MAPT and Alzheimer disease: Evidence suggests that AD neuropathology begins with deposition of Aβ, then led by the formation of neurofibrillary tangles caused by hyperphosphorylated tau.50 A study by Luo et al.51 examined the sequence of AD biomarker changes in cognitively normal individuals and found that changes in CSF AB42/40 can appear as early as approximately 46 years, whilst CSF p-tau181 had a change point of approximately 60 years of age.