Cholinergic degeneration in association with tau pathology and evidence of sex differences

Introduction Nearly two-thirds of Alzheimer's disease (AD) patients are women. While AD is associated with several pathological and neurodegenerative processes, including the accumulation of amyloid-beta plaques, the spread of phosphorylated tau tangles, and the dysfunction of the cholinergic neurotransmission system, the neurobiological mechanisms contributing to the disproportional impact of AD on women remains unclear. While several recent studies, including our work, report elevated tau deposition in women, it remains unclear how sex differences in tau burden contribute to the progression of neurodegenerative processes leading to cognitive decline and higher AD prevalence in women. Throughout the progression of AD, the most consistent losses are seen in cholinergic neurons, where these losses negatively affect cognition, particularly in attention, learning, and memory formation. In-vitro models suggest that the cholinergic neuron loss may be due to the toxic interaction of extracellular tau with cholinergic muscarinic M1/M3 receptors leading to cholinergic cell death. This model is supported by post-mortem studies in both animal models and AD patients showing significant reduction of the cholinergic neurons in tau-affected brain regions. The relationship between tau and cholinergic loss has not yet been established in in-vivo human brain. Methods We examined cross-sectional imaging data from 84 clinically normal (CN) elderly participants from Alzheimer's Disease Neuroimaging Initiative (ADNI). These included structural magnetic resonance imaging (MRI) and [18F]flortaucipir positron emission tomography (PET). The degeneration of basal forebrain cholinergic system (BFCS) was measured using the VBM toolbox in SPM 12. As the BFCS nuclei lack clear anatomical borders on MRI scans, we used previously published cytoarchitectonic maps of BFCS sub-regions to identify the nucleus basalis of Meynert (NBM), which is one of the earliest AD-affected regions in BFCS. We used ADNI processed [18F]flortaucipir PET standardized uptake value ratios (SUVRs) in Braak stage composite regions I, II-II, II-IV, and V-VI that approximate the spread of tau as depicted by Braak and Braak to estimate the regional tau burden. Linear regression models were used to examine the associations between individual Braak composite regions (predictors) and NBM volume (outcome) while accounting for age, APOE status and amyloid-positivity as covariates. Results Our preliminary findings from CN women supports a significant association between early tau burden, measured with [18F]Flortaucipir SUVR in the entorhinal cortex and hippocampus, and NBM atrophy (beta = -0.17, p = 0.04;). By comparison, we did not find a significant association in age-matched men (beta = -0.1, p = 0.07). Women also exhibited a higher tau burden than men (p = 0.045 in Braak I-II ROI PET SUVR). Moreover, we detected neither a sex difference in Amyloid status nor an association between Amyloid positivity and NBM. Conclusions This is the first in-vivo study that examines the relationship between early tau pathology and cholinergic loss. Our preliminary data supports that higher tau burden in early Braak-stage regions is associated with greater degeneration in NBM. As tau is more extensive in women than men, the effects of tau on cholinergic neurons may contribute to sex differences in cholinergic loss. One of the limitations of our current structural method is that it does not capture the brain-wide degeneration of cholinergic neurons outside of the basal forebrain to identify significant sex differences in global cholinergic, particularly in subjects with mild cognitive impairment (MCI) where sex differences in [18F]Flortaucipir SUVR is more prominent than in CN and where sex differences are seen across multiple Braak-stage regions. Funding This research was supported by R01 AG066159-01 (Newhouse) and R01 MH121620 (Taylor)