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. 2024 Jun 1;81(6):619-629.
doi: 10.1001/jamaneurol.2024.0784.

Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease

Naomi Kouri  1 , Isabelle Frankenhauser  1   2 , Zhongwei Peng  3 , Sydney A Labuzan  1 , Baayla D C Boon  1 , Christina M Moloney  1 , Cyril Pottier  1 , Daniel P Wickland  3 , Kelsey Caetano-Anolles  1 , Nick Corriveau-Lecavalier  4   5 , Jessica F Tranovich  1 , Ashley C Wood  1 , Kelly M Hinkle  1 , Sarah J Lincoln  1 , A J Spychalla  4 , Matthew L Senjem  4 , Scott A Przybelski  6 , Erica Engelberg-Cook  1 , Christopher G Schwarz  4 , Rain S Kwan  3 , Elizabeth R Lesser  3 , Julia E Crook  3 , Rickey E Carter  3 , Owen A Ross  1 , Christian Lachner  7 , Nilüfer Ertekin-Taner  1   8 , Tanis J Ferman  7 , Julie A Fields  9 , Mary M Machulda  9 , Vijay K Ramanan  5 , Aivi T Nguyen  10 , R Ross Reichard  10 , David T Jones  4   5 , Jonathan Graff-Radford  5 , Bradley F Boeve  5 , David S Knopman  5 , Ronald C Petersen  5 , Clifford R Jack Jr  4 , Kejal Kantarci  4 , Gregory S Day  8 , Ranjan Duara  11 , Neill R Graff-Radford  8 , Dennis W Dickson  1 , Val J Lowe  4 , Prashanthi Vemuri  4 , Melissa E Murray  1
Affiliations

Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease

Naomi Kouri et al. JAMA Neurol. .

Abstract

Importance: Factors 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.

Objectives: To 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 participants: This 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 measures: Clinicopathologic 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).

Results: Of 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 < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .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 < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .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 relevance: Findings 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Boon reported receiving grants from Alzheimer Nederland during the conduct of the study. Dr Schwarz reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Ross reported receiving grants from NIH/National Institute of Neurological Disorders and Stroke (NINDS), Department of Defense, Florida State James and Esther King Biomedical Research Program, The Michael J. Fox Foundation, American Parkinson Disease Association Center for Advanced Research, and American Brain Foundation during the conduct of the study. Dr Lachner reported receiving grants from NIH/National Institute on Aging (NIA) during the conduct of this study. Dr Ertekin-Taner reported receiving grants from NIH/NIA; being associate director of the Mayo Clinic Center for Clinical and Translational Sciences Institutional Career Development (KL2) Core; being a member of the Framingham Heart Study Executive Committee; and being a member of the NIH TREAT-AD Consortium Executive Advisory Board during the conduct of the study. Dr Ferman reported receiving grants from NIH/NIA/NINDS and from the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program during the conduct of the study. Dr Machulda reported receiving grants from NIH during the conduct of the study. Dr Ramanan reported receiving grants from NIH and the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program; providing educational content for Medscape; being an associate editor for the Journal of Alzheimer’s Disease; being a co–principal investigator for a clinical trial supported by the Alzheimer’s Association; and being a site clinician for clinical trials supported by Eisai, the Alzheimer’s Treatment and Research Institute at USC, and Transposon Therapeutics Inc during the conduct of the study. Dr J. Graff-Radford reported receiving grants from NIH and serving on the data safety monitoring board for StrokeNET during the conduct of the study. Dr Boeve reported receiving grants from NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, the Little Family Foundation, the Ted Turner and Family LBD Functional Genomics Program, American Brain Foundation, and for clinical trials sponsored by Alector, Cognition Therapeutics, and Transposon during the conduct of the study. Dr Knopman reported receiving grants from NIH, serving on a data safety monitoring board for the DIAN study and for a tau therapeutic for Biogen but received no personal compensation; being a site investigator in the Biogen aducanumab trials and an investigator in a clinical trial sponsored by Lilly Pharmaceuticals and the University of Southern California; and serving as a consultant for Samus Therapeutics, Roche, and Alzeca Biosciences but received no personal compensation. Dr Petersen reported receiving grants from NIH; serving as a consultant for Biogen, Roche, Merck, Genentech (on the data safety monitoring board), Nestle, and Eisai; and receiving publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003) and UpToDate during the conduct of the study. Dr Jack reported receiving grants from NIH and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic; serving on an independent data monitoring board for Roche; serving as a speaker for Eisai and a consultant for Biogen, but he received no personal compensation from any commercial entity during the conduct of the study. Dr Day reported receiving grants from NIH/NIA/NINDS, the Alzheimer’s Association, and Chan Zuckerberg Initiative; serving as a consultant for Parabon Nanolabs Inc, a Topic Editor (Dementia) for DynaMed (EBSCO), and the co–project principal investigator for a clinical trial in anti-NMDAR encephalitis, which receives support from Horizon Pharmaceuticals; developing educational materials for PeerView Media and Continuing Education; owning stock in ANI pharmaceuticals; in addition, his institution has received support from Eli Lilly for development and participation in an educational event promoting early diagnosis of symptomatic Alzheimer disease, and in-kind contributions of radiotracer precursors for tau-PET neuroimaging in studies of memory and aging (via Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly) during the conduct of this study. Dr N. Graff-Radford reported receiving grants from NIH, Biogen, Eli Lilly, and Axovant; taking part in multicenter trials supported by AbbVie, Eli Lilly, and Biogen outside the submitted work; serving on the editorial board of Alzheimer Disease and Therapy; and receiving publishing royalties from UpToDate Inc during the conduct of this study. Dr Dickson reported receiving grants from NIH/NIA/NINDS, the Mangurian Foundation Lewy Body Dementia Program at Mayo Clinic, and the Robert E. Jacoby Professorship during the conduct of this study; being an editorial board member of Acta Neuropathologica, Annals of Neurology, Brain, Brain Pathology, and Neuropathology; and being editor in chief of American Journal of Neurodegenerative Disease. Dr Lowe reported receiving grants from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, the NIH (NIA, NCI), and the MN Partnership for Biotechnology and Medical Genomics and serving as a consultant for Bayer Schering Pharma, Philips Molecular Imaging, Piramal Imaging, AVID Radiopharmaceuticals, Eisai Inc, and Eli Lilly during the conduct of this study. Dr Vemuri reported receiving grants from NIH and speaker fees from Miller Medical Communications during the conduct of this study. Dr Murray reported receiving grants from NIH/NIA, the State of Florida, and Eli Lilly and Company and serving as a paid consultant for Avid Radiopharmaceuticals during the conduct of this study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Clinicopathologic Heterogeneity in Alzheimer Disease (AD)
Corticolimbic index (CLix) quantitatively defines corticolimbic vulnerability as a continuous measure (range, 0-40) calculated from the means and proportions of thioflavin-S–positive neurofibrillary tangle counts from hippocampus (CA1 and subiculum) and association cortices (superior temporal, inferior parietal, and middle frontal). A, The frequency of CLix scores in the Florida Autopsied Multiethnic (FLAME-AD) series. B, CLix scores by age at symptomatic onset. C, CLix scores stratified by atypical, nonamnestic clinical syndrome. D, Lolliplot of clinicopathologic variable importance from random forest regression model.
Figure 2.
Figure 2.. Association Between Structural Magnetic Resonance Imaging (sMRI) and Tau–Positron Emission Tomography (PET) With Corticolimbic Tangle Distribution
A, Mapping the inverse association between structural volume from 3T MRI and corticolimbic index (CLix) demonstrates greater medial temporal lobe volume associating with lower CLix score consistent with a hippocampal sparing Alzheimer disease (AD) phenotype. The color bar indicates the value of the T statistic with greater volume loss shown in warmer colors. The arrowhead on structural MRI points to hippocampus. The adjoining scatterplot (C) of hippocampal volume reveals a strong association with CLix, which shows that a lower hippocampal volume associated with higher CLix score consistent with limbic predominant AD phenotype. B, Mapping the inverse association between flortaucipir tau-PET uptake and CLix demonstrates significant uptake in extra-temporal lobe cortical structures consistent with higher tau load in hippocampal sparing AD. The color bar indicates the value of the T statistic with higher tracer uptake shown in warmer colors. The arrowhead on tau-PET map points to posterior cingulate and cuneus region. The adjoining scatterplot (D) of posterior cingulate and cuneus tau-PET uptake reveals a strong association with CLix, which shows that lower cortical tau-PET uptake in posterior cingulate and cuneus associated with higher CLix score consistent with a limbic predominant AD phenotype. SUVR indicates standard uptake value ratio.
Figure 3.
Figure 3.. Digital Pathology Measures of Alzheimer Disease (AD) Pathology and Glial Activation
Thioflavin-S fluorescent dye was used to manually count advanced neurofibrillary tangles, including mature tangles (left solid tangle) and ghost tangles (right tangle with splayed fibrils). Digital pathology was used to quantify markers of AD pathology and glial activation on serially stained 5-μm formalin-fixed, paraffin-embedded tissue sections in the digital pathology subgroup across 5 brain regions (note the illustration of the brain in panel A): CA1 (closed circle, hippocampus inset) and subiculum (open circle, hippocampus inset), as well as superior temporal, inferior parietal, and middle frontal association cortices. A, Thioflavin-S fluorescence microscopy was used to develop corticolimbic index (CLix) methodology and create the CLix R package (R Project for Statistical Computing) enabling quantification of AD corticolimbic tangle distribution. Antibodies used in this study included markers of hyperphosphorylated tau (phosphorylation-dependent anti-tau antibody 8 [AT8]), AD-specific tau conformers (anti-tau AD antibody [GT-38]), amyloid-β (6F/3D), astrogliosis (glial fibrillary acidic protein [GFAP]), and activated microglia/macrophages (CD68). A and B, The top row displays representative photomicrographs for each marker and the bottom row displays corresponding markup images of positive immunoreactivity (red on the markup images represents chromogen-positive pixels, blue represents negative pixels using the positive pixel count macro [GT-38, 6F/3D, and GFAP], and yellow and blue represent negative pixels for the color deconvolution macros [AT8 and CD68]). Radar plots are used to depict quantitative neuropathologic data with the axis increasing from the center (zero) to the circumference of the plot maxing at highest median. Higher scores signify higher number of thioflavin-S tangle counts or higher-percentage immunopositive staining. Scale bar for each panel = 25 μm. Brain image was created with BioRender.com. IP indicates inferior parietal; MF, middle frontal; ST, superior temporal.
See this image and copyright information in PMC

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