This study confirms a relationship in vivo between one CVRF (DBP) and one marker of established disease (BMI) with brain Aβ burden measured by PiB-PET studies. Plasma cortisol levels also positively correlated with PiB scores. Our study shows that, in agreement with epidemiological evidence, there is a link between CVRF and a biomarker of Aβ deposition, namely PiB-PET scores. One previous study has reported a difference in weight based on the CSF signature according to previously reported epidemiological data [32
]. To our knowledge, no other study has assessed the relationship of CVRF and AD in vivo, and there are only limited neuropathological studies reporting this association [33
]. The inverse correlation between BMI and PiB-PET score measures could reflect the loss of weight that occurs in preclinical stages of AD [11
The increasing trend of dementia incidence attributable to CVRF has been explained either by the additive effect of cerebrovascular pathology and AD pathology lowering the threshold for clinical symptoms [37
] or by CVRF enhancing the underlying neurodegenerative process. Given the association between intracranial atherosclerosis and dementia in neuropathological studies [39
], and the increase of Aβ deposition caused by oligemia and hypoxia, it is possible that these CVRF may contribute to mechanisms underlying AD [37
]. Our study indicates that DBP may mediate cognitive deficits that are not only due to microvasculature damage but also due to Aβ deposition [13
]. One explanation for finding only an association with DBP can be that the blood pressure decrease that occurs at presymptomatic stages of AD mainly affects SBP [13
], and that DBP changes are not so affected by disease evolution [44
], so that in the regression model SBP does not add any additional information to DBP. Another possible explanation is that the endothelial dysfunction is more dependent on DPB at older ages.
The absence of an increased burden of Aβ burden in subjects with fasting glucose impairment is consistent with previous neuropathological studies [47
] and animal models that described increased cerebrovascular changes without an increase of amyloid burden [48
Cortisol has been related to Aβ deposition and memory deficits in normal transgenic mice [49
] and to hippocampal atrophy in human brain magnetic resonance imaging studies [21
]. This study confirms the relation between cortisol and brain Aβ deposition in human subjects.
No correlation was found between acute-phase proteins and PiB scores. This is in agreement with a recent imaging and autopsy study that found no correlation between a marker of activated microglia (3
H-PK11195) and PiB-PET scores [51
], whereas the results of in vivo studies are conflicting [52
]. In the autopsy study, a correlation with number of glial fibrillary acidic protein immunoreactive cells was found, indicating a relation with astrocytosis [51
]. Larger studies with patients at different stages of AD might be necessary to assess whether inflammation is present only at certain stages of the disease.
We did not find an association between cholesterol levels and PiB-PET score. One reason is that at stages where the disease is already symptomatic, the presence of hypertension still predicts further greater cognitive decline, whereas there is no association with the presence of hypercholesterolemia [45
]. Another reason can be the distribution of cholesterol levels among the different diagnostic groups. Although not statistically significant, cholesterol levels were higher in our AD group, which is in disagreement with cross-sectional and longitudinal studies performed at late life [55
One of the difficulties in longitudinal epidemiological studies is to discern the underlying pathology or pathologies. Not all studies confirm the causal link between hypertension and AD [57
]. With aging, mixed dementia increases in large autopsy series [3
]. Therefore, the use of imaging techniques that distinguish the presence of the different substrates that can account for cognitive decline becomes crucial.
Our study has several strengths, such as the detailed clinical and biomarker characterization of the sample as well as the standardized protocols applied in ADNI. However, there are also some weaknesses inherent to this study, including the exclusion criteria used in ADNI, which prevented subjects with severe vascular disease from entering the study, and therefore subjects with serious vascular events are not represented in the ADNI cohort. Besides this, the skewed representation of the most impaired cases of MCI with lack of patients in early stages is a further limitation, because the complete spectrum of the continuum between subjects with no underlying neurodegenerative disease and subjects with AD neuropathology in a dementia stage could not be represented. Finally, this study represents a cross-sectional analysis that does not allow establishing whether the loss of weight represents an effect of the disease evolution and whether the DBP increases Aβ deposition in the brain.
In conclusion, our study favors the hypotheses of an association between DBP and cortisol and the amyloid cascade, and it underlines the utility of biomarkers not only as a diagnostic tool but also as a means to study the course and etiology of AD in vivo.