SORL1mutations in early- and late-onset Alzheimer disease.
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 withSORL1mutations 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 withSORL1mutations.


RESULTS
SORL1alterations 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 forSORL1mutations 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 andSORL1mutations merits further investigation.
John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.
Michael L
ML
Cuccaro
John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.
Regina M
RM
Carney
John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.
Yalun
Y
Zhang
John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.
Christopher
C
Bohm
John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.
Brian W
BW
Kunkle
John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.
Badri N
BN
Vardarajan
John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.
Patrice L
PL
Whitehead
John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.
Holly N
HN
Cukier
John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.
Richard
R
Mayeux
John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.
Peter
P
St George-Hyslop
John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.
Margaret A
MA
Pericak-Vance