Joshua M Shulman1, Ismael Al-Ramahi1, Juan Botas1, Fatima Chavez1, Kelly Erikson Carter1, Sarah H Elsea1, Michelle Etoundi1, Jamie C Fong1, Andrea Franco2, Mohammed Hamdan1, Jianhong Hu1, George R Jackson1, Tom V Lee1, Olivier Lichtarge1, Chi-Ying R Lin1, Zhandong Liu1, Valerie Lozano1, Mirjana Maletic-Savatic1, Janet Malek1, Nicole Matute2, Amy L McGuire1, Luis D Medina3, Donna Muzny1, Maria B Pascual2, Valory Pavlik1, Christine B Rizk1, Jill Robinson1, Hiba Saade1, Chad Shaw1, Hadley Smith4, Jonathan Sober1, Juan B Toledo2, Nora Vanegas-Arroyave1, Eric Venner1, Kimberly Walker1, Melissa Yu1, Bo Yuan1, Huda Zoghbi1, Joseph Masdeu2
1Baylor College of Medicine, 2Houston Methodist Hospital, 3University of Houston, 4Harvard Medical School
Objective:
To establish a precision neurology workflow for Alzheimer’s disease (AD) and related dementias, and assess its impact.
Background:
AD is clinically, pathologically, and genetically heterogeneous. Precision medicine promises individualized risk assessment, etiologic diagnoses, and targeted therapies.
Design/Methods:
We enrolled 194 participants with or without cognitive complaints from memory clinics (56%) and the Houston community (44%). Participants received neurocognitive assessments, AD blood/neuroimaging biomarkers, metabolomics, and genome sequencing. Personalized genome reports detailed 208 high-penetrance dementia genes, 3 susceptibility alleles, polygenic risk scores, 7 pharmacogenetic alleles, and 59 medically-actionable genes unrelated to AD. Promising novel genetic variants were also prioritized using machine learning algorithms for functional testing in experimental models. Following comprehensive results disclosure, surveys measured perceptions, psychological impact, self-efficacy, quality of life, advance planning, and health behaviors.
Results:
Our cohort mean age is 69 years (range=41-93; 56% female) and represents Houston’s diversity (65% Non-Hispanic White; 31% Hispanic/Latino; 8% African American; 4% Asian). Clinical consensus diagnoses included normal cognition (40%), mild cognitive impairment (40%), AD (17%), or other dementias (3%). Among 167 subjects with completed genomes, 3 had high-penetrance alleles (PSEN1, SORL1, ABCA7), 47% carried APOE-e4, and 4 had secondary findings (LPL, MSH6, PMS2, TSC2). Among participants with AD or MCI, we observed a striking divergence in biomarkers for AD pathophysiology within subgroups recruited from the clinic (75%) versus community (33%) settings. We identified 11 individuals with normal cognition and positive AD biomarkers. To date, 137 participants have received their study results. Based on 2-month post-disclosure surveys, we have not detected evidence of increased participant worry, and 75% reported making behavioral changes to improve brain health, including increased mentally stimulating activities, exercise, and/or dietary modifications.
Conclusions:
Overall, these results establish feasibility for our precision neurology workflow and are suggestive of more heterogeneous etiologies for dementia among individuals recruited from the community setting.
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