gene frameshift mutations in Alzheimer's disease.

Background: The pathogenic missense mutations of the gelsolin () gene lead to familial amyloidosis of the Finnish type (FAF); however, our previous study identified frameshift mutations existed in patients with Alzheimer's disease (AD). The genotype-phenotype heterogeneity and the role of frameshift mutations in patients with AD are unclear.

Method: In total, 1192 patients with AD and 1403 controls were screened through whole genome sequencing, and 884 patients with AD were enrolled for validation. Effects of mutations were evaluated in vitro. GSN, Aβ42, Aβ40 and Aβ42/40 were detected in both plasma and cerebrospinal fluid (CSF).

Results: Six patients with AD with P3fs and K346fs mutations (0.50%, 6/1192) were identified, who were diagnosed with AD but not FAF. In addition, 13 patients with AD with frameshift mutations were found in the validation cohort (1.47%, 13/884). Further in vitro experiments showed that both K346fs and P3fs mutations led to the loss of function in inhibiting Aβ-induced toxicity. Moreover, a higher level of plasma (p=0.001) and CSF (p=0.005) GSN was observed in AD cases than controls, and a positive correlation was found between the CSF GSN and CSF Aβ42 (r=0.289, p=0.009). Besides, the GSN level was initially increasing and then decreasing with the disease course and cognitive decline.

Conclusions: frameshift mutations may be associated with AD. An increase in plasma GSN is probably a compensatory reaction in AD, which is a potential biomarker for early AD.