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.

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Background: Neurofilament light chain (NfL) is known as a promising biomarker for risk stratification and disease monitoring of dementia due to Alzheimer's disease, but the underlying pathophysiological substrates remain largely elusive. Moreover, it is uncertain whether NfL levels are able to capture changes in cognitive performance prior to the onset of clinical cognitive decline. We studied the relation of plasma NfL with cognition and structural brain imaging markers in a general population without dementia.Method: Plasma level of NfL was measured using the Simoa NF-light™ assay in 4,207 dementia-free participants of the population-based Rotterdam Study cohort (mean age 71.6 years, 57% women). Participants underwent repeated cognitive assessment, and a subset of 970 had brain MRI. We used linear and logistic regression (crosssectional) and mixed-effects models (longitudinal) to determine the association of plasma NfL with (changes in) cognition and brain tissue volumetry, white matter integrity and markers of cerebral small-vessel disease (lacunes, white matter hyperintensities and microbleeds).Result: At baseline, higher plasma NfL level was significantly associated with a worse cognitive performance (g-factor: β=-0.06 95%CI -0.12;0), and more specifically with lower test scores on the Stroop 3 test (β=-0.07 95%CI -0.12;-0.01), and Perdue Pegboard (β=-0.12 95%CI -0.18;-0.06). Similarly, among 2,850 participants with repeated cognitive assessment, baseline NfL level was significantly associated with a stronger decline in cognition (g-factor (β=-0.02 95%CI -0.04;0), driven by faster decline on Stroop 1 & 2 tests (β=-0.03 95% -0.04;-0.01, β=-0.03 95%CI -0.05;-0.02, Figure 1).In participants with brain MRI, NfL level was significantly associated at baseline with larger volumes of white matter hyperintensities (β= 0.12 95%CI 0.04;0.20), more lacunar infarcts (OR= 1.69 95%CI 1.20;2.39), and worse fractional anisotropy (β=-0.10 95%CI -0.18;-0.02) and mean diffusivity (β=0.09 95%CI 0.02;0.16), but not with grey matter volumes. Plasma NfL level was not significantly related to progression of structural brain changes over time (n=738).