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

Abstract

Beta-secretase 1 (BACE1) is considered as the key enzyme in amyloidβ formation.Previous works suggest that high BACE1 activity may be present in brain, cerebrospinal fluid and serum of patients with late-onset Alzheimer's disease (LOAD) as well as mild cognitive impairment (MCI). Therefore, we evaluated whether serum BACE1 activity increases in MCI patients and is associated with the progression from MCI to dementia. BACE1 activity was measured in the serum of 259 MCI patients (162 amnestic-aMCI, 97 non-amnestic-naMCI) and 204 healthy Controls. After a median follow-up of 32 months (range: 10-153), 116 MCI progressed to dementia (87 aMCI and 29 naMCI). Serum BACE1 activity was higher in MCI compared with Controls (p < 0.001), and in aMCI with brain atrophy compared with naMCI without brain atrophy (p = 0.04). No difference in BACE1 activity emerged between converter and non-converter MCI, and this was true for both aMCI and naMCI. However, among aMCI with better cognitive performance (n. 163, MMSE score ≥24/30) those converting to dementia had higher BACE1 activity compared to stable ones (p = 0.05). This was not associated with an increased risk to develop dementia (hazard ratio: 1.65; 95% confidence interval: 0.67-4.01). In conclusion, serum BACE1 activity significantly increased in MCI patients (both amnestic and non-amnestic) compared with Controls.Moreover, higher serum BACE1 activity was observed only among aMCI with a better cognitive performance who progressed to dementia, suggesting that a dysregulation of this enzyme might be an early event primarily associated with neurodegeneration.

Early elevation of BACE1 in dementia

“…More intriguingly, a recent longitudinal study has shown that plasma BACE1 level is associated with progressive axonal damage/neurodegeneration in AD critical brain region, already in cognitively and physically healthy individuals (at risk of AD) [ 6 ]. Consistently, we have also observed an association between high BACE1 and the presence of brain atrophy in aMCI [ 5 ].…”

“…In other words, for MCIs with pronounced cognitive symptoms, the impact of tauopathy and inflammation may be dominant and mask the contribution of BACE1 in the progression to the disease. Apparently, the results we obtained by Cox model (median follow up of 32 months) do not support the use of serum BACE1 activity as prediction biomarker for AD and dementia in general [ 5 ]. However, it must be underscored that our final sample was definitely underpowered for this kind of analysis.…”

“…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 ]. This recent investigation has revealed that serum BACE1 activity: 1) is similarly higher (around 30%) in both aMCI and naMCIs as compared to healthy controls; 2) is higher in aMCI converting to dementia compared to stable MCI when considering patients with a less compromised cognitive status; 3) is not a predictor of conversion from aMCI to dementia.…”

Increased Serum Beta-Secretase 1 Activity is an Early Marker of Alzheimer’s Disease

“…Increasing evidences show the potential of serum/plasma BACE1 levels as an early biomarker of cognitive decline [ 11, 12 ]. The increase of almost 61% of BACE1 serum activity we achieved, is in line with 53% increase in MCI and 68% in AD showed by Shen and co-authors [ 11 ], and of 30% in late onset AD reported by Zuliani et al (2021) [ 13 ].…”

Neutrophil–Lymphocytes Ratio as Potential Early Marker for Alzheimer’s Disease

“…General and neuropsychological examinations, including standardized Mini-Mental State Examination (MMSE [ 25 ], upon permission from PAR was granted to use this scale), geriatric depression scale, and CDR, were carried out as previously described [ 26 ]. The functional status was evaluated by basic and instrumental activities of daily living (BADL and IADL, respectively) [ 27 ]. Demographic and medical history data (e.g., hypertension, CHD, stroke, diabetes, chronic obstructive pulmonary disease) were collected by trained personnel [ 27 ].…”