Shengmei Ma

Anti-Tau Antibodies that Block Tau Aggregate Seeding In Vitro Markedly Decrease Pathology and Improve Cognition In Vivo

Tau aggregation occurs in neurodegenerative diseases including Alzheimers disease and many other disorders collectively termed tauopathies. trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.

Age and amyloid effects on human central nervous system amyloid-beta kinetics.

Age is the single greatest risk factor for Alzheimers disease (AD), with the incidence doubling every 5 years after age 65. However, our understanding of the mechanistic relationship between increasing age and the risk for AD is currently limited. We therefore sought to determine the relationship between age, amyloidosis, and amyloid‐beta (Aβ) kinetics in the central nervous system (CNS) of humans.

Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease

Objective: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD). Methods: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years ± 0.92, range 0.89–4.19) after controlling for estimated years from expected symptom onset, APOE ε4 allelic status, and education. Results: In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination. Conclusions: Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials.

Factors Associated With the Onset and Persistence of Post-Lumbar Puncture Headache

IMPORTANCE This study assesses factors associated with the most common adverse event following lumbar puncture. OBJECTIVE To identify factors associated with the risk, onset, and persistence of post-dural puncture headache (PDPH). DESIGN, SETTING, AND PARTICIPANTS We performed univariate and multivariable analyses of 338 lumbar punctures in the Dominantly Inherited Alzheimer Network observational study using linear mixed models, adjusting for participant-level and family-level random effects. MAIN OUTCOMES AND MEASURES We directly evaluated associations of 3 post-lumbar puncture outcomes (immediate postprocedural headache, PDPH at 24-hour follow-up, and PDPH receiving a therapeutic blood patch) with participant age and sex, positioning, collection method, needle size, needle insertion site, and cerebrospinal fluid (CSF) volume collected. RESULTS The incidence of adverse events included 73 immediate postprocedural headaches (21.6%), 59 PDPHs at 24-hour follow-up (17.5%), and 15 PDPHs receiving a therapeutic blood patch (4.4%). Greater volume of CSF collected was associated with increased risk of immediate postprocedural headache, largely owing to a nonlinear increase in risk on collection of volumes above 30 mL (odds ratio, 3.73 for >30 mL and 0.98 for <17 mL). In contrast, collection of higher volumes showed a protective effect in decreasing rates of PDPH at 24-hour follow-up and rates of PDPH receiving a therapeutic blood patch (odds ratio, 0.35 per 10 mL). Although differences in needle size did not reach statistical significance, no participant in the 24G needle group received a therapeutic blood patch compared to 8 of 253 for the larger 22G needles. CONCLUSIONS AND RELEVANCE Factors that acutely lower CSF pressure (eg, seated positioning or extracting very high volumes of CSF) may be associated with transient post-lumbar puncture headache, without increasing rates of persistent PDPH or therapeutic blood patch. Collection of up to 30 mL of CSF appears to be well tolerated and safe.

Role of ABCA7 loss-of-function variant in Alzheimer's disease: a replication study in European-Americans

IntroductionA recent study found a significant increase of ABCA7 loss-of-function variants in Alzheimer’s disease (AD) cases compared to controls. Some variants were located on noncoding regions, but it was demonstrated that they affect splicing. Here, we try to replicate the association between AD risk and ABCA7 loss-of-function variants at both the single-variant and gene level in a large and well-characterized European American dataset.MethodsWe genotyped the GWAS common variant and four rare variants previously reported for ABCA7 in 3476 European–Americans.ResultsWe were not able to replicate the association at the single-variant level, likely due to a lower effect size on the European American population which led to limited statistical power. However, we did replicate the association at the gene level; we found a significant enrichment of ABCA7 loss-of-function variants in AD cases compared to controls (P = 0.0388; odds ratio =1.54). We also confirmed that the association of the loss-of-function variants is independent of the previously reported genome-wide association study signal.ConclusionsAlthough the effect size for the association of ABCA7 loss-of-function variants with AD risk is lower in our study (odds ratio = 1.54) compared to the original report (odds ratio = 2.2), the replication of the findings of the original report provides a stronger foundation for future functional applications. The data indicate that different independent signals that modify risk for complex traits may exist on the same locus. Additionally, our results suggest that replication of rare-variant studies should be performed at the gene level rather than focusing on a single variant.

Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits

Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes, and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels, and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r, and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects, and complex disease associations in the same locus.

SORL1 variants across Alzheimer's disease European American cohorts.

The accumulation of the toxic Aβ peptide in Alzheimer’s disease (AD) largely relies upon an efficient recycling of amyloid precursor protein (APP). Recent genetic association studies have described rare variants in SORL1 with putative pathogenic consequences in the recycling of APP. In this work, we examine the presence of rare coding variants in SORL1 in three different European American cohorts: early-onset, late-onset AD (LOAD) and familial LOAD.

Age and Amyloid Effects on Human CNS Amyloid-Beta Kinetics

Age is the single greatest risk factor for Alzheimers disease (AD), with the incidence doubling every 5 years after age 65. However, our understanding of the mechanistic relationship between increasing age and the risk for AD is currently limited. We therefore sought to determine the relationship between age, amyloidosis, and amyloid‐beta (Aβ) kinetics in the central nervous system (CNS) of humans.

CEREBROSPINAL FLUID ENDOPHENOTYPES PROVIDE INSIGHT INTO BIOLOGY UNDERLYING ALZHEIMER'S DISEASE

REGULATION_OF_AXONOGENESIS >10 >10 CDC42_PROTEIN_SIGNAL_TRANSDUCTION >10 >10 REGULATION_OF_NEUROGENESIS >10 6.97310 REGULATION_OF_SYNAPSE_STRUCTURE_AND_ACTIVITY >10 8.67310 LEARNING_AND_OR_MEMORY 2.40310 5.02310 REGULATION_OF_ANATOMICAL_STRUCTURE_MORPHOGENESIS 6.05310 7.05310 HOMOPHILIC_CELL_ADHESION 1.07310 7.92310 PROTEIN_TETRAMERIZATION 8.73310 1.65310 LIPID_HOMEOSTASIS 1.62310 3.02310 NEURITE_DEVELOPMENT 1.62310 3.69310 AXONOGENESIS 2.51310 3.69310 NEURON_DIFFERENTIATION 1.94310 3.46310 NEURON_DEVELOPMENT 1.94310 4.99310 GENERATION_OF_NEURONS 2.70310 1.41310 CELLULAR_MORPHOGENESIS_DURING_DIFFERENTIATION 3.11310 5.10310 CELL_CELL_ADHESION 4.35310 9.45310 PROTEIN_DIMERIZATION_ACTIVITY 4.79310 5.10310 NEUROGENESIS 1.16310 1.85310 PHOSPHOLIPID_BINDING 1.26310 9.98 310 PROTEIN_HOMODIMERIZATION_ACTIVITY 9.38 310 7.12 310 Podium Presentations: Sunday, July 16, 2017 P218

SORL1 VARIANTS ACROSS ALZHEIMER’S DISEASE COHORTS IN EUROPEAN AMERICANS

novel SNVs in ABCA7 (p-value1⁄4 2.6310) and EFTUD1 (p-value 1⁄4 4.9310), and a novel SNV downstream of BIN1 (p-value 1⁄4 5.4310). Conclusions: Conditional and joint analyses of IGAP Stage I data identified three novel loci, two in previously identified genes and one in a gene not previously identified as being associated with LOAD risk. Replication results with IGAP Stage II data were consistent with the initial findings.