Theorizing that the APOEε4 Variant Increases Alzheimer's Risk Through Increased Microglial Inflammation

It is well established that the ε4 variant of APOE increases the risk of Alzheimer's disease, but there is no firm consensus as to why this is the case. Theories abound. Researchers here suggest that the mechanism of interest is increased neuroinflammation, as APOEε4 increases the tendency for the innate immune cells known as microglia to become activated and inflammatory in the aging brain. There has been an increased focus on chronic inflammation in Alzheimer's disease in recent years, particularly given the continued failure to produce meaningful patient benefits via clearance of amyloid-β, with some researchers going so far as to suggest it is the primary driving mechanism in the onset and progression of the condition.

Alzheimer's disease (AD) is a multifactorial disorder neuropathologically characterized by amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Among the multiple pathogenic processes involved in AD etiology, neuroinflammation, commonly associated with microglial reactivity, has been increasingly recognized. Microglial activation plays a key role in the accumulation of AD hallmark proteinopathies, rather than being merely an epiphenomenon of their deposition. Specifically, recent observations from animal and human studies suggest that microglial activation precedes and may drive tau spread over the neocortex, from the medial temporal to association and primary sensory structures. Such microglial activation is synaptotoxic, affects brain connectivity, and predicts clinical decline. Aβ pathology can trigger microglial activation in AD, but Aβ plaques and activated microglia only partially overlap topographically in the human brain, and microglial activation may occur before demonstrable Aβ deposition.

Using complementary positron emission tomography (PET) radiotracers for the topographical quantification of microglial activation, Aβ, and tau accumulation across the brain, we investigated the association between the APOEε4 genotype, microglial activation, Aβ, and tau in a cohort of individuals across the aging and AD continuum. We hypothesized that APOEε4 is associated with microglial activation independently of AD hallmark proteinopathies. We then tested whether microglial activation mediates the effects of APOEε4 on tau accumulation, neurodegeneration, and clinical impairment.

We found that APOEε4 carriers presented increased microglial activation relative to noncarriers in regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOEε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOEε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOEε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.