Is amyloid-β harmful to the brain? Insights from human imaging studies

Abstract

Although the amyloid-β protein associated with the Alzheimer's disease plaque has been detectable in living people for over a decade, its importance in the pathogenesis of Alzheimer's disease is still debated. The frequent presence of amyloid-β in the brains of cognitively healthy older people has been interpreted as evidence against a causative role. If amyloid-β is crucial to the development of Alzheimer's disease, it should be associated with other Alzheimer's disease-like neurological changes. This review examines whether amyloid-β is associated with other biomarkers indicative of early Alzheimer's disease in normal older people. The preponderance of evidence links amyloid-β to functional change, progressive brain atrophy, and cognitive decline. Individuals at greatest risk of decline seem to be those with evidence of both amyloid-β and findings suggestive of neurodegeneration. The crucial question is thus how amyloid-β is related to brain degeneration and how these two processes interact to cause cognitive decline and dementia.

Keywords: Alzheimer’s disease; ageing; amyloid; biomarkers; neurodegeneration.

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Figures

The presence of β-amyloid in the brain may represent a preclinical stage of Alzheimer’s disease, but this is controversial. Jagust examines the association between β-amyloid and biomarkers of Alzheimer’s disease in cognitively normal older people, concluding that β-amyloid is harmful to the brain in a manner consistent with Alzheimer’s disease.

Figure 1

Two different conceptualizations of how amyloid-β affects neurological outcomes. Asummarizes a preclinical staging scheme for Alzheimer’s disease in which amyloid-β deposition is the initiating event. In this scheme, brain amyloid-β deposition alone constitutes Stage 1 of preclinical Alzheimer’s disease, followed by Stage 2 in which amyloid-β leads to neurodegeneration. In Stage 3, subtle cognitive dysfunction insufficient to establish dementia or mild cognitive impairment, occurs. This scheme posits neurodegeneration as the invariable mediator between amyloid-β and cognition.Bsuggests an alternative view in which neurodegeneration and amyloid-β are independent processes. Neurodegeneration without amyloid-β has been referred to as suspected non-Alzheimer pathology (SNAP). In this scheme, either neurodegeneration or amyloid-β alone may lead to cognitive dysfunction, although the two together may produce synergistic harmful effects.