- Lower hemoglobin levels were linked with higher dementia risk over 9 years of follow-up.
- Anemia was associated with elevated Alzheimer’s blood biomarkers including p-tau217 and neurofilament light chain.
- Dementia risk was highest when anemia coexisted with abnormal Alzheimer’s biomarkers.
Lower hemoglobin levels were associated with progressively higher dementia risk and elevated blood concentrations of Alzheimer’s disease biomarkers, data from a Swedish cohort study suggested.
In a study of 2,300 older adults without dementia, anemia was cross-sectionally associated with higher levels of serum phosphorylated tau 217 (p-tau 217; β=0.22), neurofilament light chain (NfL; β=0.25) and glial fibrillary acidic protein (GFAP; β=0.08), reported Martina Valletta, MD, of the Karolinska Institute in Stockholm, and co-authors.
Anemia was longitudinally associated with a higher risk of incident dementia over a mean follow-up of 9 years (HR 1.66, 95% CI 1.21-2.28), Valletta and colleagues reported in JAMA Network Open.
The highest dementia risk occurred when anemia and elevated biomarkers coexisted, the researchers said. For older adults with low hemoglobin and high NfL, for example, the HR was 3.64 (95% CI 2.39-5.56).
These findings suggested that anemia may interact with neuropathologic processes, potentially accelerating dementia development, Valletta and co-authors noted.
“Dementia risk was particularly high when anemia co-occurred with high levels of blood biomarkers reflecting Alzheimer’s disease pathology, neurodegeneration, and glial activation. This suggests a biological interplay between anemia and neuropathology, in which low hemoglobin may not only contribute to neuropathology but also reduce the brain’s resilience to it,” the researchers wrote.
“Taken together, our findings suggest anemia is a clinically relevant factor in the context of dementia risk stratification and is possibly a modifiable target in dementia prevention strategies,” they added.
A causal role of anemia in dementia etiology could have substantial public health implications, observed Frank Wolters, MD, PhD, of Erasmus MC-University Medical Center in Rotterdam, the Netherlands.
“Anemia is present in 25% of the global population, with the highest prevalence in countries that are expected to have the steepest increases in dementia incidence,” Wolters wrote in an accompanying editorial.
The biomarker-level observations in the Swedish study “provide novel evidence that connects hemoglobin directly to Alzheimer’s disease,” he noted. “Although the cross-sectional design in this respect did not allow for formal mediation analyses, results point at least toward a joint role of Alzheimer’s pathology and anemia, in line with earlier observations linking hemoglobin to plasma amyloid-beta,” he pointed out.
To move findings from observation to effective intervention, “mechanistic insight is mandatory,” Wolters emphasized. “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,” he added.
Valletta and colleagues studied participants in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study. Participants enrolled from 2001 to 2004 were followed up every 3 or 6 years according to age through 2019.
The analysis included 2,282 dementia-free participants with a median age of 72.2 years; 61.6% were female. Analyses were adjusted for age cohort, sex, educational level, chronic kidney disease, heart disease, cerebrovascular disease, cancer, underweight, iron and vitamin supplement intake, and interleukin-6 levels.
Hemoglobin level was measured at baseline, and anemia was defined according to World Health Organization criteria as a blood hemoglobin level of 12 g/dL or less for women and 13 g/dL or less for men. A total of 199 participants had anemia.
Alzheimer’s biomarkers were measured in blood samples taken at baseline. Incident dementia was diagnosed based on DSM-IV criteria. Over a mean follow-up of 9.3 years, 362 participants (15.9%) developed dementia.
“In a previous study by our group, anemia emerged as one of the chronic conditions most significantly associated with elevated levels of Alzheimer’s disease blood biomarkers. Expanding that evidence, in this study we also included p-tau217, currently regarded as the most specific blood biomarker for Alzheimer’s disease, and we observed that all biomarker levels tended to be higher as hemoglobin levels declined, following a nonlinear dose-response association,” Valletta and colleagues noted.
“These findings suggest a more nuanced relation between hemoglobin levels, Alzheimer’s disease blood biomarkers, and dementia beyond the definition of anemia itself,” they wrote.
The study had several limitations, the researchers acknowledged. Hemoglobin levels ranged from 8.2 to 17.6 g/dL, and most anemia cases were normocytic, limiting analysis of more extreme values and other anemia subtypes. Alzheimer’s biomarkers were measured in serum, which typically produces lower concentrations than plasma. Blood biomarkers also were available only at baseline.
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