Penn at AAIC 2022: Heterogeneity in ADRD and more

Leading researchers, clinicians, and community organizations from around the world gathered last week at the 2022 Alzheimer’s Association International Conference (AAIC) to showcase the latest advances in dementia-related research and care. Among them were many Penn affiliates, including IOA Co-Directors, David A. Wolk, MD and Eddie Lee, MD, PhD, as well as other Penn Alzheimer’s Disease Researcher Center (Penn ADRC) and Penn Frontotemporal Degeneration Center (Penn FTD Center) colleagues. 

Several key themes of Alzheimer’s disease and related disorders (ADRD) research that is focused on here at Penn were present at this year’s AAIC conference – in particular, looking at heterogeneity of ADRD and how social determinants of health, health disparities, and diversity relate to dementia, as well as the role of biomarkers such as cerebral spinal fluid (CSF), MRI, epigenetics, and tau and TDP-43 proteins. 

Below is a sample of some of the exciting Penn-related research presented at this year’s conference:

Social Determinants of Health

  • Pilot Study of Social and Structural Determinants of Health (SSDOH) Measures in the UPenn Alzheimer’s Disease Research Center
    Shana Stites

    Life circumstances such as experiences, opportunities, and challenges can be important social and structural determinants of health that may help explain heterogeneity in cognitive, functional, and interventional outcomes in Alzheimer’s disease and related dementias (ADRDs). 

    Using a diverse cohort of older adults, this study uses self-reported measures in 6 categories: 1) Education, 2) Occupation, 3) Economic Status and Strain, 4) Subjective Stress, 5) Early Life Stressors, and 6) Subjective Social Support and Status. 

    It is believed that understanding this information may explain disease mechanisms and modifiers as well as support discovery of disease modifying treatments across diverse populations. 
  • Social epigenetics of racial disparities in aging
    Isabel Yannatos; Sharon X Xie; Rebecca Brown and Corey T McMillan

    This study quantified biological aging using epigenetic measures of DNA methylation — which typically acts as a volume knob to control the expression of different genes — and then evaluated how DNA methylation aging differed across racial groups and how different aspects of the environment, such as neighborhood deprivation and air pollution, contribute to the disparity in biological aging. Using a large public data repository, the Health and Retirement Study, findings from the study showed that black individuals have more accelerated aging than white individuals and that individual socioeconomic status explains a large portion of the disparity in rate of aging. In addition, inequitable levels of neighborhood deprivation and different vulnerabilities to fine particulate matter air pollution between racial groups contribute to the disparity in biological aging.

    “While it has been well established that there are disparities in aging, this research provides a novel perspective that aims to uncover the biological mechanisms of these disparities,” said Corey T. McMillan, PhD, Associate Professor of Neurology at the University of Pennsylvania. 

Fluid Biomarkers

  • Appropriateness of Applying Cerebrospinal Fluid Biomarker Cutoffs from Alzheimer’s Disease to Parkinson’s Disease
    Weinshel S, Irwin DJ, Zhang P, Weintraub D, Shaw LM, Siderowf A, Xie SX

    A major gap in the field of biomarker researcher is the need for established cutpoints to detect Alzheimer’s disease (AD) co-pathology in Parkinson’s disease (PD) since this has significant impact on prognosis. This study looks at the utility of cutpoints for AD CSF biomarkers in PD patients and uniquely examined previously published cutpoints for AD pathology established in AD patient cohorts in the PPMI PD cohort. It was determined that cutpoints for tau and AB in CSF may be most accurate when developed specifically for PD cohorts rather than using previous diagnostic thresholds established for AD patients since PD pathology may influence CSF tau and AB in a manner distinct from AD.
  • Plasma GFAP:NfL discriminates FTLD-tau from FTLD-TDP 
    Katheryn A Q Cousins; Leslie M. Shaw; Alice Chen-Plotkin; Eddie B Lee; John Q Trojanowski; Vivianna M Van Deerlin; Corey T McMillan; Murray Grossman and David J. Irwin, MD 

    This study examined novel plasma biomarkers (glial fibrillary astrocytic protein, GFAP and neurofilament light chain NFL) in an autopsy confirmed cohort of frontotemporal lobar degeneration (FTLD). A major gap in the field of FTLD research is the inability to diagnosis and differentiate the two main prioteinopathies that cause FTLD clinical syndromes: tauopathies (FTLD-Tau) and TDP-43 proteinopathies (FTLD-TDP). This study is unique in that it uses rare autopsy and genetic confirmed plasma samples to systematically account for the heterogenous underlying pathology of FTLD. Importantly, the main results find robust differences in GFAP/NFL ration in FTLD-Tau > FTLD-TDP and that this had high diagnostic accuracy in both a training autopsy cohort and an independent living sample of PSP-Tau and ALS-TDP with known pathology. See the full poster below.

Tau and TDP-43

  • Tau burden is associated with cross-sectional and longitudinal neurodegeneration in the medial temporal lobe in cognitively normal individuals 
    Long Xie, Laura EM Wisse, Sandhitsu R. Das, Xueying Lyu, Robin de Flores, Paul A. Yushkevich, and David A. Wolk

    This study demonstrates that the presence of tau-based neurofibrillary tangle pathology, one of the hallmark pathological features of AD, is associated with an increased rate of brain atrophy in the memory region of the brain, the medial temporal lobe. “Interestingly, this seems to occur whether or not amyloid plaques, the other hallmark pathology of AD, is present. This suggests that a form of age-related tauopathy in memory regions, which is ubiquitous in aging, may be a potential driver of age-related memory change and potential target for treatment,” explained David A. Wolk, MD, Co-Director of the IOA and Director of Penn’s Alzheimer’s Disease Research Center. See the full poster below.
  • Modules of genotypic variance reflect heterogeneity across TDP-43 proteinopathies Barbara E Spencer; David J. Irwin; Vivianna M Van Deerlin; Eddie B Lee; Lauren Elman; Colin Quinn; Murray Grossman; David A. Wolk and Corey T McMillan 

    Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are typically characterized as a motor or cognitive disorder, respectively, but share a common neuropathological source of disease with TDP-43 pathology inclusions.  However, it is not known why some individuals with TDP-43 pathology inclusions present clinically with ALS, some present with FTD, and others with both. This team of Penn Medicine researchers hypothesized that shared genetic risk variants across these conditions may lead to the shared pathology, while disparate genetic risk variants may lead to the disparate cognitive or motor impairments. Using a novel statistical application, they identified sets of both shared and disparate variants associated with these conditions and believe these disparate genetic risk variants may reveal disease-specific vulnerabilities that drive the disparate clinical impairments seen in these conditions.

    “Disentangling clinical and genetic heterogeneity in FTD and ALS may help inform the development of therapeutic targets to attenuate the course of these devastating neurodegenerative diseases,” said Barbara E. Spencer, PhD, a postdoctoral fellow at the Penn Frontotemporal Degeneration Center. See the full poster below.

AAIC also paid tribute to John Q. Trojanowski, MD, PhD, past IOA Director, and “giant” in the field of neurodegenerative disease research with a memorial session. 

At AAIC in 2018, Dr. Trojanowski received the Alzheimer’s Association’s 2018 Khalid Iqbal Lifetime Achievement Award. The award, named in honor of Khalid Iqbal, PhD, one of three founders of the Alzheimer’s research conference in 1988, recognizes individuals who have made significant fundamental contributions to Alzheimer’s research.

More highlights from this year’s AAIC:

Next year’s AAIC will be held July 16-20, 2023 in Amsterdam, Netherlands. Learn more here.

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