Basal forebrain volume selectively and reliably predicts the cortical spread of Alzheimer’s degeneration

Abstract

Alzheimers disease neuropathology is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model posits that Alzheimers neurodegeneration starts in the entorhinal cortices, before spreading to temporoparietal cortex. Challenging this model, we previously provided evidence that degeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration (Schmitz and Spreng, 2016). There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and determining if these comparisons generalize across independent samples. Here we addressed the sequence of pathological staging in Alzheimers disease using two independent samples of the Alzheimers Disease Neuroimaging Initiative (N1 = 284; N2 = 553) with harmonized CSF assays of amyloid (A{beta}) and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over two years. We derived measures of gray matter degeneration in a priori NbM and the entorhinal regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy which tests whether baseline gray matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive pathological spread favored the NbM[->]entorhinal over the entorhinal[->]NbM model. This evidence generalized across the independent samples (N1: r=0.20, p=0.03; N2: r=0.37, p<0.001). We also showed that CSF concentrations of pTau/A{beta} moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread (t826=2.55, p=0.01). The moderating effect of CSF was robust to additional factors, including clinical diagnosis (t826=1.65, p=0.49). We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM[->]entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating the prevailing staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question the prevailing view of Alzheimers disease pathogenesis.