Plasma biomarkers are promising tools for the screening and diagnosis of dementia in clinical settings. We analyzed plasma levels of Alzheimer’s core biomarkers, neurofilament light chain (NfL) and glial fibrillary acid protein (GFAP), through single-molecule Array in 108 patients with Alzheimer’s (AD, cerebrospinal fluid with an amyloid+ tau+ neurodegeneration+ profile), 73 patients with frontotemporal dementia (FTD, 24 with genetic diagnosis), and 54 controls. The best area under the curve (AUC) was used to assess the discriminative power. Patients with AD had lower Aß42/40 ratios and NfL levels, along with higher levels of p-tau181 and GFAP, compared with FTD patients. Single biomarkers discriminated well between dementia patients and controls: the Aß42/40 ratio (AUC:0.86) or GFAP (AUC:0.83) was found for AD, and the NfL (AUC:0.84) was found for FTD patients. However, a combination of two (NfL with p-tau181, or the GFAP/NfL ratio, AUCs ~0.87) or three biomarkers (NfL, P-tau181, and Aß42/40 ratio, AUC: 0.90) was required to distinguish between AD and FTD. Biomarker profiles were similar across different FTD phenotypes, except for carriers of PGRN mutations, who had higher levels of NfL than C9orf72 expansion carriers. In our series, NfL alone provided the best distinction between FTD and controls, while a combination of two or three biomarkers was required to obtain good discrimination between AD and FTD.

ADAM10 is the main α-secretase acting in the non-amyloidogenic processing of APP. We hypothesized that certain rare ADAM10 variants could increase the risk for AD by conferring the age-related downregulation of α-secretase. The ADAM10 gene was sequenced in 103 AD cases (82% familial) and 96 cognitively preserved nonagenarians. We examined rare variants (MAF < 0.01) and determined their potential association in the AD group with lower CSF protein levels, as analyzed by means of ELISA, and Western blot (species of 50 kDa, 55 kDa, and 80 kDa). Rare variants were found in 15.5% of AD cases (23% early-onset, 8% late-onset) and in 12.5% of nonagenarians, and some were group-specific. All were intronic variants except Q170H, found in three AD cases and one nonagenarian. The 3′UTR rs74016945 (MAF = 0.01) was found in 6% of the nonagenarians (OR 0.146, p = 0.057). Altogether, ADAM10 total levels or specific species were not significantly different when comparing AD with controls or carriers of rare variants versus non-carriers (except a Q170H carrier exhibiting low levels of all species), and did not differ according to the age at onset or APOE genotype. We conclude that ADAM10 exonic variants are uncommon in AD cases, and the presence of rare intronic variants (more frequent in early-onset cases) is not associated with decreased protein levels in CSF.