Image: Scene from the ADRC's Clinicopathological Correlation Conference
Read these snapshots of current research at the UW Alzheimer's Disease Research Center, spanning findings in neurology, precision medicine, genetic risk, and vascular brain health.
As published in Dimensions Magazine - Spring 2019
*Only UW-affiliated researchers are listed
Neurology
Bilingualism in Primary Progressive Aphasia: A Retrospective Study on Clinical and Language Characteristics. A. Costa et al. Alzheimer Disorders & Associated Disorders, January 2019 // Kimiko Domoto-Reilly
Primary progressive aphasia, or PPA, is a neurodegenerative disorder that impairs language abilities over time, such as speaking and word finding. The international team, including the ADRC’s Dr. Kimiko Domoto-Reilly, MD, recognized an interesting opportunity to study the manifestation of language decline in PPA patients who were bilingual, or spoke two or more languages. They asked about the influence of speaking multiple languages on the progression of diseases that specifically damage the language networks of the brain. Can bilingualism confer resilience to the brain’s language networks or delay symptom onset? Does an English speaker’s native language hold up better than their Spanish as primary progressive aphasia progresses? What language should an individual’s speech therapy focus on? In general, there is conflicting evidence on whether being bilingual has a protective effect on neurodegenerative diseases, such as Alzheimer’s disease.
The researchers studied 33 patients with diagnoses of one of the three types of primary progressive aphasia: the nonfluent, semantic, and logopenic variants. They found that the group as a whole showed the same level of impairment in both first and second languages, supporting the idea that neurodegeneration has a blanket effect on language. However, each variant of primary progressive aphasia showed subtle differences of impairment between the two languages. These results reveal that researchers need to better assess language in different variants of PPA, including other influential factors such as the person’s age of becoming fluent, proficiency, and which language was dominant in their life. In an increasingly multilingual world, the researchers anticipate an increasing need for a multilingual approach to research and care management in neurodegenerative diseases, in order to improve the reliability of diagnosis and access to tailored speech therapies.
Precision Medicine Approaches
Genetic data and cognitively defined late-onset Alzheimer’s disease subgroups. S. Mukherjee et al. Molecular Psychiatry, December 2018 // Shubhabrata Mukherjee, Emily Trittschuh, Madeline Wessels, Juliana Bauman, Mackenzie Moore, Seo-Eun Choi, Joanne Rich, Diana K.N Louden, R. Elizabeth Sanders, Thomas J. Grabowski, Thomas Bird, Susan McCurry, C. Dirk Keene, Eric B. Larson, ACT Study researchers, Paul K. Crane
ADRC researchers recently made a leap forward in the aim to classify patients with Alzheimer’s disease into subtypes, an approach that may open the door for personalized treatments. In collaboration with many other institutions, the researchers put 4,050 people with late-onset Alzheimer’s disease into groups based on their most prominent type of cognitive symptoms at the time of diagnosis. These included memory, executive functioning, language, visuospatial functioning. Then, they dug into everyone’s genetics. The team searched the participants’ genetic data to find biological differences across these cognitive groups. Taking this novel approach, they found 33 single nucleotide polymorphisms (SNPs) – specific locations throughout the genome – where the genetic association was very strong for one of the subgroups. These genetic-cognitive relationships were stronger than the strongest effects found by the much larger International Genomics of Alzheimer’s Project Consortium in which Alzheimer’s disease was treated as a single homogeneous condition. The study also found a strong relationship between a particular variant of the APOE gene and risk for the memory loss subgroup. The APOE4 allele is a risk factor for developing Alzheimer’s disease for people with European ancestry. It now appears to influence which cognitive subtype of Alzheimer’s a person is likely to have, if they develop symptoms.
This study is an important step toward improving insight into the types of variability that clinicians see in the initial cognitive symptoms of late onset Alzheimer’s and the genetic factors that seem to make certain circuits in the brain vulnerable or resilient to Alzheimer’s pathology. Additionally, the study sets forth a new platform for the discovery of genetic variants linked to distinct clinical types of Alzheimer’s disease and the design of targeted treatments.
Genetic Risk
Alternative splicing in a presenilin 2 variant associated with Alzheimer disease. J. Braggin et al. Annals of Clinical and Translational Neurology, March 2019 // Jacquelyn E. Braggin, Stephanie A. Bucks, Meredith M. Course, Carole L. Smith, Bryce Sopher, Leah Osnis, Kiel D. Shuey, Kimiko Domoto-Reilly, Christina Caso, Chizuru Kinoshita, Kathryn P. Scherpelz, Thomas J. Grabowski, Gwenn A. Garden, Debby Tsuang, Caitlin Latimer, Luis F. Gonzalez‐Cuyar, C. Dirk Keene, Richard S. Morrison, Kristoffer Rhoads, Ellen M. Wijsman, Michael O. Dorschner, Jessica E. Young, Paul N. Valdmanis, Thomas D. Bird, Suman Jayadev
A collaboration of ADRC researchers has led to a discovery about the genetic cause of a rare form of early-onset Alzheimer’s disease, with surprising implications for the general aging population as well. They focused on individuals in two families harboring a ‘frameshift’ mutation within the presenilin 2 gene (PSEN2), previously identified for the first time by ADRC researchers in 2010. To understand a frameshift, think of the affected section of DNA as a series of linked train cars, except that several train cars get disconnected by accident. It’s too short to be sent to its destination. However, it was unclear to the researchers why that frameshift causes severe disease. Drawing on a multidisciplinary array of ADRC resources, they studied genetic data and postmortem brain tissue, and they used patient cells to measure molecular hallmarks of Alzheimer’s disease.
The team found that the PSEN2 gene of these patients indeed generates abnormal instructions for making protein, as expected. However, working with the UW Valdmanis lab, the team uncovered the presence of an additional set of flawed instructions that are not unique to this mutation, but that also appear in other cases of Alzheimer’s disease and in normal aging brains. This finding opens the door to the possibility that age-related changes in PSEN2 expression may be involved in Alzheimer’s risk in the general population. It is only when the bad instructions are decoded in the genomes of people with the frameshift in the PSEN2 gene, the researchers report, that a perfect storm of toxic proteins could result and eventually lead to early-onset Alzheimer’s. Their study highlights the importance of understanding the link between PSEN2 and Alzheimer’s disease.
Vascular Brain Health
Vascular Risk Factors and Findings on Brain MRI of Elderly Adult American Indians: The Strong Heart Study. D. Shibata et al. Neuroepidemiology, February 2019 // Dean Shibata, Astrid Suchy-Dicey, Cara Carty, Tara Madhyastha, T Ali, L Best, Thomas J. Grabowski, WT Longstreth, Dedra Buchwald
Stroke and cardiovascular disease are known to put people at risk for vascular brain disease, Alzheimer’s disease, and cognitive decline. While cardiovascular disease is prevalent in American Indians, the risk factors for the impacts on the brain have not been well-studied in this population. The Strong Heart Study, started in 1988 by funding from the National Heart, Lung, and Blood Institute, is the most extensive examination of cardiovascular disease in more than 4,500 American Indians from 13 tribes across three geographic regions of the U.S. Surviving members of the study cohort have participated in many examinations ever since. In this iteration of the study, conducted by the ADRC Satellite Core, some of the Strong Heart Study participants returned for tests related to brain health. The researchers analyzed MRI brain scans of 789 elderly American Indian participants. The study’s findings offer more evidence of the significant role of diabetes and high blood pressure in age-related brain damage, as seen in other studied populations. The results underscore the importance of better diagnosis, monitoring, and preventive measures to reduce vascular brain injury in American Indians.
-Genevieve Wanucha
