Alzheimerʹs disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis

Summary There is evidence that production and turnover of CSF help to clear toxic molecules such as amyloid-β peptide (Aβ) from the interstitial-fluid space of the brain to the bloodstream. Two changes in CSF circulatory physiology have been noted as part of ageing: first, a trend towards lower CSF production, hence a decrease in CSF turnover; and second, greater resistance to CSF outflow. Our hypothesis is that, all else being equal, the initially dominant physiological change determines whether CSF circulatory failure manifests as Alzheimerʹs disease (AD) or as normal-pressure hydrocephalus (NPH). If CSF production failure predominates, AD develops. However, if resistance to CSF outflow predominates, NPH results. Once either disease process takes hold, the risk of the other disorder may rise. In AD, increased deposition of Aβ in the meninges leads to greater resistance to CSF outflow. In NPH, raised CSF pressure causes lower CSF production and less clearance of Aβ. The disorders may ultimately converge in vulnerable individuals, resulting in a hybrid as has been observed in several clinical series. We postulate a new nosological entity of CSF circulatory failure, with features of AD and NPH. NPH–AD may cover an important subset of patients who carry the diagnosis of either AD or NPH