Cerebrospinal fluid biomarkers for Alzheimer's disease in patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis with the C9ORF72 repeat expansion.

BACKGROUND: The C9ORF72 expansion is one of the most common causes of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The C9ORF72 expansion is associated with TDP-43 and p62 neuropathology, and amyloid plaques and neurofibrillary tangles are not common in patients with the C9ORF72 expansion. Therefore, we hypothesized that cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease [AD; Aß1-42, total tau (T-tau) and phospho-tau] are normal in these patients. METHODS: The CSF Aß1-42, T-tau and phospho-tau levels were measured in 40 Finnish patients with the C9ORF72 expansion (29 FTLD, 10 ALS and 1 FTLD-ALS) using ELISA. RESULTS: A decreased Aß1-42 level was found in 25% of cases, while there were only single cases with changes in the t-Tau or phospho-tau level. The patients with abnormal biomarkers fulfilled the clinical criteria of the behavioral variant frontotemporal dementia and expressed no clinical signs of AD. CONCLUSIONS: In clinical diagnostics, a decreased CSF Aß1-42 level does not exclude the C9ORF72 expansion associated with FTLD.

GRN variant rs5848 reduces plasma and brain levels of granulin in Alzheimer's disease patients.

Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer's disease (AD). Here, we report that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Similarly, the mRNA levels of granulin were decreased with respect to A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Our findings suggest that the A allele of rs5848 is functionally relevant by reducing the expression of granulin.