title: Where, when, and in what form does sporadic Alzheimer's disease begin?
abstract: OBJECTIVE
  Intraneuronal lesions consisting of abnormal tau protein are seen to develop from the beginning until the end-phase of the pathological process underlying Alzheimer's disease. This review highlights the earliest phase of this process.
  
  
  RESULTS
  Development of abnormal tau frequently begins during childhood or puberty in nuclei of the lower brainstem sending diffuse projections to the cerebral cortex. Nonfibrillar abnormal tau material first occurs in the proximal axon of projection neurons in the locus coeruleus. Subsequently, a similar material (pretangle material) fills the somatodendritic compartment. In contrast with the pretangle material in cell bodies and dendrites, the nonfibrillar material in the axon normally does not convert into stable fibrillary inclusions.
  
  
  CONCLUSIONS
  Projection neurons (not only those of the locus coeruleus) are sturdy and can survive for a lifetime despite the existence of Alzheimer-related abnormal tau. Currently, little understood mechanisms most probably exist that enable neurons to fulfill their general functions even when severe tau pathology is present. The proclivity of predisposed neuronal types to develop abnormal tau may be intrinsic to the human brain. However, the tempo of disease progression reveals considerable individual differences, thereby offering opportunities to study conditions that may modify disease progression.
authors.affiliation: Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical Research, University of Ulm, Ulm, Germany. heiko.braak@uni-ulm.de
authors.forename: Heiko
authors.initials: H
authors.lastname: Braak
authors.forename: Kelly
authors.initials: K
authors.lastname: Del Tredici
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D008125:Locus Coeruleus / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins