Biological Aging May Be a Risk Factor for Incident Dementia

A recent study indicates that advanced biological aging could be a potential risk factor for incident dementia, mediated through the reduction of brain structures.1

“With the rising impact of dementia around the world, identifying risk factors and implementing preventive measures is essential,” said lead investigator Yacong Bo, PhD, of Zhengzhou University in China, in a statement. 2 “While none of us can change our chronological age, we can influence our biological age through lifestyle factors such as diet and exercise.”

Research has suggested that biological age, determined by factors such as lung function, blood pressure, and cholesterol, is linked to dementia. A study published this year reported that shorter protective caps on chromosomes called telomeres, a proposed marker of accelerated biological aging, may be linked to an increased risk of dementia.3 The study had shown that compared with people with longer leukocyte telomeres, people with shorter ones had a 19% greater risk of dementia.

Another study also showed that individuals in the highest quartile of phenotypic age acceleration, an indicator for accelerated biological aging calculated by 9 clinical blood biomarkers and chronological age, had the greatest dementia risk.4

Although research has suggested a link between biological aging and dementia, limited data exist on this association. Investigators aimed to investigate the relationship between biological age and incident dementia, along with examining the underlying neurobiological mechanisms.1

Leveraging data from the UK Biobank, the study included 280,918 participants (mean chronological age: 56.80 years; 54.59%) who did not have diagnosed dementia at baseline. Biological age was assessed from clinical traits using the Klemera-Doubal method biological age (KDM-BA) and PhenoAge algorithms. Biomarkers examined for biological age included lung function, blood pressure, cholesterol, average cell volume, ad white blood cell count. The team evaluated the genetic risk of dementia using the apolipoprotein E (APOE) ε4 genotype and polygenic risk scores (PRSs).

Investigators evaluated the associations of biological age and the combined effect of genetic risk and biological age with dementia using Cox proportional hazard regression models. They conducted a mediation analysis to assess the potential roles of brain structures, such as gray matter volume, cortical mean thickness, and cortical surface area, in the link between biological age and dementia.

Over a median follow-up of 13.58 years, 4770 participants developed dementia. The analysis showed every increase in KDM-BA accelerations and PhenoAge accelerations were linked to a 14% (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.10 – 1.18) and 15% (HR, 1.15; 95% CI, 1.12 – 1.19) greater incidence of dementia, respectively.

Participants who later developed dementia had an average chronological age of 65 years at baseline, compared to an average age of 57 years among those who did not develop dementia. Those who developed dementia had a mean biological age of 55 years, compared with individuals with no dementia who had a mean age of 45 years.

Participants with APOE ε4 and the highest PhenoAge accelerations had the greatest risk of dementia (HR, 4.20; 95% CI, 3.69 – 4.78) compared with those with non-APOE ε4 and the lowest PhenoAge accelerations (P < .001). Participants with the most advanced biological age were about 30% more likely to develop dementia than those without.

The study did not find any significant medication effects of polygenic risk scores on the association between biological age accelerations and dementia when examining the KDM-BA acceleration (P = .347) and PhenoAge acceleration (P = .279). They also did not find a significant effect of APOE ε4 on the association between KDM-BA accelerations and dementia (P = 0.212).

Furthermore, the mediation analysis demonstrated that the identified gray matter volume, cortical mean thickness, and cortical surface area slightly mediated the association between biological age accelerations and incident dementia, ranging from 6.64% to 17.98% of participants.

Although this study does not prove that advanced biological age causes dementia, the research shows an association.

“These brain structure changes explain some, but not all, of the association between advanced biological age and dementia,” Bo said. “These results support the hypothesis that advanced biological age may contribute to the development of dementia by causing a widespread change in brain structures.

References

1. Bo Y, Sun L, Hou S, Zhang F, Zhang H, Feng X, Zhuo S, Feng S, Chang H, Zhang X, Wang Z, Yu Z, Zhao X. Associations of Accelerated Biological Aging With Dementia and the Mediation Role of Brain Structure: Findings From a Longitudinal Study. Neurology. 2025 May 27;104(10):e213616. doi: 10.1212/WNL.0000000000213616. Epub 2025 Apr 30. PMID: 40305743.

2. Derman, C. Shorter Telomere Length Linked to Increased Risk of Stroke, Dementia, Depression. HCPLive. February 3, 2025. https://www.hcplive.com/view/shorter-telomere-length-linked-increased-risk-stroke-dementia-depression. Accessed May 9, 2025.

3. Does Your Biological Age Affect Your Risk of Dementia? News Wise. April 24, 2025. https://www.newswise.com/articles/does-your-biological-age-affect-your-risk-of-dementia. Accessed May 9, 2025.

4. Ye, Z., Lang, H., Xie, Z. et al. Associations of combined accelerated biological aging and genetic susceptibility with incident dementia: a prospective study in the UK Biobank. BMC Med 22, 425 (2024). https://doi.org/10.1186/s12916-024-03640-4