Kacie Deters

Plasma Tau Association with Brain Atrophy in Mild Cognitive Impairment and Alzheimer’s Disease

BACKGROUND Peripheral (plasma) and central (cerebrospinal fluid, CSF) measures of tau are higher in Alzheimers disease (AD) relative to prodromal stages and controls. While elevated CSF tau concentrations have been shown to be associated with lower grey matter density (GMD) in AD-specific regions, this correlation has yet to be examined for plasma in a large study. OBJECTIVE Determine the neuroanatomical correlates of plasma tau using voxel-based analysis. METHODS Cross-sectional data for 508 ADNI participants were collected for clinical, plasma total-tau (t-tau), CSF amyloid (Aβ42) and tau, and MRI variables. The relationship between plasma tau and GMD and between CSF t-tau and GMD were assessed on a voxel-by-voxel basis using regression models. Age, sex, APOEɛ4 status, diagnosis, and total intracranial volume were used as covariates where appropriate. Participants were defined as amyloid positive (Aβ+) if CSF Aβ42 was <192 pg/mL. RESULTS Plasma tau was negatively correlated with GMD in the medial temporal lobe (MTL), precuneus, thalamus, and striatum. The associations with thalamus and striatum were independent of diagnosis. A negative correlation also existed between plasma tau and GMD in Aβ+ participants in the MTL, precuneus, and frontal lobe. When compared to CSF t-tau, plasma tau showed a notably different associated brain atrophy pattern, with only small overlapping regions in the fusiform gyrus. CONCLUSION Plasma tau may serve as a non-specific marker for neurodegeneration but is still relevant to AD considering low GMD was associated with plasma tau in Aβ+ participants and not Aβ-participants.

Genome-wide association study of language performance in Alzheimer’s disease

HighlightsWe identified novel genetic variants associated with language performance.Minor allele variants in GLI3 are associated with worse language performance.Anatomical changes in language regions associated with language composite score.Developmental and glutamate pathways were related to lower language performance. Abstract Language impairment is common in prodromal stages of Alzheimer’s disease (AD) and progresses over time. However, the genetic architecture underlying language performance is poorly understood. To identify novel genetic variants associated with language performance, we analyzed brain MRI and performed a genome‐wide association study (GWAS) using a composite measure of language performance from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 1560). The language composite score was associated with brain atrophy on MRI in language and semantic areas. GWAS identified GLI3 (GLI family zinc finger 3) as significantly associated with language performance (p < 5 × 10−8). Enrichment of GWAS association was identified in pathways related to nervous system development and glutamate receptor function and trafficking. Our results, which warrant further investigation in independent and larger cohorts, implicate GLI3, a developmental transcription factor involved in patterning brain structures, as a putative gene associated with language dysfunction in AD.

VISUAL LEARNING ON THE COGSTATE BATTERY IS ASSOCIATED WITH AMYLOID, TAU, AND NEURODEGENERATION IN COGNITIVELY NORMAL OLDER ADULTS

Frontal lobe 0.27 0.51 0.46 0.04 0.46 0.20 Parietal lobe 0.25 0.51 0.38 -0.04 0.36 0.20 Temporal lobe 0.28 0.56 0.51 0.16 0.52 0.33 Occipital lobe 0.25 0.38 0.47 0.19 0.33 0.21 Precuneus 0.21 0.58 0.54 0.01 0.51 0.20 Ant Cingulate 0.25 0.47 0.55 0.20 0.57* 0.21 Post Cingulate 0.38 0.56 0.68* 0.33 0.65* 0.39 Cerebellar gray 0.26 0.43 0.46 0.11 0.46 0.26 Hippocampus 0.65* 0.53 0.74* 0.79* 0.65* 0.62*

ASSOCIATION OF [18F]AV-1451 TAU MARKERS WITH COGNITIVE AND NEURODEGENERATION MEASURES: PRELIMINARY ANALYSIS IN THE ADNI COHORT

P1-261 ASSOCIATION OF [F]AV-1451 TAU MARKERS WITH COGNITIVE AND NEURODEGENERATION MEASURES: PRELIMINARYANALYSIS IN THE ADNI COHORT Shannon L. Risacher, Kacie Deters, Adam J. Schwarz, Sergey Shcherbinin, John D. West, William J. Jagust, Clifford R. Jack, Jr., Michael W. Weiner, Andy J. Saykin, Alzheimer’s Disease Neuroimaging Initiative, Indiana Alzheimer Disease Center, Indianapolis, IN, USA; 2 Indiana University School of Medicine, Indianapolis, IN, USA; Eli Lilly and Company, Indianapolis, IN, USA; University of California Berkeley, Berkeley, CA, USA; Mayo Clinic, Rochester, MN, USA; 6 University of California, San Francisco, San Francisco, CA, USA. Contact e-mail: srisache@iupui.edu

Gwas identifies gli3 as a novel gene for language deficits and cortical changes in older adults at-risk for Alzheimer’s disease

than mice with APP or tau expression (Figure). The cognitive deficits developed well before the first plaques or pre-tangles and coincided with changes in parvalbumin-positive (PV) interneurons and PV plexus in the dentate gyrus (DG) of the hippocampus. Disruption of this inhibitory circuit was followed by progressive and selective neurodegeneration of DG, a phenomena that was not observed in mice expressing single APP or tau. Conclusions:Data on MAO tTa:APPsi model indicate that starting as early as middle age, sensitivity to toxic effects of Ab appears to increase. Using the same MAO approach, we show that co-expression of APP and tau augments cognitive deficits and results in neurodegeneration of DG. PV interneurons of DG did not produce APP or tau, however appeared to have high vulnerability to the effects of APP and tau initiating the cascade that culminated in neurodegeneration of dentate granule cells.