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The cerebrospinal fluid neurogranin (Ng)/β‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) ratio may reflect synaptic affection resulting from reduced beta‐amyloid (Aβ) clearance. We hypothesize that increased Ng/BACE1 ratio predicts the earliest cognitive decline in Alzheimer's disease.    Methods  We compared Ng/BACE1 levels between cases with subjective cognitive decline (n = 18) and mild cognitive impairment (n = 20) both with amyloid plaques and healthy controls ( APOE ‐ε4+, n = 16;  APOE ‐ε4‐, n = 20). We performed regression analyses between cerebrospinal fluid levels, baseline hippocampal and amygdala volumes, and pertinent cognitive measures (memory, attention, Mini Mental State Examination [MMSE]) at baseline and after 2 years.    Results  Ng/BACE1 levels were elevated in both subjective cognitive decline and mild cognitive impairment compared to healthy controls. Higher Ng/BACE1 ratio was associated with lower hippocampal and amygdala volumes; lower baseline memory functions, attention, and MMSE; and significant decline in MMSE and memory function at 2‐year follow‐up.    Discussion  High Ng/BACE1 ratio predicts cognitive decline also in preclinical cases with amyloid plaques.

Cerebrospinal fluid neurogranin/β‐site APP‐cleaving enzyme 1 predicts cognitive decline in preclinical Alzheimer's disease