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

Neurology. 2022 Oct 11;99(15):e1619-e1629. doi: 10.1212/WNL.0000000000200930. Epub 2022 Aug 2.


Background and objectives: Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals.

Methods: The contribution of amyloid and tau pathology was assessed through 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 (WMLs) on 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 aged 70 years, 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 the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of Aβ38 and p-tau also contributed to cholinergic WM 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 nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T201 = -1.55; p = 0.123).

Discussion: In cognitively unimpaired older individuals, WMLs 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease* / diagnostic imaging
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Amyloid / metabolism
  • Amyloid beta-Peptides / metabolism
  • Amyloidogenic Proteins / metabolism
  • Amyloidosis*
  • Apolipoprotein E4 / genetics
  • Biomarkers
  • Cholinergic Agents
  • Diffusion Tensor Imaging
  • Female
  • Humans
  • Male
  • White Matter* / pathology
  • tau Proteins / metabolism


  • Amyloid
  • Amyloid beta-Peptides
  • Amyloidogenic Proteins
  • Apolipoprotein E4
  • Biomarkers
  • Cholinergic Agents
  • tau Proteins