The Pathophysiology of Alzheimer’s Disease

The underlying pathophysiology of AD is important in understanding why particular biomarkers have been developed and is depicted in Figure 12.1. AD involves abnormal functioning of amyloid precursor protein, which leads to an excess of amyloid-β in the cortex. This excess of amyloid-β is thought to lead to faulty accumulation of tau proteins, which in turn leads to synaptic dysfunction and neuronal death.² The pathological hallmarks of AD are amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated tau. Compared to amyloid-β plaque formation, hyperphosphorylated tau and neurofibrillary tangles are more closely correlated with neurodegeneration and clinical symptoms.⁸

Figure 12.1 A hypothetical model of the pathophysiological cascade in Alzheimer’s disease.

Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 280–92.

The difference between genetic profiles, other risk factors for dementia, and cognitive reserve may explain the variation in lag time between the development of Alzheimer’s pathology and dementia itself. Cognitive reserve is given as one explanation of why there is such individual variability in the time taken between developing Alzheimer’s pathology and clinical symptoms (Figure 12.2). The greater your cognitive reserve, the more insult you can endure before displaying cognitive symptoms. Cognitive reserve is an active process which can be strengthened by, for example, education and mental activity.⁹

Figure 12.2 Cognitive reserve in ageing and Alzheimer’s disease (AD). With high cognitive reserve, more AD pathology can be tolerated before symptoms develop.

Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol 2012; 11: 1006–12

Biomarkers

The main biomarkers of AD can be divided by two major pathological processes: amyloid-β deposition and neurodegeneration. Hence, main biomarkers focus on:

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  measures of brain amyloid-β deposition;

  
  
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  measures of markers of neurodegeneration.

The two key methods currently of detecting amyloid-β deposition are by measuring amyloid-β levels in the cerebrospinal fluid (CSF) and through positron emission tomography (PET) amyloid imaging.⁵ Amyloid-β₄₂ is the most likely type of amyloid to aggregate and is the most commonly measured amyloid variant. Where there is significant amyloid-β accumulation, levels of amyloid-β₄₂ in the CSF are low and there is increased amyloid tracer retention on PET imaging.¹⁰

Plasma amyloid can also be detected, but plasma amyloid-β₄₂ has hitherto been used less frequently than CSF owing to its lower sensitivity and specificity. Recently, however, there have been further advances in finding a suitable method to detect biomarkers in the blood.¹¹ Acquiring blood, unlike CSF, requires a much less invasive procedure and, unlike PET scanning, is less costly. The researchers, by using immunoprecipitation and mass spectrometry, were able to achieve roughly 90% accuracy (using ¹¹C-labelled Pittsburgh Compound B ([¹¹C]PiB) PET as their gold standard) in the detection of amyloid-β biomarkers. They concluded:

Two recent studies show developments in finding new biomarkers for AD. Preische et al. showed that increased CSF and serum levels of neurofilament light chain are associated with early neurodegeneration in AD;¹² and Nation et al. revealed that CSF soluble platelet-derived growth factor receptor β shows potential as an early biomarker of AD as it detects blood–brain barrier dysfunction early.¹³

Neurodegeneration is measured by various indicators: increased concentrations of CSF total tau (t-tau) and phosphorylated tau (p-tau), hypermetabolism on fluorodeoxyglucose (FDG) PET imaging, and atrophy in structural MRI: t-tau is a more direct marker of neuronal degeneration and p-tau is a marker of neurofibrillary tangles.³

Both CSF amyloid-β₄₂ and tau protein have been found to reflect the degree of amyloid load and neurofibrillary abnormality accurately at autopsy.¹⁴ Similarly, amyloid imaging strongly correlates with the pathological burden of disease at autopsy,¹⁵ and with concentrations of amyloid-β in CSF.¹⁶

A significant number of cognitively healthy older people will have evidence of amyloid-β deposition both at autopsy and in biomarkers of CSF and PET amyloid imaging. The number of individuals who are biomarker ‘amyloid positive’ but ‘clinically negative’ varies from 20% to 40%,¹⁰ which is similar to autopsy findings.¹⁷ One theory is that if ‘amyloid-positive’ individuals lived longer they would eventually develop symptoms of AD.

Jack et al. have proposed a model to represent the progression of Alzheimer’s pathology (Figure 12.3).² In this model, amyloid-β deposition occurs first, years before the onset of clinical symptoms. The duration of this phase may vary, depending on the individual’s cognitive reserve and risk factors for AD. Next, tau-mediated neurodegeneration begins, which is evident from changes on structural imaging. Finally, there is progression to cognitive impairment and clinical symptoms become evident. Important to the biomarker model is that Aβ accumulation alone is not sufficient to cause dementia.²

Figure 12.3 Accumulation of markers of disease over time. In this hypothetical model, amyloid-β markers are the first to become abnormal, followed by markers of neurodegeneration, followed by clinical symptoms. MCI, mild cognitive impairment.

Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 2010; 9: 119–28

Ocular biomarkers are less well-known biomarkers of AD. Ocular biomarkers have been proposed for several reasons. First, individuals with AD often present with visual deterioration, and this appears to predate cognitive changes. Second, the retina is easily visualized and ocular biomarkers do not require invasive tests such as lumbar puncture. There are many proposed ocular biomarkers, which we shall not discuss exhaustively here. For instance, micro-ribonucleic acid (RNA) can be found in tear fluid and is implicated in the regulation of amyloid. Other important approaches include detecting retinal amyloid-β accumulation, or an assessment of functional and clinical changes within the visual system.¹⁸ Amyloid-β detection in the retina has been performed with or without contrast-enhanced imaging. Further work is required to determine whether amyloid accumulation detected in the retina is reflective of brain deposition and, indeed, predictive of future cognitive impairment. Functional changes to the visual system include changes in neuronal responses, such as reduced visually evoked potentials over the occipital cortex, and interrupted neurotransmission between photoreceptors in the retina. Further ocular biomarkers include ‘fixation and movement errors’, where there is failure to fixate or follow a target, and reduced eye movements.¹⁸

Do CSF Biomarkers Accurately Predict Who Will Develop Alzheimer’s Dementia?

Using biomarkers to help predict who will develop dementia already has a significant history, particularly in determining which individuals with MCI are most at risk of developing AD. In this population, there is evidence that biomarkers enhance diagnostic specificity and prognostication.^{19, 20–25}

The combination of high CSF t-tau and p-tau with low CSF amyloid-β₄₂ has been termed the ‘Alzheimer’s disease signature’⁷ and is highly predictive of AD, as confirmed in three large multicentre studies: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study, the Development of Screening Guidelines and Criteria for Predementia AD (DESCRIPA) study, and the Swedish Brain Power project. The CSF AD signature has been shown to increase diagnostic accuracy significantly even at a prodromal stage, with a sensitivity of 90–95% and a specificity of about 90% for AD.^{26, 27}

De Meyer et al. studied participants from the ADNI.⁷ The ADNI was established in 2004 to determine whether biomarkers could predict progression from MCI to AD. Their sample included cognitively normal individuals, individuals with MCI, and individuals with AD. The AD signature was detected in 90% of individuals with AD, 72% of those with MCI, and 36% of cognitively healthy individuals. In individuals with MCI and an AD signature, the diagnostic sensitivity of progression to AD was 90%, with a specificity of 64%. In addition, the combination simply of high CSF p-tau and low CSF amyloid-β₄₂ correctly identified 100% of individuals with MCI who progressed to AD.

Hansson et al. found that the AD signature had a sensitivity of >90% and specificity of >85% for individuals with MCI who subsequently developed AD. ²¹ Similarly, Van Rossum et al. found that the combination of CSF amyloid-β₄₂ with either p-tau or t-tau was highly predictive of the development of AD from MCI, with an odds ratio of 18.1 (95% confidence interval [CI] 9.6–32.4).²⁸

Most of this evidence relates to individuals who already have MCI. If pathological changes really do start decades before the onset of clinical symptoms, is it possible to tell at this very early stage who will develop AD in their later years? There have not been enough longitudinal studies to answer this conclusively, although some studies have found that amyloid-β positivity confers an increased risk of progression to AD; ^{25, 29, 30–34} and two found that plasma biomarkers and imaging (MRI and FDG PET) can predict cognitively normal individuals who are at risk of cognitive decline.^{35, 36} Fagan et al. found that non-cognitively impaired individuals with the AD signature progress to symptomatic cognitive impairment more quickly than do the remainder of the cohort.²⁹

Are CSF Biomarkers Useful in People Who Already Have Alzheimer’s Disease?

A marked reduction in CSF amyloid-β₄₂ has consistently been noted in patients at different stages of AD. On the one hand, an isolated low amyloid-β₄₂ is not sufficiently specific for a diagnosis. Non-AD dementias, such as Lewy body disease and vascular dementia, are also associated with low CSF amyloid-β₄₂.³ CSF p-tau appears to be the most specific CSF biomarker, distinguishing AD from non-Alzheimer’s dementias.³⁷ On the other hand, combinations of CSF biomarkers appear to enhance the sensitivity of an AD diagnosis, but there is no consensus as to which specific combination has the greatest accuracy.³ CSF biomarkers may also have a role in predicting the course of AD. Snider et al. found that individuals with AD and the CSF AD signature progressed more rapidly than those without.²⁶ Markers of amyloid load tend to remain constant throughout the course of AD, whereas t-tau and p-tau rise as AD progresses.⁷