CSF beta-amyloid and white matter damage: a new perspective on Alzheimer's disease

Objective To assess the connection between amyloid pathology and white matter (WM) macrostructural and microstructural damage in demented patients compared with controls. Methods Eighty-five participants were recruited: 65 with newly diagnosed Alzheimer's disease (AD), non-AD dementia or mild cognitive impairment and 20 age-matched and sex-matched healthy controls. beta-amyloid 1-42 (A beta) levels were determined in cerebrospinal fluid (CSF) samples from all patients and five controls. Among patients, 42 had pathological CSF A beta levels (A beta(+)), while 23 had normal CSF A beta levels (A beta(-)). All participants underwent neurological examination, neuropsychological testing and brain MRI. We used T2-weighted scans to quantify WM lesion loads (LLs) and diffusion-weighted images to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses. Results We found an increased WM-LL in A beta(+) compared with both, healthy controls (p=0.003) and A beta(-) patients (p=0.02). Interestingly, CSF A beta concentration was the best predictor of patients' WM-LL (r=-0.30, p<0.05) when using age as a covariate. Lesion apparent diffusion coefficient value was higher in all patients than in controls (p=0.0001) and correlated with WM-LL (r=0.41, p=0.001). In A beta(+), WM-LL correlated with WM microstructural damage in the left peritrigonal WM (p<0.0001). Conclusions WM damage is crucial in AD pathogenesis. The correlation between CSF A beta levels and WM-LL suggests a direct link between amyloid pathology and WM macrostructural and microstructural damage.