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.

阿尔茨海默病 (AD) 具有多种临床和病理学定义的亚型，但这种异质性的根本原因尚未明确。除了其他神经退行性疾病临床表型外，罕见的TREM2变异还会显着增加临床 AD 的风险。 TREM2变异是否与非典型临床或病理学定义的 AD 亚型相关尚不清楚。我们在此研究了尸检证实的队列中与TREM2风险变异相关的临床和病理特征。 TREM2变异病例更常与非遗忘性临床综合征相关。从病理学角度来看， TREM2变异病例与神经原纤维缠结密度的非典型分布相关，海马 NFT 负担相对于新皮质 NFT 积累显着降低。此外，NFT 密度而非淀粉样蛋白负荷与营养不良性小胶质细胞的增加相关。 TREM2变异病例与合并病理的患病率、范围或严重程度增加无关。这些临床病理学特征表明， TREM2变异通过改变神经原纤维变性和 tau 依赖性小胶质细胞营养不良的分布，导致海马保留和非遗忘性 AD 表型，从而导致 AD 的临床和病理异质性。