Vascular risk and genetics of sporadic late-onset Alzheimer's disease.

In recent years, it is becoming apparent that genes may play an important role in the development of late-onset Alzheimer’s disease (LOAD), and genetic studies could unravel new clues. Based on a growing vascular hypothesis for the pathogenesis of LOAD and other dementias, there is increasing interest for environmental and genetic vascular factors. Polymorphisms in different susceptibility genes already implicated in vascular disease risk are now also being suggested as possible genetic markers for increased risk of developing LOAD; however, many of these studies have shown conflicting results. Thus far, the apolipoprotein E (APOE) gene seems to be the only vascular susceptibility factor that is agreed to play a role in the multifactorial pathogenesis of AD although emerging genetic and biological evidence is now strengthening the case for additional inclusion of angiotensin I-converting enzyme 1 (ACE1) into this category. This review will focus on the current knowledge on genetic and nongenetic vascular factors likely to be involved in LOAD, with special emphasis placed on the APOE and ACE1 genes

Apolipoprotein E (APOE) polymorphism influences serum APOE levels in Alzheimer's disease patients and centenarians.

Vascular factors may play a role in the etiology of Alzheimer’s disease (AD) and increased serum apolipoprotein E (APOE) levels in AD could be of interest, as APOE concentration is associated with vascular disease. Aims of this study were to evaluate the inluence of APOE genotype on serum APOE levels, and, secondly, to study serum APOE concentrations in relation to age and AD. APOE genotypes, serum total cholesterol, LDL cholesterol, HDL cholesterol, total cholesterol/HDL cholesterol ratio, triglycerides, and serum APOE were performed on 52 healthy centenarians, 49 AD patients, 45 age-matched controls, and 72 young healthy adults. In all study population a significant trend in reduction of serum APOE levels from APOE E2- to E4 carriers was observed.The diffeerence in serumAPOE levels amonga ge groups signi¢cantly decreased in E4 carriers only, includingH DL cholesterol; no significant differences between AD patients and age-matched controls were found. In these highly selected populations, APOE genotype distribution strongly influences serum APOE concentration, not suggesting, at present, a possible role as a biochemical marker for AD, but only as a putative longevity factor

The pathophysiology of restricted repetitive behavior

Restricted, repetitive behaviors (RRBs) are heterogeneous ranging from stereotypic body movements to rituals to restricted interests. RRBs are most strongly associated with autism but occur in a number of other clinical disorders as well as in typical development. There does not seem to be a category of RRB that is unique or specific to autism and RRB does not seem to be robustly correlated with specific cognitive, sensory or motor abnormalities in autism. Despite its clinical significance, little is known about the pathophysiology of RRB. Both clinical and animal models studies link repetitive behaviors to genetic mutations and a number of specific genetic syndromes have RRBs as part of the clinical phenotype. Genetic risk factors may interact with experiential factors resulting in the extremes in repetitive behavior phenotypic expression that characterize autism. Few studies of individuals with autism have correlated MRI findings and RRBs and no attempt has been made to associate RRB and post-mortem tissue findings. Available clinical and animal models data indicate functional and structural alterations in cortical-basal ganglia circuitry in the expression of RRB, however. Our own studies point to reduced activity of the indirect basal ganglia pathway being associated with high levels of repetitive behavior in an animal model. These findings, if generalizable, suggest specific therapeutic targets. These, and perhaps other, perturbations to cortical basal ganglia circuitry are mediated by specific molecular mechanisms (e.g., altered gene expression) that result in long-term, experience-dependent neuroadaptations that initiate and maintain repetitive behavior. A great deal more research is needed to uncover such mechanisms. Work in areas such as substance abuse, OCD, Tourette syndrome, Parkinson’s disease, and dementias promise to provide findings critical for identifying neurobiological mechanisms relevant to RRB in autism. Moreover, basic research in areas such as birdsong, habit formation, and procedural learning may provide additional, much needed clues. Understanding the pathophysioloy of repetitive behavior will be critical to identifying novel therapeutic targets and strategies for individuals with autism