plaque regression | Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Posts Tagged ‘plaque regression’

Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Posted in Atherogenic Processes & Pathology, Best evidence, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Ca2+ triggered activation, Calcium Signaling, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Coagulation Therapy and Internal Bleeding, Computational Biology/Systems and Bioinformatics, Congenital Heart Disease, Curation, Cytoskeleton, Diabetes Mellitus, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Experimental validation, Explanatory, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Human Immune System in Health and in Disease, Immunodiagnostics, International Global Work in Pharmaceutical, Medical and Population Genetics, Medical Devices R&D and Inventions, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Nitric Oxide in Health and Disease, Nutrigenomics, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacogenomics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Pre-Clinical Animal Model Development, Proteomics, Technology Advance Assessment of, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Research, Translational Science, tagged acute myocardial infarction, Antiplatelet drug, atheromatous plaque, AVV genotype 2, Biomarker discovery, cardiac biomarkers, Cardiovascular disease, clotting, coronary artery plaque, disease etiology, endothelial cell, genetic biomarkers, genomics, Hypertension, nutraceuticals, Nutrition, Personalized medicine, plaque regression, plaque rupture, platelet activation, platelet aggregation, platelets, Preventive medicine, risk factors, therapetic targets, threatment targets, type 2DM on January 6, 2014| Leave a Comment »

Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Author: Larry H. Bernstein, MD, FCAP

The articles within Chapters and Subchapters you have just read have been organized into four interconnected parts.

Genomics and Medicine
Epigenetics – Modifyable Factors Causing CVD
Determinants of CVD – Genetics, Heredity and Genomics Discoveries
Individualized Medicine Guided by Genetics and Genomics Discoveries

The first part established the

rapidly evolving science of genomics
aided by analytical and computational tools for the identification of nucleotide substitutions, or combinations of them

that have a significant association with the development of

cardiovascular diseases,
hypercoagulable state,
atherosclerosis,
microvascular disease,
endothelial disruption, and
type-2DM, to name a few.

These may well be associated with increased risk for stroke and/or peripheral vascular disease in some cases,

essentially because the involvement of the circulation is systemic in nature.

Part 1

establishes an important connection between RNA and disease expression. This development has led to

the necessity of a patient-centric approach to patient-care.

When I entered medical school, it was eight years after Watson and Crick proposed the double helix. It was also

the height of a series of discoveries elucidating key metabolic pathways.

In the period since then there have been treatments for some of the important well established metabolic diseases of

carbohydrate,
protein, and
lipid metabolism,

such as – glycogen storage disease, and some are immense challenges, such as

Tay Sachs, or
Transthyretin-Associated amyloidosis.

But we have crossed a line delineating classical Mendelian genetics to

multifactorial non-linear traits of great complexity and

involving combinatorial program analyses to resolve.

The Human Genome Project was completed in 2001, and it has opened the floodgates of genomic discovery. This resulted in the identification of

genomic alterations in

cardiovascular disease,
cancer,
microbial,
plant,
prion, and
metabolic diseases.

This has also led to

the identification of genomic targets
that are either involved in transcription or
are involved with cellular control mechanisms for targeted pharmaceutical development.

In addition, there is great pressure on the science of laboratory analytics to

codevelop with new drugs,
biomarkers that are indicators of toxicity or
of drug effectiveness.

I have not mentioned the dark matter of the genome. It has been substantially reduced, and has been termed dark because

this portion of the genome is not identified in transcription of proteins.

However, it has become a lightning rod to ongoing genomic investigation because of

an essential role in the regulation of nuclear and cytoplasmic activities.

Changes in the three dimensional structure of these genes due to

changes in Van der Waal forces and internucleotide distances lead to
conformational changes that could have an effect on cell activity.

Part 2

is an exploration of epigenetics in cardiovascular diseases. Epigenetics is

the post-genomic modification of genetic expression
by the substitution of nucleotides or by the attachment of carbohydrate residues, or
by alterations in the hydrophobic forces between sequences that weaken or strengthen their expression.

This could operate in a manner similar to the conformational changes just described. These changes

may be modifiable, and they
may be highly influenced by environmental factors, such as

smoking and environmental toxins,
diet,
physical activity, and
neutraceuticals.

While neutraceuticals is a black box industry that evolved from

the extraction of ancient herbal remedies of agricultural derivation
(which could be extended to digitalis and Foxglove; or to coumadin; and to penecillin, and to other drugs that are not neutraceuticals).

The best examples are the importance of

n-3 fatty acids, and
fiber
dietary sulfur (in the source of methionine), folic acid, vitamin B12
arginine combined with citrulline to drive eNOS
and of iodine, which can’t be understated.

In addition, meat consumption involves the intake of fat that contains

the proinflammatory n-6 fatty acid.

The importance of the ratio of n-3/n-6 fatty acids in diet is not seriously discussed when

we look at the association of fat intake and disease etiology.

Part 2 then leads into signaling pathways and proteomics. The signaling pathways are

critical to understanding the inflammatory process, just as
dietary factors tie in with a balance that is maintained by dietary intake,
- possibly gut bacteria utilization of delivered substrate, and
- proinflammatory factors in disaease.

These are being explored by microfluidic proteomic and metabolomic technologies that were inconceivable a half century ago.

This portion extended into the diagnosis of cardiovascular disease, and

elucidated the relationship between platelet-endothelial interaction in the formation of vascular plaque.

It explored protein, proteomic, and genomic markers

for identifying and classifying types of disease pathobiology, and
for following treatment measures.

Part 3

connected with genetics and genomic discoveries in cardiovascular diseases.

Part 4

is the tie between life style habits and disease etiology, going forward with

the pursuit of cardiovascular disease prevention.

The presentation of walking and running, and of bariatric surgery (type 2DM) are fine examples.

It further discussed gene therapy and congenital heart disease. But the most interesting presentations are

in the pharmacogenomics for cardiovascular diseases, with

volyage-gated calcium-channels, and
ApoE in the statin response.

This volume is a splendid example representative of the entire collection on cardiovascular diseases.

Read Full Post »

Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases

Posted in Atherogenic Processes & Pathology, Best evidence, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Coagulation Therapy and Internal Bleeding, Congenital Heart Disease, Cytoskeleton, Diabetes Mellitus, Diagnostic Immunology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Evidence-based decision-making, Experimental validation, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, HTN, Human Immune System in Health and in Disease, Immunodiagnostics, Innovation in Immunology Diagnostics, International Global Work in Pharmaceutical, Medical and Population Genetics, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacogenomics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Pre-Clinical Animal Model Development, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Technology Transfer: Biotech and Pharmaceutical, Theoretic convergence, Translational Effectiveness, Translational Research, Translational Science, tagged adipokine, Antiplatelet drug, atheromatous plaque, AVV genotype 2, biomarker assays, Biomarker discovery, CaKMII overactive in obesity, cardiac biomarkers, Circulation Endothelial Progenitor Cells, comorbidities - type 2 DM, Endothelial Cell Coagulation Activation, Endothelial cells, endothelial damage, Endothelial Dysfunction, epigenetic, genomics, Nutritional Supplements, plaque regression, plaque rupture, platelet activation, platelet aggregation, platelet and clot formation, resistin, subintimal plaque, target of both insulin resistance and type 2 diabetes, type 2 DM on January 5, 2014| Leave a Comment »

Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases

Author and Curator: Larry H Bernstein, MD, FCAP

This introduction is to a thorough evaluation of a rich source of research literature on the genomic influences, which may have variable strength in the biological causation of atherosclerosis, microvascular disease, plaque formation, not necessarily having expressing, except in a multivariable context that includes the environment, dietary factors, level of emotional stress, sleep habits, and the daily activities of living for affected individuals. The potential of genomics is carried in the DNA, copied to RNA, and this is most well studied in the micro RNAs (miRNA). The miRNA has been explored for the appearance in the circulation of specific miRNAs that might be associated with myocyte or endothelial cell injury, and they are also being used as targets for therapeutics by the creation of silencing RNAs (siRNA). The extent to which there is evidence of success in these studies is limited, but is being translated from animal studies to human disease. There is also a long history of the measurement of circulating enzymes and isoenzymes (alanine amino transferase, creatine kinase, and lactate dehydrogenase, not to leave out the adenylate kinase species specific to myocardium), and more recently the release of troponins I and T, and the so far still not fully explored ischemia modified albumin, or of miRNAs for the diagnosis of myocardial infarction.

There is also a significant disagreement about the value of measuring high sensitivity C reactive protein (hs-CRP), which has always been a marker for systemic inflammatory disease, in both chronic rheumatic and infectious diseases having a broad range, so that procalcitonin has appeared to be better for that situation, and for early diagnosis of sepsis. The hs-CRP has been too easily ignored because of

1. the ubiquitous elevations in the population
2. the expressed concerns that one might not be inclined to treat a mild elevation without other risk factors, such as, LDL cholesterolemia, low HDL, absent diabetes or obesity. Nevertheless, hs-CRP raises an reasonable argument for preventive measures, and perhaps the use of a statin.

There has been a substantial amount of work on the relationship of obesity to both type 2 diabetes mellitus (T2DM) and to coronary vascular disease and stroke. Here we bring in the relationship of the vascular endothelium, adipose tissue secretion of adiponectin, and platelet activation. A whole generation of antiplatelet drugs addresses the mechanism of platelet activation, adhession, and interaction with endothelium. Very interesting work has appeared on RESISTIN, that could bear some fruit in the treatment of both obesity and T2DM.

It is important to keep in mind that epigenomic gene rearrangements or substitutions occur throughout life, and they may have an expression late in life. Some of the known epigenetic events occur with some frequency, but the associations are extremely difficult to pin down, as well as the strength of the association. In a population that is not diverse, epigenetic changes are passed on in the population in the period of childbearing age. The establishment of an epigenetic change is diluted in a diverse population. There have been a number of studies with different findings of association between cardiovascular disease and genetic mutations in the Han and also in the Uyger Chinese populations, which are distinctly different populations that is not part of this discussion.

This should be sufficient to elicit broad appeal in reading this volume on cardiovascular diseases, and perhaps the entire series. Below is a diagram of this volume in the series.

PART 1 – Genomics and Medicine
Introduction to Genomics and Medicine (Vol 3)
Genomics and Medicine: The Physician’s View
Ribozymes and RNA Machines
Genomics and Medicine: Genomics to CVD Diagnoses
Establishing a Patient-Centric View of Genomic Data

VIDEO: Implementing Biomarker Programs P Ridker	PART 2 – Epigenetics – Modifiable Factors Causing CVD
	Diseases Etiology
	Environmental Contributors Implicated as Causing CVD
	Diet: Solids and Fluid Intake and Nutraceuticals
	Physical Activity and Prevention of CVD
	Psychological Stress and Mental Health: Risk for CVD
	Correlation between Cancer and CVD

PART 3 Determinants of CVD – Genetics, Heredity and Genomics Discoveries

Introduction

Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)

Functional Characterization of CV Genomics: Disease Case Studies @ 2013 ASHG

Leading DIAGNOSES of CVD covered in Circulation: CV Genetics, 3/2010 – 3/2013

Commentary on Biomarkers for Genetics and Genomics of CVD

PART 4 Individualized Medicine Guided by Genetics and Genomics Discoveries

Preventive Medicine: Cardiovascular Diseases

Walking and Running: Similar Risk Reductions for Hypertension, Hypercholesterolemia,
DM, and possibly CAD
http://pharmaceuticalintelligence.com/2013/04/04/walking-and-running-similar-risk-reductions-for-hypertension-hypercholesterolemia-dm-and-possibly-cad/

Prevention of Type 2 Diabetes: Is Bariatric Surgery the Solution?
http://pharmaceuticalintelligence.com/2012/08/23/prevention-of-type-2-diabetes-is-bariatric-surgery-the-solution/

Gene-Therapy for CVD

Congenital Heart Disease/Defects

Medical Etiologies: EBM – LEADING DIAGNOSES, Risks		Pharmacogenomics for Cardio- vascular Diseases
Signaling Pathways		Response to Rosuvastatin in Patients With Acute Myocardial Infarction: Hepatic Metabolism and Transporter Gene Variants Effect http://pharmaceuticalintelligence.com/2014/ 01/02/response-to-rosuvastatin-in-patients- with-acute-myocardial-infarction-hepatic- metabolism-and-transporter-gene-variants-effect/
Proteomics and Metabolomics		Voltage-Gated Calcium Channel and Pharmaco- genetic Association with Adverse Cardiovascular Outcomes: Hypertension Treatment with Verapamil SR (CCB) vs Atenolol (BB) or Trandolapril (ACE) http://pharmaceuticalintelligence.com/2014/01/02/ voltage-gated-calcium-channel-and-pharmacogenetic- association-with-adverse-cardiovascular-outcomes- hypertension-treatment-with-verapamil-sr-ccb-vs- atenolol-bb-or-trandolapril-ace/
		SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR http://pharmaceuticalintelligence.com/2014/01/02/snps-in-apoe-are-found-to-influence-statin-response-significantly-less-frequent-variants-in-pcsk9-and-smaller-effect-sizes-in-snps-in-hmgcr/

Read Full Post »

Alzheimer’s Disease Conundrum – Are We Near the End of the Puzzle?

Posted in Advanced Drug Manufacturing Technology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Innovations in Neurophysiology & Neuropsychology, International Global Work in Pharmaceutical, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Molecular Genetics & Pharmaceutical, Pharmaceutical Industry Competitive Intelligence, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged Alois Alzheimer, Alzheimer, Alzheimer Disease, Alzheimers Disease, ApoE, BCHE brain imaging, Beta amyloid, biomarkers, cellular inflammatiory response, CLU, conitive loss, Decode Genetics, dementia, Icelanders, innovative applications, Kári Stefánsson, mapping, Massachusetts General Hospital, Picalm, plaque regression, Tau protein on March 9, 2013| 1 Comment »

Alzheimer’s Genomic Diagnosis and Treatment

Curator: Larry H Bernstein, MD, FCAP

Gene Mutation Protects Against Alzheimer’s

by Greg Miller on 11 July 2012
Brain preserver. A newly discovered gene mutation appears to protect against Alzheimer’s disease. Credit: Alzheimer’s Disease Education and Referral Center/NIA/NIH
http://news.sciencemag.org/sciencenow/2012/07/gene-mutation-protects-against-a.html

A rare mutation that alters a single letter of the genetic code protects people from the

memory-robbing dementia of Alzheimer’s disease.

The DNA change may inhibit the buildup of β amyloid, the

protein fragment that forms the hallmark plaques in the brains of Alzheimer’s patients.
The mutation affects a gene called APP,
which encodes a protein that gets broken down into pieces,
including β amyloid.

Researchers previously identified more than 30 mutations to APP, none of them good. Several of these changes increase β amyloid formation and cause

• a devastating inherited form of Alzheimer’s that afflicts people in their 30s and 40s—

• much earlier than the far more common “late-onset” form of Alzheimer’s

that typically strikes people their 70s and 80s.

The new mutation, discovered from whole-genome data from 1795 Icelanders for variations in APP that protect against Alzheimer’s, appears to do the opposite. The mutation interferes with one of the enzymes that breaks down the APP protein and causes a 40% reduction in β amyloid formation

New pharmacological strategies for treatment of Alzheimer’s disease: focus on disease modifying drugs.
Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F.
University of Catania, Viale Andrea Doria 6, Catania, Italy.
Br J Clin Pharmacol. 2012 Apr;73(4):504-17. doi: 10.1111/j.1365-2125.2011.04134.x.

Current approved drug treatments for Alzheimer disease (AD) include

cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the
NMDA receptor antagonist memantine.

These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop ‘disease modifying drugs’ hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success,

it is crucial to have biomarkers for early detection of AD-related brain dysfunction,
- usable before clinical onset.

Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy,

with specific cut off values validated in clinical practice.

Disease modifying drugs developed so far include drugs to

reduce β amyloid (Aβ) production,
drugs to prevent Aβ aggregation,
drugs to promote Aβ clearance,
drugs targeting tau phosphorylation and assembly

None of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from

methodological flaws to
fundamental understanding of AD pathophysiology and biology.

Diagnostic criteria applicable to presymptomatic stages of AD have now been published.

These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. http://www.ncbi.nlm.nih.gov/pubmed/22035455

Gene mutation defends against Alzheimer’s disease
Rare genetic variant suggests a cause and treatment for cognitive decline.
Ewen Callaway 11 July 2012
http://www.nature.com/news/gene-mutation-defends-against-alzheimer-s-disease-1.10984

J. NIETH/CORBIS
Almost 30 million people live with Alzheimer’s disease worldwide, a staggering health-care burden that is expected to quadruple by 2050. Yet doctors can offer no effective treatment, and scientists have been unable to pin down the underlying mechanism of the disease.
Research published this week offers some hope on both counts – few people carry a genetic mutation that naturally prevents them from developing the condition – 0.5% of Icelanders have a protective gene, as are 0.2–0.5% of Finns, Swedes and Norwegians. Icelanders who carry it have a 50% better chance of reaching age 85, are more than five times more likely to reach it 85 without Alzheimer’s. The mutation seems to put a brake on the milder mental deterioration that most elderly people experience. Carriers are about 7.5 times more likely than non-carriers to reach the age of 85 without major cognitive decline, and perform better on the cognitive tests that are administered thrice yearly to Icelanders who live in nursing homes.
The discovery not only confirms the principal suspect that is responsible for Alzheimer’s, it also suggests that the disease could be

an extreme form of the cognitive decline seen in many older people.

The mutation — the first ever found to protect against the disease — lies in a gene that produces

amyloid-β precursor protein (APP),
which has an unknown role in the brain

APP was discovered 25 years ago in patients with rare,

inherited forms of Alzheimer’s that strike in middle age.
In the brain, APP is broken down into a smaller molecule called amyloid-β.

Visible clumps, or plaques, of amyloid-β found in the autopsied brains of patients are a hallmark of Alzheimer’s.
Scientists have long debated whether the plaques are a cause of the neurodegenerative condition

or a consequence of other biochemical changes associated with the disease.

The latest finding supports other genetics studies blaming amyloid-β, according to Rudolph Tanzi, a neurologist at the Massachusetts General Hospital in Boston and a member of one of the four teams that discovered APP’s role in the 1980s.
If amyloid-β plaques were confirmed as the cause of Alzheimer’s, it would bolster efforts to develop drugs that block their formation, says Kári Stefánsson, chief executive of deCODE Genetics in Reykjavik, Iceland, who led the latest research. He and his team first discovered the mutation by comparing the complete genome sequences of 1,795 Icelanders with their medical histories. The researchers then studied the variant in nearly 400,000 more Scandinavians.
This suggests that Alzheimer’s disease and cognitive decline are two sides of the same coin, with a common cause — the build-up of amyloid-β plaques in the brain, something seen to a lesser degree in elderly people who do not develop full-blown Alzheimer’s. A drug that mimics the effects of the mutation, might slow cognitive decline as well as prevent Alzheimer’s.
Stefánsson and his team discovered that the mutation introduces a single amino-acid alteration to APP. This amino acid is close to the site where an enzyme called

β-secretase 1 (BACE1) ordinarily snips APP into smaller amyloid-β chunks —
and the alteration is enough to reduce the enzyme’s efficiency.

Stefánsson’s study suggests that blocking β-secretase from cleaving APP has the potential to prevent Alzheimer’s, but Philippe Amouyel, an epidemiologist at the Pasteur Institute in Lille, France, says “it is very difficult to identify the

precise time when this amyloid toxic effect could still be modified”.

“If this effect needs to be blocked as early as possible in life to protect against Alzheimer’s disease, we will need to propose a new design for clinical trials” to identify an effective treatment.

The results demonstrate that whole-genome sequencing can uncover very rare mutations that might offer insight into common diseases.

disease risk, may be determined by genetic variants that slightly tilt the odds of developing disease
In this case a rare mutant may provide very key mechanistic insights into Alzheimer’s

Jonsson, T. et al. Nature http://dx.doi.org/10.1038/nature11283 (2012).
Kang, J. et al. Nature 325, 733–736 (1987).
Goldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti, U. & Gajdusek, D. C. Science 235, 877–880 (1987).

BHCE genetic data combined with brain imaging using agent florbetapir connects the BHCE gene to AD plaque buildup. BHCE is an enzyme that breaks down acetylcholine in the brain, which is depleted early in the disease and results in memory loss. http://www.genengnews.com/

New Alzheimer’s Genes Found
Gigantic Scientific Effort Discovers Clues to Treatment, Diagnosis of Alzheimer’s Disease
By Daniel J. DeNoon
WebMD Health News Reviewed by Laura J. Martin, MD
http://www.webmd.com/alzheimers/news/20110403/new-alzheimers-genes-found

A massive scientific effort has found five new gene variants linked to Alzheimer’s disease. The undertaking involved analyzing the genomes of nearly 40,000 people with and without Alzheimer’s. This study was undertaken by two separate research consortiums in the U.S. and in Europe, which collaborated to confirm each other’s results.
Four genes had previously been linked to Alzheimer’s. Three of them affect only the risk of relatively rare forms of Alzheimer’s. The fourth is APOE, until now the only gene known to affect risk of the common, late-onset form of Alzheimer’s. Roughly 27% of Alzheimer’s disease can be attributed to the five new gene variants. Even though Alzheimer’s is a very complex disease, the new findings represent a large chunk of Alzheimer’s risk, according to Margaret A. Pericak-Vance, PhD, of the U.S. consortium –

20% of the causal risk of Alzheimer’s disease and
32% of the genetic risk.

Alzheimer’s Tied to Mutation Harming Immune Response
By GINA KOLATA Published: November 14, 2012 in NY Times
http://www.nytimes.com/2012/11/15/health/gene-mutation-that-hobbles-immune-response-is-linked-to-alzheimers.html?_r=0
Alzheimer’s researchers and drug companies have for years concentrated on one hallmark of Alzheimer’s disease: the production of toxic shards of a protein that accumulate in plaques on the brain.
Two groups of researchers working from entirely different starting points have converged on a mutated gene involved in another aspect of Alzheimer’s disease:

the immune system’s role in protecting against the disease.

The mutation is suspected of interfering with

the brain’s ability to prevent the buildup of plaque.

When the gene is not mutated, white blood cells in the brain spring into action,

gobbling up and eliminating the plaque-forming toxic protein, beta amyloid.

As a result, Alzheimer’s can be staved off or averted. People with the mutated gene have a threefold to fivefold increase in the likelihood of developing Alzheimer’s disease in old age.

Comparing Differences

Dr. Julie Williams’s, Cardiff, Wales (European team leader) report identified CLU and Picalm. A second study published in Nature Genetics, by Philippe Amouyel from Institut Pasteur de Lille in France, pinpointed CLU and CR1. The greatest inherited risk comes from the APOE gene, discovered in 1993 by a team led by Allen Roses, now director of the Deane Drug Discovery Institute at Duke UMC, in Durham, North Carolina.
The findings “are beginning to give us insight into the biology, but I don’t think you can expect treatments overnight,” Dr. Michael Owen (Cardiff, Wales) said. Instead, the genes will show a mosaic of risk, and “the key issue is what hand of cards you’re dealt,” he said.

Promise for Early Diagnosis
BHCE genetic data combined with brain imaging using agent florbetapir connects the BHCE gene to AD plaque buildup. BHCE is an enzyme that breaks down acetylcholine in the brain, which is depleted early in the disease and results in memory loss.

Dr. Bernstein’s comments:

There has been a long history of failure of drugs to slow down the progression of Alzheimer’s. Regression of the plaques has not corresponded with retention of cognitive ability, which has been behind the arguments over beta amyloid or tau.
We now have two particularly interesting mutations –
1. ApoE gene mutation that increases risk
2. APP mutation that quite dramatically affects retention of cognition

Alzheimer’s Disease: Green Tea Extract Found To Interfere With The Formation Of Amyloid Plaques (medicalnewstoday.com)
Aging Brain – The Specific Gene That Causes It (belmarrahealth.com)
The Pathogenic Aβ43 Is Enriched in Familial and Sporadic Alzheimer Disease (plosone.org)
Damaged blood vessels loaded with amyloid worsen cognitive impairment in Alzheimer’s disease (eurekalert.org)
Major step toward an Alzheimer’s vaccine (nextbigfuture.com)
Damaged blood vessels loaded with amyloid worsen cognitive impairment in Alzheimer’s disease (medicalxpress.com)
Top Signs You are at Risk for Alzheimer’s (belmarrahealth.com)
A Reliable Way to Detect Endogenous Murine β-Amyloid (plosone.org)

β-amyloid fibrils. (Photo credit: Wikipedia)

English: PET scan of a human brain with Alzheimer’s disease (Photo credit: Wikipedia)

Depiction of amyloid precursor protein processing, created by I. Peltan Ipeltan (Photo credit: Wikipedia)

English: Diagram of how microtubules desintegrate with Alzheimer’s disease Français : La protéine Tau dans un neurone sain et dans un neurone malade Español: Esquema que muestra cómo se desintegran los microtúbulos en la enfermedad de Alzheimer (Photo credit: Wikipedia)

English: Histopathogic image of senile plaques seen in the cerebral cortex in a patient with presenile onset of Alzheimer disease. Bowdian stain. The same case as shown in a file “Alzheimer_dementia_(1)_presenile_onset.jpg”. (Photo credit: Wikipedia)