HAI Book 2025 - Flipbook - Page 275
Ziontz, Jacob
Pathological asymmetry in early onset AD reflects heterogenous disease
trajectories
Jacob Ziontz1, Piyush Maiti1, Jiaxiuxiu Zhang1, Konstantinos Chiotis1, Ganna Blazhenets1,
Salma Rocha1, Ranjani Shankar1, Alinda Amuiri1, Daniel Schonhaut1, Dustin Hammers2, Ani
Eloyan3, Robert Koeppe4, Maria Carrillo5, Bradford Dickerson6, Liana Apostolova7, Gil
Rabinovici1, Renaud La Joie1
1
Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, US
Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, US
3
Department of Biostatistics, Brown University School of Public Health, Providence, RI, US
4
Department of Radiology, University of Michigan, Ann Arbor, MI, US
5
Medical & Scientific Relations Division, Alzheimer’s Association, Chicago, IL, US
6
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, US
7
Department of Radiology, Mayo Clinic, Rochester, MN, US
2
Background: Asymmetrical AD pathology has been observed in atypical variants and even cognitively unimpaired
(CU) individuals, but how asymmetry presents and changes over time in early-onset AD (EOAD) is unknown.
Methods: We included 373 amyloid-PET-positive patients under 65 years with MCI or mild dementia and 92 CU
individuals (10 amyloid-PET-positive, 82 amyloid-PET-negative) from the Longitudinal Early Onset AD study
(LEADS). Patient clinical phenotypes were amnestic or nonamnestic EOAD, primary progressive aphasia (PPA), or
posterior cortical atrophy. Participants had florbetaben and flortaucipir PET, MRI, and neuropsychological testing
at baseline; 206 individuals had 1-3 follow-up imaging visits. We used Freesurfer7.1 segmentation to compute a
global asymmetry index for the three imaging modalities reflecting left/right hemisphere signal difference relative
to overall cortical signal. We defined symmetrical, left-, and right-lateralized groups using a threshold of +/-2SD
from the CU amyloid-PET-negative mean for each modality.
Results: Asymmetry was observed across modalities, most prevalent in flortaucipir followed by cortical volume
and florbetaben. Both left and right asymmetry was evident in all clinical phenotypes, though PPA individuals were
systematically left-lateralized. Lateralization and degree of asymmetry between modalities were correlated
within individuals, particularly between flortaucipir and atrophy (Figure 1). Adjusting for age, sex, education, and
overall cortical signal, individuals with lateralized flortaucipir and atrophy performed worse than those with
symmetrical signal across domains (Figure 2). Notably, left-lateralized individuals performed worst in verbal
fluency while right-lateralized individuals performed worst in visuospatial processing (all p < 0.001). Longitudinally,
flortaucipir asymmetry decreased over time while volumetric asymmetry increased. Flortaucipir decline was
particularly driven by individuals with greater cortical signal abnormality at baseline (Figure 3).
Conclusion: Asymmetry and resulting cognitive impairment are common across clinical phenotypes in EOAD,
reflecting intermediate levels of biomarker abnormality. Asymmetry thus varies with disease progression in
amyloid, tau, and finally atrophy, declining longitudinally as pathology accumulates contralaterally.
HAI2025 - 275
