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Four diseases cause most deaths
Heart and metabolic disease
Metabolic disease rarely causes death directly, but it forms the foundation under the other three. For atherosclerosis, blood tests are a very good predictor of risk when they look at the right things, mainly ApoB, plus markers of inflammation, endothelial health, and metabolic health.
Cancer and dementia
Cancer is the blind spot. Biomarkers help little, though metabolic ill health is the second leading modifiable cause of cancer after smoking, and the hyperinsulinemia that comes with obesity is probably what drives it. For dementia, particularly Alzheimer's disease, the markers overlap heavily with those for heart disease, and genetic testing adds more than the APOE gene alone.
Health span
Health span, which spans the cognitive, physical, and emotional domains, gets far less from biomarkers. Functional tests do more: DEXA, CPET, VO2 max, zone two lactate, and fat oxidation testing. Nothing in a biomarker offers much insight into the emotional domain.
Why is metabolic disease the foundation?
Insulin resistance and high insulin levels feed into plaque formation in arteries, growth signaling in tumors, and changes in the brain. Researchers led by Eric Steen and Suzanne de la Monte asked in a 2005 paper whether Alzheimer's disease amounts to type 3 diabetes, after finding impaired insulin signaling in Alzheimer's brains. The Centers for Disease Control and Prevention lists excess body weight as a risk factor for at least 13 types of cancer.
Why can't blood tests catch cancer early?
Cancer is hundreds of different diseases, and a small tumor often sheds very little detectable material into the blood. Classic markers such as PSA and CA-125 are used mostly to monitor known disease because benign conditions can raise them and some cancers do not. Blood tests that search for tumor DNA across many cancers are being evaluated in large trials, with sensitivity for early-stage disease the central question.
Why does ApoB beat LDL cholesterol?
LDL cholesterol measures the weight of cholesterol carried in LDL particles, while ApoB counts the particles themselves. A 2019 meta-analysis in JAMA Cardiology by Allan Sniderman and colleagues found ApoB more strongly associated with cardiovascular risk than LDL cholesterol or non-HDL cholesterol. The two numbers can disagree when each particle carries little cholesterol, as often happens in metabolic disease.
How does APOE change Alzheimer's risk?
APOE comes in three common versions, called E2, E3, and E4. A 1993 paper in Science by Elizabeth Corder and colleagues found that the E4 version raised the risk of late-onset Alzheimer's disease and lowered the age of onset with each copy. Carrying two E4 copies is associated with roughly eight to twelve times the risk of carrying two E3 copies.
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