Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features.

Mutations of three different genes, encoding ß-amyloid precursor protein (APP), presenilin 1 and presenilin 2 are associated with familial Alzheimer's disease (AD). Recently, the APP mutation A673V has been identified that stands out from all the genetic defects previously reported in these three genes, since it causes the disease only in the homozygous state (Di Fede et al. in Science 323:1473-1477, 2009). We here provide the detailed neuropathological picture of the proband of this family, who was homozygous for the APP A673V mutation and recently came to death. The brain has been studied by histological and immunohistochemical techniques, at the optical and ultrastructural levels. Cerebral Aß accumulation and tau pathology were severe and extensive. Peculiar features were the configuration of the Aß deposits that were of large size, mostly perivascular and exhibited a close correspondence between the pattern elicited by amyloid stainings and the labeling obtained with immunoreagents specific for Aß40 or Aß42. Moreover, Aß deposition spared the neostriatum while deeply affecting the cerebellum, and therefore was not in compliance with the hierarchical topographical sequence of involvement documented in sporadic AD. Therefore, the neuropathological picture of familial AD caused by the APP recessive mutation A673V presents distinctive characteristics compared to sporadic AD or familial AD inherited as a dominant trait. Main peculiar features are the morphology, structural properties and composition of the Aß deposits as well as their topographic distribution in the brain.

A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis.

beta-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 beta-amyloid (Abeta) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Abeta 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.

Pharmacokinetics and Safety of a Potential Antidementia Compound, CL 275,838, after Multiple Oral Doses in Patients with Dementia of Alzheimer Type or Vascular Dementia.

The multiple-dose pharmacokinetics and safety of a new potential antidementia compound, CL 275,838, were examined in two randomized, double-blind, parallel-group, placebo-controlled studies. The Alzheimer Disease Assessment Scale (ADAS) was employed to preliminarily assess the patients' cognitive and the behavioral profiles. In the first study, nine patients with Alzheimer type or vascular dementia were treated for 2 weeks with daily doses of 50 mg. In the second study, nine other patients, selected with the same inclusion/exclusion criteria and treated following the same experimental design, were given 100 mg day(minus sign1) CL 275,838. At the lower dose, no side effects were detected; in the 100-mg day(minus sign1) study, mild drowsiness (one patient) and moderate agitation (two patients) were observed. Laboratory tests showed no changes in either study, apart from a slight, transient increase in serum bilirubin in one patient given 100 mg. At the dose of 50 mg, no patients showed any modification on the ADAS, whereas three patients given 100 mg showed some improvement. During the 2 weeks of oral dosing, predose plasma concentrations of the parent compounds and its metabolites II and IV increased but not in proportion to the dose, although at both doses, accumulation was essentially complete within 10 days. At 50 mg, the mean steady-state C(max) and C(ss) of the parent compound were similar to those reached in young males after a comparable regimen. Mean steady-state metabolite-to-parent drug ratios were higher in patients than in healthy individuals, although there was wide variation in our patient group. Mean washout t(1/2) of the parent compound (34 h) and its metabolites II (37 h) and IV (41 h) were longer than in young men and were similar in all cases to those observed after single doses in healthy elderly subjects. After 100 mg, mean C(max) and C(ss) of the unchanged compound rose more than proportionally and the apparent t(1/2) tended to rise, compared with the lower dose. Mean steady-state oral clearance decreased, changing the metabolite-to-parent drug ratios, suggesting nonlinear kinetics after several relatively high oral doses. This might explain why the higher dose was less well tolerated.