Stable HbA1c Levels Linked to Lower Alzheimer Risk in Older Adults with Diabetes

Patricia C. Underwood, PhD

Credit: William F. Connell School of Nursing

A new study suggests older adults with diabetes who maintain HbA1c stability in individualized target ranges over time are linked to a lower risk of Alzheimer Disease and related dementias.¹

“Our findings further define the potential role of glycemic excursions and risks of developing [Alzheimer Disease and related dementias],” wrote investigators, led by Patricia C. Underwood, PhD, from William F. Connell School of Nursing at Boston College. “Our results confirm that extremes of glucose levels, as measured by average HbA1c, are associated with an increase in dementia incidence.”

Research has shown diabetes increases one’s risk for Alzheimer Disease.² Factors such as hypoglycemia, hyperglycemia, and glycemia variability are linked to the increased risk of Alzheimer Disease and related dementias.

Investigators sought to assess the link between hemoglobin A1c (HbA1c) time in range and incidence of Alzheimer Disease and related dementias in older veterans with diabetes.¹ The team used HbA1c time in range, a measure of glycemic control over time within specific ranges, as the mean HbA1c may not capture the dynamic factors linking diabetes to Alzheimer’s Disease and related dementias.

Investigators conducted a study leveraging administrative and healthcare utilization data from the Veterans Health Administration and Medicare from January 1, 2004, to December 31, 2018. The sample included 374,021 veterans with diabetes aged ≥ 65 years (mean age: 73.2 years) with majority (99%) male. Additionally, 87% were White, followed by 11% Black, 1% Hispanic, 1% as other, and 0.4% Asian.

Participants had ≥ 4 HbA1c tests during the 3-year baseline period between January 1, 2005, and December 31, 2024. The mean baseline HbA1c level was 7%. The percentages of patients in each HbA1c target range were as followed: 6% to 7% (25.2% of participants), 7% to 8% (34.4% of participants), 7.5% to 8.5% (33.4% of participants), and 8% to 9% (7.4% of participants).

HbA1c time in range was determined as the percentage of days during the baseline period when HbA1c levels fell within individualized target ranges, based on clinical characteristics and life expectancy. A greater HbA1c time in range was considered more favorable.

Investigators analyzed the data from July to December 2023. At the 10-year follow-up, 11% developed Alzheimer Disease and related dementias. An adjusted cox proportional hazards progression model demonstrated an HbA1c time in range ≤ 20% was linked to a greater risk of incident Alzheimer Disease and related dementias when compared to an HbA1c TIR of ≥ 80% (hazard ratio, 1.19; 95% CI, 1.16 to 1.23).

Investigators observed the direction of out-of-range HbA1c levels was linked to incident Alzheimer Disease and related dementias. A greater time below range below ≥ 60%, compared with ≥ 60% time in range was linked to a significantly increased risk (hazard ratio (HR, 1.23; 95% confidence interval [CI], 1.19 to 1.27).

“Our results clarify the association between glycemic control and dementia incidence by showing a significant association between HbA1c stability and reduced dementia incidence,” investigators wrote. “These results suggest that in addition to preventing hypoglycemia, maintaining higher HbA1c TIR over time may decrease dementia incidence.”

The findings remained significant after excluding individuals who used medications associated with a hypoglycemia risk, such as insulin or sulfonylureas at baseline, at baseline. The findings also remained significant when excluding individuals who experienced hypoglycemia events at baseline.

Investigators wrote the findings were limited by the sample mostly containing older men, the fact this was an observational study, and not having access to data such as social determinants of health, food insecurity, diabetes self-care behaviors, and APOE4. The study also did not show maintaining a greater HbA1c time in strategy could be used as a strategy to reduce risks for Alzheimer Disease and related dementias.

“These results affirm the benefits of applying personalized HbA1c target ranges based on age, life expectancy, and comorbidities,” investigators wrote. “Clinicians should work with patients to ensure HbA1c stability to reduce ADRD risk in older adults with diabetes.”

References

1. ^{Underwood PC, Zhang L, Mohr DC, et al. Glycated Hemoglobin A1c Time in Range and Dementia in Older Adults With Diabetes. JAMA Netw Open. 2024;7(8):e2425354. doi:10.1001/jamanetworkopen.2024.25354}
2. ^{Budson, A. What's the relationship between diabetes and dementia? Harvard Health Publishing. July 12, 2021. https://www.health.harvard.edu/blog/whats-the-relationship-between-diabetes-and-dementia-202107122546. Accessed August 12, 2024.}