Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer`s disease

Importance: Understanding asymmetry in spatial tau positron emission tomography (PET) patterns in Alzheimer's disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored. Objective: To investigate whether asymmetric tau PET burden is associated with behavioral symptoms and cognitive profiles. Design: This cross-sectional study analyzed temporal lobe tau PET laterality, alongside memory, executive, language, and behavioral data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Setting: Cognitively unimpaired (CU) and impaired (CI) from ADNI with available tau PET. Participants: A temporal tau laterality index was calculated to define 'asymmetry-extreme' groups (individuals with laterality indices greater than two standard deviations from the mean). In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated controlling for age, sex, education, and the tau burden on the contralateral side. Main Outcomes and Measures: The study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory, and composite scores for memory, executive function, and language. Results: 858 individuals (mean age=73.9+/-7.7 years, 434 (50%) females) were included, comprising 438 CU (53.4%) and 420 CI participants (48.9%). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Worse behavioral symptoms were observed with higher right, temporal tau (B(SE)=5.13(2.4), p-value=0.04) whereases worse language performance was associated with greater left temporal tau (B(SE)=0.37(0.1), p-value=0.04). Worse memory and executive function were associated with higher tau in both right and left temporal lobes. Within these extreme groups, four patterns of tau PET uptake were observed: anterior temporal, typical AD, typical AD with frontal involvement, and posterior. Similar associations were seen in the full cohort analysis, right temporal tau was associated with worse behavior (B(SE)=7.19 (2.9), p-value=0.01) and left temporal tau was associated with worse language (B(SE)=1.4(0.2), p-value<0.0001). Conclusions and Relevance: Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Deeper characterization of behavioral and socioemotional measures is needed to understand right sided asymmetry in the context of AD. Key Points Question: What is the influence of tau asymmetry on behavior and cognition in Alzheimer`s disease? Findings: In this cross-sectional study, elevated right temporal tau levels were linked to heightened behavioral symptoms, whereas increased left temporal tau levels were associated with greater language symptoms. Four distinct right/left asymmetric tau patterns were present: anterior temporal, typical AD without frontal involvement, typical AD with frontal involvement, and posterior. Meaning: Within typical AD, heterogeneity in behavioral and language characteristics is associated with tau PET asymmetry. Existing AD staging overlooks disease asymmetry. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by NIH/NIA ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All Alzheimers Disease Neuroimaging Initiative (ADNI) participants provided written informed consent in compliance with local IRBs. For up-to-date information, see www.adni-info.org. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at www.adni-info.org