Preclinical Alzheimer's Disease: Intervention Timing and Blood Biomarker Limits

The series was sponsored independently by Eli Lilly.

"Preclinical Alzheimer's Disease: Intervention Timing and Blood Biomarker Limits" takes up the question of how best to use the long window before symptoms appear, with Dr. Reuben weighing the promise of prevention against current limits.

Dr. Reuben explains that the biological definition of Alzheimer's disease creates a window of up to 20 years in which intervention might stop the process. He compares it to heart disease, one of the biggest success stories of the past 50 years. High cholesterol came first, then plaques, then heart attacks or strokes.

In Alzheimer's disease, the first stage is a biological marker without disease. The second is the tau protein, the equivalent of plaque, and the third is damage and loss of neurons. Ideally, treatment begins once a marker turns positive, which explains the optimism about anti-amyloid drugs.

These drugs clear amyloid well, but the evidence that they improve or cure the disease is much weaker. Two trials treating cognitively unimpaired people with positive biomarkers are in progress, and one may report any day.

Dr. Reuben calls blood-based biomarkers a potential breakthrough, since the alternatives are spinal taps or expensive imaging. He does not think they are ready yet. Roughly 80% of blood pTau is produced outside the brain, which can cause false positives. Early assays also had reagent problems.

The biggest issue is performance in people without symptoms. Predictive value depends on prevalence, so a healthy 60-year-old whose parent developed Alzheimer's at 85 is far more likely to receive a false positive. Follow people for 25 years and nearly all convert, but many will die first.

These are difficult conversations, because there is currently little to offer a symptom-free person with a positive result. Approved anti-amyloid drugs cover mild cognitive impairment and early dementia, not cognitively unimpaired people with positive biomarkers.

In "Alzheimer's Disease Treatment Selection: Anti-Amyloid Uptake and Stage-Based Care," Dr. Reuben turns to who should be prioritized for testing and therapy, why anti-amyloid uptake has lagged, and how management differs by stage.