Neurodegeneration — 2

Given those developments, let’s delve into the two most widespread neurodegenerative diseases. We will spend most time on Alzheimer’s because the confluence of new insights and medical technologies has had the most results there—so far.

ALZHEIMER’S DISEASE

Two proteins with Greek letter designations—β-amyloid (Aβ) and Tau (Τ)—are center stage in the drama of Alzheimer’s disease. When misfolded, they self-assemble to form Aβ plaques and neurofibrillary tangles (NFT), respectively, that propagate, disrupting neural circuits and brain cell function. In particular, the misfolding and aggregation of Aβ is the basis of the amyloid cascade hypothesis, the seminal disease-causing event that ultimately leads to Alzheimer’s disease. More than three decades after it was conceived, it remains as a hypothesis, because the data supporting the central and unequivocal role of Aβ is mixed.

As seen in figure 7.2, this process evolves over decades. In the earliest stage, Aβ (secreted from cells as monomers, developing to fibrils) forms plaques that drive immune cell activation. Tau pathology kicks in years later, which adds to loss of brain circuit synapses and function well before there is the onset of cognitive impairment.

Late-onset Alzheimer’s disease accounts for 95 percent of the people who get the disease. It has high heritability between about 60 to 80 percent, although less than the 90 percent heritability of early onset (before age sixty-five years) Alzheimer’s. The association of late-onset Alzheimer’s with more than fifty genetic loci has enhanced our understanding of the underlying pathophysiology, which is not only related to β-amyloid and Tau proteins. A model that factors in all the known genetic pathways includes our immune response; how we handle cholesterol; our brain blood supply, which is affected by β-amyloid deposits; and how we remove proteins and engulf waste and toxic substances into our cells. Even more has been learned by single-cell sequencing approaches to blood vessel cells among others, reinforcing the role of many different genomic pathways.

Figure 7.2. Evolution of brain biologic abnormalities in the years before (and subsequent to) cognitive impairment and symptomatic Alzheimer’s disease. NFT-neurofibrillary tangles. Adapted from Justin Long et al., “Alzheimer disease: An update on pathobiology and treatment strategies,” Cell 179, no. 2 (October 2019): 312–39, https://doi.org/10.1016/j.cell.2019.09.001.

Knowing that it takes decades for the development of Alzheimer’s disease in concert with its prelude of cognitive impairment, there has long been a search for some sign that the disease is coming, a biomarker. A few decades’ warning would give us the opportunity to intervene and potentially halt the degenerative process. The potential for markers from the cerebrospinal fluid has been intensely explored but is of little practical value given the lack of appeal for people to undergo a lumbar puncture. A breakthrough in the field came with the discovery of a plasma protein known as phosphorylated tau217 (p-tau217), and the ratio of phosphorylated to nonphosphorylated Tau, that was as good or superior to cerebrospinal fluid tests. The blood test for p-tau217 was more accurate, at a level of 91 percent, than cognitive tests and CT scans in people with memory problems. In a prospective study of more than twelve hundred patients, that compared favorably to primary care physicians (without the help of p-tau217), who had accuracy of only 61 percent of the time in their diagnosis, and neurologists 73 percent of the time.