In cognitively unimpaired individuals, elevated cerebrospinal fluid neurofilament light (NfL) concentration is associated with reduced white matter microstructure, as indicated by decreased fractional anisotropy and increased mean diffusivity on diffusion tensor imaging, while plasma NfL concentration shows no such association, suggesting cerebrospinal fluid NfL reflects early axonal damage in preclinical Alzheimer’s disease.

When nerve fibers in the brain start to break down due to early Alzheimer’s changes, they release a protein called NfL into the fluid surrounding the brain. This fluid, called CSF, picks up the protein quickly because it is right next to the damaged nerves. The blood-brain barrier, which acts like a filter between the brain and blood, keeps most of this protein from entering the bloodstream at first. Only when the damage gets worse and the filter starts to leak does enough NfL get into the blood to be detected. That’s why CSF shows the damage early, but blood does not.