Theresa M. Harrison

An Alzheimer's Disease Genetic Risk Score Predicts Longitudinal Thinning of Hippocampal Complex Subregions in Healthy Older Adults.

Abstract Variants at 21 genetic loci have been associated with an increased risk for Alzheimer’s disease (AD). An important unresolved question is whether multiple genetic risk factors can be combined to increase the power to detect changes in neuroimaging biomarkers for AD. We acquired high-resolution structural images of the hippocampus in 66 healthy, older human subjects. For 45 of these subjects, longitudinal 2-year follow-up data were also available. We calculated an additive AD genetic risk score for each participant and contrasted this with a weighted risk score (WRS) approach. Each score included APOE (apolipoprotein E), CLU (clusterin), PICALM (phosphatidylinositol binding clathrin assembly protein), and family history of AD. Both unweighted risk score (URS) and WRS correlated strongly with the percentage change in thickness across the whole hippocampal complex (URS: r = −0.40; p = 0.003; WRS: r = −0.25, p = 0.048), driven by a strong relationship to entorhinal cortex thinning (URS: r = −0.35; p = 0.009; WRS: r = −0.35, p = 0.009). By contrast, at baseline the risk scores showed no relationship to thickness in any hippocampal complex subregion. These results provide compelling evidence that polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex. This work also supports the paradigm of studying genetic risk for disease in healthy volunteers. Together, these findings will inform clinical trial design by supporting the idea that genetic prescreening in healthy control subjects can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness.

Altered memory-related functional connectivity of the anterior and posterior hippocampus in older adults at increased genetic risk for Alzheimer's disease.

The hippocampal complex is affected early in Alzheimers disease (AD). Increasingly, altered functional connectivity of the hippocampus is recognized as an important feature of preclinical AD. Carriers of the APOEɛ4 allele are at an increased risk for AD, which could lead to altered hippocampal connectivity even in healthy older adults. To test this hypothesis, we used a paired‐associates memory task to examine differences in task‐dependent functional connectivity of the anterior and posterior hippocampus in nondemented APOEɛ4 carriers (n = 34, 18F) and noncarriers (n = 46, 31F). We examined anterior and posterior portions of the hippocampus separately to test the theory that APOEɛ4‐mediated differences would be more pronounced in the anterior region, which is affected earlier in the AD course. This study is the first to use a psychophysiological interaction approach to query the context‐dependent connectivity of subregions of the hippocampus during a memory task in adults at increased genetic risk for AD. During encoding, APOEɛ4 carriers had lower functional connectivity change compared to baseline between the anterior hippocampus and right precuneus, anterior insula and cingulate cortex. During retrieval, bilateral supramarginal gyrus and right precuneus showed lower functional connectivity change with anterior hippocampus in carriers. Also during retrieval, carriers showed lower connectivity change in the posterior hippocampus with auditory cortex. In each case, APOEɛ4 carriers showed strong negative connectivity changes compared to noncarriers where positive connectivity change was measured. These differences may represent prodromal functional changes mediated in part by APOEɛ4 and are consistent with the anterior‐to‐posterior theory of AD progression in the hippocampus. Hum Brain Mapp 37:366–380, 2016.

Hippocampal thinning linked to longer TOMM40 poly-T variant lengths in the absence of the APOE ε4 variant

The translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with apolipoprotein E (APOE), has received attention more recently as a promising gene in Alzheimers disease (AD) risk. TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD‐related morphology changes.

GENDER DIFFERENCES IN MEMORY-RELATED FUNCTIONAL CONNECTIVITY IN AGING AND GENETIC RISK FOR AD

analyzed, and the method employed (Table 1). Gene pathway and network enrichment analyses were performed on the genetic findings to get a better understanding of these findings. Results: The number of ADNI genetic association publications in 2013 is 50, in which 20 papers used only APOE, and 30 papers used the GWAS and sequencing data. Among all these papers, multiple types of AD related phenotypes including clinical status, structural and functional neuroimaging, fluid biomarkers, and neuropsychological assessment, were employed as qualitative or quantitative traits to find novel risk genetic variants. Table 1 shows the classification of papers based on various genotype, phenotype, and method applied. Besides the previously known top 10 AD genes, 26 additional genetic association findings were identified by different approaches. For example, 11 new susceptible loci were reported by a large-scale meta-analytical GWAS [1] and SPON1 was discovered by two independent studies [2-3]. Enrichment analyses of thesemajor findings identified 6 immune response pathways (p<0.01), three development pathways (p<0.006), and an inflammation process network (p1⁄47.7e-5). Conclusions: Genetic studies of multidimensional ADNI phenotypes continue to confirm known AD genetic risk factors and discover novel susceptibility loci. With the recent release of ADNI whole genome sequencing data, we expect to see future studies addressing not only common variants but also rare variants, and identifying functional variants instead of tag SNP associations. Reference [1] Lambert et al., Nature Genetics, 2013, 45(12):1452-8. [2] Jahanshada et al., Proc Natl Acad Sci USA, 2013, 110(12):4768-73. [3] Sherva, et al., Alzheimers Dement, 2014, 10(1):45-52.

LONGITUDINAL TAU-PET AND ATROPHY IN HEALTHY OLDER ADULTS AND THOSE WITH ALZHEIMER’S DISEASE

relationships varied by group (Figure 5) but were particularly prominent in the sMCs. Conclusions:We found overlapping spatial patterns of biomarker change in ADAD, with pathological changes consistently located in the precuneus and lateral parietal regions across all four biomarkers. The degree of beta-amyloid, hypometabolism, and cortical thinning were all strongly correlated with tau pathology measured with flortaucipir.

HUMAN IN VIVO TAU PATHOLOGY, IMPAIRED NREM SLEEP OSCILLATIONS AND MEMORY DECLINE IN AGING

O1-03-03 HUMAN IN VIVO TAU PATHOLOGY, IMPAIRED NREM SLEEP OSCILLATIONS AND MEMORY DECLINE IN AGING Joseph R. Winer, Bryce A. Mander, Randolph F. Helfrich, Anne Maass, Theresa M. Harrison, Suzanne L. Baker, Robert T. Knight, William J. Jagust, Matthew P. Walker, University of California Berkeley, Berkeley, CA, USA; University of California Irvine, Irvine, CA, USA; University of Oslo, Oslo, Norway; German Center for Neurodegenerative Diseases, Magdeburg, Germany; Lawrence Berkeley National Laboratory, Berkeley, CA, USA; University of California, Berkeley, Berkeley, CA, USA. Contact e-mail: jwiner@berkeley.edu

EFFECTS OF TAU AND AMYLOID DEPOSITION MEASURED BY PET ON DOMAIN-SPECIFIC MEMORY FUNCTION IN OLD AGE

IC-P-101 EFFECTS OF TAU AND AMYLOID DEPOSITION MEASURED BY PET ON DOMAIN-SPECIFIC MEMORY FUNCTION IN OLD AGE AnneMaass, David Berron, TheresaM. Harrison, Suzanne L. Baker, Taylor J. Mellinger, Kaitlin N. Swinnerton, Rachel K. Bell, Emrah D€uzel, William J. Jagust, Jenna N. Adams, German Center for Neurodegenerative Diseases, Magdeburg, Germany; University of California Berkeley, Berkeley, CA, USA; Institute of Cognitive Neurology and Dementia Research, Otto von Guericke University, Magdeburg, Germany; Lawrence Berkeley National Laboratory, Berkeley, CA, USA; University of California Berkeley, Berkeley, CA, USA. Contact e-mail: anne.maass@dzne.de

EXPLAINING [18F]-AV-1451 VARIABILITY IN HEALTHY CONTROLS ACROSS THE LIFESPAN

IC-02-03 EXPLAINING [F]-AV-1451 VARIABILITY IN HEALTHY CONTROLS ACROSS THE LIFESPAN Suzanne L. Baker, Theresa M. Harrison, Anne Maass, Renaud La Joie, William J. Jagust, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; University of California Berkeley, Berkeley, CA, USA; German Center for Neurodegenerative Diseases, Magdeburg, Germany; University of California, San Francisco, San Francisco, CA, USA; University of California, Berkeley, Berkeley, CA, USA. Contact e-mail: slbaker@lbl.gov

Generalized Psychophysiological Interaction (PPI) Analysis of Memory Related Connectivity in Individuals at Genetic Risk for Alzheimer's Disease

In neuroimaging, functional magnetic resonance imaging (fMRI) measures the blood-oxygenation-level dependent (BOLD) signal in the brain. The degree of correlation of the BOLD signal in spatially independent regions of the brain defines the functional connectivity of those regions. During a cognitive fMRI task, a psychophysiological interaction (PPI) analysis can be used to examine changes in the functional connectivity during specific contexts defined by the cognitive task. An example of such a task is one that engages the memory system, asking participants to learn pairs of unrelated words (encoding) and recall the second word in a pair when presented with the first word (retrieval). In the present study, we used this type of associative memory task and a generalized PPI (gPPI) analysis to compare changes in hippocampal connectivity in older adults who are carriers of the Alzheimers disease (AD) genetic risk factor apolipoprotein-E epsilon-4 (APOEε4). Specifically, we show that the functional connectivity of subregions of the hippocampus changes during encoding and retrieval, the two active phases of the associative memory task. Context-dependent changes in functional connectivity of the hippocampus were significantly different in carriers of APOEε4 compared to non-carriers. PPI analyses make it possible to examine changes in functional connectivity, distinct from univariate main effects, and to compare these changes across groups. Thus, a PPI analysis may reveal complex task effects in specific cohorts that traditional univariate methods do not capture. PPI analyses cannot, however, determine directionality or causality between functionally connected regions. Nevertheless, PPI analyses provide powerful means for generating specific hypotheses regarding functional relationships, which can be tested using causal models. As the brain is increasingly described in terms of connectivity and networks, PPI is an important method for analyzing fMRI task data that is in line with the current conception of the human brain.

Weighted and unweighted genetic risk scores are associated with longitudinal cortical thinning of hippocampal complex subregions

Background:To date, 21 genetic loci have been identified where specific variants increase an individual’s risk for sporadic, late-onset Alzheimer Disease (AD). An important unresolved question is whether or not polygenic risk scores that use combinations of these risk loci increase power to detect changes in neuroimaging endophenotypes for AD. Furthermore, the optimal method to create polygenic risk scores is an active field of research. Methods: In a preliminary study, we acquired high-resolution structural images of the hippocampus in 47 healthy, older subjects. For 14 of these subjects, longitudinal two-year follow-up datawere also available. Unweighted andweighted genetic AD-risk scores were calculated for each subject. The unweighted risk score (URS)was the sumof family history ofAD (0 if negative history or 1 if positive history),APOE4 alleles (0,1, or 2), CLU risk alleles (0,1, or 2) and PICALM risk alleles (0,1, or 2). The weighted risk scores (WRS) usedpublishedodds ratios (OR) toweight the relative contribution of these risk factors before summing: positive family history OR1⁄42, APOE4 OR1⁄43, CLU minor allele OR1⁄40.9, PICALM minor allele OR1⁄40.9. Results: For the cross-sectional cohort, both URS and WRS showed no relationship to thickness in any hippocampal subregion. For the longitudinal cohort, URS and WRS correlated strongly to percent change in thickness across the whole hippocampus (URS r1⁄4-0.85, p1⁄40.0001; WRS r1⁄4-0.63, p1⁄40.015), driven by strong relationships in the entorhinal cortex (URS r1⁄4-0.66, p1⁄40.01; WRS r1⁄4-0.73, p1⁄40.003) and CA23/dentate gyrus (URS r1⁄4-0.66, p1⁄40.01; WRS r1⁄4-0.65, p1⁄40.01), two anterior subregions. In a multiple regression including age and sex as predictors, models with URS (beta1⁄4-2.16, p1⁄40.0003) and WRS (beta1⁄47.01, p1⁄40.014) predicting percent change in thickness across the whole hippocampus were significant (URS model p1⁄40.009; WRS model p1⁄40.03). Conclusions: These results provide compelling evidence that polygenic AD-risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus. Our findings also show that the relationships between our polygenic risk score and hippocampal thinning are not mediated by weighting risk score components with published ORs.