Alzheimer's Imaging Consortium.

Background: Autosomal Dominant Alzheimer's Disease (ADAD) is a rare and early-onset form of Alzheimer's disease with a familial pattern of inheritance. While the pathological features of ADAD, such as amyloid plaques and neurofibrillary tangles, have been extensively studied, the involvement of white matter (WM) neuroinflammation is not well-explored. In sporadic AD, the hindered ratio (HR) derived from diffusion basis spectrum imaging (DBSI) has been used to study neuroinflammation in WM. This study aims to investigate the potential role of WM neuroinflammation as an early driver in the progression of ADAD using DBSI.

Method: This study included 104 participants from the Dominantly Inherited Alzheimer Network (DIAN) Observational Study. 60 participants were identified as mutation carriers of pathologic variants in PSEN1, PSEN2, or APP. Estimated years until symptom onset (EYO) were calculated for each participant based on previous methods (1). Participants' demographics are summarized in Table 1. Diffusion MRI was acquired using a multi-b value scheme (bmax =2000 s/mm2 and 28 directions) (2). The DBSI-HR was quantified and obtained from the JHU white matter tracts. Non-parametric Kruskal-Wallis and Chi-square tests were employed to compare demographic variables. The DBSI-HR on each WM tract as a function of EYO was explored using generalized additive mixed models. All statistical tests were conducted in R4.2.2 (R Core Team). Age, sex, education, and APOE e4 carrier status were adjusted as covariates.

Result: Demographic data are summarized in Table 1. Mutation carriers had an elevated averaged DBSI-HR for total WM tracts compared to non-carriers (Fig. 1). Mutation carriers displayed divergent trends from non-carriers prior to the expected symptom onset for the posterior thalamic radiation (-5.87 EYO, Fig. 2), tapetum (-2.9 EYO), and sagittal stratum (-1.20 EYO).

Conclusion: DBSI-HR measurements indicate increased WM neuroinflammation in the posterior thalamic radiation, tapetum, and sagittal stratum prior to symptom onset in ADAD. We have recently identified these three WM tracts as having the earliest change in DBSI-HR in sporadic AD. Together, these findings suggest that WM neuroinflammation occurs prior to onset of AD symptoms.