Alzheimer's Disease In Old Age Research Articles

Uric acid and late-onset Alzheimer's disease: results from the ReGAl 2.0 project.

It has been suggested that oxidative stress may have a role in the pathogenesis of Alzheimer's disease (AD). Serum uric acid (UA) could exert neuroprotective effects via its antioxidant capacities. Many studies investigated serum UA levels in subjects with AD, but to date, results are conflicting and evidence in old age subjects is weak. In this study, we assess whether serum UA levels would be altered in the AD old age subjects compared to those of initial cognitive impairment and healthy controls. This is a retrospective study with data gathered from the ReGAl 2.0 project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer's disease), a large Italian multicentric clinical-based study. A cohort of232 subjects, including 65 (healthy controls HC), 95 mild cognitive impairment (MCI), and 72 AD, were included in the study. Serum UA was measured in all subjectsby routine laboratory method. The sample population includes 232 subjects, mostly women with a mean age of 79.16 ± 5.64 (range 66-93) years. No significant difference was found in gender distribution between groups. No significant correlation was found in all populations between age and uric acid levels. AD group had significantly lower UA levels as compared with HC. The association of uric acid with AD presence after adjusting for age, gender, body mass index (BMI) and creatinine levels showed that uric acid level was independently associated with the diagnosis of AD. These data indicate that serum UA is reduced in AD, supporting that UA may have a potential protective role against AD in old age.

Attitude toward own aging as a risk factor for cognitive disorder in old age: 12-year evidence from the ILSE study.

Previous research has demonstrated the harmful impact of subjective aging processes (e.g., negative age self-stereotyping) on normal cognitive aging in different domains of cognitive functioning, such as memory, executive function, and fluid abilities. Recently, subjective aging has also been linked to important biomarkers of Alzheimer's disease (AD) and dementia-related outcomes, indicating associations with pathological cognitive aging. With data from the Interdisciplinary Longitudinal Study of Adult Development and Aging (ILSE), the present study extends this research by examining the long-term effect of attitude toward own aging (ATOA) on expert-based clinical diagnosis of mild cognitive impairment (MCI) and AD in old age. In the study, 260 initially cognitively healthy participants with a mean age of 62.5 years were followed for 12 years. In the course of the study, 103 participants developed MCI and 14 received diagnosis of AD. Logistic regression models showed that baseline ATOA predicted future clinical diagnoses of MCI and AD 12 years later, while controlling for sociodemographic, genetic, and health variables. Although theoretically suggested, evidence for a mediating role of leisure-activity level and control beliefs was scarce. Our findings add to the emerging literature supporting negative views of aging as a risk factor for cognitive disorder in old age. (PsycINFO Database Record

Candidate SNP Markers of Familial and Sporadic Alzheimer's Diseases Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters.

While year after year, conditions, quality, and duration of human lives have been improving due to the progress in science, technology, education, and medicine, only eight diseases have been increasing in prevalence and shortening human lives because of premature deaths according to the retrospective official review on the state of US health, 1990-2010. These diseases are kidney cancer, chronic kidney diseases, liver cancer, diabetes, drug addiction, poisoning cases, consequences of falls, and Alzheimer's disease (AD) as one of the leading pathologies. There are familial AD of hereditary nature (~4% of cases) and sporadic AD of unclear etiology (remaining ~96% of cases; i.e., non-familial AD). Therefore, sporadic AD is no longer a purely medical problem, but rather a social challenge when someone asks oneself: “What can I do in my own adulthood to reduce the risk of sporadic AD at my old age to save the years of my lifespan from the destruction caused by it?” Here, we combine two computational approaches for regulatory SNPs: Web service SNP_TATA_Comparator for sequence analysis and a PubMed-based keyword search for articles on the biochemical markers of diseases. Our purpose was to try to find answers to the question: “What can be done in adulthood to reduce the risk of sporadic AD in old age to prevent the lifespan reduction caused by it?” As a result, we found 89 candidate SNP markers of familial and sporadic AD (e.g., rs562962093 is associated with sporadic AD in the elderly as a complication of stroke in adulthood, where natural marine diets can reduce risks of both diseases in case of the minor allele of this SNP). In addition, rs768454929, and rs761695685 correlate with sporadic AD as a comorbidity of short stature, where maximizing stature in childhood and adolescence as an integral indicator of health can minimize (or even eliminate) the risk of sporadic AD in the elderly. After validation by clinical protocols, these candidate SNP markers may become interesting to the general population [may help to choose a lifestyle (in childhood, adolescence, and adulthood) that can reduce the risks of sporadic AD, its comorbidities, and complications in the elderly].

Recent rodent models for Alzheimer’s disease: clinical implications and basic research

Alzheimer's disease (AD) is the most common origin of dementia in the elderly. Although the cause of AD remains unknown, several factors have been identified that appear to play a critical role in the development of this debilitating disorder. In particular, amyloid precursor protein (APP), tau hyperphosphorylation, and the secretase enzymes, have become the focal point of recent research. Over the last two decades, several transgenic and non-transgenic animal models have been developed to elucidate the mechanistic aspects of AD and to validate potential therapeutic targets. Transgenic rodent models over-expressing human β-amyloid precursor protein (β-APP) and mutant forms of tau have become precious tools to study and understand the pathogenesis of AD at the molecular, cellular and behavioural levels, and to test new therapeutic agents. Nevertheless, none of the transgenic models of AD recapitulate fully all of the pathological features of the disease. Octodon degu, a South American rodent has been recently found to spontaneously develop neuropathological signs of AD in old age. This review aims to address the limitations and clinical relevance of transgenic rodent models in AD, and to highlight the potential for O. degu as a natural model for the study of AD neuropathology.

Vascular Factors and Markers of Inflammation in Offspring With a Parental History of Late-Onset Alzheimer Disease

Alzheimer disease (AD) is a complex disorder with a strong heritable component. Amyloid pathology, vascular factors, and inflammation are postulated to be involved in its pathogenesis, but causality has not been established unequivocally. To identify heritable traits in middle age that contribute to AD. We used a proven family design, comparing middle-aged offspring with and without a parental history of AD. In such a design, the offspring under study are enriched for risk factors of AD but do not yet have the disease. The Netherlands. Two hundred six offspring of 92 families with a parental history of late-onset AD and 200 offspring of 97 families without a parental history of AD. The APOE epsilon4 genotype, vascular factors, production capacity of pro- and anti-inflammatory cytokines upon stimulation with lipopolysaccharide, and circulating markers of inflammation. All outcome measures were assessed in the offspring only and not in the parental generation. More offspring with a parental history of AD carried APOE epsilon4 than those without a parental history of the disease (47% vs 21%, P < .001). Those with a parental history of AD also had higher systolic blood pressures (P = .006), higher diastolic blood pressures (P < .001), and lower ankle brachial indices (P = .005) when compared with offspring without a family history of dementia. Production capacity of pro-inflammatory cytokines in offspring with a parental history of AD was also different, with higher levels of IL-1beta (interleukin 1beta) (P < .001), IL-1beta to IL-1ra ratio (P < .001), tumor necrosis factor alpha (P = .008), IL-6 (P = .04), and interferon gamma (P = .01). All of these positive associations were independent of APOE epsilon4 genotype. Hypertension and the expression of an innate pro-inflammatory cytokine profile in middle age are early risk factors of AD in old age. For the offspring of affected families, it provides clues for screening and preventive strategies, of which blood pressure control can be implemented directly.

Parental history of Alzheimer disease associated with lower plasma apolipoprotein E levels

Variation in APOE genotype is a determinant of Alzheimer disease (AD), but the risk associated with variation in plasma apoE levels has yet to be determined. Here, we studied offspring with and without a parental history of AD to identify the effect of plasma apoE levels at middle age on the risk of late-onset AD. Some 203 offspring from 92 families with a parental history of AD were compared with 197 offspring from 97 families without a parental history of AD. APOE genotypes and plasma apoE levels were assessed in all offspring. Difference in plasma apoE level between subjects with and without a parental history of AD was calculated using robust linear regression, both stratified and adjusted for APOE genotype. Offspring with a parental history of AD were more likely to be an APOE epsilon4 allele carrier (46% vs 21%, p < 0.001) than offspring without such a parental history. Mean plasma apoE levels strongly decreased from epsilon2 to epsilon3epsilon3 to epsilon4 carriers (p < 0.001). Offspring with a parental history of AD had lower plasma apoE levels than subjects without such a history, both in analyses adjusted for APOE genotype (difference: -0.21 mg/dL, p = 0.02) and when using standardized Z scores, when stratified for APOE genotype (difference: -0.22, p = 0.009). Our findings suggest that lower plasma apoE levels in middle age could be a risk factor for Alzheimer disease in old age, independent of APOE genotype.

Attention and Executive Control Predict Alzheimer Disease in Late Life: Results From the Berlin Aging Study (BASE)

<h3>Objective</h3> Longitudinal studies of neuropsychological changes in the preclinical phase of Alzheimer disease (AD) have yielded mixed results. Although some studies report tests of episodic memory, others report tests of attention and executive functions as reliable predictors of subsequent AD. Following theoretical models of neuropsychological processes before AD onset, the authors examined the predictive value of attention and executive function in the preclinical phase of AD in old age. <h3>Methods</h3> Authors studied the cognitive performance of 187 initially normal participants of the Berlin Aging Study, a community-based representative sample of Berlin citizens age 70 to 103, over a period of 4 years. Tests of attention and executive function (Digit Letter Test, Trailmaking Part B Test, Digit Symbol Substitution Test, and Identical Pictures Test) and of learning and recall functions (Activity Recall, Memory for Text, and Paired-Associate Learning) were administered at baseline. Diagnosis of AD was made according to NINCDS-ADRDA criteria (probable AD). Receiver operating characteristics curve analyses and Cox regression analyses were used to assess the diagnostic accuracy and predictive value of the neuropsychological tests at baseline for incident AD after 4 years. <h3>Results</h3> After 4 years, 15 participants had developed AD. Tests of attention and executive function discriminated best between nonconverters and incident AD cases. A similar pattern was found in survival analyses; attention and executive function tests, together with tests of learning and recall, significantly predicted incident AD over and above age, gender, and education. <h3>Conclusion</h3> These results support theoretical models of attention and executive function in the preclinical phase of AD in old age.

Attention and Executive Control Predict Alzheimer Disease in Late Life: Results From the Berlin Aging Study (BASE)

Longitudinal studies of neuropsychological changes in the preclinical phase of Alzheimer disease (AD) have yielded mixed results. Although some studies report tests of episodic memory, others report tests of attention and executive functions as reliable predictors of subsequent AD. Following theoretical models of neuropsychological processes before AD onset, the authors examined the predictive value of attention and executive function in the preclinical phase of AD in old age. Authors studied the cognitive performance of 187 initially normal participants of the Berlin Aging Study, a community-based representative sample of Berlin citizens age 70 to 103, over a period of 4 years. Tests of attention and executive function (Digit Letter Test, Trailmaking Part B Test, Digit Symbol Substitution Test, and Identical Pictures Test) and of learning and recall functions (Activity Recall, Memory for Text, and Paired-Associate Learning) were administered at baseline. Diagnosis of AD was made according to NINCDS-ADRDA criteria (probable AD). Receiver operating characteristics curve analyses and Cox regression analyses were used to assess the diagnostic accuracy and predictive value of the neuropsychological tests at baseline for incident AD after 4 years. After 4 years, 15 participants had developed AD. Tests of attention and executive function discriminated best between nonconverters and incident AD cases. A similar pattern was found in survival analyses; attention and executive function tests, together with tests of learning and recall, significantly predicted incident AD over and above age, gender, and education. These results support theoretical models of attention and executive function in the preclinical phase of AD in old age.

STUDENTJAMA. The clinical relevance of genomic variation.

DRIVEN BY THE RECENT SEQUENCING OF THE HUMAN GEnome, the field of genetics has evolved to include the study of interindividual genomic variation. This emerging discipline focuses on the 0.1% of our genome that makes each individual genetically unique. Understanding genomic variation may improve the prediction of disease susceptibility, prognosis, and response to drug therapy, although a number of challenges will need to be addressed before this approach can be integrated into standard clinical practice. The study of interindividual genomic variation involves the identification and evaluation of single-nucleotide polymorphisms (SNPs), which are sites of variability in the nucleotide sequence of the human genome, as well as haplotypes, which are collections of SNPs that are inherited in blocks. Unlike genetic mutations, SNPs represent sites of genetic variability where the least common allele is present in at least 1% of the population. Although genetic mutations account for many rare, highly penetrant, monogenic diseases such as cystic fibrosis and sickle cell anemia, common conditions such as ischemic heart disease are thought to result from an interplay between multiple SNPs and environmental or lifestyle factors. Molecular technologies have recently enabled the mapping of SNPs across the human genome, an advance that will facilitate the study of how collections of polymorphisms may act in concert to influence clinical outcomes. The study of SNPs may lead to improved prediction of disease susceptibility and prognosis. Individuals with polymorphisms in apolipoprotein (Apo) E4 have an increased likelihood of developing Alzheimer disease in old age. Specific polymorphisms in 2C and 1-adrenergic receptors appear to act in synergy to increase the risk for heart failure. An SNP in the promoter region of the gene encoding the serotonin transporter was found to moderate the influence of stressful life events on the onset of depression. SNPs may also modify the penetrance of disease mutations. The clinical outcome of certain patients with cystic fibrosis, for example, may be influenced by a polymorphism in the promoter region of the gene encoding mannose-binding lectin. Identification of SNPs may also help individualize drug therapy, with the goal of maximizing efficacy and limiting toxicity. Individual differences in the genes encoding drug targets, metabolic enzymes, and transport proteins may contribute to the variation in drug response commonly observed in patients. More than 20 SNPs, for example, have been identified in the cytochrome (CYP) p450 system, a family of hepatic enzymes that metabolize the majority of drugs used in clinical practice. Some SNPs decrease the activity of these enzymes and lead to increased drug levels and risk of toxicity, while others increase their activity and result in subtherapeutic concentrations. Tailoring drug dosage to unique SNP profiles may therefore represent a more rational approach to prescribing drugs. Patients who have CYP269 polymorphisms, for example, have a higher risk of bleeding when taking warfarin, and could thus be given lower doses. Despite the potential value of studying SNPs, there are important limitations to this approach. First, there are considerable analytic challenges in identifying multiple SNPs across the genome that collectively increase the risk for particular diseases or outcomes. Second, some diseases that can be predicted by SNPs may not be preventable, creating difficult clinical and ethical dilemmas about whether such tests should be performed. Third, some SNPs may be more prevalent in certain racial and ethnic groups, potentially leading to inequalities in the application of genetic information to clinical care. Without extensive study, it is also uncertain how genetic risks (particularly when small) should be used in conjunction with other risk factors to guide clinical decisions. For instance, a variant of the cardiac sodium channel gene SCN5A present in 13.2% of African Americans leads to a slightly increased risk for cardiac arrhythmia. The overall risk for this outcome, however, is also influenced by a number of other factors including hypokalemia, the use of specific medications, and the presence of structural heart disease. Despite these challenges and limitations, the potential benefit of using SNPs to guide medical practice is fueling the development of improved SNP maps and a human haplotype map that incorporates genomic data from different ethnic groups.

Language in adults with Down syndrome

In this paper, we will try to supply at least a partial answer to the three following questions. First, what language levels are reached by adults with Down syndrome? Second, is there progress in language or some aspects of it beyond adolescence and during the adult years? This question is related to the issue of a critical period for language development raised by Eric Lenneberg (1967). Third, what is the effect of ageing on the language of persons with Down syndrome, including those who develop Alzheimer disease in old age?