Hypothesis Of Alzheimer Research Articles

Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer's disease.

Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals. The comorbidity of the two neurological disorders represents a grave health threat to older populations. This review presents a brief background of the development of novel concepts and their clinical potentials. The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca 2+ influx is critical for neuronal function. An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca 2+ mainly via N-methyl-D-aspartate receptors, particularly of those at the extrasynaptic site. This Ca 2+ -evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity. Furthermore, mild but sustained Ca 2+ increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic, but gradually set off deteriorating Ca 2+ -dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways. Based on the Ca 2+ hypothesis of Alzheimer's disease and recent advances, this Ca 2+ -activated "silent" degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis. The N-methyl-D-aspartate receptor subunit GluN3A, primarily at the extrasynaptic site, serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity. Ischemic stroke and Alzheimer's disease, therefore, share an N-methyl-D-aspartate receptor- and Ca 2+ -mediated mechanism, although with much different time courses. It is thus proposed that early interventions to control Ca 2+ homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia. This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.

Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.

The "amyloid cascade" hypothesis of Alzheimer's disease (AD) pathogenesis invokes the accumulation in the brain of plaques (containing the amyloid-β protein precursor [AβPP] cleavage product amyloid-β [Aβ]) and tangles (containing hyperphosphorylated tau) as drivers of pathogenesis. However, the poor track record of clinical trials based on this hypothesis suggests that the accumulation of these peptides is not the only cause of AD. Here, an alternative hypothesis is proposed in which the AβPP cleavage product C99, not Aβ, is the main culprit, via its role as a regulator of cholesterol metabolism. C99, which is a cholesterol sensor, promotes the formation of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), a cholesterol-rich lipid raft-like subdomain of the ER that communicates, both physically and biochemically, with mitochondria. We propose that in early-onset AD (EOAD), MAM-localized C99 is elevated above normal levels, resulting in increased transport of cholesterol from the plasma membrane to membranes of intracellular organelles, such as ER/endosomes, thereby upregulating MAM function and driving pathology. By the same token, late-onset AD (LOAD) is triggered by any genetic variant that increases the accumulation of intracellular cholesterol that, in turn, boosts the levels of C99 and again upregulates MAM function. Thus, the functional cause of AD is upregulated MAM function that, in turn, causes the hallmark disease phenotypes, including the plaques and tangles. Accordingly, the MAM hypothesis invokes two key interrelated elements, C99 and cholesterol, that converge at the MAM to drive AD pathogenesis. From this perspective, AD is, at bottom, a lipid disorder.

Polyamine Dysregulation and Nucleolar Disruption in Alzheimer's Disease.

A hypothesis of Alzheimer's disease etiology is proposed describing how cellular stress induces excessive polyamine synthesis and recycling which can disrupt nucleoli. Polyamines are essential in nucleolar functions, such as RNA folding and ribonucleoprotein assembly. Changes in the nucleolar pool of anionic RNA and cationic polyamines acting as counterions can cause significant nucleolar dynamics. Polyamine synthesis reduces S-adenosylmethionine which, at low levels, triggers tau phosphorylation. Also, polyamine recycling reduces acetyl-CoA needed for acetylcholine, which is low in Alzheimer's disease. Extraordinary nucleolar expansion and/or contraction can disrupt epigenetic control in peri-nucleolar chromatin, such as chromosome 14 with the presenilin-1 gene; chromosome 21 with the amyloid precursor protein gene; chromosome 17 with the tau gene; chromosome 19 with the APOE4 gene; and the inactive X chromosome (Xi; aka "nucleolar satellite") with normally silent spermine synthase (polyamine synthesis) and spermidine/spermine-N1-acetyltransferase (polyamine recycling) alleles. Chromosomes 17, 19 and the Xi have high concentrations of Alu elements which can be transcribed by RNA polymerase III if positioned nucleosomes are displaced from the Alu elements. A sudden flood of Alu RNA transcripts can competitively bind nucleolin which is usually bound to Alu sequences in structural RNAs that stabilize the nucleolar heterochromatic shell. This Alu competition leads to loss of nucleolar integrity with leaking of nucleolar polyamines that cause aggregation of phosphorylated tau. The hypothesis was developed with key word searches (e.g., PubMed) using relevant terms (e.g., Alzheimer's, lupus, nucleolin) based on a systems biology approach and exploring autoimmune disease tautology, gaining synergistic insights from other diseases.

Testing causality in the association between amyloid‐β and tau in genetically identical twins

AbstractBackgroundThe amyloid‐cascade hypothesis of Alzheimer’s disease posits that there is a causal relationship between amyloid‐β (Aβ) and tau pathology. However, the mechanism through which Aβ would cause tau remains unclear. We cannot exclude the possibility of an additional underlying factor influencing Aβ at one time‐point and tau at a later time‐point. One such potential underlying factor can be genetic variation among individuals. This study aimed to examine the relationship between Aβ and tau, taking potential genetic confounding into account using a genetically identical twin design.MethodsWe included 70 identical twins (35 pairs) from the EMIF‐AD PreclinAD study with normal baseline cognition. We extracted baseline global [18F]flutemetamol (Aβ)‐PET binding potential (BPND) and 4‐year follow‐up [18F]flortaucipir (tau)‐PET BPND in a temporal meta‐region‐of‐interest. If Aβ is causally related to tau, the twin with more Aβ should also have more tau compared to the co‐twin. We tested this using regional and voxel‐wise within‐pair difference models, in which the within‐pair difference in Aβ is regressed on the within‐pair difference in tau. The resulting effect represents an association that is free of confounding due to factors that are shared between twins of the same pair, which includes genetic factors (twins are genetically identical), but also shared demographic (e.g. sex, age) and shared environmental (e.g. raised in the same family) factors.ResultsParticipant characteristics are shown in Table 1. Total group analysis showed that global Aβ‐PET BPND was associated with temporal tau‐PET BPND (β=0.49, p<0.001) (Fig‐1A). The twin‐difference model replicated this. We observed a highly comparable effect size for the association between within‐pair differences in global Aβ‐PET and within‐pair differences in temporal tau‐PET (β=0.56, p<0.001) (Fig‐1B). Compared to the total group voxel‐wise analysis, we observed an overlapping (and more widespread) pattern when regressing within‐pair differences in global Aβ‐PET on within‐pair differences in voxel‐wise tau‐PET, except for effects on tau in the medial temporal lobe (Fig‐2).ConclusionOur within‐pair difference results show that the association between Aβ and tau is minimally affected by confounding by genetic variation. Our voxel‐wise results support a causal association between global Aβ and tau outside of the medial temporal lobe.

COVID-19 and Alzheimer's disease: Meninges-mediated neuropathology.

BackgroundSARS‐CoV‐2 the causative agent of COVID‐19 displays a broad range of pathophysiology. Cytokine storms associated with COVID‐19 damage the blood‐brain barrier (BBB) and allow pro‐inflammatory factors to invade the brain, further promoting neurodegeneration. While SARS‐CoV‐2 viral RNA and proteins have been detected in brain tissues, the mechanisms of neuroinvasion remain unknown. COVID‐19 has had a disproportionate impact on those suffering from neurodegenerative disorders such as Alzheimer’s disease (AD). Understanding the mechanisms of SARS‐CoV‐2 neuroinvasion is crucial to study the long‐term neurocognitive effects of COVID‐19 on AD pathology. Viruses can infiltrate the brain through the meninges via infected immune cells. The meninges regulate the immune surveillance of the brain and play a key role in the efflux of pathogens from the brain. Meningeal dysfunction has been demonstrated to exacerbate amyloid‐beta pathogenesis. In this study, we explore the neuroinvasion pathway of SARS‐CoV‐2 through the meninges and its effect on AD pathology.Method5x FAD x hACE2 mice were inoculated intranasally with a sublethal dose of SARS‐CoV‐2. The mice were maintained for 2 weeks. Mouse brains and meninges were harvested. The tissue was stained and immunofluorescence imaging was conducted to study viral proliferation and immune responses. Histo‐cytometry was conducted for quantitative imaging analysis. Gene expression studies were done using Nanostring assays. All experiments involving the SARS‐Cov‐2 virus were carried out in a BSL3 facility.ResultThis ongoing study demonstrates the proliferation of the SARS‐CoV‐2 virus in the brain via meningeal lymphatics. SARS‐CoV‐2 infection resulted in increased neuroinflammation. Additionally, inflammatory responses induced meningeal dysfunction resulting in increased amyloid‐beta pathology and cerebrospinal fluid drainage.ConclusionGiven the increasing evidence for a viral hypothesis of Alzheimer’s Disease it is extremely important to study the neurodegenerative effects of COVID‐19 which has affected millions worldwide. We demonstrate that SARS‐CoV‐2 infiltrates the brain via the meninges promoting neuroinflammation. Furthermore, amyloid‐beta pathologies are exacerbated by COVID‐19 in animal models providing preclinical evidence of the long‐term neurodegenerative effects of COVID‐19.

Prolongation of metallothionein induction combats A\xdf and \u03b1-synuclein toxicity in aged transgenic Caenorhabditis elegans

Neurodegenerative disorders (ND) like Alzheimer’s (AD), Parkinson’s (PD), Huntington’s or Prion diseases share similar pathological features. They are all age dependent and are often associated with disruptions in analogous metabolic processes such as protein aggregation and oxidative stress, both of which involve metal ions like copper, manganese and iron. Bush and Tanzi proposed 2008 in the ‘metal hypothesis of Alzheimer’s disease’ that a breakdown in metal homeostasis is the main cause of NDs, and drugs restoring metal homeostasis are promising novel therapeutic strategies. We report here that metallothionein (MT), an endogenous metal detoxifying protein, is increased in young amyloid ß (Aß) expressing Caenorhabditis elegans, whereas it is not in wild type strains. Further MT induction collapsed in 8 days old transgenic worms, indicating the age dependency of disease outbreak, and sharing intriguing parallels to diminished MT levels in human brains of AD. A medium throughput screening assay method was established to search for compounds increasing the MT level. Compounds known to induce MT release like progesterone, ZnSO4, quercetin, dexamethasone and apomorphine were active in models of AD and PD. Thioflavin T, clioquinol and emodin are promising leads in AD and PD research, whose mode of action has not been fully established yet. In this study, we could show that the reduction of Aß and α-synuclein toxicity in transgenic C. elegans models correlated with the prolongation of MT induction time and that knockdown of MT with RNA interference resulted in a loss of bioactivity.

Human amyloid-\u03b2 enriched extracts: evaluation of in vitro and in vivo internalization and molecular characterization

BackgroundIntracerebral inoculation of extracts from post-mortem human Alzheimer’s disease brains into mice produces a prion-like spreading effect of amyloid-β. The differences observed between these extracts and the synthetic peptide, in terms of amyloid-β internalization and seed and cell-to-cell transmission of cytosolic protein aggregates, suggest that brain extracts contain key contributors that enhance the prion-like effect of amyloid-β. Nevertheless, these potential partners are still unknown due to the complexity of whole brain extracts.MethodsHerein, we established a method based on sequential detergent solubilization of post-mortem samples of human brains affected by Alzheimer’s disease that strongly enrich amyloid-β aggregates by eliminating 92% of the remaining proteins. Internalization of Aβ1–42 from the enriched AD extracts was evaluated in vitro, and internalization of fluorescent-labeled AD extracts was also investigated in vivo. Furthermore, we carried out a molecular characterization of the Aβ-enriched fraction using label-free proteomics, studying the distribution of representative components in the amygdala and the olfactory cortex of additional human AD brain samples by immunohistochemistry.ResultsAβ1–42 from the enriched AD extracts are internalized into endothelial cells in vitro after 48 h. Furthermore, accumulation of fluorescent-labeled Aβ-enriched extracts into mouse microglia was observed in vivo after 4 months of intracerebral inoculation. Label-free proteomics (FDR < 0.01) characterization of the amyloid-β-enriched fraction from different post-mortem samples allowed for the identification of more than 130 proteins, several of which were significantly overrepresented (i.e., ANXA5 and HIST1H2BK; p < 0.05) and underrepresented (i.e., COL6A or FN1; p < 0.05) in the samples with Alzheimer’s disease. We were also able to identify proteins exclusively observed in Alzheimer’s disease (i.e., RNF213) or only detected in samples not affected by the disease (i.e., CNTN1) after the enrichment process. Immunohistochemistry against these proteins in additional tissues revealed their particular distribution in the amygdala and the olfactory cortex in relation to the amyloid-β plaque.ConclusionsIdentification and characterization of the unique features of these extracts, in terms of amyloid-β enrichment, identification of the components, in vitro and in vivo cell internalization, and tissue distribution, constitute the best initial tool to further investigate the seeding and transmissibility proposed in the prion-like hypothesis of Alzheimer’s disease.

Dysregulation of Intracellular Calcium Signaling in Alzheimer's Disease.

Calcium (Ca2+) hypothesis of Alzheimer's disease (AD) gains popularity. It points to new signaling pathways that may underlie AD pathogenesis. Based on calcium hypothesis, novel targets for the development of potential AD therapies are identified. Recent Advances: Recently, the key role of neuronal store-operated calcium entry (nSOCE) in the development of AD has been described. Correct regulation of nSOCE is necessary for the stability of postsynaptic contacts to preserve the memory formation. Molecular identity of hippocampal nSOCE is defined. Perspective nSOCE-activating molecule, prototype of future anti-AD drugs, is described. Endoplasmic reticulum Ca2+ overload happens in many but not in all AD models. The nSOCE targeting therapy described in this review may not be universally applicable. There is a need to determine whether AD is a syndrome with one critical signaling pathway that initiates pathology, or it is a disorder with many different signaling pathways that are disrupted simultaneously or one after each other. It is necessary to validate applicability of nSOCE-activating therapy for the development of anti-AD medication. There is an experimental correlation between downregulated nSOCE and disrupted postsynaptic contacts in AD mouse models. Signaling mechanisms downstream of nSOCE which are responsible for the regulation of stability of postsynaptic contacts have to be discovered. That will bring new targets for the development of AD-preventing therapies. Antioxid. Redox Signal. 29, 1176-1188.

Phospholipids and calmodulin modulate the inhibition of PMCA activity by tau

The disruption of Ca2+ signaling in neurons, together with a failure to keep optimal intracellular Ca2+ concentrations, have been proposed as significant factors for neuronal dysfunction in the Ca2+ hypothesis of Alzheimer's disease (AD). Tau is a protein that plays an essential role in axonal transport and can form abnormal structures such as neurofibrillary tangles that constitute one of the hallmarks of AD. We have recently shown that plasma membrane Ca2+-ATPase (PMCA), a key enzyme in the maintenance of optimal cytosolic Ca2+ levels in cells, is inhibited by tau in membrane vesicles. In the present study we show that tau inhibits synaptosomal PMCA purified from pig cerebrum, and reconstituted in phosphatidylserine-containing lipid bilayers, with a Ki value of 1.5±0.2nM tau. Noteworthy, the inhibitory effect of tau is dependent on the charge of the phospholipid used for PMCA reconstitution. In addition, nanomolar concentrations of calmodulin, the major endogenous activator of PMCA, protects against inhibition of the Ca2+-ATPase activity by tau. Our results in a cellular model such as SH-SY5Y human neuroblastoma cells yielded an inhibition of PMCA by nanomolar tau concentrations and protection by calmodulin against this inhibition similar to those obtained with purified synaptosomal PMCA. Functional studies were also performed with native and truncated versions of human cerebral PMCA4b, an isoform that has been showed to be functionally regulated by amyloid peptides, whose aggregates constitutes another hallmark of AD. Kinetic assays point out that tau binds to the C-terminal tail of PMCA, at a site distinct but close to the calmodulin binding domain. In conclusion, PMCA can be seen as a molecular target for tau-induced cytosolic calcium dysregulation in synaptic terminals.This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.

Generation and deposition of Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease.

As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid‐β peptide (Aβ) species, which are released from a C‐terminal amyloid precursor protein fragment by γ‐secretase. Mutations in its catalytic subunit presenilin‐1 (PS1) increase the Aβ42 to Aβ40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major argument for this hypothesis is the observation that the nearly inactive PS1 L435F mutant, paradoxically, causes FAD. We now show that the very little Aβ generated by PS1 L435F consists primarily of Aβ43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of Aβ43 is not due to a trans‐dominant effect of this mutant on WT presenilin. Furthermore, we found Aβ43‐containing plaques in brains of patients with this mutation. The aberrant generation of Aβ43 by this particular mutant provides a direct objection against the presenilin hypothesis.

Editorial: Siegfried Hoyer's concept of Alzheimer pathophysiology.

The concept of central insulin resistance and dysfunctional insulin signaling in Alzheimer's Disease (AD) has been developed by Siegfried Hoyer in 1985-2000. It is widely recognized that the mechanisms underlying neuronal energy deficiency and in particular to elucidate insulin/insulin receptor cascade deficiencies are some of the most relevant proximate characteristics of sporadic AD. The imbalance between cerebral oxygen utilization and cerebral glucose utilization may cause rise in reactive oxygen species production and this might be causal for synapse degeneration. This concept has been substantiated by work on postmortem Alzheimer brains and has been translated back into the streptozotozin animal model, which has stimulated much further research by other researchers. Finally, the insulin hypothesis of Alzheimer's disease has currently advanced into a potential therapeutic avenue.

Research challenges ‘cytokine storm’ hypothesis of Alzheimer’s disease

Research challenges ‘cytokine storm’ hypothesis of Alzheimer’s disease

Mapping memory binding onto the connectome's temporal dynamics: toward a combined biomarker for Alzheimer's disease.

The classical amyloid cascade hypothesis of Alzheimer's disease (AD) has driven research and clinical practice for several decades. It states that the deposition of the amyloid-β peptide in the brain parenchyma initiates a sequence of events that ultimately lead to atrophy and AD dementia. This proposal stimulated the study of specific brain regions mapped along the neurodegeneration sequence (e.g., hippocampus) and their associated impaired functions (e.g., episodic memory). Although anticipated by Mesulam more than 20 years ago (e.g., Mesulam and Asuncion Moran, 1987), it was not until recently that this view has started to change, largely due to the disappointing results of trials relying on the beta-amyloid cascade hypothesis and its variants, e.g., the synaptic beta-amyloid hypothesis.

Vascular hypothesis of Alzheimer’s disease: role of apoE and apoE receptors

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease that has emerged as the most prevalent form of late-life dementia in humans [1]. Production of amyloid-b (Ab) from the amyloid precursor protein (APP) and its subsequent accumulation, aggregation and deposition in the brain are central events in the pathogenesis of AD [1]. Cerebral amyloid angiopathy (CAA) is a major pathological feature of AD where amyloid spreads and deposits throughout the blood vessel walls in the central nervous system. These pathogenic events induce a specific clinical presentation profile including cerebral hemorrhage, stroke, ischemic infarctions, subarachnoid hemorrhage, seizures, cognitive impairment and dementia [2]. While Ab is a key molecule in AD, epidemiological studies have shown that several well-established risk factors for AD, including diabetes mellitus, atherosclerosis, stroke, hypertension, transient ischemic attacks, microvessel pathology and smoking, have a vascular component that reduces cerebral perfusion [3]. In fact, detection of regional cerebral hypoperfusion through neuroimaging techniques can preclinically identify individuals at risk for AD. Further, cerebral hypoperfusion precedes hypometabolism, cognitive decline, and neurodegeneration in AD [3]. Therefore, disturbance of cerebrovascular system is likely a major contributor to AD pathogenesis. Among the three human apolipoprotein E (apoE) isoforms (E2, E3 and E4), APOE4 is the strongest genetic risk factor for late-onset AD. The most consistent finding that differentiates apoE4 from apoE3 is their respective roles in brain Ab clearance, where apoE4 is less efficient than apoE3 in promoting Ab clearance [4]. In addition, APOE4 also increases the risk for CAA and vascular dementia [4]. Because apoE4 is known to damage blood-brain barrier (BBB) integrity and reduces small cerebral vessels [5], apoE is likely involved in the maintenance of cognitive function through regulating the function of cerebrovascular systems.

Correction: The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

Correction: The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

CR1 and the “Vanishing Amyloid” Hypothesis of Alzheimer’s Disease

CR1 and the “Vanishing Amyloid” Hypothesis of Alzheimer’s Disease

γ-Secretase Pharmacology: What Pharmacology Will Work for Alzheimer's Disease?

This special issue focuses on γ-secretase modulators (GSMs) and inhibitors (GSIs), two classes of small molecules with the potential to test the amyloid hypothesis of Alzheimer's disease. Recent clinical trials of GSI and GSM, including semagacestat, avagacestat, and R-flurbiprofen, have been discontinued for lack of efficacy and/or side effects, the mechanisms of which have not been elucidated. Detrimental effects of GSIs on cognition observed in AD patients may be linked to the accumulation of C-terminal fragment of APP (C99 or CTFβ). The stimulating effects of GSIs on skin cancer in AD patients have been linked to their inhibition of Notch processing. The lack of efficacy of the GSM R-flurbiprofen in AD patients has been explained with its low potency and poor ability to cross the blood-brain barrier. The two review articles and three research articles address key issues for GSI and GSM, namely, Notch-related side effects and drug-like properties, respectively. Although other amyloid-related approaches are continuing in clinical trials, including anti-Aβ antibodies and β-site amyloid precursor protein cleaving enzyme (BACE) inhibitors, it still remains to be seen whether or not they can decrease amyloid or Aβ for a sufficient period of time at tolerable doses in patients. Therefore, renewed efforts toward GSIs and GSMs appear justified.

Correction: The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

Correction: The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

The role of animal models in advancing amyloid-beta immunotherapy to the clinic

The amyloid-beta (Aβ) hypothesis of Alzheimer's disease (AD) causality is now well into its third decade and is finally entering a phase of rigorous clinical testing in numerous late stage clinical trials. The use of Aβ-based animal models of AD has been essential to the discovery and/or preclinical validation of many of these therapeutic approaches. While several neuropathologically based results from preclinical studies have translated nicely into AD patients, the full clinical value of Aβ-directed therapies awaits results from trials now in progress.

No Association of VEGF Polymorphims with Alzheimer’s Disease

The vascular hypothesis of Alzheimer's disease (AD) has brought the vascular endothelial growth factor (VEGF) into focus. The genomic region including the VEGF gene has been linked to AD and single nucleotide polymorphisms (SNPs) of the VEGF have in previous studies been associated with AD risk. To further evaluate these findings, we genotyped two SNPs in the VEGF gene (rs699947 [-2578]) and rs1570360 [-1154]) by TaqMan Allelic Discrimination in a study sample including AD patients (n = 801) and controls (n = 286). In a subgroup of the population these SNPs were analyzed in relation to APOE epsilon4 genotype, to cerebrospinal fluid biomarkers (T-tau, P-tau, and beta(42)-Amyloid) as well as to neuropathological markers for AD (neurofibrillary tangles and senile plaques). No significant associations with risk for AD or any of the studied biomarkers could be found in this study, thus not supporting VEGF as being a major risk gene for AD.