OBJECTIVE: To characterize the clinical and molecular effect of mutations in the 
sortilin-related receptor (SORL1) gene.
METHODS: We performed whole-exome sequencing in early-onset Alzheimer disease 
(EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional 
studies of select variants. The phenotypic consequences associated with SORL1 
mutations were characterized based on clinical reviews of medical records. 
Functional studies were completed to evaluate β-amyloid (Aβ) production and 
amyloid precursor protein (APP) trafficking associated with SORL1 mutations.
RESULTS: SORL1 alterations were present in 2 EOAD families. In one, a SORL1 
T588I change was identified in 4 individuals with AD, 2 of whom had parkinsonian 
features. In the second, an SORL1 T2134 alteration was found in 3 of 4 AD cases, 
one of whom had postmortem Lewy bodies. Among LOAD cases, 4 individuals with 
either SORL1 A528T or T947M alterations had parkinsonian features. Functionally, 
the variants weaken the interaction of the SORL1 protein with full-length APP, 
altering levels of Aβ and interfering with APP trafficking.
CONCLUSIONS: The findings from this study support an important role for SORL1 
mutations in AD pathogenesis by way of altering Aβ levels and interfering with 
APP trafficking. In addition, the presence of parkinsonian features among select 
individuals with AD and SORL1 mutations merits further investigation.