Age-dependent biphasic alterations and protein-activity decoupling of plasma BACE1 in major depressive disorder

Major depressive disorder (MDD) in late life is associated with an increased risk of Alzheimer's disease (AD), but the molecular basis for this depressiondementia continuum remains poorly understood. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) processes both beneficial substrates (e.g., neuregulin-1 for synaptic plasticity) and pathological substrates (e.g., amyloid precursor protein for Aβ generation), making it a candidate molecular bridge. We hypothesized that plasma BACE1 levels would exhibit distinct age-dependent alteration patterns in MDD.

Using a retrospective single-blind design, we enrolled 52 older (65-80 years) and 55 younger (30-40 years) MDD patients, with 75 age-matched healthy controls from the Beijing Biobank of Clinical Resources-Mental Disorders. Plasma BACE1 protein was measured by ELISA and enzymatic activity via FRET using an APP Swedish mutation substrate. Depression severity was assessed using HAMD; cognitive function using WCST.

Plasma BACE1 protein levels were significantly lower in MDD patients than in HCs (P = 0.029). A two-way ANOVA revealed a significant Age × Diagnosis interaction (F(1, 178) = 19.264, P < 0.001), formally supporting the biphasic pattern: young MDD patients showed a ~41% reduction (P < 0.001), while older MDD patients showed a numerical increase (P = 0.051). BACE1 enzymatic activity did not differ among groups, and no protein-activity correlation was observed within any subgroup, indicating a "decoupling" between protein expression and catalytic function. Plasma BACE1 protein levels in older MDD patients negatively correlated with executive dysfunction (WCST failure-to-maintain-set; r = -0.281, P = 0.044), while BACE1 activity in young MDD patients negatively correlated with age (r = -0.276, P = 0.042). A significant Age × Sex interaction (F(1, 178) = 6.756, P = 0.010) revealed an agedependent sexual dimorphism: young male controls had higher BACE1 levels than young female controls (P = 0.010), a pattern that reversed direction in older controls and was attenuated in both MDD subgroups.

These findings reveal a substrate-selective, age-dependent, and sexinformed biphasic alteration of plasma BACE1 in MDD, supporting a unifying framework in which the same enzyme is associated with depressive pathology in young patients (via loss of beneficial substrate processing) and neurodegenerative transition in older patients (via pathological substrate cleavage), with the depression-dementia continuum as the mechanistic bridge.