PRIYA PALTA, PHD, MHS
Assistant Professor of Medical Sciences and Epidemiology (in Medicine)

The objective of this talk is to provide a broad overview of the vascular contributions to brain health, with a specific focus on findings from the Atherosclerosis Risk in Communities (ARIC) Cohort Study, a prospective epidemiologic cohort study. With extensive characterization of behaviors, biomarkers, comorbidities, and other covariates, and their change over 30+ years, ARIC has contributed to our understanding of the role of mid- and late-life cardiovascular disease risk factors and modifiers on cognitive decline, dementia, and cerebral outcomes. Specifically, we will present findings from our study of the relationship between physical activity and changes in physical activity from mid-life on cognitive decline, dementia, and brain MRI markers.

JOSE GUTIERREZ, MD, MPH
Assistant Professor of Neurology

Brain arterial dilatation is an understudied phenotype that relates to vascular disease and dementia. We propose a change in the paradigm of brain large artery disease that goes beyond atherosclerosis and/or stenosis, and incorporates brain arterial dilatation as a distinct phenotype. We have shown that brain arterial diameters are associated non-linearly with cognition, so that individuals with narrowed or dilated brain arteries have poorer cognitive performance compared with those with average diameters. Brain arterial dilatation may occur with genetic syndromes, but it is unclear whether genetic predisposing factors exist in the general population. It is plausible that the mechanical effects of brain arterial dilatation over the distal arteriolar and capillary flow may disrupt cerebral autoregulation, and explain the relationship with parenchymal functions such as cognition. The role of brain arterial dilatation in Alzheimer dementia is the focus of recently awarded R01 and an incoming R01 submission.

GIUSEPPE TOSTO, MD, PHD
Assistant Professor of Neurology (in the Taub Institute and in the Gertrude H. Sergievsky Center)

Although the contribution of cerebrovascular disease to late-onset Alzheimer's disease (LOAD) has been debated, cerebrovascular disease is present in up to 70% of patients compared with only 15%-20% of healthy elderly at postmortem examination; mixed pathology is now considered a primary cause of Alzheimer's-related dementia. In particular, small vessel cerebrovascular disease (visualized by MRI as white matter hyperintensities - WMH) has been proved to be important in the context of LOAD. WMH severity predicts incident diagnosis, rate of cognitive decline in mild cognitive impairment and in LOAD, and increases risk for future development of LOAD.

We used data from a cross-sectional and longitudinal multiethnic community-based study to generate an MRI measure associated with episodic memory by combining WMH, infarcts, hippocampal volumes, and cortical thicknesses quantified from MRI. The combined MRI measure was replicated and validated using autopsy data, clinical diagnoses, cerebrospinal fluid biomarkers and amyloid PET.

PATRICK LAO, PHD
Postdoctoral Research Scientist Scientist in the Gertrude H. Sergievsky Center, the Brickman Laboratory

The aim of these analyses was to determine the relationships between amyloid and tau accumulation, atrophy, and cerebrovascular disease (CVD) in various stages of AD. Methods: The ADNI dataset was used to investigate amyloidosis, CVD, and neurodegeneration in normal controls (n=224), MCI (n=291), and AD (n=93) groups. In our dataset, we investigated tauopathy, CVD, and neurodegeneration in amyloid negative control (n=17), amyloid positive control (n=7), and amyloid positive MCI/AD groups (n=13). Scan acquisition is ongoing.

Results: In the ADNI dataset, higher amyloid and white matter hyperintensity (WMH) were independently associated with cortical thickness (CT), higher baseline WMH was associated with cortical thinning over time, and higher baseline WMH was associated with amyloid accumulation over time. In our dataset, tau was higher and CT was lower in amyloid positive MCI/AD compared to amyloid negative control. WMH increased with age, but was not different by groups. Currently, non-significant associations were positive between tau and WMH, negative between tau and CT, and negative between WMH and tau.

Conclusion: Amyloid, tau, and neurodegeneration biomarkers yield important insight into the classification and staging of AD. However, CVD biomarkers have been shown to play a role in a well-characterized cohort and should be explicitly considered in AD studies.

DAPHNA SHOHAMY, PHD
Professor of Psychology

From robots to humans, the ability to learn from experience turns a rigid response system into a flexible, adaptive one. This lecture will discuss the neural and cognitive mechanisms by which memory shapes behavior. The lecture will focus on how interactions between the hippocampus and striatum support learning and memory, and the consequences for how decisions are made. Results emerging from this work challenge the traditional view of separate learning systems and advance understanding of how memory biases decisions in both adaptive and maladaptive ways.

YUNGLIN ELAINE GAZES, PHD
Assistant Professor of Neuropsychology (in Neurology and the Taub Institute)

I will provide a brief introduction of an increasingly popular MRI technique for quantifying the microstructure of the brain called diffusion weighted imaging (DWI). Some popular models of DWI will be discussed, and in particular, a weakness in the popular DTI model will be presented while also recommending more accurate models to adopt. For my own research, I will discuss how DWI is used to understand why some cognitive abilities decline with age but others remain stable until past 60 years of age. I will also be requesting collaboration to examine the relationship between diffusivity and histology measures from post mortem brains in order to understand if and how DWI reflects the underlying brain microstructure in vivo.

SABRINA ALVES SIMOES SPASSOV, PHD
Associate Research Scientist in the Taub Institute, the Scott Small Laboratory

Anatomical studies have pinpointed a specific subregion of the brain selectively vulnerable to Alzheimer's disease (AD). Molecular studies have identified endosomal trafficking defects as a cell biological driver of AD. Whether and how endosomal trafficking links to anatomical vulnerability remains unknown. Here we address these questions by investigating multiple mouse models deficient in different components of retromer, a protein assembly that is central to endosomal trafficking. We first established that, more than any other cells, neurons are enriched with a functionally distinct retromer that is dedicated to endosomal recycling. Second, we find that depleting the neuronal-enriched retromer caused preferential dysfunction in the specific subregion vulnerable to AD, the transenthorinal cortex (TEC). Our studies suggest that this preferential targeting can be in part explained by a distinct expression profile of retromer and other related proteins dedicated to endosomal recycling. Finally, given the known vulnerability of this region in AD, we are currently finishing a set of fMRI and biochemical studies to further investigate if a similar phenomena is happening in AD brains. Together with other recent findings our results suggest a unified mechanism for disease vulnerability.

NEHA S. RAGHAVAN, PHD
Postdoctoral Research Fellow in the Gertrude H. Sergievsky Center, the Richard Mayeux Laboratory

The genetic bases of late-onset Alzheimer's disease remain uncertain. Our goal was to identify and characterize the frequency and impact of ultra-rare variants in late-onset Alzheimer's disease using whole-exome sequencing in 20,197 individuals. We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design. We identified 19 cases carrying extremely rare SORL1 loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls (p = 2.17 x 10-8; OR 36.2 [95%CI 5.8 - 1493.0]). Age-at-onset was nearly seven years earlier for patients with SORL1 qualifying variant compared with non-carriers. This study implicates ultra-rare, loss-of-function variants in SORL1 as a significant genetic risk factor for late-onset Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in LOAD cases and controls.

ELEANNA VARANGIS BURNS, PHD
Postdoctoral Research Scientist in the Gertrude H. Sergievsky Center, the Yaakov Stern Laboratory

Research on the cognitive neuroscience of aging has identified myriad neurocognitive processes that are affected by the aging process, with a focus on identifying brain-based biomarkers of cognitive impairment in aging. The present study aimed to test whether inter-network connectivity among 6 cognitive networks is sensitive to age-related changes in neural efficiency and cognitive functioning. A factor analytic connectivity approach was used to model network interactions during 11 cognitive tasks grouped into 4 primary cognitive domains: vocabulary, perceptual speed, fluid reasoning, and episodic memory. Results showed that both age and task domain were related to inter-network connectivity, and that some of the connections among the networks were associated with performance on the in-scanner tasks. These findings show that inter-network connectivity among several cognitive networks is not only affected by aging and task demands, but also shows a relationship with task performance. As such, future studies examining inter-network connectivity in aging should consider multiple networks, and multiple task conditions, in order to better measure dynamic patterns of network flexibility over the course of cognitive aging.

YIYI MA, PHD
Postdoctoral Research Scientist, the Philip De Jager Laboratory

Background: RNA processing is disrupted in a specific, reproducible manner in Alzheimer's disease (AD). We conducted a study to compare the differences in RNA editing events across brain regions and evaluate whether they are affected by AD.

Method: We used RNAseq data of 630 unpaired dorsolateral prefrontal cortex (DLPFC) samples from participants in the Religious Order Study and the Memory and Aging Project (ROSMAP); 204 paired ROSMAP samples of DLPFC, anterior and posterior cingulate cortex; 568 paired samples of brain regions of BM10, BM22, BM36, and BM44 from Mount Sinai Brain Bank (MSBB); and 458 paired samples of temporal cortex and cerebellum from Mayo RNAseq Stusy (MAYO). Edited RNA sites were called by GATK. We filtered those events with <10% frequency. Logistic and linear regressions were applied for the association analysis of AD risk and pathologies.

Result: Different brain regions are similar in both the number of called events and average level of editing across all the subjects. For the differential regional tests within each paired datasets, we did not observe any editing events with significant fold change greater than 2 for ROSMAP and MSBB, and in MAYO, only two out of total common 26,169 events with significant fold change greater than 2. Using unpaired ROSMAP as discovery and paired datasets as replication, we have identified ORAI2 editing with AD status in all subjects (P=4.6E-06 and 6.2E-04 for discovery and replication in MAYO Cerebellum), and 2 loci associated with AD status in female, which are located at SYT11 (P=1.7E-06, 7.4E-5 and 0.04 in discovery, replication in MAYO temporal cortex and MSBB BM44) and SOD1 (P=4.3E-06 and ≤0.01 in discovery and replication in MAYO temporal cortex, MSBB BM44, and ROSMAP paired datasets). Mediation analysis suggested that ORAI2 influences the deposition of neuritic amyloid plaques which then contributes to the cascade of Tau accumulation and cognitive decline.

Conclusion: Besides RNA splicing, our results suggest the enrichment of RNA editing events in AD patients and some potential target loci, which are necessary for further replications and validations.

CATHERINE COOK KACZOROWSKI, PHD
Associate Professor, Evnin Family Chair in Alzheimer's Research, the Jackson Laboratory

An individual's genetic makeup plays a large role in determining susceptibility to Alzheimer's disease (AD), but has largely been ignored in preclinical studies. To test the hypothesis that incorporating genetic diversity into mouse models of AD would improve translational potential, we combined a well-established mouse model of AD with a genetically diverse reference panel to generate mice that harbor identical high-risk human mutations but differ across the remainder of their genome. We first show that genetic variation profoundly modifies the impact of human AD mutations on both cognitive and pathological phenotypes. We then validate this panel as an AD model by demonstrating high degree of genetic, transcriptomic, and phenotypic overlap with human AD. Overall, work here both introduces a novel AD mouse population as an innovative and reproducible resource for the study of mechanisms underlying AD and provides evidence that preclinical models incorporating genetic diversity may better translate to human disease.

ELIZABETH BRADSHAW, PHD
Adler Assistant Professor of Neurological Sciences (in Neurology, the Taub Institute, and the Institute for Genomic Medicine)

Genome-wide association studies have identified and validated several genes, such as CD33, associated with AD susceptibility that directly implicate the innate immune system. CD33 is expressed on the surface of innate immune cells. We demonstrated that individuals with the Alzheimer’s disease-associated risk genotype have increased expression of CD33 on the surface of their innate immune cells compared to those with the protective genotype. The risk allele is also associated with diminished internalization of amyloid-β1-42 peptide and accumulation fibrillar amyloid on in vivo imaging. An intronic variant in TREM1, another myeloid-specific gene that leads to decreased expression of TREM1 on the cell surface of myeloid cells, is associated with an increased burden of neuritic amyloid plaques and more rapid cognitive decline. TREM1 has been identified as an amplifier of the immune response and also associated with protection from apoptosis. The combination of our work looking at CD33 and TREM1 suggest that the genetic risk leads to a more suppressed phenotype of innate immune cells (increased CD33, a suppressive molecule and a decrease of TREM1, an activating molecule).

GUNNAR HARGUS, MD, PHD
Assistant Professor of Pathology and Cell Biology

Frontotemporal dementia (FTD) is a frequent form of early-onset dementia and can be caused by mutations in MAPT encoding the microtubule-associated protein TAU. Because of limited availability of neural cells from patients' brains, the underlying mechanisms of neurodegeneration in FTD are poorly understood. We have derived induced pluripotent stem cells (iPSCs) from individuals with FTD-associated MAPT mutations and have differentiated them into mature neurons and astrocytes using optimized differentiation protocols. Patient iPSC-derived neurons demonstrated pronounced TAU pathology with increased fragmentation and phospho-TAU immunoreactivity, decreased neurite extension, and increased but reversible oxidative stress response to inhibition of mitochondrial respiration. Patient iPSC-derived astrocytes expressed increased levels of 4R-TAU isoforms, also demonstrated increased vulnerability to oxidative stress and induced apoptosis in previously healthy neurons when co-cultured over a period of several weeks. Our studies highlight the utility of patient iPSCs to elucidate the role of neurons and astrocytes in the pathogenesis of FTD.

ALEJANDRO CHAVEZ, MD, PHD
Assistant Professor of Pathology and Cell Biology

Construction of genetic variant libraries with phenotypic measurement is central to advancing today's functional genomics and remains a grand challenge. Here, we introduce a Cas9-based approach for generating pools of mutants with defined genetic alterations (deletions, substitutions, and insertions), along with methods for tracking their fitness en masse. Our platform allows fundamental biology questions to be investigated in a quick, easy, and affordable manner.