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Prevention of Alzheimer's disease in high risk groups: statin therapy in subjects with PSEN1 mutations or heterozygosity for apolipoprotein E epsilon 4

DOI: 10.1186/alzrt55

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Abstract:

To date, there have been no systematic treatment studies on subjects with presenilin (PSEN) mutations [1] who inherit an autosomal dominant form of early onset familial Alzheimer's disease (AD). The principal objective of this review is to summarize the existing published pilot studies that address the issues of presymptomatic intervention in early onset familial AD and to compare these results with analogous treatment studies in hyperlipidemic subjects who are heterozygous for apolipoprotein Eε4 (ApoEε4). Our decision to focus on studies of presymptomatic rather than symptomatic subjects was based on the premise that most putative therapies for AD are likely to have more demonstrable effects on normal subjects compared to those with overt AD whose brains have already been subject to extensive neurodegenerative changes. We also recognize that it is not yet known whether any preventative opportunities that may arise as a consequence of an understanding of the pathogenesis of PSEN1 mutations will be applicable to the vastly larger number of cases of mild cognitive impairment and late onset AD (LOAD).Both groups of subjects exhibit early increased brain deposition of amyloid-beta 42 (Aβ42), which many researchers [2,3] have proposed is either a direct or intermediary toxic agent in the genesis of the neurodegeneration that subsequently leads to AD. Homozygotes for ApoEε4 are at far greater risk for late onset AD than are heterozygotes, but we did not identify a sufficiently large enough group of the former to comprise a separate study group. Decreases in cerebral spinal fluid (CSF) Aβ42 levels precede cognitive decline in subjects with PSEN1 mutations [4,5]. Consequently, in these subjects there is a window of opportunity - estimated as at least 4 to 12 years - to evaluate the ability of any putative prophylactic therapy to decrease, arrest or reverse abnormalities in Aβ42 metabolism many years before clinical symptoms of AD occur. For example, increased levels of CSF

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