Late-onset Sporadic Alzheimer's Disease Research Articles

A novel polymorphic purine complex at the 1.5 kb upstream region of the human caveolin‐1 gene and risk of Alzheimer's disease; Extra‐short alleles and accumulated allele homozygosity

Crucial interaction of caveolin-1 (CAV1) with beta- and gamma-secretases, and aberrant expression of the gene encoding this protein in Alzheimer's disease (AD) support a role for CAV1 in the pathophysiology of this disease. We report a novel polymorphic purine complex stretching approximately 150 bp of genomic DNA at the 1.5 kb upstream region of the human CAV1 gene, alleles and genotypes of which are associated with sporadic late-onset AD. Extra-short alleles were observed in the case group that were absent in the control subjects. Remarkably, 63% of these alleles were observed to be homozygous in length, forming 23.7% of the homozygote length compartment in the AD cases (chi(2) = 19.08, df = 1, P < 0.000007). Increased homozygosity for length was also observed at this region in the Alzheimer's cases, for the allele lengths shared by the case and control groups [(chi(2) = 30.75, df = 1, P < 0.0000000, OR = 4.54, CI 95% (2.56-8.3)]. This region contains GGAA and GAAA motifs, the consensus binding sites for the Ets and IRF family transcription factors, respectively, and is highly conserved in distantly related non-human primates in respect with location and motif sequence. The effect of this complex sequence on the expression of CAV1, and the related mechanisms in the pathophysiology of AD remain to be clarified.

How fast will it go, doc?

“How fast will it go, doc?” This is one of the most unsettling questions asked by frightened relatives of patients with newly diagnosed Alzheimer disease (AD). Although on average the duration of AD from diagnosis to death is around 10 years, variability is large, with a significant proportion of patients with duration shorter than 5 years and others of 20 years and longer. A number of clinical and genetic features have been found in early studies to be associated with faster disease progression, such as parkinsonism and psychosis,1 aphasia,2 and apoE genotype.3 However, some of these findings can now be interpreted as being due to contamination of the study groups with dementia with Lewy bodies, frontotemporal dementia, and genetic forms of dementia, all known to have faster progression and lower survival than sporadic late onset AD.4,5 Prediction of disease progression in patients with true AD …

Genetic analysis of tumor necrosis factor-α (TNF-α) G-308A and Saitohin Q7R polymorphisms with Alzheimer's disease

Neuroinflammation and abnormal phosphorylation of TAU proteins have been implicated in the etiology of Alzheimer's disease (AD). Several studies have suggested the G-308A promoter polymorphism in one of the proinflammatory cytokine genes tumor necrosis factor-alpha (TNF-alpha) encoding TNF-alpha may be associated with AD pathogenesis. Association between the Q7R polymorphism in saitohin (STH), a gene nested within the intron of the Tau gene, has also been reported. To determine whether these two polymorphisms contribute to the risk for late-onset AD (LOAD) in Chinese, we have investigated 207 sporadic LOAD patients and 222 healthy controls. The associations of the AA genotype and A-allele with LOAD (chi(2) = 8.74, df = 1, P = 0.0031, and chi(2) = 4.47, df = 1, P = 0.035) were found. After stratifying by apolipoprotein E allele 4 (APOE epsilon4) status, increased LOAD risks associated with the AA genotype and A-allele only in the APOE epsilon4 non-carriers (chi(2) = 9.21, df = 1, P = 0.002; chi(2) = 10.02, df = 1, P = 0.0015) were seen. These results suggested that the TNF-alpha gene G-308A polymorphism might be a risk factor for LOAD and dependent on APOE epsilon4 status in Chinese. Homozygous Q/Q of STH Q7R polymorphism was the only one genotype found in either LOAD group or controls. No R allele was detected in LOAD and control groups. The extremely rare frequency of the ancestral R allele differs sharply from that observed in studies in the Caucasian population, suggesting obvious ethnic differences.

Polymorphisms at the β2-adrenergic receptor gene influence Alzheimer's disease susceptibility

Increasing evidence indicates that the β2-adrenergic receptor (β2-AR) may play an important role in Alzheimer's disease (AD). We investigated the effect of two polymorphisms in the β2-AR gene: Gly16Arg and Gln27Glu for the risk of sporadic Late Onset Alzheimer's Disease (LOAD) in 109 patients and 109 healthy controls matched for sex and age in a Han Chinese population. Results revealed that both the 16Gly allele and the 27Glu allele of the β2-AR gene were associated with an increased risk of LOAD ( P = 0.009, OR = 1.652 and P = 0.002, OR = 2.846, respectively), and they also showed a highly significant interaction with the Apolipoprotein E gene (APOE) ε4 allele (OR = 4.200 and 9.441, respectively). Examination of the haplotypes identified the Gly16Glu27 haplotype to increase the risk of LOAD ( P = 0.004). Our results suggest that variations in the β2-AR gene play an important role in the pathogenesis of sporadic LOAD, and interact with the ε4 allele to markedly increase the LOAD risk.

JNK and ERK1/2 pathways have a dual opposite effect on the expression of BACE1

The activity of β-secretase (BACE1), the endo-protease essential for the production of amyloid β (Aβ) peptides, is increased in brain of late-onset sporadic Alzheimer's disease (AD), and oxidative stress is the potential cause of this event. Oxidative stress up-regulates the expression and the activity of BACE1 in cellular and animal models, through a mechanism that involves the increase of γ-secretase cleavage on APP and the activation of c-jun N-terminal kinase/activator protein 1 (JNK/AP1) pathway. We further characterized the cellular pathways that control BACE1 expression under oxidative stress. We investigated the involvement of extracellular signal regulated MAP kinase (ERK1/2) pathway in the regulation of BACE1 expression, since it has been recently shown that ERK1/2 is an endogenous regulator of the γ-secretase activity. We found that ERK1/2 pathway negatively modulates BACE1 expression and activity. Moreover, we observed that conditions that abrogate the γ-secretase activity favor the activation of signalling pathways that promote cell survival, such as ERK1/2 and the serine/threonine kinase Akt/protein kinase B (Akt). These data suggest that the positive or negative cellular responses to oxidative stress parallel the activities of the β- and the γ-secretase. ERK1/2 and JNK pathways are involved in this bipartite response, which can lead to neurodegeneration or neuroprotection depending on the cellular and environmental conditions or cooperation with other signalling pathways such as Akt cascade.

Can Diet Modifications Play a Preventative Role in the Onset of Alzheimer’s Disease?

Alzheimer’s disease (AD) is a growing public health concern with potentially devastating effects. At present, there are no methods of prevention or any known cures for the disease. While genetic factors are relevant in early-onset cases, they are less relevant in late-onset sporadic AD, which is the most common form [1]. Research seeking to find drugs to slow its progression may pay off – someday. However, as the disease typically strikes very late in life, delaying its symptoms could be a good cure for many people. For example, it is now widely accepted that delaying the onset of the disease by even 5 years can cut its incidence in half. Indeed, clinical and epidemiological evidence points to lifestyle factors, including nutrition, as being crucial in delaying the onset of AD. Mounting evidence suggests that brain cells are remarkably responsive to what somebody is doing or eating. Among other nongenetic factors influencing AD, recent studies strongly support the hypothesis that certain dietary factors, such as the Mediterranean diet, may play a beneficial role in the relative risk for AD clinical dementia. Indeed, the effect of diet in AD has been an area of research that has produced enlightening results. More importantly, the evidence supporting a direct link between nutrition and AD neuropathology and dementia continues to grow, as the mechanistic pathways are defined and their biochemical functions scrutinized. Most remarkably, there is also evidence that high caloric intake in the form of saturated fat promotes AD-type neuropathology and, conversely, caloric restriction via reduced carbohydrate intake can prevent it. This evidence is very exciting and is consistent, in part, with current epidemiological studies, which suggest that obesity and diabetes are associated with a more than fourfold increased risk for developing AD. Clarifying the mechanisms through which certain dietary lifestyle factors and caloric intake may ultimately influence AD neuropathology will provide new avenues for the design of ‘therapeutic lifestyle strategies’ to treat AD, and possibly other neurodegenerative disorders.

Sodium lactate differently alters relative EEG power and functional connectivity in Alzheimer’s disease patients’ brain regions

Bilateral temporo-parietal hypoperfusion and decreased glucose metabolism are characteristic in vivo findings in Alzheimer's disease (AD). Lactate is a metabolic vasodilator and is known to induce increased cerebral blood flow in healthy adults. The present study addresses the issue whether sodium lactate infusion affects functional state and resulting electroencephalographic patterns of AD patients. Twelve late-onset sporadic AD probands participated in this self-control study. The relative power and synchronization likelihood (SL) values of the electroencephalographic samples were calculated and compared off-line before and after sodium lactate infusion (0.5 M, 5 ml/kg body weight). Based on the reactivity to sodium lactate the scalp could be divided into three parts; no significant changes were seen in the seriously damaged (P3-P4) areas. The moderately affected regions in the close neighborhood showed a paradoxic inactivation with electroencephalographic slowing, a likely consequence of the metabolic-like steal effect of the near-normal areas outside. These results indicate a diminished vascular and/or metabolic reserve capacity to sodium lactate challenge in AD and confirm the formerly described electroencephalographic abnormalities.

The association of mitochondrial aldehyde dehydrogenase gene (ALDH2) polymorphism with susceptibility to late-onset Alzheimer's disease in Chinese

A functional polymorphism of mitochondrial aldehyde dehydrogenase gene (ALDH2 1/2 polymorphism) can influence the accumulation of acetaldehyde which may have a role in Alzheimer's disease (AD), and is widely prevalent among Mongoloids. Therefore ALDH2 1/2 polymorphism may represent a good candidate for genetic risk factors for AD, especially in East Asian. A case-control study from Japan found that ALDH2*2 was associated with late-onset AD (LOAD), interacting synergistically with the presence of the apolipoprotein E allele 4 (APOE epsilon4). But the subsequent studies in Koreans didn't find the similar result. To determine whether the ALDH2 gene 1/2 polymorphism contributes to the risk for LOAD in Chinese, we have investigated 188 sporadic LOAD patients and 223 healthy controls from Chinese. A significantly increased risk of AD in the carriers of ALDH2*2 allele (OR=3.11, 95% CI 2.06-4.69, P<0.001) was observed. After stratifying by APOE epsilon4 status, increased LOAD risks associated with the ALDH2 2 allele carriers only in the APOE epsilon4 non-carriers (chi2=31.79, df=1, P<0.001) and with the 2-allele in either groups (chi2=6.64 df=1, P=0.0099 and chi2=37.38, df=1, P<0.001) were seen. These results suggested that the ALDH2 gene 1/2 polymorphism might be a risk factor for LOAD and dependent on APOE epsilon4 status in Chinese.

Association Between Alzheimer’s Disease and the NOS3 gene Glu298Asp Polymorphism in Chinese

The oxidative stress caused by nitric oxide (NO) in the brain has been proposed as a pathogenic mechanism in Alzheimer's disease. Endothelial NO synthase (ecNOS) produces the majority of circulating NO. The biological functional and genetic association studies suggested that the Glu298Asp polymorphism of the ecNOS gene (NOS3) may be a genetic risk factor for late-onset Alzheimer's disease (LOAD). To investigate an association between the NOS31 Glu298Asp polymorphism and sporadic LOAD in Chinese, we examined 338 LOAD patients and 378 healthy controls. The associations of the Glu/Glu genotype and Glu allele with LOAD (chi2 = 9.12, df = 1, P = 0.003 by genotype; chi2 = 8.37, df = 1, P = 0.038 by allele) were found. After stratifying by apolipoprotein E allele 4 (APOE epsilon 4) status, increased LOAD risks associated with the Glu/Glu genotype and Glu allele only in the APOE epsilon 4 noncarriers (chi2 = 6.28, df = 1, P = 0.012 by genotype; chi2 = 5.62, df = 1, P = 0.018 by allele) were seen. These results suggest that the NOS3 gene Glu298Asp polymorphism might be a risk factor for LOAD and dependent on APOE epsilon 4 status in Chinese.

C‐338A Polymorphism of the Endothelin‐Converting Enzyme (ECE‐1) Gene and the Susceptibility to Sporadic Late‐Onset Alzheimer’s Disease and Coronary Artery Disease

The human endothelin-converting enzyme (ECE) is involved in β-amyloid synthesis and regulation of the endothelin-1 (ET-1) vasoconstricting peptide. We investigated the distribution of the C-338A polymorphism of the ECE-1b gene in sporadic late-onset Alzheimer’s disease (LOAD) and in coronary artery disease (CAD) to verify its role in the onset of these two complex diseases. Two cohorts of 458 Italian Caucasian LOAD patients and 165 CAD patients were examined for the C-338A polymorphism and compared with respective control samples (260 and 106 subjects, respectively). The A allele was less present in LOAD patients than in controls, but an at limits statistically significant difference was achieved only in subjects aged less than 80 years, where only the AA genotypes appeared to have a protective role against the onset of the sporadic LOAD. For the overall CAD sample the pattern was similar and significant differences were observed only in subjects non carrying the apolipoprotein E (APOE) e*4 allele, where the A allele carrying genotypes had a protective role against the onset of the disease.

Apolipoprotein E and amyloidogenesis.

Alzheimer's amyloid beta-protein (A beta) is a modified, pathogenic form of a constitutive host protein, soluble amyloid beta-protein (sA beta). Both are conformational isomers encoded by the gene for the beta-amyloid precursor protein (APP), located on chromosome 21. sA beta and A beta have identical sequence but are thought to differ in their secondary structure and physicochemical properties, hence they are conformational isomers. sA beta is easily degraded, while A beta is particularly resistant. A beta has a high beta-pleated sheet content, while sA beta is thought to be more random-coil and/or alpha-helical. A beta, unlike sA beta, adopts an amyloidogenic conformation, forms aggregates and gives rise to fibrils. Most early-onset forms of Alzheimer's disease (AD) have been linked to mutations of the presenilin 1, presenilin 2 or APP genes, located on chromosomes 14, 1 and 21, respectively. Their relationship to amyloidogenesis is being investigated. On the other hand, the major risk factor for the most common form, sporadic and familial late-onset AD, is the presence of the apoE epsilon 4 allele. Recent studies have shown that a 10 kDa C-terminal fragment of apoE is complexed to A beta in neuritic plaques and that apoE isoforms can modulate amyloid formation in vitro. Moreover, thrombin cleavage of apoE generates a similar C-terminal fragment that can form amyloid-like fibrils. Thus neuritic plaques may contain both A beta and apoE amyloid fibrils. AD can be neuropathologically defined by the presence of several interacting proteins that can adopt an amyloidogenic conformation. This has led us to hypothesize that in AD, amyloidosis may be reactive rather than causative.

Statin-Like Drugs for the Treatment of Brain Cholesterol Loss in Alzheimers Disease

Aging is one of the most significant risk factors for neurological disorders including Alzheimer's Disease (late-onset AD and sporadic AD), the most common form of dementia. AD is characterized by progressive atrophy and loss of neurons resulting in cognitive deficits, confusion and dementia, culminating in childlike helplessness and death. One of the major pathological hallmarks of the disease are amyloid plaques, composed primarly of insoluble fibrils of Abeta peptide: this molecule derives from the processing of the transmembrane amyloid precursor protein (APP) by different secretases and its production is a physiological event, but the anormal increase in Abeta levels appears to be toxic both in vitro and in vivo. Being APP cleavage a membrane event the involvement of lipids in alterations of this cleavage is assumable. Cholesterol is the most abundant lipid in cellular membranes and is an essential component of them, determining the fluidity and biophysical properties. In fact, genetic studies of the risk of AD have reported association with polymorphism in some cholesterol related genes like the allele epsilon4 of the apolipoprotein E, cholesterol 24-hydroxylase (CYP46A1), ATP-binding cassette transporter a1 (ABCA1) and the lipoprotein receptor-related protein (LRP). Moreover a recent publication shows a downregulation of Seladin-1 (which catalyze the last step of cholesterol biosynthesis) in affected neurons in Alzheimer's Disease. Post-mortem analysis of AD brains reveal a loss in cholesterol content and this make the therapeutical use of statin-like drugs quite a lot controversial. Taking together their clinical trials results and the large body of literature regarding lipid profile alterations in AD, it is actually unclear how much these agents can be helpful or not for affected patients.

Genetic heterogeneity of Alzheimer's disease: Complexity and advances

Most of what we know about the pathological process of Alzheimer's disease (AD) results from research on the amyloid cascade hypothesis. This hypothesis in turn is derived largely from the characterization of rare disease-causing mutations in three genes, which code for the amyloid precursor protein (APP), presenilin 1 (PS-1) and presenilin 2 (PS-2) and account for most cases of early-onset autosomal dominant familial AD. These genetic findings also suggested that better understanding of the genetic components of AD, even in the late-onset sporadic forms of the disease, might help to identify central pathways of the AD process and lead to the rapid development of active molecules. Twin studies have reinforced the rationale of this approach, for they indicate that more than 50% of the late-onset AD risk may be attributable to genetic factors. The 1993 discovery that the apolipoprotein E4 (ApoE4) allele is genetically associated with increased risk in both sporadic and familial late-onset Alzheimer's disease strongly supports the validity of this genetic approach. Further progress based on this major finding has nonetheless been disappointing and raises questions about it. First, despite intensive researches, the exact role of APOE in the pathophysiological process still remains unknown. Second, the APOE gene is the only gene so far recognized as a consistent genetic determinant of sporadic forms of AD, even though numerous studies have looked for such genes; these disappointing results suggest persistent methodological limitations. However, recent methodologies allowing new strategies may allow important breakthrough.

The molecular link between beta- and gamma-secretase activity on the amyloid beta precursor protein.

Alzheimer's disease (AD) is characterized by an accumulation in the brain of amyloid beta peptides (Abeta). The production of Abeta requires two sequential cleavages induced by beta- and gamma-secretases on the beta-amyloid precursor protein (APP). Altered activity of these secretases is involved in the pathogenesis of AD. The expression and activity of beta-secretase (BACE1) is augmented in the brain in late-onset sporadic AD. Mutant presenilin 1 (PS1), the major genetic defect of early-onset familial AD (FAD), alters the activity of gamma-secretase, leading to increased production of Abeta42. Here we review the role of oxidative stress as a molecular link between the beta- and the gamma-secretase activities, and provide a mechanistic explanation of the pathogenesis of sporadic late-onset AD. We also discuss evidence for a role of the same mechanism in the pathogenesis of familial AD carrying PS1 mutations.

Polimorfismo da apolipoproteína e nos familiares em primeiro grau de pacientes com doença de Alzheimer familial ou esporádica

Apolipoprotein E (apo E) has been recognized as a risk factor for Alzheimer disease (AD). To analyze apo E polymorphism in first-degree relatives of patients with familial or sporadic late-onset AD comparing with families without AD. Forty patients with familial or sporadic late-onset of AD, being both groups classified as probable, according of NINCS-ADRDAs criteria. Allele epsilon3 was the most frequent in all of these groups. Higher frequency of epsilon4 when comparing the relatives of the probands with the relatives of the control group (p<0,0001) was observed. Allele epsilon2 showed significant difference only between relatives of familial AD and relatives of control group (p=0,026). Apo E polymorphism has not differentiated familial from sporadic AD. The study of families allows to amplify the alelles epsilon2 and epsilon4 representative, revealing, their value as protecting factor and of risk for AD, respectively.

A High-Density Whole-Genome Association Study Reveals That APOE Is the Major Susceptibility Gene for Sporadic Late-Onset Alzheimer's Disease

While the apolipoprotein E (APOE) epsilon allele is a well-established risk factor for late-onset Alzheimer's disease (AD), initial genome scans using microsatellite markers in late-onset AD failed to identify this locus on chromosome 19. Recently developed methods for the simultaneous assessment of hundreds of thousands of single nucleotide polymorphisms (SNPs) promise to help more precisely identify loci that contribute to the risk of AD and other common multigenic conditions. We sought here to demonstrate that more precise identification of loci that are associated with complex, multi-genic genetic disorders can be achieved using ultra-high-density whole-genome associations by demonstrating their ability to identify the APOE locus as a major susceptibility gene for late-onset AD, despite the absence of SNPs within the APOE locus itself, as well as to refine odds ratios (ORs) based on gold-standard phenotyping of the study population. An individualized genome-wide association study using 502,627 SNPs was performed in 1086 his-topathologically verified AD cases and controls to determine the OR associated with genes predisposing to Alzheimer's disease. As predicted, ultra-high-density SNP genotyping, in contrast to traditional microsatellite-based genome screening approaches, precisely identified the APOE locus as having a significant association with late-onset AD. SNP rs4420638 on chromosome 19, located 14 kilobase pairs distal to the APOE epsilon variant, significantly distinguished between AD cases and controls (Bonferroni corrected p value = 5.30 x 10(-34), OR = 4.01) and was far more strongly associated with the risk of AD than any other SNP of the 502,627 tested. This study provides empirical support for the suggestion that the APOE locus is the major susceptibility gene for late-onset AD in the human genome, with an OR significantly greater than any other locus in the human genome. It also supports the feasibility of the ultra-high-density whole-genome association approach to the study of AD and other heritable phenotypes. These whole-genome association studies show great promise to identify additional genes that contribute to the risk of AD.

The Arg194Trp polymorphism in DNA repair gene XRCC1 and the risk for sporadic late-onset Alzheimer's disease

Alzheimer's disease (AD) is defined pathologically by the presence of beta-amyloid plaques, neurofibrillary tangles and extensive neuronal loss. Evidence indicates that increased DNA damage may contribute to neuronal loss in AD. Recently, it has been shown that in AD neurons have a reduced capacity for some types of DNA repair. Polymorphisms in DNA repair genes may be associated with differences in repair efficiency of DNA damage. Variants of several DNA repair genes, including the base excision repair gene XRCC1, have been described previously. We hypothesised that Arg194Trp polymorphism of XRCC1 gene may contribute to genetic susceptibility for AD. In order to test this hypothesis, we investigated Arg194Trp polymorphism at the XRCC1 gene in the DNA samples of 98 patients with AD and 95 healthy subjects. The frequency of the Trp allele was more pronounced among cases (11.2%) compared with controls (5.8%). On combining the homozygous and heterozygous variants of each codon, the variants seemed to be at twofold risk of AD, although the risk estimates were not statistically significant (OR=1.95, 95% CI 0.88-4.34, p=0.09). In addition, the 194Trp allele revealed a borderline significance (OR=2.05, 95% CI 0.96-4.37, p=0.056). According to our results, it may be speculated that the polymorphic variants of XRCC1 codon 194 have a role in the development of AD.

Greater frequency of subcortical lesions in severely demented patients with early onset Alzheimer’s disease

Background Recent data have shown that in the early stages of Alzheimer’s disease (AD), vascular brain lesions might promote the progression of cognitive decline or might even precede neuronal damage. Methods Ischemic brain lesions, recognized on computed tomography or magnetic resonance imaging, were analyzed retrospectively in 72 patients with early and late onset sporadic AD. Results All types of ischemic lesions occurred more frequently in the AD patients than in the controls. Analysis of subgroups of early and late onset AD patients diagnosed by magnetic resonance imaging showed a more frequent occurrence of subcoritcal lesions in severely demented patients with early onset AD. Conclusions The non-stroke subcortical ischemic lesions occurring more frequently in our AD patients might be recognized as the concomitant vascular pathology that characterizes severely demented patients with early onset sporadic AD.

Neuronal Pentraxin 1 Contributes to the Neuronal Damage Evoked by Amyloid-β and Is Overexpressed in Dystrophic Neurites in Alzheimer's Brain

Accumulation of amyloid-beta (Abeta) is thought to play a central role in the progressive loss of synapses, the neurite damage, and the neuronal death that are characteristic in brains affected by Alzheimer's disease. However, the mechanisms through which Abeta produces such neurotoxicity remain unclear. Because Abeta depresses synaptic activity, we investigated whether the neurotoxicity of Abeta depends on the expression of NP1, a protein involved in excitatory synapse remodeling that has recently been shown to mediate neuronal death induced by reduction in neuronal activity in mature neurons. We found that treatment of cortical neurons in culture with Abeta produces a marked increase in NP1 protein that precedes apoptotic neurotoxicity. Silencing NP1 gene expression by RNA interference (short hairpin RNA for RNA interference) prevents the loss of synapses, the reduction in neurite outgrowth, and the apoptosis evoked by Abeta. Transgene overexpression of NP1 reproduced these neurotoxic effects of Abeta. Moreover, we found that NP1 was increased in dystrophic neurites of brains from patients with sporadic late-onset Alzheimer's disease. Dual immunohistochemistry for NP1 and tau showed that NP1 colocalizes with tau deposits in dystrophic neurites. Furthermore, NP1 colocalized with SNAP-25 (synaptosomal-associated protein of 25 kDa) in the majority of dystrophic neurites surrounding amyloid deposits. NP1 was also increased in cell processes surrounding amyloid plaques in the cerebral cortex and hippocampus of APP/PS1 (mutant amyloid precursor protein/presenilin 1) transgenic mice. These findings show that NP1 is a key factor for the synapse loss, the neurite damage, and the apoptotic neuronal death evoked by Abeta and indicate that Abeta contributes to the pathology of Alzheimer's disease by regulating NP1 expression.

APOE Genotype and Cholesterol Levels in Lewy Body Dementia and Alzheimer Disease: Investigating Genotype–Phenotype Effect on Disease Risk

APOE is the most recognized genetic risk factor for sporadic late-onset Alzheimer disease (AD). The role of APOE genotype in Lewy body dementia (LBD) is still unknown as well as the relationship between APOE genotype and cholesterol levels. The objective of this study was to explore the association between APOE genotype and cholesterol levels in patients with LBD and those with AD. Eighty-two patients with LBD were consecutively enrolled as well as a comparable number of patients with AD and comparison group. Each subject underwent a clinical and neuropsychologic evaluation and APOE genotyping. The distribution of APOE genotypes significantly differed between AD and LBD cases compared with the comparison group, with the APOE epsilon4+ (epsilon4+/epsilon4 + or epsilon4+/epsilon4-) genotype more frequent in patient subgroups. Different models have been fitted, and total APOE epsilon4-hypercholesterolemia complete interaction effect was claimed in predicting their relationship on disease outcome. Subjects with hypercholesterolemia and heterozygous for APOE epsilon4 allele had more than threefold risk to develop AD compared both with the comparison group and with those with LBD. The risk to develop AD in hypercholesterolemic and APOE epsilon4 homozygous subjects was 13-fold compared with the comparison group and those with LBD. Conversely, there was not evidence for APOE epsilon4-hypercholesterolemia complete interaction effect in LBD and in the comparison group. This study highlighted that APOE is a risk factor not only for AD, but also for LBD, and that the APOE-cholesterol pathway differently affects AD and LBD. This approach may aid the search for the identification of an interactive effect of APOE genotype and modifiable risk factors, i.e., hypercholesterolemia, eventually resulting in individualized and effective cholesterol-lowering therapy in at-risk subjects.