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. 2024 Oct;50(5):e13009.
doi: 10.1111/nan.13009.

Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology

Baayla D C Boon  1   2   3   4   5 , Irene Frigerio  4   5 , Danae de Gooijer  2 , Tjado H J Morrema  2 , John Bol  4   5 , Yvon Galis-de Graaf  4   5 , Martijn Heymans  6 ; Netherlands Brain Bank  7 ; Melissa E Murray  1 ; Normal Aging Brain Collection Amsterdam  4 ; Sven J van der Lee  3   8 , Henne Holstege  3   8 , Wilma D J van de Berg  4   5 , Laura E Jonkman  4   5 , Annemieke J M Rozemuller  2   5 , Femke H Bouwman  3   5 , Jeroen J M Hoozemans  2   5
Affiliations

Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology

Baayla D C Boon et al. Neuropathol Appl Neurobiol. 2024 Oct.

Abstract

Aims: Although the neuroanatomical distribution of tau and amyloid-β is well studied in Alzheimer's disease (AD) (non)-amnestic clinical variants, that of neuroinflammation remains unexplored. We investigate the neuroanatomical distribution of activated myeloid cells, astrocytes, and complement alongside amyloid-β and phosphorylated tau in a clinically well-defined prospectively collected AD cohort.

Methods: Clinical variants were diagnosed antemortem, and brain tissue was collected post-mortem. Typical AD (n = 10), behavioural/dysexecutive AD (n = 6), posterior cortical atrophy (PCA) AD (n = 3), and controls (n = 10) were neuropathologically assessed for AD neuropathology, concurrent pathology including Lewy body disease, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and vascular pathology. For quantitative assessment, we analysed the corticolimbic distribution of phosphorylated tau, amyloid-β, CD68, MHC-II, C4b, and glial fibrillary acidic protein (GFAP) using digital pathology.

Results: Phosphorylated tau was distinctly distributed in each variant. In all variants, amyloid-β was neocortical-dominant, with a notable increase in the middle frontal cortex of behavioural/dysexecutive AD. Typical AD and PCA AD had no concurrent Lewy body disease, whereas three out of six cases with behavioural/dysexecutive AD did. LATE-NC stage >0 was observed in three AD cases, two typical AD (stage 1/3), and one behavioural/dysexecutive AD (stage 2/3). Vascular pathology was present in each variant. In typical AD, CD68 and MHC-II were hippocampal-dominant. In behavioural/dysexecutive AD, C4b was elevated in the middle frontal and inferior parietal cortex. In PCA AD, MHC-II was increased in the fusiform gyrus, and GFAP in parietal cortices. Correlations between AD neuropathology and neuroinflammation were distinct within variants.

Conclusions: Our data suggests that different involvement of neuroinflammation may add to clinical heterogeneity in AD, which has implications for neuroinflammation-based biomarkers and future therapeutics.

Keywords: Alzheimer's disease; amyloid; astrocytes; complement; myeloid cells; tau proteins.

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Conflict of interest statement

Dr Boon reports grants from Alzheimer Nederland during the conduct of the study; Frigerio, de Gooijer, Morrema, Bol, Galis, Dr Heymans declare no competing interests; Dr Murray reported grants from NIH/NIA, the State of Florida, and Eli Lilly and Company, and served as a paid consultant for Avid Radiopharmaceuticals during the conduct of this study; Dr Van der Lee is part of the GeneMINDS consortium, which is powered by Health~Holland, Top Sector Life Sciences & Health and receives co-financing from Vigil Neuroscience, Prevail therapeutics and Brain Research Center, all funding is paid to his institution. He was funded for this study by NWO (#733050512, PROMO-GENODE: a PROspective study of MOnoGEnic causes Of Dementia) a substantial donation by Edwin Bouw Fonds and Dioraphte and received further funding for the GeneMINDS consortium, which is powered by Health~Holland, Top Sector Life Sciences & Health. He is part of the YOD-INCLUDED project, which is funded by ZonMw (project no. 10510032120002) and is part of the Dutch Dementia Research Programme. He is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007), de Hersenstichting, Edwin Bouw Fonds, Gieskes-Strijbisfonds, Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). Dr Van de Berg was financially supported by grants from Dutch Research council (ZonMW), Stichting Parkinson Fonds, Alzheimer association, Michael J Fox foundation, Parkinson Association and Health Holland. Dr van de Berg performed contract research for Hoffmann-La Roche, Roche Tissue Diagnostics, Crossbeta Sciences, DiscovericBio. All payments were made to the institution. Dr Van de Berg participates in the scientific advisory board of GT Gain Therapeutics SA; Dr Jonkman reports grants from the Alzheimer Association, Alzheimer Netherlands, Michael J Fox Foundation for Parkinson’s disease, Stichting Parkinson Fonds, Health Holland public-private partnership, and the Netherlands Organization for Health Research and Development. All payments were made to the institution; Prof. Dr Rozemuller reports no competing interests; Dr Bouwman performs contract research for Optina Dx and Optos, she has been an invited speaker at Roche and has been invited for expert testimony at Biogen. All funding is paid to her institution; Dr Hoozemans received grants from the Dutch Research Council (ZonMW) and, Alzheimer Netherlands, performed contract research or received grants from Merck, ONO Pharmaceuticals, Janssen Prevention Center, DiscovericBio, AxonNeurosciences, Roche, Genentech, Promis, Denali, FirstBiotherapeutics, and Ensol Biosciences. All payments were made to the institution. Dr Hoozemans participates in the scientific advisory board of Alzheimer Netherlands and is editor-in-chief for Acta Neuropathologica Communications.

Figures

Fig. 1.
Fig. 1.
Qualitative and quantitative distribution of Alzheimer’s disease pathology in AD clinical variants. Representative images of immunohistochemistry for phosphorylated tau (A) and amyloid-β (B) show the qualitative distribution in the hippocampal CA1 region and middle frontal gyrus of controls, typical, behavioural/dysexecutive, and posterior cortical atrophy Alzheimer’s disease. The scale bar applies to all images. Heatmaps on the bottom show the quantitative distribution of phosphorylated tau (C) and amyloid-β (D) in the different clinical variants (columns) over all analysed brain regions (rows). A low immunoreactive burden is expressed as blue and a high burden as red. See color-coding scale on the right of each heatmap for colour to immunoreactive area (%) scale. AD Alzheimer’s disease; Bv/dys behavioural/dysexecutive; CA cornu ammonis; MFG middle frontal gyrus; PCA posterior cortical atrophy.
Fig. 2.
Fig. 2.
Qualitative and quantitative distribution of activated myeloid cell markers in AD clinical variants. Representative images of immunohistochemistry for CD68 (A) and MHC-II (B) show the qualitative distribution in the hippocampal subiculum and superior parietal lobule of controls, typical, behavioural/dysexecutive, and posterior cortical atrophy Alzheimer’s disease. The scale bar applies to all images. Heatmaps on the bottom show the quantitative distribution of CD68 (C) and MHC-II (D) in the different clinical variants (columns) over all analysed brain regions (rows). A low immunoreactive burden is expressed as blue and a high burden as red. See the colour-coding scale on the right of each heatmap for colour to immunoreactive area (%) scale. AD Alzheimer’s disease; Bv/dys behavioural/dysexecutive; CA cornu-ammonis; MFG middle frontal gyrus; PCA posterior cortical atrophy.
Fig. 3.
Fig. 3.
Qualitative and quantitative distribution of complement factor C4b and reactive astrocytes in AD clinical variants. Representative images of immunohistochemistry for C4b (A) and GFAP (B) show the qualitative distribution in the hippocampal CA1 region and middle frontal gyrus of controls, typical, behavioural/dysexecutive, and posterior cortical atrophy Alzheimer’s disease. The scale bar applies to all images. Heatmaps on the bottom show the quantitative distribution of C4b (C) and GFAP (D) in the different clinical variants (columns) over all analysed brain regions (rows). A low immunoreactive burden is expressed as blue and a high burden as red. See the colour-coding scale on the right of each heatmap for colour to immunoreactive area (%) scale. AD Alzheimer’s disease; Bv/dys behavioural/dysexecutive; CA cornu ammonis; GFAP glial fibrillary acidic protein; PCA posterior cortical atrophy; SPL superior parietal lobule; Sub subiculum.
Fig. 4.
Fig. 4.
The profile of AD neuropathology and neuroinflammatory burden for each AD clinical variant across selected brain regions. Radar plots visualize the profile of mean immunoreactive burden of each studied marker (counterclockwise: phosphorylated tau, amyloid-β, C4b, GFAP, CD68, and MHC-II) in the middle frontal gyrus (A), the middle temporal gyrus (B), the inferior parietal lobule (C), and the superior parietal lobule (D) in the four clinical variants (see E for legend). Scales for each marker are illustrated in the corresponding radial axis of radar plot C. Scales represent the percentage of immunoreactive area and are applicable to all plots. Aβ amyloid-β; AD Alzheimer’s disease; Bv/dys behavioural/dysexecutive; GFAP glial fibrillary acidic protein; PCA posterior cortical atrophy; pTau phosphorylated tau.
See this image and copyright information in PMC

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