SYMPOSIUM: Clearance of Aβ from the Brain in Alzheimer's Disease: Foreword

Most research into the pathogenesis of Alzheimer's disease (AD) over the past two decades has been influenced by the amyloid cascade hypothesis: that the neurological and neuropathological abnormalities in AD are all ultimately initiated by the accumulation of Aβ—particularly Aβ42—within the brain 1, 2, 3, 4. While the hypothesis itself does not distinguish between abnormalities in the production of Aβ and abnormalities in its removal, the evidence that underpins the hypothesis has been heavily weighted on the “supply” side of the equation, that is, the finding that Down syndrome patients with triplication of the APP gene, and patients with familial AD because of APP and presenilin mutations, all have overproduction of Aβ—either of both major forms of Aβ or specifically of Aβ42. The in vitro toxicity of Aβ and the exacerbation of tangle pathology in mice transgenic for mutant APP as well as mutant tau have also been adduced in support of the amyloid cascade hypothesis but its mainstay has been the relationship between AD and overproduction of Aβ42.

Given the circumstances that led to formulation of the amyloid cascade hypothesis, it is perhaps not surprising that research into possible abnormalities of Aβ removal in AD was for a long time very limited. Yet evidence of increased production of Aβ or Aβ42 in most cases of sporadic AD is weak. Increased β‐secretase‐1 activity has been reported (5), but other findings suggest that this probably occurs only after Aβ has started to accumulate (6). Work in the late 1990s and early part of the present decade started to elucidate the ways in which Aβ is removed from the brain. These are diverse and probably include drainage along the basement membranes of blood vessels, degradation by a range of enzymes, transport (by several proteins) across the blood–brain barrier and processes that involve the immune system. The multiplicity of ways in which Aβ can be removed suggests considerable redundancy in the system, and this has presented a challenge to researchers trying to identify the role of any single one of these removal pathways in the development of AD. However, recent studies have identified several pathways of Aβ removal that function abnormally in AD. The findings are summarized in the present symposium, whose authors have been responsible for many of the recent advances in this field.

It seems unlikely that impaired function of any one pathway of Aβ removal will prove sufficient to cause AD in otherwise normal young adults. However, we suggest that the cumulative effect of age, systemic disease, genetic and environmental factors in reducing the effectiveness of multiple pathways of Aβ removal is likely to be the main cause of AD in most patients.