A new study published in the journal JAMA Neurology in April 2020 seems to indicate that higher brain amyloid levels represent early Alzheimer's disease (AD).
What is amyloid?
Amyloid-beta is a significant biomarker of AD. A biomarker is "a characteristic that can be objectively measured and evaluated as an indicator of a normal or pathologic process, or as a measure of response to therapy," according to the Biomarker Working Group 2001. The use of amyloid and other biomarkers heralded the shift of AD trial design from the assessment of clinically evident disease to the detection of early AD, for disease modification and treatment.
The beta-amyloid peptide, amyloid plaques growing on a neuron. It consists of about 30 amino acids and aggregates to amyloid plaques, that may damage and kill neurons. Image Credit: Juan Gaertner / Shutterstock
With the use of biomarkers, investigators have come to appreciate the continuum of biochemical and pathological changes that occur in AD. There is evidence to support the hypothesis that AD begins with preclinical changes, which then progress steadily to late clinical stages, namely, dementia. Thus, drug development has now shifted from the treatment of early and late dementia to preventing the progression of the disease in the early stages, and to prevent any symptoms from emerging at all by modifying the underlying disease process.
Amyloid-beta is one of several breakdown products of a larger protein called amyloid precursor protein. One of these forms is called beta-amyloid 42 and accumulates between neurons in the form of plaques. This build-up disrupts cell functioning.
Amyloid is associated with another abnormal protein called tau, which occurs in the form of neurofibrillary tangles. Tau is typically associated with microtubules, which are part of the cell skeleton and intracellular transport pathways. Changes in the chemical composition of tau cause it to break free from the microtubules and adhere to other tau molecules. As a result, tau threads are formed, which end up in tangles inside the brain's nerve cells. Such tangles inhibit neuronal transport, depriving the neuron of nutrition, and depriving the neuron of the power to communicate freely and effectively via synapses.
As amyloid levels increase within the brain, perhaps indicative of greater levels of inflammation within the brain, a critical level is reached, at which point tau tangles rapidly propagate throughout the brain.
One reason why inflammation is linked to amyloid build-up is the accumulation of abnormal microglia and astrocytes, both glial cells concerned with the removal of waste, debris, and unwanted proteins. This, in turn, may be due to environmentally-mediated genetic defects.
The earliest data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study looks as if amyloid build up in the brain mirrors early AD. When the individual is asymptomatic or has no clinical features, a higher level of amyloid is linked to lower scores on cognitive testing, a family history of the disease, and a decline in daily cognitive function. The data is now freely available to all researchers.
The A4 trial is a prevention trial that began in 2014 and will end in late 2022. It is aimed at identifying the effectiveness of the monoclonal antibody drug solanezumab at preventing or treating cognitive decline, for use in cognitively normal people with high amyloid levels. Amyloid is considered by many scientists to be the characteristic feature of AD. It has been the focus of many trials seeking to identify treatments for people who show features of the disease.
The study was motivated by the need to find out if previous trials were "intervening too late in the disease process to be effective." This has been a significant problem with older trials that target AD. Researcher Richard J. Hodes says, "A4 is pioneering in the field because it targets amyloid accumulation in older adults at risk for developing dementia before the onset of symptoms."
The A4 trial recruited participants in the age group of 65-85 years, who were cognitively normal but had high amyloid levels. They first screened over 15,000 people who were interested and selected over 6700 people as volunteers. They then carried out cognitive testing, clinical evaluations, and genetic studies. In these rounds, 2,777 participants were found ineligible.
The next step included about 4,500 participants, on whom the researchers carried out amyloid positron emission tomography (PET). The aim was to assess amyloid accumulation within the brain. The scans showed that about 1,300 individuals had high amyloid levels. The data on all scanned individuals was made open-access. This should help enhance the recruitment of other AD trials in terms of more efficient screening.
These were included in the next round. These were all people with normal cognitive skills who had high brain amyloid levels. With respect to the ability of the scan to pick out people with amyloid but no symptoms, scientist Laurie Ryan says, "In 2014, A4 was a first-of-its-kind study. Before the availability of amyloid PET, other amyloid-targeting clinical trials may have been testing therapies in some people who didn't have amyloid."
The current data indicates, in Ryan's words, "A4 demonstrates that prevention trials can enroll high-risk individuals -- people with biomarkers for Alzheimer's who are cognitively normal. Ultimately, precision medicine approaches will be essential." The rationale for this is that AD will never have a universally applicable treatment because of the different combinations of risk factors that demand customized therapies.