Accumulation of neurofibrillary tangles and activated microglia is associated with lower neuron densities in the aphasic variant of Alzheimer’s disease

Daniel T. Ohm*, Angela J Fought, Adam Martersteck, Christina Coventry, Jaiashre Sridhar, Tamar Gefen, Sandra Weintraub, Eileen Bigio, M. Marsel Mesulam, Emily Rogalski, Changiz Geula

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


The neurofibrillary tangles (NFT) and amyloid-ß plaques (AP) that comprise Alzheimer’s disease (AD) neuropathology are associated with neurodegeneration and microglial activation. Activated microglia exist on a dynamic spectrum of morphologic subtypes that include resting, surveillant microglia capable of converting to activated, hypertrophic microglia closely linked to neuroinflammatory processes and AD neuropathology in amnestic AD. However, quantitative analyses of microglial subtypes and neurons are lacking in non-amnestic clinical AD variants, including primary progressive aphasia (PPA-AD). PPA-AD is a language disorder characterized by cortical atrophy and NFT densities concentrated to the language-dominant hemisphere. Here, a stereologic investigation of five PPA-AD participants determined the densities and distributions of neurons and microglial subtypes to examine how cellular changes relate to AD neuropathology and may contribute to cortical atrophy. Adjacent series of sections were immunostained for neurons (NeuN) and microglia (HLA-DR) from bilateral language and non-language regions where in vivo cortical atrophy and Thioflavin-S-positive APs and NFTs were previously quantified. NeuN-positive neurons and morphologic subtypes of HLA-DR-positive microglia (i.e., resting [ramified] microglia and activated [hypertrophic] microglia) were quantified using unbiased stereology. Relationships between neurons, microglia, AD neuropathology, and cortical atrophy were determined using linear mixed models. NFT densities were positively associated with hypertrophic microglia densities (P < 0.01) and inversely related to neuron densities (P = 0.01). Hypertrophic microglia densities were inversely related to densities of neurons (P < 0.01) and ramified microglia (P < 0.01). Ramified microglia densities were positively associated with neuron densities (P = 0.02) and inversely related to cortical atrophy (P = 0.03). Our findings provide converging evidence of divergent roles for microglial subtypes in patterns of neurodegeneration, which includes hypertrophic microglia likely driving a neuroinflammatory response more sensitive to NFTs than APs in PPA-AD. Moreover, the accumulation of both NFTs and activated hypertrophic microglia in association with low neuron densities suggest they may collectively contribute to focal neurodegeneration characteristic of PPA-AD.

Original languageEnglish (US)
Pages (from-to)189-204
Number of pages16
JournalBrain Pathology
Issue number1
StatePublished - Jan 2021


  • Alzheimer’s disease
  • activated microglia
  • neurofibrillary tangles
  • neurons
  • primary progressive aphasia

ASJC Scopus subject areas

  • Clinical Neurology
  • General Neuroscience
  • Pathology and Forensic Medicine


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