Changes of basal forebrain volume along the Alzheimer’s disease continuum in Down syndrome

Background Atrophy of basal forebrain (BF) cholinergic neurons is an early event in Alzheimer’s disease (AD) and is associated with cognitive impairment. Down syndrome (DS) is now recognized as a genetically determined form of AD. Therefore, people with DS represent a priority population to study biomarkers of AD pathology and neurodegeneration. Degeneration of BF neurons occurs both in sporadic AD and in DS brains with advanced AD pathology. However, the dynamics of BF atrophy and its changes with age and AT(N) biomarkers have not been studied in DS. Method We included 246 adults with DS (mean age 43.2 ±11.0 years; 43% female). Volumes of antero‐medial and posterior areas of the BF (amBF and pBF, respectively) were extracted from T1‐weighted 3T MR images using voxel‐based morphometry in SPM12 in combination with a stereotactic atlas of BF functional subdivisions (Figure 1). Differences in amBF and pBF volume in each AD clinical stage (Asymptomatic, Prodromal and Demented) were assessed with Kruskall‐Wallis and pairwise Wilcoxon tests. The relationship of BF volumes with age and AT(N) biomarkers in the cerebrospinal fluid (CSF) (amyloid‐β 42/40 ratio [aβ ratio], phosphorylated Tau 181 [pTau], total Tau [tTau] and neurofilament light [NFL]) was assessed in a subset of subjects (n = 161 [aβ ratio, pTau and tTau] and n = 95 [NFL]) with locally estimated scatterplot smoothing (LOESS) and linear regression in R, respectively. Result Volumes of amBF and pBF decreased significantly with age (Figure 2), with a steeper decline during the fifth decade of life. BF volumes also declined with AD clinical stage (Figure 3), and had significant correlations with CSF aβ ratio (p<0.001 r2 = 0.22), pTau (p<0.001 r2 = 0.20), tTau (p<0.001 r2 = 0.20) and NFL (p<0.001 r2 = 0.33) (Figure 4). Conclusion In DS, BF volume decreases with age, AT(N) biomarkers and along the cognitive stages of the AD continuum.