Some individuals seem to be resilient to AD. Although these individuals develop the classic hallmarks of the disease—bundles of amyloid plaque and neurofibrillary tau tangles—they do not develop dementia symptoms in their lifetime.
Studies suggest that resilience to the pathology may be associated with reduced levels of neuroinflammation, thought to be universal in symptomatic AD. Instead of promoting neuroinflammation, the essential immune cells in the brain—microglia and astrocytes—remain in their housekeeping state and do not become disease-associated despite a significant burden of amyloid plaques and tau tangles. Therefore, identifying predictive markers of resilience and understanding the underlying mechanisms involved may be key to therapeutically mimicking the brain’s natural protection against amyloid beta and tau, and developing novel therapies for AD that preserve cognition.
Research has shown that the higher the number of amyloid plaques and tau tangles and the wider their spread in the brain, the more likely it is for an individual to experience AD dementia symptoms. While amyloid plaques begin to accumulate 15 to 20 years before symptom onset, the spread of tau tangles has been shown to better correlate with symptom progression. However, even though neuroinflammation has also been shown to associate with symptom progression, it is largely unknown how neuroinflammation relates to tau spread and if it correlates with symptoms any differently. Thanks to a breakthrough study led by CureAlz investigator Teresa Gomez-Isla, M.D., from Massachusetts General Hospital we are learning that neuroinflammation may be preceding tau spread in symptomatic individuals with AD and its occurrence may even be a better predictor of cognitive status than the spread of tau. The results appeared in Acta Neuropathological Communications.
The study began with the research team examining markers of neuroinflammation in two brain regions that are affected at different stages of the tau spread pathway. Tau tangles spread along a known pathway affecting different regions of the brain. To stage the severity of tau spread, researchers and clinicians use the widely accepted Braak staging from I to VI which represents the increasing spread of tau tangles across the brain.
The study included postmortem brain samples from 55 individuals from three groups: one group of age-matched cognitively normal controls, and two groups of subjects with intermediate tau pathology (Braak stage III-IV), one without symptoms (i.e., the resilient group), and the other with dementia symptoms. Subjects in both the resilient and the symptomatic group had comparable amyloid plaque load. Importantly, the study cohort was free of known comorbidities, like Lewy bodies and vascular impairments, that could have otherwise contributed to an individual’s cognitive symptoms.
The research team first examined markers of neuroinflammation in the temporal pole, a region of the brain associated with emotional processing affected at the intermediate Braak stages III-IV. Then, the scientists looked at neuroinflammation markers in the visual cortex, a region of the brain responsible for visual processing affected at advanced Braak stages V-VI. Thus, intermediate tau spread at Braak stages III-IV provided the researchers a unique prospect to investigate what happens in later Braak V-VI regions in the tau pathway that precede tau tangles.
The scientists observed increased markers of neuroinflammatory and decreased markers of resting microglia and astrocytes in both the temporal pole and the visual cortex in the symptomatic group. In contrast, the same neuroinflammatory markers were not increased in the resilient and control groups. Since neuroinflammation was observed in both regions of the tau pathway in the symptomatic samples, the results of the experiments suggest that neuroinflammation preceded tau spread because of the absence of neuroinflammation in the resilient samples, the researchers concluded that neuroinflammation correlated better with cognitive symptoms than tau spread alone.
Building on their observation that cognitive symptoms are not driven solely by tau tangles, the research team next assessed if neuroinflammation is related to cellular damage that ultimately underlies the brain’s neurodegeneration and an individual’s cognition. The researchers found that early markers of cellular damage were observed in both the temporal pole and the visual cortex of symptomatic individuals leading the scientists to suggest that cell damage correlating with neuroinflammation also preceded tau spread. These results reveal the possibility that neuroinflammation may be contributing to the brain’s vulnerability in regions not yet affected by tau tangles.
Thanks to the researchers’ comprehensive analysis, which also included semiquantitative AI methods, the study shows that neuroinflammation represents an early phenomenon in AD that may precede tau deposition and likely contributes to cell damage and loss of brain function. Markers of neuroinflammation may therefore be used to predict the cognitive status of individuals at intermediate stages of tau spread. The findings of the study advance our understanding of how the absence of neuroinflammation may be conferring resilience to AD and further demonstrate that the process is an AD therapeutic target of value.
Teresa Gomez-Isla, M.D., Massachusetts General Hospital
Acta Neuropathological Communications