Chapter 97
Neurodegeneration — 3
Before p-tau217, we relied on positron emission tomography (PET) scan imaging fibrils of amyloid and Tau, which, in healthy people, predicts cognitive decline and Alzheimer’s three to five years before symptoms are manifest. But acquiring these images is expensive, not widely available, and associated with substantial radiation exposure. Other plasma proteins have been demonstrated to be quite predictive, as seen in a study of more than fifty-two thousand UK Biobank participants followed for fourteen years, with assays for almost fifteen hundred plasma proteins (such as GFAP, GDF15, and NEFL). Still, the breakthrough with p-tau217 has provided us with what is still our best biomarker by far.
The commercial test availability of p-tau217 has engendered controversy for whether healthy people should be screened and undergo treatments that have recently been shown to have modest effects. The Alzheimer’s Association advocates for screening and treatment, proposing that healthy people without symptoms but a positive p-tau217 should be classified as “Alzheimer’s Stage 1.” On the other side, cynics charge that it is simply a way for the medical industry to make money from people who aren’t actually sick. Be that as it may, more than seven million Americans with mild cognitive impairment have not been diagnosed. Use of a simple blood biomarker is likely to greatly increase the number of diagnoses from the current level of approximately 8 percent of people aged sixty years and older. If we extrapolate from previous studies of cognitively normal people, almost 16 percent of people aged sixty and 23 percent aged seventy would test positive for mild cognitive impairment. That’s a huge number of people at risk.
Still, my view in the face of the raging debate is that this test should not be done routinely in people who are cognitively intact, nor should it be used to assign a diagnosis of pre-Alzheimer’s. That is not warranted or appropriate based on what we know. However, this biomarker has considerable utility as part of a comprehensive risk assessment. It is a key component for how Alzheimer’s disease—at the individual level—may be prevented or significantly forestalled in the future.
THE APOE GENES
For over thirty years, we’ve known about one group of people who carry high risk of Alzheimer’s due to their apolipoprotein E (APOE) genotype. The APOE4 allele is the strongest genetic risk factor: two copies, which are present in only 2 percent of the Caucasian population (the prevalence varies widely by ancestry and ethnicity) and denote a fifteenfold higher risk in people of European ancestry (less in African ancestry). About a fourth of the population are APOE4 carriers with one copy and have about a threefold risk. On the other hand, the APOE2 allele lowers the risk, and APOE3 is neutral. The Mayo Clinic Study of Aging followed almost five thousand people, age fifty-five to ninety-two years, in Olmsted County, Minnesota, for 9.4 years. For carriers of APOE4 who had high PET imaging amyloid levels at age sixty-five, the lifetime risk of Alzheimer’s was 75 percent of women and 62 percent of men. In non-APOE4 individuals, that risk was reduced to 53 percent for both sexes. There appears to be sex-specific alterations in APOE4 carriers, with females more prone to white blood cell–microglia interaction that promotes amyloid plaque formation.