The impact of polygenic risk for alzheimer’s disease on neurotransmitter-related grey matter atrophy in the alzheimer continuum

Alzheimer’s disease (AD) pathology has been recently shown to accumulate in multiple brainstem nuclei in pre-cortical disease stages. However, the impact of neurotransmission alterations on brain atrophy and their genetic correlates in AD remain unexplored. This study investigated (1) associations between grey matter (GM) loss and uptake values of PET/SPECT ligands tracing concentration of multiple neurotransmitter receptors/transporters and pathways; (2) the impact of AD polygenic risk scores (AD-PRSs) on such associations along the AD continuum. T1-weighted MRI scans, genetic and clinical data were selected for 800 ADNI participants: 203 cognitively unimpaired older adults (CU), 442 with mild cognitive impairment (MCI) and 155 with AD. JuSpace was used to calculate correlations between GM volume (GMV) and the concentration of several neurotransmitters. Two PRSs, with (AD-PRS) and without APOE (AD-PRSnoAPOE), were investigated as predictors of the strength of correlation between GMV and neurotransmitters in general linear models. In both patient groups, atrophy was negatively associated with serotoninergic and dopaminergic receptors/transporters. In the whole sample, both PRSs were associated with the strength of correlation between GMV and different serotonin receptors and fluorodopa uptake. The pattern of associations was replicated in participants with evidence of amyloid pathology. GM loss in AD may be particularly affected by the alterations in serotoninergic and in presynaptic dopaminergic activity that are known to influence functioning of medio-temporal and frontal cortices. Such alterations appear to be driven by higher AD-PRS values. Investigating further neurotransmitter-related neural alterations may help clarifying neuropathological changes in pre-clinical AD and response to treatments.