Late-onset Sporadic Alzheimer's Disease Research Articles

Application of Systems Theory in Longitudinal Studies on the Origin and Progression of Alzheimer's Disease.

This chapter questions the prevailing "implicit" assumption that molecular mechanisms and the biological phenotype of dominantly inherited early-onset alzheimer's disease (EOAD) could serve as a linear model to study the pathogenesis of sporadic late-onset alzheimer's disease (LOAD). Now there is growing evidence to suggest that such reductionism may not be warranted; these suppositions are not adequate to explain the molecular complexities of LOAD. For example, the failure of some recent amyloid-centric clinical trials, which were largely based on the extrapolations from EOAD biological phenotypes to the molecular mechanisms in the pathogenesis of LOAD, might be due to such false assumptions. The distinct difference in the biology of LOAD and EOAD is underscored by the presence of EOAD cases without evidence of familial clustering or Mendelian transmission and, conversely, the discovery and frequent reports of such clustering and transmission patterns in LOAD cases. The primary thesis of this chapter is that a radically different way of thinking is required for comprehensive explanations regarding the distinct complexities in the molecular pathogenesis of inherited and sporadic forms of Alzheimer's disease (AD). We propose using longitudinal analytical methods and the paradigm of systems biology (using transcriptomics, proteomics, metabolomics, and lipidomics) to provide us a more comprehensive insight into the lifelong origin and progression of different molecular mechanisms and neurodegeneration. Such studies should aim to clarify the role of specific pathophysiological and signaling pathways such as neuroinflammation, altered lipid metabolism, apoptosis, oxidative stress, tau hyperphosphorylation, protein misfolding, tangle formation, and amyloidogenic cascade leading to overproduction and reduced clearance of aggregating amyloid-beta (Aβ) species. A more complete understanding of the distinct difference in molecular mechanisms, signaling pathways, as well as comparability of the various forms of AD is of paramount importance. The development of knowledge and technologies for early detection and characterization of the disease across all stages will improve the predictions regarding the course of the disease, prognosis, and response to treatment. No doubt such advances will have a significant impact on the clinical management of both EOAD and LOAD patients. The approach propped here, combining longitudinal studies with the systems biology paradigm, will create a more effective and comprehensive framework for development of prevention therapies in AD.

The Role of Upregulated APOE in Alzheimer's Disease Etiology.

The first and most firmly established genetic risk factor for sporadic late onset Alzheimer’s disease (LOAD) is the e4 allele of the apolipoprotein E (APOE) gene [1]. Carrying the APOEe4 variant significantly increases the lifetime risk for LOAD, with the number of copies present indicative of level of risk [1,2] and is associated with lower age of clinical disease onset [1,3–6]. Furthermore, genome-wide association studies (GWAS) for sporadic LOAD confirmed that APOE is the major susceptibility genomic region for the disease and reported significant associations with markers within the APOE linkage disequilibrium (LD) locus (contains APOE, TOMM40 and APOC1 genes). The strongest association signal (by wide margin) in these studies was found at the APOE LD region and no other LOAD-association in the human genome remotely approached the same level of significance [7–10]. However, the molecular mechanism underlying the reported genetic LOAD-associations with APOE LD region in general and APOEe4 haplotype in particular has yet to be discovered.

The nitric oxide synthase-3 codon 298 polymorphism is not associated with late-onset sporadic Alzheimer's dementia and Lewy body disease in a sample from Hungary.

An association study was performed between apolipoprotein E (apoE) polymorphism and the common structural polymorphism Glu/Asp at codon 298 of the nitric oxide synthase (NOS3) gene in late-onset sporadic Alzheimer's dementia probands (LOAD), diffuse Lewy body dementia cases (DLBD) and controls in a Hungarian sample. The frequency of individuals who carried the apoE epsilon4 allele was significantly more common in both dementia groups (LOAD, 20%; DLBD, 27%; control, 8%; control versus DLBD, chi2=13.264, degrees of freedom=2, P<0.001; control versus LOAD, chi2=6.628, degrees of freedom=2, P<0.036). However, there were no significant differences in the NOS3 genotype and allele distributions between the LOAD, DLBD and control groups. The apoE status has been found to be independent from the NOS3 codon 298 polymorphism in the examined cohort. Despite the facts that NOS3 is associated with neuritic sprouting, and aberrant neuronal and glial expression of the same molecule has been found in neurodegenerative diseases, it is unlikely that the polymorphism Glu/Asp of the NOS3 gene is involved in the development of LOAD and DLBD.

A Unified Hypothesis of Early- and Late-Onset Alzheimer's Disease Pathogenesis.

Early-onset familial Alzheimer's disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition, tau phosphorylation, formation of intracellular neurofibrillary tangles, endoreduplication and related cell cycle events in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemicalandneuropathological features for both forms of the disease. In this insight paper we provide a unifying hypothesis for EOFAD and LOSAD that proposes that the aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell division cycle is a common pathway that explains both early and late-onset forms of AD. Cell cycle abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles, and explain the biochemical (e.g. tau phosphorylation), neuropathological (e.g. neuron hypertrophy; polypoidy) and cognitive changes observed in EOFAD and LOSAD. Genetic mutations in AβPP, PSEN1, and PSEN2 that alter amyloid-β precursor protein and Notch processing drive reactivation of the cell cycle in EOFAD, while age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling and AβPP processing toward the amyloidogenic pathway drives reactivation of the cell cycle in LOSAD. In essence, AβPP and presenilin mutations initiate early, what endocrine dyscrasia initiates later: aberrant cell cycle re-entry of post-mitotic neurons leading to neurodegeneration and cognitive decline in AD. Inhibition of cell cycle re-entry in post-mitotic neurons may be a useful therapeutic strategy to prevent, slow or halt disease progression.

Cyclic Ozone Exposure Induces Gender-Dependent Neuropathology and Memory Decline in an Animal Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a major cause of dementia in the elderly. Although early-onset (familial) AD is attributed to gene mutations, the cause for late-onset (sporadic) AD, which accounts for 95% of AD cases, is unknown. In this study, we show that exposure of 6-week-old amyloid beta precursor protein (APP)/presenilin (PS1) overexpressing mice, a well-established animal model of AD, and nontransgenic littermates to a cyclic O3 exposure protocol, which mimics environmental exposure episodes, accelerated learning/memory function loss in male APP/PS1 mice but not in female APP/PS1 mice or nontransgenic littermates. Female APP/PS1 mice had higher brain levels of amyloid beta peptide (Aβ42) and Aβ40, compared with male APP/PS1 mice; O3 exposure, however, had no significant effect on brain Aβ load in either male or female mice. Our results further show that male APP/PS1 mice had lower levels of antioxidants (glutathione and ascorbate) and experienced augmented induction of NADPH oxidases, lipid peroxidation, and neuronal apoptosis upon O3 exposure, compared with female APP/PS1 mice. No significant effect of O3 on any of these parameters was detected in nontransgenic littermates. Invitro studies further show that 4-hydroxynonenal, a lipid peroxidation product which was increased in the plasma and cortex/hippocampus of O3-exposed male APP/PS1 mice, induced neuroblastoma cell apoptosis. Together, the results suggest that O3 exposure per se may not cause AD but can synergize with genetic risk factors to accelerate the pathophysiology of AD in genetically predisposed populations. The results also suggest that males may be more sensitive to O3-induced neuropathophysiology than females due to lower levels of antioxidants.

Preventing the spread of Alzheimer's disease neuropathology: a role for calcilytics?

The "amyloid cascade hypothesis" posits that an extracellular build-up of amyloid-β oligomers (Aβ-os) and polymers (fibrils) subsequently inducing toxic hyperphosphorylated (p)-Tau oligomers (p-Tau-os) and neurofibrillary tangles starts the sporadic late-onset Alzheimer's disease (LOAD) in the aged lateral entorhinal cortex. Conversely, mutated genes cause a diffuse cerebral Aβs/Aβ-os overproduction promoting early-onset familiar AD (EOFAD). Surplus exogenous Aβ-os exert toxic actions at several levels. They reach the nuclei of human astrocyte-neurons teams (ANTs) to enhance the transcription of Aβ precursor protein (APP) and β-secretase/BACE1 genes. The overexpressed APP and BACE1 proteins act in concert with γ-secretase to overproduce endogenous Aβs/Aβ-os, of which a few enter the nuclei to upkeep Aβs overproduction, while the rest gather in the cytoplasm, damage mitochondria, and are oversecreted. Simultaneously, extracellular Aβ-os bind the ANTs' calcium-sensing receptors (CaSRs) activating signalings that hinder the proteolysis and hence favor the surplus hoarding/secretion of Aβs/Aβ-os. Overreleased Aβ-os spread, reach growing numbers of adjacent ANTs to recruit them to overproduce/oversecrete further Aβ-os amounts via the just mentioned mechanisms. Alongside, Aβ•CaSR signalings elicit a noxious overproduction/overrelease of nitric oxide (NO) and vascular endothelial growth factor (VEGF)-A from ANTs' astrocytes. While astrocytes survive the toxic onslaught, neurons die. Thus, AD progression is driven by ceaselessly self-sustaining neurotoxic cycles, which engender first Aβ-os and later p-Tau-os that cooperatively destroy increasingly wider cognition-related cortical areas. Notably, a highly selective allosteric CaSR antagonist (calcilytic), like NPS 2143, does preserve human cortical postnatal HCN-1A neurons viability notwithstanding the presence of exogenous Aβ-os by suppressing the otherwise elicited oversecretion and spread of newly synthesized Aβ-os. Therefore, if given at minimal cognitive impairment or earlier stages, calcilytics could halt AD progression and preserve the patients' cortical neurons, cognitive abilities, and eventually life.

The Maze of APP Processing in Alzheimer's Disease: Where Did We Go Wrong in Reasoning?

Why has Alzheimer’s disease (AD) remained a conundrum today? The main reason is the stagnation in understanding the origins of plaques and tangles. While they are widely thought to be the products of the “aberrant” pathways, we believe that plaques and tangles result from natural aging. From this new perspective, we have proposed that age-related inefficiency of α-secretase is the underpinning for Aβ overproduction. This view contrasts sharply with the current doctrine that Aβ overproduction is the product of the “overactivated” β- and γ-secretases. Following this doctrine, it has been claimed that the two secretases are “positively identified” and that their inhibitors have “successfully reduced Aβ levels.” But, why have these studies not led to the understanding of AD or successful clinical trials? And if so, where did they go off course in reasoning? These questions may touch the basics of biological science and must be answered. In this paper, I dissected several prevailing assumptions and some influential reports with an attempt to trace the origins of the conundrum. This work led me to an original model for Aβ overproduction and also to a serious question: given the universal knowledge that boosting α-secretase reduces Aβ, a straightforward highway for intervention, then why is there such an obsession on “inhibiting β- and γ-secretases,” a much more costly and twisting road even if possible? This issue requires the attention of policymakers and all researchers. I therefore call for a game change in AD study.

Additional mechanisms conferring genetic susceptibility to Alzheimer's disease.

Familial Alzheimer’s disease (AD), mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1, and PSEN2) involved in the production of the amyloid β peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies there is a mounting list of genetic risk factors associated with common genetic variants that have been associated with sporadic AD. Besides apolipoprotein E, that presents a strong association with the disease (OR∼4), the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated with AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways, and networks rather than the contribution of specific genes.

Coding mutations in SORL1 and Alzheimer disease.

Common single nucleotide polymorphisms in the SORL1 gene have been associated with late onset Alzheimer disease (LOAD), but causal variants have not been fully characterized nor has the mechanism been established. The study was undertaken to identify functional SORL1 mutations in patients with LOAD. This was a family- and cohort-based genetic association study. Caribbean Hispanics with familial and sporadic LOAD and similarly aged controls were recruited from the United States and the Dominican Republic, and patients with sporadic disease of Northern European origin were recruited from Canada. Prioritized coding variants in SORL1 were detected by targeted resequencing and validated by genotyping in additional family members and unrelated healthy controls. Variants transfected into human embryonic kidney 293 cell lines were tested for Aβ40 and Aβ42 secretion, and the amount of the amyloid precursor protein (APP) secreted at the cell surface was determined. Seventeen coding exonic variants were significantly associated with disease. Two rare variants (rs117260922-E270K and rs143571823-T947M) with minor allele frequency (MAF) < 1% and 1 common variant (rs2298813-A528T) with MAF = 14.9% segregated within families and were deemed deleterious to the coding protein. Transfected cell lines showed increased Aβ40 and Aβ42 secretion for the rare variants (E270K and T947M) and increased Aβ42 secretion for the common variant (A528T). All mutants increased the amount of APP at the cell surface, although in slightly different ways, thereby failing to direct full-length APP into the retromer-recycling endosome pathway. Common and rare variants in SORL1 elevate the risk of LOAD by directly affecting APP processing, which in turn can result in increased Aβ40 and Aβ42 secretion.

Periodontitis: a potential risk factor for Alzheimer's disease.

The role of periodontitis as a risk factor for multiple systemic diseases is widely accepted and there is growing evidence of an association between periodontitis and sporadic late onset Alzheimer's disease (SLOAD). Recent epidemiologic, microbiologic and inflammatory findings strengthen this association, indicating that periodontal pathogens are possible contributors to neural inflammation and SLOAD. The aim of this article is to present contemporary evidence of this association.

Hypertension and Alzheimer Disease

See related article, pp 218–224 Alzheimer disease (AD) is the most common cause of dementia with the devastating consequences that everyone is aware of.1 There are 2 forms of AD: first, the familial AD represents <2% of the cases; it is inherited in an autosomal dominant pattern with symptoms typically presenting as early as 24 years of age for the most aggressive familial AD mutation identified to date, the Leu to Pro mutation at position 166 of presenilin-1.2 The second form is the sporadic late onset AD; it is much more prevalent but develops much later clinically, usually beginning after 70 or 80 years of age. AD pathology is confirmed postmortem by the accumulation of extracellular amyloid-β (Aβ) containing plaques and intracellular neurofibrillary tau tangles in the brain.3 Proteolytic γ-secretase presenilin-1 and -2 generate the amyloidogenic Aβ peptides. Although various Aβ peptide lengths are produced by γ-secretase, Aβ42 and Aβ40 are of particular interest because the additional 2 hydrophobic residues in Aβ42 increase its ability to aggregate, providing the scaffold for oligomeric and fibrillar forms of Aβ.2 The possible causal role of Aβ in AD is supported by the fact that a high Aβ42 to Aβ40 ratio is an important determinant for the onset of amyloid pathology in familial AD. Unfortunately, there is no cure for AD.1 We even doubt that a cure (meaning recovery of health) will ever be available considering that neurodegeneration is not reversible. Deep brain stimulation is still experimental, and cell therapy is associated with ethical questions. Bapineuzumab and solanezumab, 2 Aβ targeting monoclonal antibodies, have failed to meet trial cognitive end points in mild to moderate AD patients, whereas Aβ converting enzyme inhibitors did not succeed. A phase 3 trial with the γ-secretase inhibitor semagacestat …

Association Study of the TREM2 Gene and Identification of a Novel Variant in Exon 2 in Iranian Patients with Late-Onset Alzheimer's Disease

Objective: To analyze the association between TREM2 exon 2 variants and late-onset (sporadic) Alzheimer's disease (AD) in an elderly Iranian population. Materials and Methods: Exon 2 of TREM2 in a total of 131 AD patients and 157 controls was genotyped using polymerase chain reaction and Sanger sequencing. Fisher's exact test was used to compare the allele and genotype frequency between the 2 study groups. Results: One homozygous and 2 heterozygous carriers of rs75932628-T in the AD patients and 1 heterozygous carrier in the control group were identified. One novel damaging variant, G55R, was also detected in the AD patient group. The frequency of rs75932628-T as well as the amount of rare variants were higher in the AD patients than in the controls, but this did not reach a statistically significant association with AD (odds ratio: 4.8; 95% confidence interval: 0.54 to 43.6; p = 0.270). Conclusion: The rs75932628-T allele frequency in the elderly Iranian population (0.86%) was high.

Cholesterol in brain disease: sometimes determinant and frequently implicated.

Cholesterol is essential for neuronal physiology, both during development and in the adult life: as a major component of cell membranes and precursor of steroid hormones, it contributes to the regulation of ion permeability, cell shape, cell-cell interaction, and transmembrane signaling. Consistently, hereditary diseases with mutations in cholesterol-related genes result in impaired brain function during early life. In addition, defects in brain cholesterol metabolism may contribute to neurological syndromes, such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), and even to the cognitive deficits typical of the old age. In these cases, brain cholesterol defects may be secondary to disease-causing elements and contribute to the functional deficits by altering synaptic functions. In the first part of this review, we will describe hereditary and non-hereditary causes of cholesterol dyshomeostasis and the relationship to brain diseases. In the second part, we will focus on the mechanisms by which perturbation of cholesterol metabolism can affect synaptic function.

AMYLOID-BETA DEGRADATION BY HUMAN ASTROCYTES IS IMPAIRED BY APOJ AND APOE

Sporadic late onset Alzheimer's disease (AD) is associated with impaired clearance of amyloid-beta (A β) from the brain. Recently, our group showed by confocal microscopy and live cell imaging that astrocytes are capable of ingesting A β. Apolipoprotein (Apo)E and ApoJ genetic variants are risk factors to develop AD and both proteins co-localize with A β plaques. Moreover, we previously showed that ApoE and ApoJ reduced the uptake of A β oligomers by human astrocytes in vitro. Whether ApoJ and ApoE also alter the enzymatic degradation of A β in or surrounding human astrocytes remains unknown. In this study, we determined expression levels of two key enzymes in A β -degradation, neprilysin (NEP) and insulin degrading enzyme (IDE), in human astrocytes. In addition, we determined if A β oligomers and fibrils in the presence or absence of ApoJ and ApoE could alter the expression of these enzymes. To test this, we treated human astrocytes with increasing concentrations of A β oligomers and fibrils (0.1, 1 and 10 μ M) in either absence or presence of ApoJ (1 μ M) and ApoE (1 μ M) and determined NEP and IDE expression in cell lysates prepared after 18 hours. NEP and IDE expression were quantified by Western blot analysis. When exposed to A β oligomers and A β fibrils alone the expression of both NEP and IDE was dose dependently increased by approximately 50%. This effect was abrogated (20-50% reduction) when A β oligomers and fibrils, preincubated with either ApoE or ApoJ, were applied to the human astrocytes. Combined, these and our earlier results suggest that ApoJ and ApoE negatively affect A β clearance by astrocytes. Reducing the levels of ApoE and ApoJ in the brain could rescue A β clearance by human astrocytes.

Calcium-Sensing Receptors of Human Astrocyte-Neuron Teams: Amyloid-β-Driven Mediators and Therapeutic Targets of Alzheimer’s Disease

It is generally assumed that the neuropathology of sporadic (late-onset or nonfamilial) Alzheimer’s disease (AD) is driven by the overproduction and spreading of first Amyloid-βx-42 (Aβ42) and later hyperphosphorylated (hp)-Tau oligomeric “infectious seeds”. Hitherto, only neurons were held to make and spread both oligomer types; astrocytes would just remove debris. However, we have recently shown that exogenous fibrillar or soluble Aβ peptides specifically bind and activate the Ca2+-sensing receptors (CaSRs) of untransformed human cortical adult astrocytes and postnatal neurons cultured in vitro driving them to produce, accrue, and secrete surplus endogenous Aβ42. While the Aβ-exposed neurons start dying, astrocytes survive and keep oversecreting Aβ42, nitric oxide (NO), and vascular endothelial growth factor (VEGF)-A. Thus astrocytes help neurons’ demise. Moreover, we have found that a highly selective allosteric CaSR agonist (“calcimimetic”), NPS R-568, mimics the just mentioned neurotoxic actions triggered by Aβ●CaSR signaling. Contrariwise, and most important, NPS 2143, a highly selective allosteric CaSR antagonist (“calcilytic”), fully suppresses all the Aβ●CaSR signaling-driven noxious actions. Altogether our findings suggest that the progression of AD neuropathology is promoted by unceasingly repeating cycles of accruing exogenous Aβ42 oligomers interacting with the CaSRs of swelling numbers of astrocyte-neuron teams thereby recruiting them to overrelease additional Aβ42 oligomers, VEGF-A, and NO. Calcilytics would beneficially break such Aβ/CaSR-driven vicious cycles and hence halt or at least slow the otherwise unstoppable spreading of AD neuropathology

DISTINCT STRUCTURES OF B-AMYLOID IN RAPIDLY PROGRESSIVE ALZHEIMER DISEASE

While the genetic and environmental factors that increase the risk of late onset Alzheimer disease (LOAD) are well recognized, the cause of variable progression rates and phenotypes of sporadic LOAD is largely unknown. We aimed to investigate the relationship between diverse conformational structures of amyloid beta (Aβ) and variable rates of clinical decline in LOAD. Using novel biophysical methods, we analyzed conformational structural characteristics of Aβ in the posterior cingulate cortex, hippocampus, and cerebellum of 49 cases of LOAD with distinctly different disease durations, and correlated the data with clinical profiles and APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct Aβ42 particles that differ in conformational structure, size, and display of critical domains. In contrast, Aβ40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive cases demonstrated distinctly structured Aβ42 forming unique spectrum of oligomeric particles. The link between rapid clinical decline and levels of Aβ42 with distinct structural characteristics suggests that differently structured conformers play an important role in the pathogenesis od LOAD. Specifically, we assert that the variable propagation tempo and phenotypic characteristics of the disease may be encoded in the distinct structures of Aβ42 by prion-like mechanism.

Regional Neuronal Network Failure and Cognition in Late-Onset Sporadic Alzheimer Disease

The severe cognitive deficits in Alzheimer disease are associated with structural lesions in gray and white matter in addition to changes in synaptic function. The current investigation studied the breakdown of the structure and function in regional networks involving the Papez circuit and extended neocortical association areas. Cortical volumetric and diffusion tensor imaging (3T MR imaging), positron-emission tomography with (18)F fluorodeoxyglucose on a high-resolution research tomograph, and comprehensive neuropsychological assessments were performed in patients with late-onset sporadic Alzheimer disease, those with mild cognitive impairment, and elderly healthy controls. Atrophy of the medial temporal lobes was the strongest and most consistent abnormality in patients with mild cognitive impairment and Alzheimer disease. Atrophy in the temporal, frontal, and parietal regions was most strongly related to episodic memory deficits, while deficits in semantic cognition were also strongly related to reductions of glucose metabolism in the posterior cingulate cortex and temporoparietal regions. Changes in fractional anisotropy within white matter tracts, particularly in the left cingulum bundle, uncinate fasciculus, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus, were significantly associated with the cognitive deficits in multiple regression analyses. Posterior cingulate and orbitofrontal metabolic deficits appeared to be related to microstructural changes in projecting white matter tracts. Many lesioned network components within the Papez circuit and extended neocortical association areas were significantly associated with cognitive dysfunction in both mild cognitive impairment and late-onset sporadic Alzheimer disease. Hippocampal atrophy was the most prominent lesion, with associated impairment of the uncinate and cingulum white matter microstructures and hippocampal and posterior cingulate metabolic impairment.

Both Targeted Mass Spectrometry and Flow Sorting Analysis Methods Detected the Decreased Serum Apolipoprotein E Level in Alzheimer's Disease Patients

Apolipoprotein E (ApoE) polymorphism has been appreciated as a valuable predictor of Alzheimer disease (AD), and the associated ε4 allele has been recognized as an indicator of susceptibility to this disease. However, serum ApoE levels have been a controversial issue in AD, due to the great variability regarding the different target detection methods, ethnicity, and the geographic variations of cohorts. The aim of this study was to validate serum ApoE levels in relation to AD, particularly using two distinct detection methods, liquid chromatography-selected reaction monitoring (SRM) mass spectrometry and microsphere-based fluorescence-activated cell sorting (FACS) analysis, to overcome experimental variations. Also, comparison of serum ApoE levels was performed between the level of protein detection by FACS and peptide level by SRM in both control and AD patients. Results from the two detection methods were cross-confirmed and validated. Both methods produced fairly consistent results, showing a significant decrease of serum ApoE levels in AD patients relative to those of a control cohort (43 control versus 45 AD, p < 0.0001). Significant correlation has been revealed between results from FACS and SRM (p < 0.0001) even though lower serum ApoE concentration values were measured in protein by FACS analysis than in peptide-level detections by SRM. Correlation study suggested that a decrease of the serum ApoE level in AD is related to the mini-mental state exam score in both results from different experimental methods, but it failed to show consistent correlation with age, gender, or clinical dementia rating.

Cerebrovascular Pathology and Amyloid Plaque Formation in Alzheimer’s Disease

Accumulation, aggregation and deposition of the amyloid-β (Aβ) peptides in the brain are widely accepted as the central events in the pathogenesis of Alzheimer's disease (AD). Any factor that is capable of causing these events is potentially a risk factor for AD. In the last decade, evidence has accumulated to support the association between cerebral vascular diseases (CVD) and AD. CVD is known to induce amyloid deposition and affects the age of onset for sporadic AD; whereas, amyloid deposition has been shown to cause cerebrovascular degeneration. In this review, we propose a positive feedback loop between CVD and amyloid deposition. The disease cycle could be triggered by aging and/or other environmental factor-associated CVD, as in late-onset sporadic AD patients, or by over production of Aβ, as in the familial AD patients and amyloid precursor protein transgenic animals.

Association betweenε2/3/4, Promoter Polymorphism (−491A/T, −427T/C, and −219T/G) at the Apolipoprotein E Gene, and Mental Retardation in Children from an Iodine Deficiency Area, China

Background. Several common single-nucleotide polymorphisms (SNPs) at apolipoprotein E (ApoE) have been linked with late onset sporadic Alzheimer's disease and declining normative cognitive ability in elder people, but we are unclear about their relationship with cognition in children. Results. We studied −491A/T, −427T/C, and −219G/T promoter polymorphisms and ε2/ε3/ε4 at ApoE among children with mental retardation (MR, n = 130), borderline MR (n = 124), and controls (n = 334) from an iodine deficiency area in China. The allelic and genotypic distribution of individual locus did not significantly differ among three groups with Mantel-Haenszel χ 2 test (P > 0.05). However, frequencies of haplotype of −491A/−427T/−219T/ε4 were distributed as MR > borderline MR > controls (P uncorrected = 0.004), indicating that the presence of this haplotype may increase the risk of disease. Conclusions. In this large population-based study in children, we did not find any significant association between single locus of the four common ApoE polymorphisms (−491A/T, −427T/C, −219T/G, and ε2/3/4) and MR or borderline MR. However, we found that the presence of ATTε4 haplotype was associated with an increased risk of MR and borderline MR. Our present work may help enlarge our knowledge of the cognitive role of ApoE across the lifespan and the mechanisms of human cognition.