Anemia Linked to Elevated Alzheimer Biomarkers and Higher Dementia Risk

Anemia in older adults is associated with higher blood concentrations of Alzheimer disease biomarkers and an independently elevated risk of incident dementia, according to findings from a large Swedish population-based cohort.

The study, drawing on data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), found the combination of low hemoglobin and elevated Alzheimer disease blood biomarkers conferred substantially greater dementia risk than either factor alone.

Anemia Tied to Worse Biomarker Profile at Baseline

Led by Martina Valletta, MD, of the Aging Research Center at Karolinska Institutet, the study leveraged data from 2282 dementia-free adults aged 60 years or older (median age, 72.2 years; 61.6% female) and followed them for a mean of 9.3 years. As part of their inclusion in the cohort, serum concentrations of phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured at baseline using Simoa assays. For the purpose of analysis, anemia was defined per World Health Organization criteria.

At baseline, 199 participants (8.7%) had anemia, the vast majority of which was normocytic. Those with anemia had significantly higher median levels of all three biomarkers compared with participants without anemia:

• p-tau217 (0.20 vs 0.10 pg/mL)
• NfL (36.6 vs 17.0 pg/mL)
• GFAP (187.8 vs 117.4 pg/mL)

In adjusted quantile regression models, anemia was associated with higher levels of NfL (β, 0.25; 95% CI, 0.19–0.31), p-tau217 (β, 0.22; 95% CI, 0.15–0.30), and GFAP (β, 0.08; 95% CI, 0.03–0.12).

A nonlinear, inverse dose-response relationship was observed between hemoglobin level and all 3 biomarkers, with lower hemoglobin consistently associated with higher biomarker concentrations.

Dementia Hazard Amplified When Anemia and Biomarkers Co-occur

During the follow-up, 362 participants (15.9%) developed dementia. The incidence rate was more than twice as high among those with anemia (4.37 per 100 person-years) compared to those without (1.65 per 100 person-years). After adjustment for chronic kidney disease, cardiovascular disease, cancer, systemic inflammation, and other confounders, anemia remained associated with a 66% higher hazard of dementia (HR, 1.66; 95% CI, 1.21–2.28).

The joint analysis revealed the highest dementia risk among participants with both anemia and elevated biomarkers. Those with anemia and high NfL had an adjusted HR of 3.64 (95% CI, 2.39–5.56) compared with participants with normal hemoglobin and low NfL, which investigators pointed out met criteria for additive interaction (attributable proportion, 0.38; 95% CI, 0.04–0.73).

Elevated risk was also observed for anemia combined with high p-tau217 (HR, 3.01; 95% CI, 1.99–4.55) or high GFAP (HR, 3.34; 95% CI, 2.20–5.08), though additive interactions were not significant for those biomarkers.

Sex-stratified analyses suggested stronger associations in males than females across biomarker and dementia outcomes, though sex interactions were not uniformly statistically significant.

Implications for Dementia Risk Stratification

The investigators proposed 2 mechanistic interpretations of their findings:

• Anemia may reduce brain resilience, lowering the threshold at which neuropathology manifests clinically
• Elevated biomarker levels, particularly NfL, may partially mediate the relationship between anemia and dementia by reflecting neurodegeneration accelerated by chronic cerebral hypoxia.

The investigators noted adjusting for shared risk factors, such as chronic kidney disease, inflammation, and nutritional deficiencies, did not substantially attenuate the associations, which suggests these confounders do not fully account for the findings.

Limitations highlighted by investigators include the predominantly White study population, biomarker measurement limited to baseline, and exclusion of participants with missing data who were older and had greater comorbidity burden.

In an accompanying editorial, Frank J. Wolters, MD, PhD, of the Department of Epidemiology at Erasmus MC–University Medical Centre Rotterdam, reflected on the findings and next steps needed for these insights to become more actionable.

“In order to move findings from observation to effective intervention, mechanistic insight is mandatory. Such insights could come from observational studies on anemia and its causes, including use of repeated measures of hemoglobin and emulated target trials, as well as from small physiological trials,” Wolters wrote. “Given the global burden of anemia and sex differences therein, validation in geographically diverse settings, with explicit attention for sex differences, will be important to optimize dementia prevention in an equitable manner.”

References:

1. Valletta M, Vetrano DL, Qiu C, et al. Anemia and Blood Biomarkers of Alzheimer Disease in Dementia Development. JAMA Netw Open. 2026;9(4):e264029. doi:10.1001/jamanetworkopen.2026.4029

2. Wolters FJ. Hemoglobin and Anemia in Dementia Prevention—The New Face of a Familiar Protein. JAMA Netw Open. 2026;9(4):e267758. doi:10.1001/jamanetworkopen.2026.7758