Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals

Abstract

Objectives:Several pathological processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers towards the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals.Methods:The contribution of amyloid and tau pathology was assessed through cerebrospinal fluid (CSF) levels of the Aβ42/40 ratio and phosphorylated tau (p-tau). CSF Aβ38 levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions on magnetic resonance imaging (MRI). Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE 𝜀4 carriership were also included in the analysis as variables of interest.Results:We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals 70 years old, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (Increase in mean square error (IncMSE)=98.8% in external capsule pathway and IncMSE=93.3% in the cingulum pathway). Levels of Aβ38 and p-tau also contributed to cholinergic white matter degeneration, especially in the external capsule pathway (IncMSE=28.4% and IncMSE=23.4%, respectively). The Aβ42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE 𝜀4 carriers showed poorer integrity in the cingulum pathway (IncMSE=21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE=21.55%), which was independent of amyloid status as reflected by the non-significant differences in integrity when comparing amyloid positive versus amyloid negative women participants (T201=-1.55; p=0.123).Conclusions:In cognitively unimpaired older individuals, WM lesions play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.

Cholinergic white matter pathways along the Alzheimer's disease continuum

“…Further, we included WM hypointensities as an extra predictor because our clinical groups differed in WM-hypointensity load, and we had previously demonstrated that WM hypointensities make a major contribution to integrity in cholinergic WM pathways. 27 , 45 Finally, we also included age, sex and years of education to consider the contribution of these variables, as they usually influence cognitive performance. To compare the role of the integrity of the cholinergic pathways and the NBM volume along the Alzheimer’s disease continuum, we created two separate RF models: one for HC and SCD combined, and one for MCI and Alzheimer’s disease combined.…”

White matter hyperintensities in cholinergic pathways may predict poorer responsiveness to acetylcholinesterase inhibitor treatment for Alzheimer’s disease

“…Still, WMHs could be driven by other pathological processes of neurodegeneration. In one recent study evaluating the cholinergic integrity in cognitively unimpaired individuals, WMH load was not correlated with amyloid or tau amount [43].…”

Cerebrovascular co-pathology and cholinergic white matter pathways along the Lewy body continuum

“…Finally, pathway-speci c binary masks were created. To characterize the microstructure properties of the tracked cholinergic pathways, we extracted the index of mean diffusivity (MD) from the diffusion tensor model, consistent with previous studies using this tractography method [16, 17,36,41,42].…”