APOEε4 carriership associates with microglial activation independently of Aβ plaques and tau tangles

Abstract

Microglial activation is an early phenomenon in Alzheimer′s disease (AD) that may occur prior to and independently of amyloid-β (Aβ) aggregation. Recent studies in transgenic animal models suggest that the apolipoprotein E ϵ4 (APOEϵ4) allele may be a culprit of early microglial activation in AD. However, it is unclear whether the APOEϵ4 genotype is associated with microglial reactivity in the living human brain. Here, we tested whether APOEϵ4 carriership is associated with microglial activation in individuals across the aging and AD spectrum. We studied 118 individuals who had positron emission tomography (PET) for Aβ ([18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28), as well as clinical, genetic, and magnetic resonance imaging data. We found that APOEϵ4 carriership was associated with increased microglial activation mainly in early Braak-staging regions within the medial temporal cortex, and this effect of APOEϵ4 was independent of Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOEϵ4 on downstream tau accumulation, neurodegeneration, and clinical impairment. Interestingly, the physiological distribution of APOE mRNA expression, obtained from the Allen Human Atlas, predicted the patterns of APOEϵ4-related microglial activation in our population, suggesting that the deleterious effects of APOEϵ4 occur at the level of gene expression. These results support a model in which the APOEϵ4 has Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition. Our findings provide a rationale for the development of novel AD therapies targeting the interplay between ApoE and neuroinflammation.

Glial activation mediates phenotypic effects ofAPOEε4and sex in Alzheimer’s disease

“…Glial activation, tau, and neurodegenerative pathology first appear in the MTL and then spread to involve other cortical areas as cholinergic denervation becomes more widespread ( Figure 7A ). Across the aging and AD spectrum, APOEɛ4 carriers present increased microglial activation in early Braak stage regions within the MTL compared to noncarriers, which mediates Aβ-independent effects of APOEɛ4 on tau accumulation (62). The rapidly progressing limbic-amnestic phenotype indexes the spreading of pathology that is responsible for ushering APOEɛ4 carriers through prodromal stages of disease and over the dementia threshold, with a response to acetylcholinesterase-inhibitors (AChE-Is) that is apparent in the mild stage of AD (63).…”

Combined Connectomics, MAPT Gene Expression, and Amyloid Deposition to Explain Regional Tau Deposition in Alzheimer Disease

“…The advantage is that epicenter locations can be individually determined and thus allow for patient-tailored prediction of tau-PET patterns rather than relying on categorical subtyping, where the assignment of individuals to subtypes can be ambiguous. Second, for mapping gene expression, we focused in a hypothesis-driven manner on the MAPT gene, but we caution that the expression patterns of APOE, 58,59 or other yet-to-be-identified genes, may show similar or even stronger spatial similarity to tau-PET. However, given the large number of potential genes, an exploratory analysis bears the risk of overfitting and would require extensive cross-validation, which was beyond the scope of the current study.…”

Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease

“…The [ 11 C]PBR28 signal is negligible in individuals with low-affinity binding, while those with mixed affinity show a heterogeneous tracer signal . Thus, mixed- and low-affinity binders were excluded from the study to decrease the noise associated with artificial uptake variations . Importantly, previous studies have found no difference in AD biomarkers across different affinity groups .…”