Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer's disease

Abstract

Late onset Alzheimer disease (LOAD) is traditionally considered as a separate disease from vascular dementia (VAD). However, growing evidence suggests that β-amyloid (Aβ) accumulation, that initiates LOAD-related neurodegeneration, is preceded by vascular events. Previous in vitro studies showed that β-secretase 1 (BACE1), the key-enzyme of amyloidogenesis, is upregulated by cerebrovascular insult; moreover, its activity is increased both in brain and serum of LOAD patients. We aimed to investigate whether BACE1 serum activity is altered also in dementias related, or not, to cerebrovascular disease. Thus, we evaluated serum BACE1 activity in a sample of individuals, including patients with LOAD (n. 175), VAD (n. 40), MIXED (LOAD/VAD) dementia (n. 123), other types of dementia (n. 56), and healthy Controls (n. 204). We found that BACE1 was significantly higher not only in LOAD (+ 30%), but also in VAD (+ 35%) and MIXED dementia (+ 22%) (p < 0.001 for all), but not in the other types of dementia (+ 10%). Diagnostic accuracy was 77% for LOAD, 83% for VAD, and 77% for MIXED dementia. In conclusion, we showed for the first time that the increase in peripheral BACE1 activity is a common feature of LOAD and VAD, thus underlying a further pathogenic link between these two forms of dementia.

Serum beta‐secretase 1 (BACE1) activity increases in patients with mild cognitive impairment

“…By investigating a much larger sample of older individuals, we confirmed the finding of higher levels of serum BACE1 activity LOAD compared to controls, showing that this difference is independent of possible confounders including age, gender, and other risk factors for dementia (Cervellati et al, 2020). More recently, we found that BACE1 serum activity is significantly higher also in VD and MIXED (LOAD + VD), but not in other types of dementia, compared with controls (Zuliani, Trentini, et al, 2020).…”

“…Analyses were performed by SPSS for Windows statistical package, version 13.0. No sample calculation was performed and the number of subjects was determined on previous studies (Cervellati et al, 2020; Shen et al, 2018; Zuliani, Trentini, et al, 2020).…”

Early elevation of BACE1 in dementia

“…Indeed, inspired by mounting evidence of BACE1 increase in brain, CSF, and plasma, in AD patients compared to healthy controls [ 1 ], we have started to evaluate the diagnostic performance of serum activity of the enzyme. Taking a stock of our results, from the analysis of total 817 subjects, we have found that serum BACE1 activity is around 30% higher in patients with AD, vascular dementia (VD), mixed dementia (AD & VD) compared to controls [ 3 , 4 ]. Then, we moved the lens to amnestic and non-amnestic mild cognitive impairment (a- and na-MCI, respectively), with the former being more prone to convert into AD compared to the latter [ 5 ].…”

BACE1: from biomarker to Alzheimer’s disease therapeutical target

“…BACE1 concentration and activity have been found to be elevated brain and cerebrospinal fluid (CSF) of AD patients compared with normal individuals. Intriguingly, two recent large population studies [ 2 , 3 ] from our group demonstrated that this alteration is also reflected in periphery, with a 30% increase in serum BACE1 activity in AD patients compared to controls. This finding is supported by some elegant investigations from Hampel’s group [ 4 , 5 ], showing both a correlation of peripheral BACE1 with well-established AD markers (CSF Aβ and t-Tau), and with axonal degeneration and brain atrophy in individuals at high risk for AD.…”