Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers

doi:10.1016/j.bcp.2013.12.024

Biochemical Pharmacology

Volume 88, Issue 4, 15 April 2014, Pages 640-651

https://doi.org/10.1016/j.bcp.2013.12.024 Get rights and content

Abstract

The global prevalence of dementia is as high as 24 million, and has been predicted to quadruple by the year 2050. In the US alone, Alzheimer disease (AD) – the most frequent cause of dementia characterized by a progressive decline in cognitive function in particular the memory domain – causes estimated health-care costs of $ 172 billion per year. Key neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques – often surrounded by dystrophic neurites – and intracellular neurofibrillary tangles. These pathological changes are frequently accompanied by reactive microgliosis and loss of neurons, white matter and synapses. The etiological mechanisms underlying these neuropathological changes remain unclear, but are probably caused by both environmental and genetic factors. In this review article, we provide an overview of the epidemiology of AD, review the biomarkers that may be used for risk assessment and in diagnosis, and give suggestions for future research.

Graphical abstract

Introduction

The global prevalence of dementia, which is characterized by progressive deterioration in cognition, function and behavior, places a considerable burden on society. Currently, the prevalence is estimated to amount to 24 million and predicted to quadruple by the year 2050. In the US alone, Alzheimer disease (AD) – the most frequent cause of dementia – is associated with estimated health-care costs of $172 billion per year [1].

The key pathological changes observed in AD brain tissue are amyloid-β (Aβ) peptide deposited extracellularly in diffuse and neuritic plaques, and hyperphosphorylated tau (p-tau) protein, a microtubule assembly protein accumulating intracellularly as neurofibrillary tangles (NFTs). Additional changes include reactive microgliosis and widespread loss of neurons, white matter and synapses. The exact mechanisms leading to these changes remain to be determined.

Section snippets

Diagnostic criteria

Since their proposal in 1984, the key classification for the diagnosis of AD has been the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS–ADRDA) criteria [2]. These criteria combine clinical and neuropathological patterns and assign diagnoses of “possible”, “probable” and “definite AD” [2]. The AD spectrum is now recognized to be broader than was previously thought and is acknowledged to include

Prevalence and incidence

By 2005, 24.2 million people worldwide had dementia and 4.6 million new cases were arising every year [3]. Approximately 70% of these cases were attributed to AD. Among regional populations of 60 year-olds, those from North America and Western Europe are believed to exhibit the highest prevalence and incidence rate of dementia, followed by those from Latin America and China and its western-Pacific neighbors (Fig. 1a and b) [3]. For all these populations, the incidence rate for dementia

Genetic epidemiology of AD

Based on its age of onset, AD is classified into early onset AD (EOAD, onset <65 years) accounting for 1–5% of all cases, and late-onset AD (LOAD, onset ≥65 years) accounting for >95% of affecteds. While clinically indistinguishable from LOAD, EOAD is generally associated with a more rapid rate of progression and a Mendelian pattern of inheritance. Three genes (APP, PSEN1 and PSEN2) which all encode proteins involved in APP breakdown and Aβ generation, have been firmly implicated in the

Cerebrovascular disease

Cerebrovascular changes such as hemorrhagic infarcts, small and large ischemic cortical infarcts, vasculopathies and white matter changes increase the risk of dementia but the specific underlying mecahnisms remain unclear. Infarcts or white matter hyperintensies may lead directly to the damage of brain regions that are important in memory function, such as the thalamus and the thalamo-cortical projections. However, they may also increase the deposition of Aβ, which in turn can lead to cognitive

Diet

There is evidence that consumption of a Mediterranean diet, which is characterized by a high intake of plant foods and fish, with olive oil as the primary source of monounsaturated fat, a low intake of red meat and poultry and a moderate intake of wine, is associated with a reduced incidence of AD and MCI [119], [120] independent of the levels of physical activity [121] and vascular comorbidity [122]. Diets high in fish, fruit and vegetables are high in antioxidants and polyunsaturated fatty

Biomarkers

Biomarkers are useful for the determination of disease risk but are also invaluable in establishing a diagnosis. While the autosomal dominantly inherited mutations are definite markers of the disease, the additional biomarkers, that have been identified and include various measurements from CSF, blood and neuroimaging, only contribute to increasing the specificity of diagnosis.

Conclusions

Substantial progress has been made over the past few decades in understanding AD. In particlaur findings from genetic studies have pointed to specific mechanistic pathways including APP metabolism, immune response, inflammation, lipid metabolism and intracellular trafficking/endocytosis. If confirmed, these findings have the potential to open new avenues for genetic testing, prevention and treatment. However, before this gained knowledge can applied in clinical settings several issues must be

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Review - Part of the Special Issue: Alzheimer's Disease - Amyloid, Tau and BeyondAlzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers

Abstract

Graphical abstract

Introduction

Section snippets

Diagnostic criteria

Prevalence and incidence

Genetic epidemiology of AD

Cerebrovascular disease

Diet

Biomarkers

Conclusions

Lancet

Lancet

Lancet

Alzheimer's Dement

Lancet

Neurobiol Aging

Brain Res Rev

Neuron

Immunobiology

Trends Cardiovasc Med

Cell

Mol Cell Neurosci

Biochim Biophys Acta

Lancet

Neurobiol Aging

Eur J Pharmacol

Neurosci Biobehav Rev

Biochem Biophys Res Commun

Lancet

Neurobiol Aging

Clinical diagnosis of Alzheimer's disease: report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease

Neurology

Is dementia incidence declining?: trends in dementia incidence since 1990 in the Rotterdam Study

Neurology

Association of apolipoprotein E phenotypes with late onset Alzheimer's disease: population based study

BMJ

APOE-epsilon4 count predicts age when prevalence of AD increases, then declines: the Cache County Study

Neurology

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

Science

Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer's disease

Ann Neurol

Apolipoprotein E: non-cognitive symptoms and cognitive decline in late onset Alzheimer's disease

J Neurol Neurosurg Psychiatry

Apolipoprotein E type 4 allele and Alzheimer's disease: effect on age at onset and relative risk in different age groups

J Neurol

Apolipoprotein E and Alzheimer's disease: strength of association is related to age at onset

Dementia

Alzheimer's disease: the genetics of risk

Hosp Pract (Minneap)

Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals

JAMA

Prevalence of four subtypes of mild cognitive impairment and APOE in a Japanese community

Int J Geriatr Psychiatry

Transitions to mild cognitive impairments, dementia, and death: findings from the Nun Study

Am J Epidemiol

Rapid progression from mild cognitive impairment to Alzheimer's disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE epsilon4/epsilon4 genotype

Dement Geriatr Cognit Disord

Predictive utility of apolipoprotein E genotype for Alzheimer disease in outpatients with mild cognitive impairment

Arch Neurol

Apolipoprotein E epsilon 4 allele is associated with increased atrophy in progressive mild cognitive impairment: a voxel-based morphometric study

Neurodegener Dis

Apolipoprotein E epsilon4 genotype as a risk factor for cognitive decline and dementia: data from the Canadian Study of Health and Aging

CMAJ

Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment

Neurology

The association between APOE genotype and memory dysfunction in subjects with mild cognitive impairment is related to age and Alzheimer pathology

Dement Geriatr Cognit Disord

A prospective study of the clinical utility of ApoE genotype in the prediction of outcome in patients with memory impairment

Neurology

Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study

Arch Neurol

Apolipoprotein E epsilon4 association with dementia in a population-based study: the Framingham study

Neurology

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

Nat Genet

Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease

Nat Genet

Review - Part of the Special Issue: Alzheimer's Disease - Amyloid, Tau and Beyond
Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers