Important Risk Factor For Alzheimer's Disease Research Articles

Risk factors for Alzheimer's disease in Russia: a case–control study

No reliable data on risk factors of Alzheimer's disease (AD) are available in Russia. We aimed to evaluate the relative importance of various putative environmental and medical risk factors of AD in a Russian population. We conducted a hospital-based case-control study. Two hundred and sixty consecutive AD patients and an equal number of cognitive impairment-free control subjects matched for sex, age, level of education and place of birth selected from nursing homes and other long-term healthcare facilities in the Novosibirsk region for the period from 1998 to 2002 were examined. A conditional logistic regression analysis was employed to calculate odds ratios (OR) and corresponding 95% confidence intervals (CI) for various putative risk factors. Of the 260 patients with AD, 187 (72%) were females. Patients' age varied from 40 to 89 years (mean +/- SD: 69.2 +/- 7.7 years). The majority of the patients (77%) had secondary education and 12% had university education. Risk factors independently associated with AD were family history of parkinsonism among first-degree relatives (OR = 4.2; 95% CI 1.2-15.1), hypothyroidism (OR = 2.7; 95% CI 1.1-6.7), and history of head trauma with loss of consciousness (OR = 1.7; 95% CI 1.0-2.8). The most important risk factors for AD in the Russian community are family history of parkinsonism, hypothyroidism and a history of head trauma with loss of consciousness. These findings have implications for developing preventive strategies of AD.

A TrkA-to-p75NTR molecular switch activates amyloid β-peptide generation during aging

Aging is the single most important risk factor for AD (Alzheimer's disease). However, the molecular events that connect normal aging to AD are mostly unknown. The abnormal accumulation of Abeta (amyloid beta-peptide) in the form of senile plaques is one of the main characteristics of AD. In the present study, we show that two members of the neurotrophin receptor superfamily, TrkA (tyrosine kinase receptor A) and p75NTR (p75 neurotrophin receptor), differentially regulate the processing of APP (amyloid precursor protein): TrkA reduces, whereas p75NTR activates, beta-cleavage of APP. The p75NTR-dependent effect requires NGF (nerve growth factor) binding and activation of the second messenger ceramide. We also show that normal aging activates Abeta generation in the brain by 'switching' from the TrkA to the p75NTR receptor system. Such an effect is abolished in p75NTR 'knockout' animals, and can be blocked by both caloric restriction and inhibitors of nSMase (neutral sphingomyelinase). In contrast with caloric restriction, which prevents the age-associated up-regulation of p75NTR expression, nSMase inhibitors block the activation of ceramide. When taken together, these results indicate that the p75NTR-ceramide signalling pathway activates the rate of Abeta generation in an age-dependent fashion, and provide a new target for both the understanding and the prevention of late-onset AD.

How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes.

A huge amount of evidence has implicated amyloid beta (A beta) peptides and other derivatives of the amyloid precursor protein (beta APP) as central to the pathogenesis of Alzheimer's disease (AD). It is also widely recognized that age is the most important risk factor for AD and that the innate immune system plays a role in the development of neurodegeneration. Little is known, however, about the molecular mechanisms that underlie age-related changes of innate immunity and how they affect brain pathology. Aging is characteristically accompanied by a shift within innate immunity towards a pro-inflammatory status. Pro-inflammatory mediators such as tumour necrosis factor-alpha or interleukin-1 beta can then in combination with interferon-gamma be toxic on neurons and affect the metabolism of beta APP such that increased concentrations of amyloidogenic peptides are produced by neuronal cells as well as by astrocytes. A disturbed balance between the production and the degradation of A beta can trigger chronic inflammatory processes in microglial cells and astrocytes and thus initiate a vicious circle. This leads to a perpetuation of the disease.

Cholinergic activity and amyloid precursor protein processing in aging and Alzheimer's disease.

Among the neuropathological features of Alzheimer's disease (AD), are senile plaques and dysfunction of cholinergic neurotransmission are the major hallmarks. Senile plaques are formed by amyloid beta-peptides (Abeta), derived from amyloidogenic processing of a larger protein named amyloid precursor protein (APP). It has been suggested and also proved that cholinergic system plays an important role in the cognitive function of the brain and its deficit correlates well with the cognitive impairment of AD. Aging is the most important risk factor for AD. In normal aging, cholinergic system undergoes degeneration. APP processing changes with aging, probably resulting in higher amyloidogenic products. The current clinical treatments for Alzheimer's disease solely rely on cholinomimetic drugs i.e., acetylcholinesterase inhibitors. Recently, a great effort has been made to seek therapies that could reduce Abeta products by influencing APP processing. Through genetic engineering in cell lines and mice, in vitro and in vivo models for AD studies have been created. Experimental evidence obtained from the studies on these model organisms suggests that activity of cholinergic neurotransmission might have an impact on APP processing. On the other hand, the proteolytic products of APP have also been found able to influence the cholinergic system in both in vitro and in vivo models. To determine whether there exists a reciprocal interaction between cholinergic neurotransmission and APP processing is important for the development of new therapeutic strategies with high efficacy and specificity for AD.

Association between tumor necrosis factor-alpha promoter polymorphism and Alzheimer's disease.

Tumor necrosis factor-alpha (TNFalpha) gene polymorphisms have been reported to be associated with Alzheimer's disease (AD) in Caucasian populations. Three TNFalpha polymorphisms (-857, -863, and -1,031) were studied in a Chinese population. A high-risk TNFalpha haplotype (-1,031C-863C-857C) with an odds ratio of 2.54 (95% CI 1.37 to 4.79) for AD was identified. No interaction effect of APOE and TNFalpha genotypes was found, but both acted as important risk factors for AD.

Compartmentalization of β-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts

Recent epidemiological studies show a reduced prevalence of Alzheimer's disease (AD) in patients treated with inhibitors of cholesterol biosynthesis [1, 2]. Moreover, the cholesterol-transport protein, apolipoprotein E4, and elevated cholesterol are important risk factors for AD [3–5]. Additionally, in vitro and in vivo studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein (APP) to β-amyloid [6–11], the major constituent of senile plaques [12–14]. Cholesterol plays a crucial role in maintaining lipid rafts in a functional state [15]. Lipid rafts are cholesterol-enriched membrane microdomains implicated in signal transduction, protein trafficking, and proteolytic processing [15–18]. Since APP, β-amyloid, and the putative γ-secretase, presenilin-1 (PS-1), have all been found in lipid rafts [12, 19–21], we hypothesized that the recently identified β-secretase, Asp2 (BACE1) [13], might also be present in rafts. Here, we report that recombinant Asp2 expressed in three distinct cell lines is raft associated. Using both detergent and nondetergent methods, Asp2 protein and activity were found in a light membrane raft fraction that also contained other components of the amyloidogenic pathway. Immunoisolation of caveolin-containing vesicles indicated that Asp2 was present in a unique raft population distinct from caveolae. Finally, depletion of raft cholesterol abrogated association of Asp2 with the light membrane fraction. These observations are consistent with the raft localization of APP processing and suggest that the partitioning of Asp2 into lipid rafts may underlie the cholesterol sensitivity of β-amyloid production.

Alzheimer's amyloid-beta as a preventive antioxidant for brain lipoproteins.

1. Increased production of A beta in a form of lipoprotein antioxidant under the action of increased oxidative stress in aging with subsequent chelation of transition metal ions by A beta, accumulation of toxic A beta-metal lipoprotein complexes, production of reactive oxygen species, and neurotoxicity are reviewed and postulated to form the temporal sequence of events in the development of Alzheimer's disease (AD). 2. Since (i) A beta binds copper stronger than iron and other transition metals, and (ii) copper is a more efficient catalyst of oxidation than other transition metals, chelation of copper by A beta is proposed to be a most important part of this pathway. 3. Whereas this amyloid-binds-copper (ABC) model does not remove A beta peptide from its central place in our current thinking of AD, it places additional factors in the center of discussion. 4. Most importantly, they embrace pathological mechanisms known to develop in aging (which is the most important risk factor for AD), such as increased production of reactive oxygen species by mitochondria, that can be positioned upstream relative to the generation of A beta.