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J Alzheimers Dis. 2019;67(1):243-256. doi: 10.3233/JAD-180482.

Next Generation Sequencing Analysis in Early Onset Dementia Patients.

Author information

Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Department of Health Sciences, University of Genova and Division of Medical Genetics, Galliera Hospital, Genova, Italy.
Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Institute for Genomic Statistics and Bioinformatics, Bonn, Germany.
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Laboratory Alzheimer's Neuroimaging and Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
A. Nocivelli' Institute for Molecular Medicine Spedali Civili and University of Brescia, Brescia, Italy.
Fondazione Case Serena, Pontoglio, Brescia, Italy.
Fondazione Europea Ricerca Biomedica, Centro di Eccellenza Alzheimer, Ospedale Briolini Gazzaniga, Bergamo, Italy.
Laboratory of Neuroimaging of Aging (LANVIE), University Hospitals and University of Geneva, Geneva, Switzerland; Department of Internal Medicine, University Hospitals and University of Geneva, Geneva, Switzerland.



Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia.


To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE) and prion protein (PRNP) genes were also assessed.


We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping.


We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN, VCP, MAPT, FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP), and one did not show any risk mutation/variant. Overall, 69% (n = 9) of our early onset Alzheimer's disease (EAOD) patients, compared with 34% (n = 13) of sporadic late onset Alzheimer's disease (LOAD) patients and 27% (n = 73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations.


This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD.


Alzheimer’s disease; Lewy body dementia; common variants; early onset dementia; frontotemporal dementia; next generation sequencing; rare mutations

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