Diabetes and hypertension are related to amyloid-beta burden in the population-based Rotterdam Study

Higher vascular disease burden increases the likelihood of developing dementia, including Alzheimer’s disease. Better understanding the association between vascular risk factors and Alzheimer’s disease pathology at the predementia stage is critical for developing effective strategies to delay cognitive decline. In this work, we estimated the impact of six vascular risk factors on the presence and severity of in vivo measured brain amyloid-beta (Aβ) plaques in participants from the population-based Rotterdam Study. Vascular risk factors (hypertension, hypercholesterolaemia, diabetes, obesity, physical inactivity and smoking) were assessed 13 (2004–2008) and 7 years (2009–2014) prior to 18F-florbetaben PET (2018–2021) in 635 dementia-free participants. Vascular risk factors were associated with binary amyloid PET status or continuous PET readouts (standard uptake value ratios, SUVrs) using logistic and linear regression models, respectively, adjusted for age, sex, education, APOE4 risk allele count and time between vascular risk and PET assessment. Participants’ mean age at time of amyloid PET was 69 years (range: 60–90), 325 (51.2%) were women and 190 (29.9%) carried at least one APOE4 risk allele. The adjusted prevalence estimates of an amyloid-positive PET status markedly increased with age [12.8% (95% CI 11.6; 14) in 60–69 years versus 35% (36; 40.8) in 80–89 years age groups] and APOE4 allele count [9.7% (8.8; 10.6) in non-carriers versus 38.4% (36; 40.8) to 60.4% (54; 66.8) in carriers of one or two risk allele(s)]. Diabetes 7 years prior to PET assessment was associated with a higher risk of a positive amyloid status [odds ratio (95% CI) = 3.68 (1.76; 7.61), P < 0.001] and higher standard uptake value ratios, indicating more severe Aβ pathology [standardized beta = 0.40 (0.17; 0.64), P = 0.001]. Hypertension was associated with higher SUVr values in APOE4 carriers (mean SUVr difference of 0.09), but not in non-carriers (mean SUVr difference 0.02; P = 0.005). In contrast, hypercholesterolaemia was related to lower SUVr values in APOE4 carriers (mean SUVr difference −0.06), but not in non-carriers (mean SUVr difference 0.02). Obesity, physical inactivity and smoking were not related to amyloid PET measures. The current findings suggest a contribution of diabetes, hypertension and hypercholesterolaemia to the pathophysiology of Alzheimer’s disease in a general population of older non-demented adults. As these conditions respond well to lifestyle modification and drug treatment, further research should focus on the preventative effect of early risk management on the development of Alzheimer’s disease neuropathology

Predicting amyloid-beta pathology in the general population

INTRODUCTION: Reliable models to predict amyloid beta (Aβ) positivity in the general aging population are lacking but could become cost-efficient tools to identify individuals at risk of developing Alzheimer's disease. METHODS: We developed Aβ prediction models in the clinical Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study (n = 4,119) including a broad range of easily ascertainable predictors (demographics, cognition and daily functioning, health and lifestyle factors). Importantly, we determined the generalizability of our models in the population-based Rotterdam Study (n = 500). RESULTS: The best performing model in the A4 Study (area under the curve [AUC] = 0.73 [0.69–0.76]), including age, apolipoprotein E (APOE) ε4 genotype, family history of dementia, and subjective and objective measures of cognition, walking duration and sleep behavior, was validated in the independent Rotterdam Study with higher accuracy (AUC = 0.85 [0.81–0.89]). Yet, the improvement relative to a model including only age and APOE ε4 was marginal. DISCUSSION: Aβ prediction models including inexpensive and non-invasive measures were successfully applied to a general population–derived sample more representative of typical older non-demented adults.</p

Interaction Between Arteriosclerosis and Amyloid-β on Cognitive Function

Background: Dementia is a multifactorial disease, with Alzheimer’s disease (AD) and vascular pathology often co-occurring in many individuals with dementia. Yet, the interplay between AD and vascular pathology in cognitive decline is largely undetermined. Objective: The aim of the present study was to examine the joint effect of arteriosclerosis and AD pathology on cognition in the general population without dementia. Methods: We determined the interaction between blood-based AD biomarkers and CT-defined arteriosclerosis on cognition in 2,229 dementia-free participants of the population-based Rotterdam Study (mean age: 68.9 years, 52% women) crosssectionally. Results: Amyloid-β (Aβ)42 and arterial calcification were associated with cognitive performance. After further adjustment for confounders in a model that combined all biomarkers, only arterial calcification remained independently associated with cognition. There was a significant interaction between arterial calcification and Aβ42 and between arterial calcification and the ratio of Aβ42/40. Yet, estimates attenuated, and interactions were no longer statistically significant after adjustment for cardio metabolic risk factors. Conclusions: Arteriosclerosis and AD display additive interaction-effects on cognition in the general population, that are due in part to cardio metabolic risk factors. These findings suggest that joint assessment of arteriosclerosis and AD pathology is important for understanding of disease etiology in individuals with cognitive impairment.</p

Diabetes and hypertension are associated with elevated beta-amyloid burden: evidence from the prospective population-based Rotterdam Study

Background : Higher vascular risk increases the likelihood of developing dementia. Better understanding the association between vascular risk and Alzheimer’s disease (AD) pathology at the pre-dementia stage is critical for developing effective strategies to delay cognitive decline. In this work, we estimated the impact of vascular risk on the presence and severity of in-vivo measured brain beta-amyloid (Aβ) plaques in participants from the population-based Rotterdam Study. Methods : Vascular risk factors (hypertension, hypercholesterolemia, diabetes, obesity, physical inactivity, and smoking) were assessed twelve and seven years prior to 18F-florbetaben positron emission tomography (PET) in 506 dementia-free participants. Vascualr risk factors were associated with binary amyloid PET status or continuous PET readouts (SUVr values) using logistic and linear regression models respectively, adjusted for age, sex, education, APOE4 risk allele count, and time between vascular risk and PET assessment. Results : Participants’ mean age at time of amyloid PET was 68 years (range: 60-90), 262 (51.8%) were women and 158 (31.2%) carried at least one APOE4 risk allele (Figure 1). The adjusted prevalence estimates of an amyloid-positive PET status markedly increased with age (12% in 60-69y vs. 45.5% in 80-89y age-groups) and APOE4 allele count (8.3% in non-carriers vs. 34.8 to 58.8% in carriers of one or two risk allele(s); Figure 2). A diagnosis of diabetes seven years prior to PET assessment was associated with a higher risk of a positive amyloid status (OR[95%CI]=4.07[1.66–9.71], P=0.002; Figure 3) and higher SUVr values, indicating more severe Aβ pathology (standardized beta=0.478[0.205–0.750], P=0.001; Figure 4). We found evidence for an association between hypertension and higher SUVr values in APOE4 carriers, but not in non-carriers (interaction: standardized beta=0.425[0.092–0.758], P=0.013; Figure 5). Hypercholesterolemia, obesity, physical inactivity and smoking were not related to amyloid PET measures. Conclusion : The current findings suggest a contribution of diabetes and hypertension to the pathophysiology of AD. Since both conditions respond well to lifestyle modification and drug treatment, further research should be conducted to examine the preventative effect of early risk management on the development of AD neuropathology

Resistance to developing brain pathology due to vascular risk factors

Brain pathology develops at different rates between individuals with similar burden of risk factors, possibly explained by brain resistance. We examined if education contributes to brain resistance by studying its influence on the association between vascular risk factors and brain pathology. In 4111 stroke-free and dementia-free community-dwelling participants (62.9 ± 10.7 years), we explored the association between vascular risk factors (hypertension and the Framingham Stroke Risk Profile [FRSP]) and imaging markers of brain pathology (markers of cerebral small vessel disease and brain volumetry), stratified by educational attainment level. Associations of hypertension and FSRP with markers of brain pathology were not significantly different between levels of educational attainment. Certain associations appeared weaker in those with higher compared to lower educational attainment, particularly for white matter hyperintensities (WMH). Supplementary residual analyses showed significant associations between higher educational attainment and stronger resistance to WMH among others. Our results suggest a role for educational attainment in resistance to vascular brain pathology. Yet, further research is needed to better characterize determinants of brain resistance.</p

Resistance to developing brain pathology due to vascular risk factors: the role of educational attainment

Brain pathology develops at different rates between individuals with similar burden of risk factors, possibly explained by brain resistance. We examined if education contributes to brain resistance by studying its influence on the association between vascular risk factors and brain pathology. In 4111 stroke-free and dementia-free community-dwelling participants (62.9 ± 10.7 years), we explored the association between vascular risk factors (hypertension and the Framingham Stroke Risk Profile [FRSP]) and imaging markers of brain pathology (markers of cerebral small vessel disease and brain volumetry), stratified by educational attainment level. Associations of hypertension and FSRP with markers of brain pathology were not significantly different between levels of educational attainment. Certain associations appeared weaker in those with higher compared to lower educational attainment, particularly for white matter hyperintensities (WMH). Supplementary residual analyses showed significant associations between higher educational attainment and stronger resistance to WMH among others. Our results suggest a role for educational attainment in resistance to vascular brain pathology. Yet, further research is needed to better characterize determinants of brain resistance.ImPhys/Medical ImagingImPhys/Computational Imagin