Precision Neurology for Dementia
Joshua Shulman1, Nora Vanegas-Arroyave1, Jamie Fong1, Sarah Elsea1, Chi-Ying Lin1, Hiba Saade1, Fatima Chavez1, Kimberly Walker1, Bo Yuan1, Eric Venner1, Jianhong Hu1, Ariel Levchenko1, Hadley Smith2, Jill Robinson1, Belen Pascual3, Donna Muzny1, Richard Gibbs1, Amy McGuire1, Joseph Masdeu3
1Baylor College of Medicine, 2Harvard Pilgrim Health Care Institute, 3Houston Methodist Hospital
Objective:

To establish a precision medicine workflow for Alzheimer’s disease and related dementias (AD/ADRDs) and assess its impact.

Background:

AD/ADRDs are clinically, pathologically, and genetically heterogeneous. Precision medicine promises individualized, etiologic diagnosis and ultimately, targeted therapies.

Design/Methods:

27 participants have been enrolled from the Houston community (n=13) or neurology outpatient clinics (n=14) at Baylor College of Medicine or Houston Methodist Hospital, including individuals with established AD/ADRD, mild cognitive impairment (MCI), or no known cognitive impairment (NCI). Participants received (i) comprehensive neurologic and neuropsychological assessments (NACC Uniform Data Set), (ii) brain MRI and amyloid PET, and (iii) CAP-CLIA whole genome sequencing. Genome data was filtered using a virtual gene panel specifically developed for this project, including 219 causes of AD/ADRD, cardiovascular diseases, or other medically-actionable conditions unrelated to dementia, along with 3 ADRD/cardiovascular risk genes. All subjects were consented for comprehensive disclosure of dementia risk.

Results:

Participants had a mean age=70, were 41% female, and reported mixed race/ancestry (white=66%, Hispanic/Latino=18%, African American=7%, Asian=7%). Following baseline assessments and prior to neuroimaging biomarkers, participants had clinical diagnoses of AD (n=7), Lewy body dementia (n=1), MCI (n=8), and NCI (n=11). All participants were negative for known monogenic causes of dementia. 15 individuals (56%) had increased dementia risk due to APOE; two participants carried the lipoprotein(a) cardiovascular risk allele; and three individuals had medically actionable, ACMG-reportable secondary findings. Neuroimaging studies are currently being reviewed, and results will be integrated for etiologic diagnosis using the 2018 NIA-AA research (A/T/N) framework. In disclosure visits, all participants will receive precision diagnostic results and a personalized genomic risk report. Surveys will assess perspectives including perceptions of the experience, psychological impact, self-efficacy, quality of life, advance planning, and health behaviors.

Conclusions:

Overall, our experience and emerging results establish feasibility and will inform implementation of precision neurology for dementia.

10.1212/WNL.0000000000203706