Editors' ChoiceAlzheimer’s Disease

A Window of Opportunity for Alzheimer’s Disease

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Science Translational Medicine  22 Aug 2012:
Vol. 4, Issue 148, pp. 148ec150
DOI: 10.1126/scitranslmed.3004769

Alzheimer’s disease is the most common form of dementia, affecting millions of individuals worldwide. The rapidly escalating personal and public costs associated with Alzheimer’s disease makes the need for new diagnostic and therapeutic approaches of paramount importance. In rare instances, Alzheimer’s disease runs in families in an autosomal dominant fashion, and symptoms appear at much younger ages than for the more common sporadic form of the disease. One of the clinical hallmarks of hereditary Alzheimer’s disease is that the age of onset of affected offspring often mimics the age of onset of the disease in the parent. Therefore, if one knows the age of onset in the parent one can predict when symptoms will begin in the child. However, there is limited understanding of the chronology of events leading to dementia and no good tools exist for monitoring disease progression or for modifying the disease process.

In an attempt to address this, Bateman and colleagues performed a prospective trial in which several critical factors were analyzed in 128 individuals affected by hereditary Alzheimer’s disease. These included clinical and cognitive testing, cerebrospinal fluid (CSF) and blood sampling, and brain imaging with positron emission tomography technology. What they found was a cascade of events that began 25 years before any clinical symptoms were apparent. The earliest change was found in the CSF, where concentrations of a pathogenic peptide amyloid-beta (Aβ)42 began declining more than 2 decades before symptom onset. This was followed by increasing CSF concentrations of tau, another protein implicated in Alzheimer’s disease, as well as signs of brain atrophy 15 years before patients experienced symptoms. Decreased brain metabolism and memory impairment were apparent more than 10 years before the clinical diagnosis of dementia. Cognitive testing detected global cognitive dysfunction 5 years before predicted symptom onset. Interestingly, none of the unaffected family members demonstrated any of these cognitive or metabolic changes, suggesting that the process is highly specific for Alzheimer’s disease.

The results of this study suggest that dementia in Alzheimer’s disease is a very late event following a series of changes in the brain that occur over many decades. This long window provides a unique opportunity to develop new disease-modifying therapeutic modalities that could be administered before irreversible damage to brain neurons has occurred. Whereas analogous changes are likely to take place in nonfamilial forms of Alzheimer’s disease, future prospective trials are needed to generalize these results to the common sporadic later-onset forms of this disease.

R. J. Bateman et al., Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 12 July 2012 (10.1056/NEJMoa1202753). [Full Text]

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