Abstractβ-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673→valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced β-amyloid (Aβ) production and formation of amyloid fibrils in vitro. Coincubation of mutated and wild-type peptides conferred instability on Aβ aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.Acentral pathological feature of Alzheimer's disease (AD) is the accumulation of β-Aβ in the form of oligomers and amyloid fibrils in the brain (1). Aβ is generated by sequential cleavage of the APP by β-and γ-secretases and exists as short and long isoforms, Aβ1-40 and Aβ1-42 (2). Aβ1-42 is especially prone to misfolding and builds up aggregates that are thought to be the primary neurotoxic species involved in AD pathogenesis (2,3). AD is usually sporadic, but *To whom correspondence should be addressed. E-mail: ftagliavini@istituto-besta.it. Publisher's Disclaimer: This manuscript has been accepted for publication in Science. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencemag.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS. NIH Public Access Author ManuscriptScience. Author manuscript; available in PMC 2010 March 13. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript a small fraction of cases is familial (4). The familial forms show an autosomal dominant pattern of inheritance with virtually complete penetrance and are linked to mutations in the APP, presenilin 1, and presenilin 2 genes (5). The APP mutations close to the sites of β-or γ-secretase cleavage flanking the Aβ sequence overproduce total Aβ or only Aβ1-42, respectively, whereas those that alter amino acids within Aβ result in greater propensity to aggregation in vitro (6, 7).We have identified an APP mutation [Ala 673 →Val 673 (A673V)] that causes disease only in the homozygous state. The mutation consists of a C-to-T transition that results in an alanineto-valine substitution at position 673 (APP770 numbering) corresponding to position 2 of Aβ ( Fig. 1A and fig. S1) (8). The genetic defect was found in a patient with early-onset dementia and in his younger sister, who now shows multiple-domain mild cognitive impairment (MCI) In the patient, the disease presented with behavioral changes and cognitive deficits at the age of 36 years and evolved towar...

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In a double-blind, placebo-controlled, parallel-group, randomized clinical trial, we studied the efficacy of long-term (1-year) oral treatment with acetyl-L-carnitine in 130 patients with a clinical diagnosis of Alzheimer's disease. We employed 14 outcome measures to assess functional and cognitive impairment. After 1 year, both the treated and placebo groups worsened, but the treated group showed a slower rate of deterioration in 13 of the 14 outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, ideomotor and buccofacial apraxia, and selective attention. Adjusting for initial scores with analysis of covariance, the treated group showed better scores on all outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, verbal critical abilities, long-term verbal memory, and selective attention. The analysis for patients with good treatment compliance showed a greater drug benefit than for the overall sample. Reported adverse events were relatively mild, and there was no significant difference between the treated and placebo groups either in incidence or severity.

The present paper discusses the evolution of a critical plane‐based multiaxial high‐cycle fatigue criterion, known as Carpinteri–Spagnoli criterion. By proposing appropriate changes to the original formulation, the extended versions of the aforementioned criterion are able to assess smooth and notched metallic structural components subjected to different fatigue loading conditions, such as multiaxial in‐phase and out‐of‐phase synchronous cyclic loading, asynchronous cyclic loading and random loading. The results obtained through this criterion are compared with some experimental results related to relevant data reported in the literature.

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