1 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, H3A 2B4, QC, Canada. alfie.wearn@mcgill.ca.
2 Department of Physics, Concordia University, Montreal, H4B 1R6, QC, Canada.
3 Montreal Heart Institute, Montreal, H1T 1C8, QC, Canada.
4 School of Health, Concordia University, Montreal, H4B 1R6, QC, Canada.
5 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, H3A 2B4, QC, Canada.
6 McConnell Brain Imaging Centre, McGill University, Montreal, H3A 2B4, QC, Canada.
7 Department of Biomedical Engineering, McGill University, McGill, H3A 2B4, QC, Canada.
8 Department of Psychology, York University, Toronto, M3J 1P3, ON, Canada.
9 Douglas Mental Health University Institute-Research Center, Verdun, H4H 1R3, QC, Canada.
10 Department of Psychiatry, McGill University, Montreal, H3A 1A1, QC, Canada.
11 Department of Physiology & Pharmacology, Western Institute for Neuroscience, Western University, London, N6A 5C1, ON, Canada.
12 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, H3A 2B4, QC, Canada. nathan.spreng@mcgill.ca.
13 McConnell Brain Imaging Centre, McGill University, Montreal, H3A 2B4, QC, Canada. nathan.spreng@mcgill.ca.
14 Douglas Mental Health University Institute-Research Center, Verdun, H4H 1R3, QC, Canada. nathan.spreng@mcgill.ca.
15 Department of Psychiatry, McGill University, Montreal, H3A 1A1, QC, Canada. nathan.spreng@mcgill.ca.

The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer's disease (AD). They project broadly throughout the brain's white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development.