Underlying Pathophysiology

The etiology of AD is multifactorial and not well understood.13 Although there continues to be uncertainty related to the underlying factors contributing to the development of AD,14 such as environment and lifestyle components, there are known factors that need to be understood to better appreciate the complexity of this disease process. 

Amyloid Plaques

Amyloid plaque accumulation in the brain is one of the known factors associated with AD.1 Beta-amyloid is a protein fragment of amyloid precursor protein (APP).  Normally these protein fragments are broken down and eliminated, but in AD they accumulate to form hard, insoluble plaques. Amyloid plaques are composed of an extracellular beta-amyloid core surrounded by tissue enriched in lysosome-like organelles. The extracellular beta-amyloid deposits, residing within swollen neuronal axons, cause a local impairment in retrograde axonal transport.1 In this state, production and clearance of beta-amyloid are adversely affected.1

Tau and Neurofibrillary Tangles

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The protein tau forms part of a microtubule structure that supports the transport of nutrients and other substances to and from various parts of the nerve cell. 2 In AD, however, abnormal tau is produced, causing collapse of the microtubule structures. In addition, further chemical changes cause tau molecules to adhere to one another, forming threads that join to form neurofibrillary tangles (NFTs) inside neurons.2 By blocking the neuron’s transport system, these tangles disrupt signals between neurons.2 

Emerging research indicates that the complex interaction between abnormal tau and beta-amyloid may ultimately cause changes in the brain associated with AD.2 Specifically, abnormal tau accumulates in the brain regions associated with memory, whereas beta-amyloid forms plaques between neurons. When the level of beta-amyloid reaches a critical value, tau spreads rapidly throughout the brain.1,2 There is some uncertainty about whether tau is causal to the disease or a byproduct of the disease process. Although the role of tau in AD is still under investigation, changes in tau are predominantly believed to be a consequence of beta-amyloid and NFTs and, consequently, tau continues to be of major interest as an indicator of the disease mechanism.2


The etiology of AD also includes both cholinergic and glutamatergic neuronal involvement.3 In patients with AD, acetylcholine (ACh) — a neurotransmitter critical for the memory process and learning — decreases in concentration and in function.3 There also are other presynaptic cholinergic deficiencies, including cholinergic neuron loss and decreased activity of acetylcholinesterase (AChE).3 The loss in ACh efficacy and these presynaptic cholinergic changes are the primary factors in the cholinergic cascade hypothesis of AD.3 In addition, a decrease in ACh synthesis and an eventual decrease in ACh uptake by acetylcholine receptors has been documented in AD.4,5 The glutamatergic hypothesis links cognitive decline in AD to neuron damage caused by the over activation of N-methyl-d-aspartate (NMDA) receptors by glutamate.3 The prolonged low-level activation of NMDA receptors — which are critical to learning and memory — may be attributable to inadequate reuptake of glutamate by cells in the synaptic cleft.3

Inflammatory and Autoimmune Contributors

Inflammation also has been identified as a potential causative agent in neurodegeneration.6 In affected tissues, inflammatory pathway genes are activated, and these inflammatory signals precede neurodegeneration, independent of any infectious etiology.6 Thus far, pharmacologic and genetic ablation studies of multiple neurodegenerative diseases in animals indicate that inflammation is a requisite for pathology.6 This conclusion is noteworthy as it relates to AD, and it appears that inflammation plays a pivotal role in various neurodegenerative diseases.6   


Both types of AD — early-onset and late-onset — are thought to have genetic components.7 Early-onset AD occurs between the ages of 30 and 65 years and accounts for less than 10% of all cases.7 Most early-onset AD is caused by an inherited mutation in 1 of 3 genes — APP, presenilin-1 (PSEN1), and presenilin-2 (PSEN2) — which result in early-onset familial AD.7 Each of these mutations plays a role in the breakdown of APP, a protein the precise function of which is not understood fully.7  It is known, however, that the breakdown of APP contributes to the formation of amyloid plaques.7

The majority of cases of AD are late-onset, with symptoms becoming evident around age 65 years. The causes of late-onset AD are not understood fully but it is likely that a combination of genetic, environmental, and lifestyle factors contribute to a person’s risk for developing the disease.7 A specific gene has not been identified as directly causing late-onset AD, but having the ε4 genotype of the apolipoprotein E (APOE) gene on chromosome 19 has been linked to an increased risk of the disease.7

Dementia as a Disease Continuum

There is significant support for the idea of identifying AD as a biologic and clinical continuum covering the preclinical (clinically asymptomatic individuals with pathophysiologic changes reflected by biomarker evidence) and clinical (biomarker changes and clinical symptoms of cognitive and functional impairment) phases of dementia.8 These changes in the individual components of the continuum occur in a sequential progressive manner.8

The initial phase of the clinical and pathologic AD cascade starts with disordered beta-amyloid metabolism.15 Various components of AD pathology (AD-P) are known to relate differently to clinically identifiable symptoms. In autopsy studies, researchers have established a much closer correlation between neurofibrillary pathology and cognitive impairment than between amyloid pathology and cognitive impairment.16,17  The physiologic aspect of AD that correlates most highly with cognitive impairment, however, is neurodegeneration.11 Approximately 30% of the elderly with normal cognition have some level of identifiable AD-P; they meet neuropathologic criteria for AD but do not exhibit cognitive symptoms.11 Instead of simultaneous development, it appears that amyloid pathology and neurodegenerative pathology may progress on differing timelines.18

The clinical continuum includes both cognition and function components. The cognition component is comprised of episodic memory, executive function, and verbal fluency, whereas the function component includes both basic and complex ADLs.8

New Diagnostic Modalities

Screening Tools

In the primary care setting, cognitive screening tools with sufficient sensitivity are essential to allow clinicians to detect AD. Tools that clinicians may find beneficial to use include those that probe for early changes (eg, 8-item Interview to Differentiate Aging and Dementia, Cognitive Function Instrument), concise global cognitive screens (eg, Mini-Mental State Examination), and more specific tests of episodic memory impairment (eg, 5-Word test).8 If a more detailed assessment is warranted, a neuropsychological evaluation may be performed by a specialist.8,19


Biomarkers of AD typically are divided into 2 groups. The first are biomarkers associated with the accumulation of beta-amyloid, which present as abnormal tracer uptake on amyloid positron emission tomography (PET) imaging, and findings of low cerebrospinal fluid (CSF) amyloid-beta 42.12,20 The second group of biomarkers are those associated with degeneration or injury to the neurons; they present as elevated CSF tau, decreased fluorodeoxyglucose (FDG) uptake on PET scan in a specific topographic pattern of the brain and atrophy in a specific topographic pattern on structural MRI.12,20

Biomarkers studies have been conducted on research subjects with very subtle or no apparent symptoms to identify the presence of AD-P in the preclinical phase.11,12,20 Thus far, the incorporation of biomarkers has been more conservative in the diagnosis of symptomatic MCI and AD patients than in preclinical phase patients taking part in research studies.11,12 Clinical features still are considered the primary diagnostic criteria for MCI and AD, with biomarkers are viewed as adjuvant indicators. 

When possible, biomarkers are used to establish the underlying cause of the clinical impairment in the MCI phase. The intensity of the biomarker, especially markers associated with neuronal injury, also indicate the probability that the disease will progress to the AD phase within a short period of time.11,12,20

In the dementia phase, biomarkers are used to establish a higher or lower level of confidence that AD-P is the underlying cause of a patient’s dementia.11,12,20

Before use of biomarkers is adopted for all disease stages, there needs to be an intensive focus on biomarker standardization.11,12 

The levels of proteins and other cellular material in CSF can change years before identifiable symptoms of AD and other brain disorders are present.21 The most commonly used CSF biomarkers for AD are the measurement of the proteins beta-amyloid 42, tau, and phospho-tau (major components of NFTs in the brain).21 In patients with AD, beta-amyloid 42 levels in CSF are low, whereas tau and phospho-tau levels are elevated compared with levels in patients without AD.21

This article originally appeared on Clinical Advisor