Genes Involved in Cerebrospinal Fluid Production as Candidate Genes for Late-Onset Alzheimer's Disease: A Hypothesis

Abstract

: In rare patients with autosomal dominant, early-onset Alzheimer's disease (AD), pathogenic mutations in the genes encoding β-amyloid precursor protein, and the γ-secretase-complex components presenilin-1 and presenilin-2 appear to result in β-amyloid (Aβ) overproduction. The pathological accumulation of Aβ in the far more common late-onset AD is more likely to be the result of deficient clearance of Aβ. There is evidence that production and turnover of cerebrospinal fluid (CSF) help to clear toxic molecules such as Aβ from the interstitial fluid space of the brain to the bloodstream. CSF production and turnover have been shown to be decreased in aging and in pathological conditions, such as normal pressure hydrocephalus and AD. Reduced formation of CSF, with diminished clearance of Aβ, may play an important role in the onset and progression of AD. If reduced CSF turnover is a risk factor for AD, then its incidence ought to be increased under conditions of CSF circulatory failure. In this paper, the authors hypothesize that genes and variations of genes involved in the CSF production and absorption may contribute to the pathogenesis of late-onset AD.