TREM2 risk variants are associated with atypical Alzheimer’s disease

• Published in: Acta neuropathologica 2022-12, Vol.144 (6), p.1085-1102
• Main Authors: Kim, Boram, Suh, EunRan, Nguyen, Aivi T., Prokop, Stefan, Mikytuck, Bailey, Olatunji, Olamide A., Robinson, John L., Grossman, Murray, Phillips, Jeffrey S., Irwin, David J., Mechanic-Hamilton, Dawn, Wolk, David A., Trojanowski, John Q., McMillan, Corey T., Van Deerlin, Vivianna M., Lee, Edward B.
• Format: Article
• Language: English
• Subjects: Advertising executives; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Autopsy; Dystrophy; Hippocampus; Hippocampus - pathology; Humans; Medical colleges; Medicine; Medicine & Public Health; Membrane Glycoproteins - genetics; Microglia; Microglia - pathology; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - pathology; Neurofibrillary Tangles - pathology; Neurosciences; Original Paper; Pathology; Phenotypes; Receptors, Immunologic - genetics; Tau protein
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-022-02495-4

Alzheimer’s disease (AD) has multiple clinically and pathologically defined subtypes where the underlying causes of such heterogeneity are not well established. Rare TREM2 variants confer significantly increased risk for clinical AD in addition to other neurodegenerative disease clinical phenotypes. Whether TREM2 variants are associated with atypical clinical or pathologically defined subtypes of AD is not known. We studied here the clinical and pathological features associated with TREM2 risk variants in an autopsy-confirmed cohort. TREM2 variant cases were more frequently associated with non-amnestic clinical syndromes. Pathologically, TREM2 variant cases were associated with an atypical distribution of neurofibrillary tangle density with significantly lower hippocampal NFT burden relative to neocortical NFT accumulation. In addition, NFT density but not amyloid burden was associated with an increase of dystrophic microglia. TREM2 variant cases were not associated with an increased prevalence, extent, or severity of co-pathologies. These clinicopathological features suggest that TREM2 variants contribute to clinical and pathologic AD heterogeneity by altering the distribution of neurofibrillary degeneration and tau-dependent microglial dystrophy, resulting in hippocampal-sparing and non-amnestic AD phenotypes.