Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB) share clinical and molecular features. Cerebrospinal fluid (CSF) biomarkers may help the characterization of these diseases, improving the differential diagnosis. We evaluated the diagnostic performance of five CSF biomarkers across a well-characterized cohort of patients diagnosed with AD, DLB, PDD, and Parkinson’s disease (PD). A total of 208 patients were enrolled in 3 European centers. The diagnostic groups (AD, n = 48; DLB, n = 40; PDD, n = 20; PD, n = 54) were compared with cognitively healthy neurological control subjects (patients with other neurological diseases [OND], n = 46). CSF levels of fatty acid binding protein 3, heart type (FABP3), α-synuclein (α-syn), amyloid-β peptide 1–42, total tau (t-tau), and phosphorylated tau 181 (p-tau) were assessed with immunoassays. Univariate and multivariate statistical analyses were applied to calculate the diagnostic value of the biomarkers as well as their association with clinical scores. FABP3 levels were significantly increased in patients with AD and DLB compared with those with PD and OND (p < 0.001). CSF t-tau, p-tau, and α-syn were significantly higher in patients with AD than in patients with PDD, DLB, PD, and OND. Combination of FABP3 with p-tau showed high accuracy for the differential diagnosis between AD and DLB (AUC 0.92), whereas patients with AD were separated from those with PDD using a combination of p-tau, FABP3, and α-syn (AUC 0.96). CSF FABP3 was inversely associated with Mini Mental State Examination score in the whole cohort (r = −0.42, p < 0.001). The combination of CSF biomarkers linked to different aspects of neurodegeneration, such as FABP3, α-syn, and AD biomarkers, improves the biochemical characterization of AD and Lewy body disorders.

Alzheimer’s disease (AD) pathology begins decades before the onset of clinical symptoms. It is recognized as a clinicobiological entity, being detectable in vivo independently of the clinical stage by means of pathophysiological biomarkers. Accordingly, neuropathological studies that were carried out on healthy elderly subjects, with or without subjective experience of cognitive decline, reported evidence of AD pathology in a high proportion of cases. At present, mild cognitive impairment (MCI) represents the only clinically diagnosed pre-dementia stage. Several attempts have been carried out to detect AD as early as possible, when subtle cognitive alterations, still not fulfilling MCI criteria, appear. Importantly, pre-MCI individuals showing the positivity of pathophysiological AD biomarkers show a risk of progression similar to MCI patients. In view of successful treatment with disease modifying agents, in a clinical setting, a timely diagnosis is mandatory. In clinical routine, biomarkers assessment should be taken into consideration whenever a subject with subtle cognitive deficits (pre-MCI), who is aware of his/her decline, requests to know the cause of such disturbances. In this review, we report the available neuropsychological and biomarkers data that characterize the pre-MCI patients, thus proposing pre-MCI as the first clinical manifestation of AD.