Genome-wide association studies: Is there a genotype for cognitive decline in older persons with type 2 diabetes?

Angela Marie Abbatecola, Fabiola Olivieri, Andrea Corsonello, Roberto Antonicelli, Francesco Corica, Fabrizia Lattanzio

Research output: Contribution to journalArticle

Abstract

There is a dramatic increase in the number of elderly persons on a worldwide scale with an increase in chronic comorbidities, especially type 2 diabetes (T2DM) and dementia. Although cognitive faculties commonly deteriorate in non-diabetic persons as they age, several studies have concluded that diabetes is uniquely associated with cognitive decline and is associated with a two-fold risk of Alzheimer's Disease (AD). Studies have also suggested that good glycemic has shown to improve cognitive status, however whether the use of specific anti-diabetic oral agents may play an additional role in controlling against cognitive deterioration is unknown. In addition, excitotoxicity from the overstimulation of glutamate receptors is considered a major cause of neuron death in AD and statins may be promising agents for protecting against memory loss. Possible pathophysiologic mechanisms common to both T2DM and AD are glucose toxicity and a direct effect of insulin on amyloid metabolism. In fact, AD and T2DM have comparable pathological features in the islet and brain (amyloid derived from amyloid β protein (β-amyloid) in the brain in AD and islet amyloid derived from islet amyloid polypeptide in the pancreas in T2DM). Evidence is growing linking precursors of amyloid deposition in the brain and pancreas to the pathogenesis of AD and T2DM, respectively. Indeed, the need to identify agents capable of correcting such pathological features may in turn significantly protect against the accumulation of β-amyloid in the brain, known to interfere with correct cognitive function. Cholesterol may also be directly involved in β-amyloid aggregation: abnormal oxidative metabolites such as cholesterol-derived aldehydes can modify β-amyloid, firstly promoting Schiff base formation, then accelerating the early stages of amyloidogenesis. At the moment, genome-wide association studies (GWAS) have begun to elucidate the genetic architecture of chronic diseases including, T2DM and AD. Thus, one of the challenges for a successful GWAS in the future will be to identify a genotype in older persons with T2DM for good drug response, which in turn may protect against cognitive decline and AD. The literature has suggested that the use of insulin sensitizers and statins is correlated with a lower rate of cognitive decline in older persons. In this paper, we will explore recent findings regarding diverse single nucleotide polymorphisms from GWAS on T2DM, AD and both. We will also shed light on future pathways, as the basis of improving drug and diagnostics development for a better integration of genetic studies for precise drugdevelopment focusing on the role of genetic variation in maintaining metabolic control and cognitive performance.

Original languageEnglish
Pages (from-to)347-356
Number of pages10
JournalCurrent Pharmaceutical Design
Volume17
Issue number4
DOIs
Publication statusPublished - 2011

Fingerprint

Genome-Wide Association Study
Type 2 Diabetes Mellitus
Alzheimer Disease
Amyloid
Genotype
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Brain
Pancreas
Cholesterol
Insulin
Islet Amyloid Polypeptide
Amyloidogenic Proteins
Cognitive Dysfunction
Schiff Bases
Memory Disorders
Glutamate Receptors
Aldehydes
Pharmaceutical Preparations
Cognition
Single Nucleotide Polymorphism

Keywords

  • Dementia
  • Genetics aging
  • Type 2 diabetes

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

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title = "Genome-wide association studies: Is there a genotype for cognitive decline in older persons with type 2 diabetes?",
abstract = "There is a dramatic increase in the number of elderly persons on a worldwide scale with an increase in chronic comorbidities, especially type 2 diabetes (T2DM) and dementia. Although cognitive faculties commonly deteriorate in non-diabetic persons as they age, several studies have concluded that diabetes is uniquely associated with cognitive decline and is associated with a two-fold risk of Alzheimer's Disease (AD). Studies have also suggested that good glycemic has shown to improve cognitive status, however whether the use of specific anti-diabetic oral agents may play an additional role in controlling against cognitive deterioration is unknown. In addition, excitotoxicity from the overstimulation of glutamate receptors is considered a major cause of neuron death in AD and statins may be promising agents for protecting against memory loss. Possible pathophysiologic mechanisms common to both T2DM and AD are glucose toxicity and a direct effect of insulin on amyloid metabolism. In fact, AD and T2DM have comparable pathological features in the islet and brain (amyloid derived from amyloid β protein (β-amyloid) in the brain in AD and islet amyloid derived from islet amyloid polypeptide in the pancreas in T2DM). Evidence is growing linking precursors of amyloid deposition in the brain and pancreas to the pathogenesis of AD and T2DM, respectively. Indeed, the need to identify agents capable of correcting such pathological features may in turn significantly protect against the accumulation of β-amyloid in the brain, known to interfere with correct cognitive function. Cholesterol may also be directly involved in β-amyloid aggregation: abnormal oxidative metabolites such as cholesterol-derived aldehydes can modify β-amyloid, firstly promoting Schiff base formation, then accelerating the early stages of amyloidogenesis. At the moment, genome-wide association studies (GWAS) have begun to elucidate the genetic architecture of chronic diseases including, T2DM and AD. Thus, one of the challenges for a successful GWAS in the future will be to identify a genotype in older persons with T2DM for good drug response, which in turn may protect against cognitive decline and AD. The literature has suggested that the use of insulin sensitizers and statins is correlated with a lower rate of cognitive decline in older persons. In this paper, we will explore recent findings regarding diverse single nucleotide polymorphisms from GWAS on T2DM, AD and both. We will also shed light on future pathways, as the basis of improving drug and diagnostics development for a better integration of genetic studies for precise drugdevelopment focusing on the role of genetic variation in maintaining metabolic control and cognitive performance.",
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T2 - Is there a genotype for cognitive decline in older persons with type 2 diabetes?

AU - Abbatecola, Angela Marie

AU - Olivieri, Fabiola

AU - Corsonello, Andrea

AU - Antonicelli, Roberto

AU - Corica, Francesco

AU - Lattanzio, Fabrizia

PY - 2011

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N2 - There is a dramatic increase in the number of elderly persons on a worldwide scale with an increase in chronic comorbidities, especially type 2 diabetes (T2DM) and dementia. Although cognitive faculties commonly deteriorate in non-diabetic persons as they age, several studies have concluded that diabetes is uniquely associated with cognitive decline and is associated with a two-fold risk of Alzheimer's Disease (AD). Studies have also suggested that good glycemic has shown to improve cognitive status, however whether the use of specific anti-diabetic oral agents may play an additional role in controlling against cognitive deterioration is unknown. In addition, excitotoxicity from the overstimulation of glutamate receptors is considered a major cause of neuron death in AD and statins may be promising agents for protecting against memory loss. Possible pathophysiologic mechanisms common to both T2DM and AD are glucose toxicity and a direct effect of insulin on amyloid metabolism. In fact, AD and T2DM have comparable pathological features in the islet and brain (amyloid derived from amyloid β protein (β-amyloid) in the brain in AD and islet amyloid derived from islet amyloid polypeptide in the pancreas in T2DM). Evidence is growing linking precursors of amyloid deposition in the brain and pancreas to the pathogenesis of AD and T2DM, respectively. Indeed, the need to identify agents capable of correcting such pathological features may in turn significantly protect against the accumulation of β-amyloid in the brain, known to interfere with correct cognitive function. Cholesterol may also be directly involved in β-amyloid aggregation: abnormal oxidative metabolites such as cholesterol-derived aldehydes can modify β-amyloid, firstly promoting Schiff base formation, then accelerating the early stages of amyloidogenesis. At the moment, genome-wide association studies (GWAS) have begun to elucidate the genetic architecture of chronic diseases including, T2DM and AD. Thus, one of the challenges for a successful GWAS in the future will be to identify a genotype in older persons with T2DM for good drug response, which in turn may protect against cognitive decline and AD. The literature has suggested that the use of insulin sensitizers and statins is correlated with a lower rate of cognitive decline in older persons. In this paper, we will explore recent findings regarding diverse single nucleotide polymorphisms from GWAS on T2DM, AD and both. We will also shed light on future pathways, as the basis of improving drug and diagnostics development for a better integration of genetic studies for precise drugdevelopment focusing on the role of genetic variation in maintaining metabolic control and cognitive performance.

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