Association of modifiable risk factors with progression to dementia in relation to amyloid and tau pathology

Abstract

Background: Dementia preventive interventions targeting multiple modifiable risk factors are a promising approach. However, the impact of modifiable risk factors in the presence of beta-amyloid or phosphorylated-tau (p-tau) pathology is unclear.

Methods: The objective of the study was to examine the role of modifiable risk factors (vascular factors, depression, and smoking) in the progression to mild cognitive impairment (MCI) or dementia among 434 cognitively unimpaired (CU) and 611 individuals with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Vascular risk factors were summarized with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score, dichotomized into higher versus lower risk. Depression and smoking (yes/no) were categorised according to medical history or current symptoms. Analyses were stratified by beta-amyloid negative (A-) and positive (A +), p-tau negative (T-) and positive (T +), or beta-amyloid and p-tau negative (A-T-) and positive (A + T +) biomarker status. Cox proportional hazard models were adjusted for age, sex, education, baseline MMSE score, baseline hippocampal volume and ApoE4 carrier status.

Results: Higher CAIDE score was associated with increased risk of progression to all-cause dementia in most MCI subgroups: adjusted hazard ratios (aHR) [95% CI] were 3.1 [1.43; 6.53] in the A- subgroup, 1.7 [1.20-2.27] in T + , 2.6 [1.06-6.59] in A-T-, and 1.6 [1.15-2.22] in the A + T + subgroup. Smoking (yes/no) was associated with increased dementia aHR in the A + MCI subgroup: 1.6 [1.07-2.34]. Depression increased dementia aHR in the T + MCI subgroup: 1.5 [1.06-2.02]. No significant associations were found in the CU biomarker subgroups.

Conclusion: Addressing modifiable risk factors carries an important potential for reducing the risk of dementia even after the onset of Alzheimer's pathology. Knowledge of biomarker status can further optimize prevention strategies.

Keywords: Amyloid; CAIDE; Depression; MCI; Modifiable risk factors; Smoking; Tau.

Fig. 1

CAIDE Score and Dementia Progression in MCI by beta-amyloid/p-tau Status. The pale lines in the figure represent the biomarker-negative group, the solid lines represent the biomarker-positive group, the red lines represent the modifiable risk factor-positive group, and the grey lines represent the modifiable risk factor-negative group. The shaded areas represent the confidence intervals. Disease-free survival means no progression to dementia. A CAIDE as a modifiable risk factor in MCI A-/A + participants. B CAIDE as a modifiable risk factor in MCI T-/T + participants. C CAIDE as a modifiable risk factor in MCI A-T-/A + T + participants

Fig. 2

Smoking and Dementia Progression in MCI by beta-amyloid /p-tau Status. The pale lines in the figure represent the biomarker-negative group, the solid lines represent the biomarker-positive group, the red lines represent the modifiable risk factor-positive group, and the grey lines represent the modifiable risk factor-negative group. The shaded areas represent the confidence intervals. Disease-free survival means no progression to dementia. A Smoking as a modifiable risk factor in MCI A-/A + participants. B Smoking as a modifiable risk factor in MCI T-/T + participants

Fig. 3

Depression and Dementia Progression in MCI by beta-amyloid /p-tau Status. The pale lines in the figure represent the biomarker-negative group, the solid lines represent the biomarker-positive group, the red lines represent the modifiable risk factor-positive group, and the grey lines represent the modifiable risk factor-negative group. The shaded areas represent the confidence intervals. Disease-free survival means no progression to dementia. A Depression at baseline as a modifiable risk factor in MCI A-/A + participants. B Depression at baseline as a modifiable risk factor in MCI T-/ T + participants. C Depression at baseline as a modifiable risk factor in MCI A-T-/A + T + participants