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

Abstract

Alzheimer’s disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer’s degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration 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. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer’s disease using two independent samples of the Alzheimer’s Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-β and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-β moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. 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 a prior influential 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 a prevailing view of Alzheimer’s disease pathogenesis.

The relationship between cholinergic system brain structure and function in healthy adults and patients with mild cognitive impairment

“…In our MCI patients, as expected, basal forebrain volumes were smaller than in the healthy volunteers 17 . This agrees with the notion that the loss of basal forebrain volume precedes the cortical expression of AD degeneration 22 , 23 . However, unlike in healthy volunteers, there was no relationship between the structural measure of the cholinergic brain and SAI.…”

Oxidative Phosphorylation Is Dysregulated Within the Basocortical Circuit in a 6-month old Mouse Model of Down Syndrome and Alzheimer’s Disease

“…BFCN degeneration is an early pathological feature of both DS and AD and coincides with cognitive decline early in disease onset and throughout progression (Yates et al, 1980;Sendera et al, 2000;Mufson et al, 2002Mufson et al, , 2008Iulita et al, 2014). Recent imaging evidence indicates volume reductions in the basal forebrain (BF) predicts entorhinal cortex loss and cortical spread of degeneration in AD and correlates with AD biomarkers (Grothe et al, 2013;Cavedo et al, 2020;Fernández-Cabello et al, 2020;Teipel et al, 2020), suggesting BF dysfunction is one of the earliest pathological changes during the development of AD.…”

Improving Anti-Neurodegenerative Benefits of Acetylcholinesterase Inhibitors in Alzheimer’s Disease: Are Irreversible Inhibitors the Future?

“…In vivo longitudinal imaging studies indicate that degeneration of the basal forebrain in prodromal AD precedes and predicts entorhinal pathology and memory impairment [25]. Changes in basal forebrain volume is also a reliable indicator of cortical spread of AD-induced neurodegeneration, which supports the contention that basal forebrain neurodegeneration is an upstream triggering event in the development of AD [26]. Atrophy of the basal forebrain, in particular, also predicts cortical amyloid burden [27].…”