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Neurobiology of Alzheimer ’ s Disease: Integrated Molecular, Physiological, Anatomical, Biomarker, and Cognitive Dimensions

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ABSTRACT

Background: Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder with interrelated molecular, physiological, anatomical, biomarker, and cognitive dimensions. Methods: This article reviews the biological changes (genetic, molecular, and cellular) underlying AD and their correlation with the clinical syndrome. Results: Dementia associated with AD is related to the aberrant production, processing, and clearance of beta-amyloid and tau. Beta-amyloid deposition in brain follows a distinct spatial progression starting in the basal neocortex, spreading throughout the hippocampus, and eventually spreading to the rest of the cortex. The spread of tau pathology through neural networks leads to a distinct and consistent spatial progression of neurofibrillary tangles, beginning in the transentorhinal and hippocampal region and spreading superolaterally to the primary areas of the neocortex. Synaptic dysfunction and cell death is shown by progressive loss of cerebral metabolic rate for glucose and progressive brain atrophy. Decreases in synapse number in the dentate gyrus of the hippocampus correlate with declining cognitive function. Amyloid changes are detectable in cerebrospinal fluid and with amyloid imaging up to 20 years prior to the onset of symptoms. Structural atrophy may be detectable via magnetic resonance imaging up to 10 years before clinical signs appear. Conclusion: This review highlights the progression of biological changes underlying AD and their association with the clinical syndrome. Many changes occur before overt symptoms are evident and biomarkers provide a means to detect AD pathology even in patients without symptoms.

No MeSH data available.


Related in: MedlinePlus

Overview figure integrating genetic and pathologic aspects of Alzheimer’s disease. Double bowed arrows imply multifaceted interacting processes. Colors indicate the major categories of activities involved. Dysregulated lipid processing can lead to Aβ aggregation and/or decreased clearance. Aβ aggregation is compounded by increased Aβ production related to early onset genes. Tau hyperphosphorylation can produce neurofibrillary tangles, cell death, and transmitter deficits. These processes are influenced by late onset genes affecting endocytosis, immune function, and synaptic integrity. Abbreviations: Aβ = β-amyloid; ApoE = apolipoprotein E; APP = amyloid precursor protein; PS1 = presenilin 1; PS2 = presenilin 2.
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Figure 1: Overview figure integrating genetic and pathologic aspects of Alzheimer’s disease. Double bowed arrows imply multifaceted interacting processes. Colors indicate the major categories of activities involved. Dysregulated lipid processing can lead to Aβ aggregation and/or decreased clearance. Aβ aggregation is compounded by increased Aβ production related to early onset genes. Tau hyperphosphorylation can produce neurofibrillary tangles, cell death, and transmitter deficits. These processes are influenced by late onset genes affecting endocytosis, immune function, and synaptic integrity. Abbreviations: Aβ = β-amyloid; ApoE = apolipoprotein E; APP = amyloid precursor protein; PS1 = presenilin 1; PS2 = presenilin 2.

Mentions: The most common risk genes associated with AD susceptibility have roles in lipid processing, immune function, endocytosis, or synaptic integrity (Fig. 1). Many genetic risk factors are associated with late-onset AD (after 65 years of age or older). Apolipoprotein E (APOE) is the most well-known risk factor gene. APOE is involved in cholesterol transport in CSF and in binding and clearance of beta-amyloid (Aβ) in the brain [5]. Of its 3 major alleles (ε2, ε3, and ε4), the APOE ε4 allele confers the greatest risk for developing late-onset familial and sporadic AD, most likely by reducing cholesterol efflux from neuronal cells and astrocytes, and by binding and depositing Aβ [5]. The prevalence of this allele is approximately 15% in the general population and approximately 40%in patients with AD [6]. The ε2 allele appears to play a protective role against AD [5].


Neurobiology of Alzheimer ’ s Disease: Integrated Molecular, Physiological, Anatomical, Biomarker, and Cognitive Dimensions
Overview figure integrating genetic and pathologic aspects of Alzheimer’s disease. Double bowed arrows imply multifaceted interacting processes. Colors indicate the major categories of activities involved. Dysregulated lipid processing can lead to Aβ aggregation and/or decreased clearance. Aβ aggregation is compounded by increased Aβ production related to early onset genes. Tau hyperphosphorylation can produce neurofibrillary tangles, cell death, and transmitter deficits. These processes are influenced by late onset genes affecting endocytosis, immune function, and synaptic integrity. Abbreviations: Aβ = β-amyloid; ApoE = apolipoprotein E; APP = amyloid precursor protein; PS1 = presenilin 1; PS2 = presenilin 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384474&req=5

Figure 1: Overview figure integrating genetic and pathologic aspects of Alzheimer’s disease. Double bowed arrows imply multifaceted interacting processes. Colors indicate the major categories of activities involved. Dysregulated lipid processing can lead to Aβ aggregation and/or decreased clearance. Aβ aggregation is compounded by increased Aβ production related to early onset genes. Tau hyperphosphorylation can produce neurofibrillary tangles, cell death, and transmitter deficits. These processes are influenced by late onset genes affecting endocytosis, immune function, and synaptic integrity. Abbreviations: Aβ = β-amyloid; ApoE = apolipoprotein E; APP = amyloid precursor protein; PS1 = presenilin 1; PS2 = presenilin 2.
Mentions: The most common risk genes associated with AD susceptibility have roles in lipid processing, immune function, endocytosis, or synaptic integrity (Fig. 1). Many genetic risk factors are associated with late-onset AD (after 65 years of age or older). Apolipoprotein E (APOE) is the most well-known risk factor gene. APOE is involved in cholesterol transport in CSF and in binding and clearance of beta-amyloid (Aβ) in the brain [5]. Of its 3 major alleles (ε2, ε3, and ε4), the APOE ε4 allele confers the greatest risk for developing late-onset familial and sporadic AD, most likely by reducing cholesterol efflux from neuronal cells and astrocytes, and by binding and depositing Aβ [5]. The prevalence of this allele is approximately 15% in the general population and approximately 40%in patients with AD [6]. The ε2 allele appears to play a protective role against AD [5].

View Article: PubMed Central - PubMed

ABSTRACT

Background: Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder with interrelated molecular, physiological, anatomical, biomarker, and cognitive dimensions. Methods: This article reviews the biological changes (genetic, molecular, and cellular) underlying AD and their correlation with the clinical syndrome. Results: Dementia associated with AD is related to the aberrant production, processing, and clearance of beta-amyloid and tau. Beta-amyloid deposition in brain follows a distinct spatial progression starting in the basal neocortex, spreading throughout the hippocampus, and eventually spreading to the rest of the cortex. The spread of tau pathology through neural networks leads to a distinct and consistent spatial progression of neurofibrillary tangles, beginning in the transentorhinal and hippocampal region and spreading superolaterally to the primary areas of the neocortex. Synaptic dysfunction and cell death is shown by progressive loss of cerebral metabolic rate for glucose and progressive brain atrophy. Decreases in synapse number in the dentate gyrus of the hippocampus correlate with declining cognitive function. Amyloid changes are detectable in cerebrospinal fluid and with amyloid imaging up to 20 years prior to the onset of symptoms. Structural atrophy may be detectable via magnetic resonance imaging up to 10 years before clinical signs appear. Conclusion: This review highlights the progression of biological changes underlying AD and their association with the clinical syndrome. Many changes occur before overt symptoms are evident and biomarkers provide a means to detect AD pathology even in patients without symptoms.

No MeSH data available.


Related in: MedlinePlus