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Association of Vascular Risk Factors With β-Amyloid Peptide
The author:Go Top Peptide Biotech    Released in:2021年04月09日
摘要:Association of Vascular Risk Factors With β-Amyloid Peptide and Tau Burdens in Cognitively Unimpaired Individuals and Its Interaction With Vascular Medication Use

The neuropathological hallmarks of Alzheimer disease (AD) include cerebral β-amyloid peptide (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. Vascular risk factors, such as dyslipidemia and hypertension, are thought to modify AD risk by promoting both cardiovascular disease and Aβ accumulation.1While this dual vascular pathway hypothesis is attractive, results have been mixed. Cholesterol levels and blood pressure (BP) outside of reference ranges, as well as combined vascular risk scores, have been associated with increased Aβ burden in some studies,2-7 but other studies have had conflicting results.8,9 A few studies also found direct and indirect associations of vascular risk factors with increased tau burden,8,10-12 potentially moderated through Aβ burden; however, a 2009 study13 did not find these associations. Such inconsistent results might be explained by potential moderation by vascular medications.3,14 Depending on treatment duration and type,14,15 the use of statins and antihypertensive drugs may be associated with providing protection against Aβ deposition.16,17 Participants using these vascular medications might even have experienced adverse effects of vascular risk factors over many years, but successful treatment preceding data collection could obscure the associations of these vascular risk factors with AD pathogenesis. We examined whether use of vascular medications moderate the association of vascular risk factors (ie, cholesterol levels, BP, and a combined vascular risk score) with factors associated with AD pathogenesis (ie, Aβ and tau burdens) in middle- to late-aged individuals who were cognitively unimpaired and had a family history of AD. A first-degree family history of AD is associated with a 2- to 3-fold increased risk for AD,18 making individuals with such a family history of AD ideal for studying mechanisms associated with AD at an asymptomatic stage, which is the optimal time for prevention. Our principal hypothesis was that an association between vascular risk factors and AD pathogenesis would be stronger among individuals who did not use any medications to treat vascular risk factors (untreated cohort) than in individuals using vascular medications (treated cohort).


Associations of Vascular Risk Factors With Global Aβ and Entorhinal Tau SUVR Measured by PET 

Among participants who underwent PET, no association of vascular risk factors, either as individual factors or combined as FCRP score, was found with global cerebral Aβ deposition. However, interaction analyses showed that among participants not using vascular medications, higher Aβ deposition as measured by PET was associated with higher total cholesterol (unstandardized β = −0.002 [SE, 0.001]; P = .02), low-density lipoprotein cholesterol (β = −0.002 [SE, 0.001]; P = .006), systolic BP (β = −0.006 [SE, 0.002]; P = .02), pulse pressure (β = −0.007 [SE, 0.002]; P = .004), and Framingham Coronary Risk Profile score (β = −0.038 [SE, 0.011]; P = .001), but such associations were absent in participants who used vascular medications (Figure 1 and Table 2). 

Figure 1. Associations of Vascular Risk Factors and β-Amyloid Peptide (Aβ) Burden as Measured by Positron Emission Tomography

Association of Vascular Risk Factors With β-Amyloid Peptide

Table 2. Associations of Vascular Risk Factors With Global Cerebral Aβ Burden Measured by Positron Emission Tomography

Association of Vascular Risk Factors With β-Amyloid Peptide

Discussion

Our finding that lipid-lowering and antihypertensive medications moderated the associations of vascular risk factors with Aβ burden could have clinical implications. It has been suggested that cardiovascular medication might reduce AD risk by lowering arterial stiffness, leading to increased cerebral blood flow and Aβ clearance.16,37 However, results from a randomized clinical trial38 and a meta-analysis of cohort studies39 have been mixed. Other factors, such as treatment duration, participants’ age at treatment onset, and medication type, appear to be important to the association of vascular risk factor burden with AD-related end points.6,15 Interestingly, the mean Aβ burden was similar in our treated and untreated cohorts. An alternative explanation for why an association of vascular risk factors with Aβ burden was not observed in treated participants might be that vascular risk factors were successfully lowered in most treated participants, but Aβ deposition had started before treatment onset. Figure 1 suggests this, at least with lipid levels: the treated cohort had cholesterol levels within reference ranges, but they may still have experienced adverse effects of their hypercholesterolemia before it was treated. This question may depend also on their medication type, timing, and duration.


Strengths and Limitations 

Our study has some strengths, including its reliance on middle- to late-aged individuals at risk for AD, thereby perhaps exposing events in the initial accumulation of Aβ burden, that is, a time when vascular risk factors may remain a promising target for disease prevention. The fact that PET findings were substantiated, at least in part, by observations in CSF biomarkers associated with AD lends further credence to the association of vascular risk factors with Aβ burden in such individuals.Different PET and CSF findings might also reflect the measurement of different components of Aβ burden.49 The prevalence of vascular risk factors in our cohort was generally comparable to that of the general US population,50 except that current smoking status was approximately 10-fold lower in the PREVENT-AD cohort, suggesting that our results are extendible to further populations. Our study also has some limitations. We cannot exclude the possibility that participants in the treated cohort may have had healthier lifestyles (eg, more regular exercise, maintaining healthy weight, reduced alcohol consumption and smoking) because of an increased awareness of health concerns. Such health consciousness may also have influenced our results. Other limitations of the study include its cross-sectional design and that BP values were assessed from only 1 measurement instead of determining a mean of multiple measurements at enrollment. Studies with larger sample sizes are warranted to investigate sex-specific associations of vascular risk factors with AD pathogenesis.


Conclusions

The findings of this cross-sectional study suggest that an individual’s use of vascular medications is an important consideration when studying any association of vascular risk factors and AD pathogenesis. Our findings also suggest the importance of targeting both systemic vascular burden and Aβ burden in interventional studies of healthy individuals at risk of AD. Given the current lack of effective AD treatments, the identification of modifiable risk factors associated with development of presymptomatic AD trajectories should be of considerable interest for AD prevention research.


References:

Theresa Köbe, PhD1,2Julie Gonneaud, PhD1,2Alexa Pichet Binette, MSc1,2et alPierre-François Meyer, PhD1,2Melissa McSweeney, MSc1,2Pedro Rosa-Neto, MD, PhD1,2,3John C. S. Breitner, MD, MPH1,2Judes Poirier, PhD, MD (Hon)1,2Sylvia Villeneuve, PhD1,2,3,4; for the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) Research Group

JAMA Netw Open. 2020;3(2):e1920780. doi:10.1001/jamanetworkopen.2019.20780


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