Exome sequencing in dementia with Lewy bodies

Abstract

Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.

Figure 1

Clinical and pathological characteristics of the 91 dementia with Lewy body (DLB) cases. Top left: frequency of each pathological category (BS, brain stem; L, limbic; N, neocortical; UC, unclassified). Top right: BRAAK neurofibrillary tangle stage of patients (UC, unclassified). Bottom: table of the clinical and pathological data for all the 91 cases of DLB. Data are mean (s.d.). Motor features were defined by documented evidence of a Parkinsonian movement disorder by an assessing clinician.

Figure 2

Kaplan–Meier survival curves for DLB patients by APOE allele. Kaplan–Meier survival curves for DLB patients by APOE allele carrying at least one APOE ɛ4 allele (n=43, blue line), compared with non-APOE ɛ4 carriers (n=39, green line). Despite there being no significant difference in the age of onset of the DLB (see Results), APOE ɛ4 carriers (a) lived for a shorter period of time following diagnosis (P=0.036, log rank, Mantel–Cox test), and thus (b) died at a younger age (P=0.005, log rank, Mantel–Cox test) that non-APOE ɛ4 carriers. DLB, dementia with Lewy body.