Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease
Authors: Kouri Naomi , Frankenhauser Isabelle , Peng Zhongwei , Labuzan Sydney A. , Boon Baayla D. C. , Moloney Christina M. , Pottier Cyril , Wickland Daniel P. , Caetano-Anolles Kelsey , Corriveau-Lecavalier Nick , Tranovich Jessica F. , Wood Ashley C. , Hinkle Kelly M. , Lincoln Sarah J. , Spychalla A. J. , Senjem Matthew L. , Przybelski Scott A. , Engelberg-Cook Erica , Schwarz Christopher G. , Kwan Rain S. , Lesser Elizabeth R. , Crook Julia E. , Carter Rickey E. , Ross Owen A. , Lachner Christian , Ertekin-Taner Nilüfer , Ferman Tanis J. , Fields Julie A. , Machulda Mary M. , Ramanan Vijay K. , Nguyen Aivi T. , Reichard R. Ross , Jones David T. , Graff-Radford Jonathan , Boeve Bradley F. , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Kantarci Kejal , Day Gregory S. , Duara Ranjan , Graff-Radford Neill R. , Dickson Dennis W. , Lowe Val J. , Vemuri Prashanthi , Murray Melissa E. 
Published: April 2024

ImportanceFactors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement.ObjectivesTo examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy.Design, Setting, and ParticipantsThis cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses.Main Outcomes and MeasuresClinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET).ResultsOf the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P &amp;lt; .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P &amp;lt; .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P &amp;lt; .001). Hippocampal MRI volume (Spearman ρ = −0.45; P &amp;lt; .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P &amp;lt; .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02).Conclusions and RelevanceFindings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.