Synaptic dysfunction is linked to
cognitive symptoms in
Alzheimer's disease. Thus, measurement of synapse
proteins in cerebrospinal fluid may be useful
biomarkers to monitor synaptic degeneration. Cerebrospinal fluid levels of the postsynaptic
protein neurogranin are increased in
Alzheimer's disease, including in the predementia stage of the disease. Here, we tested the performance of cerebrospinal fluid
neurogranin to predict
cognitive decline and
brain injury in the
Alzheimer's Disease Neuroimaging Initiative study. An in-house immunoassay was used to analyse
neurogranin in cerebrospinal fluid samples from a cohort of patients who at recruitment were diagnosed as having
Alzheimer's disease with
dementia (n = 95) or
mild cognitive impairment (n = 173), as well as in cognitively normal subjects (n = 110). Patients with
mild cognitive impairment were grouped into those that remained cognitively stable for at least 2 years (stable
mild cognitive impairment) and those who progressed to
Alzheimer's disease dementia during follow-up (progressive
mild cognitive impairment). Correlations were tested between baseline cerebrospinal fluid
neurogranin levels and baseline and longitudinal
cognitive impairment, brain
atrophy and
glucose metabolism within each diagnostic group. Cerebrospinal fluid
neurogranin was increased in patients with
Alzheimer's disease dementia (P < 0.001), progressive
mild cognitive impairment (P < 0.001) and stable
mild cognitive impairment (P < 0.05) compared with controls, and in
Alzheimer's disease dementia (P < 0.01) and progressive
mild cognitive impairment (P < 0.05) compared with stable
mild cognitive impairment. In the
mild cognitive impairment group, high baseline cerebrospinal fluid
neurogranin levels predicted
cognitive decline as reflected by decreased Mini-Mental State Examination (P < 0.001) and increased
Alzheimer's Disease Assessment Scale-cognitive subscale (P < 0.001) scores at clinical follow-up. In addition, high baseline cerebrospinal fluid
neurogranin levels in the
mild cognitive impairment group correlated with longitudinal reductions in cortical
glucose metabolism (P < 0.001) and hippocampal volume (P < 0.001) at clinical follow-up. Furthermore, within the progressive
mild cognitive impairment group, elevated cerebrospinal fluid
neurogranin levels were associated with accelerated deterioration in
Alzheimer's Disease Assessment Scale-cognitive subscale (β = 0.0017, P = 0.01). These data demonstrate that cerebrospinal fluid
neurogranin is increased already at the early clinical stage of
Alzheimer's disease and predicts cognitive deterioration and disease-associated changes in metabolic and structural
biomarkers over time.