Anemia, iron deficiency, and blood biomarkers for Alzheimer disease: clinical interpretation and dementia risk stratification.

Anemia and iron deficiency are common in older adults, yet their relevance to blood biomarkers for Alzheimer disease (AD) remains underappreciated. As these biomarkers move into clinical pathways, their interpretation depends not only on assay performance but also on comorbidity, kidney function, inflammation, and nutritional status. Against this backdrop, anemia, absolute iron deficiency, and functional iron deficiency are better viewed as distinct hematopoietic nutritional phenotypes than as background covariates, with important implications for interpreting the amyloid-β42/40 ratio, phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Current human data link anemia and iron-restricted states to higher dementia risk and to variation in plasma p-tau217, GFAP, and NfL; kidney function, body mass index (BMI), inflammation, and multimorbidity further shift biomarker distributions and cutoff interpretation. Among available analytes, p-tau217 is closest to routine clinical use within validated intended-use diagnostic pathways; however, its interpretation remains assay- and cutoff-specific and depends on pretest probability, gray-zone handling, kidney function, BMI, hemoglobin, ferritin, and transferrin saturation. Mechanistic work supports plausible links involving impaired oxygen delivery, disrupted iron-mitochondrial bioenergetics, hepcidin-mediated functional iron restriction, and glial, myelin, and blood-brain barrier vulnerability, although a complete human causal chain has not been established. Current evidence therefore favors phenotype-aware interpretation over hemoglobin-only screening or biomarker-only reading. In memory clinics and geriatric practice, complete blood count and iron studies may provide useful interpretive context in selected patients, particularly when multimorbidity, chronic kidney disease (CKD), inflammation, nutritional vulnerability, fatigue, or low or low-normal hemoglobin could affect biomarker interpretation or downstream decisions. Future studies should test whether, and in whom, correcting iron-related phenotypes changes biomarker-guided risk stratification, biomarker trajectories, or clinical decisions.