.1101/2021.09.02.21262642 ◽

2021 ◽

Author(s):

Daniel J. Panyard ◽

Justin McKetney ◽

Yuetiva K. Deming ◽

Autumn R. Morrow ◽

Gilda E. Ennis ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Multiple Testing ◽

Large Scale ◽

Csf Biomarkers ◽

Multiple Testing Correction ◽

Comparative Performance ◽

Amyloid A ◽

Altered Glucose ◽

Associated Proteins

A major hallmark of Alzheimer's disease (AD) is the aggregation of misfolded proteins (β-amyloid (A) and hyperphosphorylated tau (T)) in the brain. As these proteins can be monitored by cerebrospinal fluid (CSF) measures, the AD proteome in CSF has been of particular interest. Here, we conducted a proteome-wide assessment of the CSF in an AD cohort among participants with and without AD pathology (n = 137 total participants: 56 A-T-, 39 A+T-, and 42 A+T+; 915 proteins analyzed), identifying a diverse set of proteins in the CSF enriched for extracellular and immune system processes. We then interrogated the proteome using the amyloid, tau, and neurodegeneration (ATN) framework of AD and a panel of 9 CSF biomarkers for neurodegeneration and neuroinflammation. After multiple testing correction, we identified a total of 61 proteins significantly associated with AT group (P < 5.46 x 10-5; strongest was SMOC1, P = 1.87 x 10-12) and 636 significant protein-biomarker associations (P < 6.07 x 10-6; strongest was a positive association between neurogranin and EPHA4, P = 2.42 x 10-25) across all measures except for interleukin-6, which had no significantly associated proteins. Community network and pathway enrichment analyses highlighted three biomarker-associated protein networks: one related to amyloid and tau measures, one to CSF neurogranin, and one to the remaining CSF biomarkers. Glucose metabolic pathways were enriched primarily among the amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, both of which were replicated as strongly associated with AD (P = 1.07 x 10-19 and P = 7.43 x 10-14, respectively) in an independent CSF proteomics cohort (n = 717 participants). Comparative performance of the CSF proteome in predicting AT categorization was high (mean AUC range 0.891-0.924 with number of protein predictors ranging from 37-97) relative to other omic predictors from the genome, CSF metabolome, and demographics from the same cohort of individuals. Collectively, these results emphasize the importance of the CSF proteome relative to other omics and implicate glucose metabolic dysregulation as amyloid and tau pathology emerges in AD.

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Polymorphism C in the serotonin transporter gene (SLC6A4) in questionable dementia and Alzheimer's disease

Neuroscience Letters ◽

10.1016/j.neulet.2008.04.076 ◽

2008 ◽

Vol 438 (3) ◽

pp. 335-339 ◽

Cited By ~ 5

Author(s):

Davide Seripa ◽

Marilisa Franceschi ◽

Grazia D’Onofrio ◽

Francesco Panza ◽

Leandro Cascavilla ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Serotonin Transporter ◽

Serotonin Transporter Gene ◽

Transporter Gene ◽

Questionable Dementia

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Different Inflammatory Signatures in Alzheimer’s Disease and Frontotemporal Dementia Cerebrospinal Fluid

Journal of Alzheimer s Disease ◽

10.3233/jad-201565 ◽

2021 ◽

pp. 1-12

Author(s):

Gustaf Boström ◽

Eva Freyhult ◽

Johan Virhammar ◽

Daniel Alcolea ◽

Hayrettin Tumani ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Frontotemporal Dementia ◽

Multiple Testing ◽

Current Knowledge ◽

Inflammatory Marker ◽

Cross Sectional ◽

Csf Levels ◽

Multi Center Study

Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing. Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95%confidence interval [CI] 1.14–1.53, q = 0.018; MCI/AD: FC = 1.53, 95%CI 1.20–1.94, q = 0.045; and FTD: FC = 1.42, 95%CI 1.10–1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05). Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.

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Genome-wide screen to identify genetic loci associated with cognitive decline in late-life depression

International Psychogeriatrics ◽

10.1017/s1041610220001143 ◽

2020 ◽

pp. 1-9

Author(s):

D. C. Steffens ◽

M. E. Garrett ◽

K. L. Soldano ◽

D. R. McQuoid ◽

A. E. Ashley-Koch ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Multiple Testing ◽

Academic Medical Center ◽

Late Life ◽

Late Life Depression ◽

Gwas Analysis ◽

Genome Wide ◽

A Genome

ABSTRACT Objective: This study sought to conduct a comprehensive search for genetic risk of cognitive decline in the context of geriatric depression. Design: A genome-wide association study (GWAS) analysis in the Neurocognitive Outcomes of Depression in the Elderly (NCODE) study. Setting: Longitudinal, naturalistic follow-up study. Participants: Older depressed adults, both outpatients and inpatients, receiving care at an academic medical center. Measurements: The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery was administered to the study participants at baseline and a minimum of twice within a subsequent 3-year period in order to measure cognitive decline. A GWAS analysis was conducted to identify genetic variation that is associated with baseline and change in the CERAD Total Score (CERAD-TS) in NCODE. Results: The GWAS of baseline CERAD-TS revealed a significant association with an intergenic single-nucleotide polymorphism (SNP) on chromosome 6, rs17662598, that surpassed adjustment for multiple testing (p = 3.7 × 10−7; false discovery rate q = 0.0371). For each additional G allele, average baseline CERAD-TS decreased by 8.656 points. The most significant SNP that lies within a gene was rs11666579 in SLC27A1 (p = 1.1 × 10−5). Each additional copy of the G allele was associated with an average decrease of baseline CERAD-TS of 4.829 points. SLC27A1 is involved with processing docosahexaenoic acid (DHA), an endogenous neuroprotective compound in the brain. Decreased levels of DHA have been associated with the development of Alzheimer’s disease. The most significant SNP associated with CERAD-TS decline over time was rs73240021 in GRXCR1 (p = 1.1 × 10−6), a gene previously linked with deafness. However, none of the associations within genes survived adjustment for multiple testing. Conclusions: Our GWAS of cognitive function and decline among individuals with late-life depression (LLD) has identified promising candidate genes that, upon replication in other cohorts of LLD, may be potential biomarkers for cognitive decline and suggests DHA supplementation as a possible therapy of interest.

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Functional decline in the elderly with MCI: Cultural adaptation of the ADCS-ADL scale

Revista da Associação Médica Brasileira ◽

10.1590/1806-9282.63.07.590 ◽

2017 ◽

Vol 63 (7) ◽

pp. 590-599 ◽

Cited By ~ 2

Author(s):

Fabiana Carla Matos da Cunha Cintra ◽

Marco Túlio Gualberto Cintra ◽

Rodrigo Nicolato ◽

Laiss Bertola ◽

Rafaela Teixeira Ávila ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Likelihood Ratio ◽

Predictive Value ◽

Functional Decline ◽

Positive Likelihood Ratio ◽

Negative Likelihood Ratio ◽

Control Group ◽

P Value ◽

Cognitive Screening

Summary Objective: Translate, transcultural adaptation and application to Brazilian Portuguese of the Alzheimer’s Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale as a cognitive screening instrument. Method: We applied the back translation added with pretest and bilingual methods. The sample was composed by 95 elderly individuals and their caregivers. Thirty-two (32) participants were diagnosed as mild cognitive impairment (MCI) patients, 33 as Alzheimer’s disease (AD) patients and 30 were considered as cognitively normal individuals. Results: There were only little changes on the scale. The Cronbach alpha coefficient was 0.89. The scores were 72.9 for control group, followed by MCI (65.1) and by AD (55.9), with a p-value < 0.001. The ROC curve value was 0.89. We considered a cut point of 72 and we observed a sensibility of 86.2%, specificity of 70%, positive predictive value of 86.2%, negative predictive value of 70%, positive likelihood ratio of 2.9 and negative likelihood ratio of 0.2. Conclusion: ADCS-ADL scale presents satisfactory psychometric properties to discriminate between MCI, AD and normal cognition.

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