RESUMEN
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.
Asunto(s)
Proteínas del Tejido Nervioso/genética , Proteinopatías TDP-43/genética , Anciano , Expansión de las Repeticiones de ADN , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Femenino , Lóbulo Frontal/metabolismo , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/inmunología , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Antígenos HLA-DQ/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular , Mutación con Pérdida de Función , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/fisiología , Canales de Potasio/genética , Progranulinas/genética , Progranulinas/fisiología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas/genética , Proteínas/fisiología , ARN Mensajero/biosíntesis , Factores de Riesgo , Análisis de Secuencia de ARN , Sociedades Científicas , Proteinopatías TDP-43/inmunología , Población Blanca/genéticaRESUMEN
BACKGROUND: It is unclear whether self- or informant-based subjective cognition better distinguishes emotional factors from early-stage Alzheimer's disease (AD). METHODS: Healthy members (n = 447) of the Arizona apolipoprotein E (APOE) cohort and their informants completed the self and informant paired Multidimensional Assessment of Neurodegenerative Symptoms questionnaire (MANS). RESULTS: Decline on the MANS was endorsed by 30.6% of members and 26.2% of informants. Self- and informant-based decliners had higher scores of psychological distress and slightly lower cognitive scores than nondecliners. Over the next 6.7 years, 20 developed mild cognitive impairment (MCI). Converters were older at entry than nonconverters (63.8 [7.0] vs 58.8 [7.3] years, P = .003), 85% were APOE ε4 carriers (P < .0001), and they self-endorsed decline earlier than informants (58.9 [39.2] vs 28.0 [40.4] months before MCI; P = .002). CONCLUSIONS: Self- and informant-based subjective decline correlated with greater psychological distress and slightly lower cognitive performance. Those with incident MCI generally self-endorsed decline earlier than informants.
Asunto(s)
Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/psicología , Autoinforme , Estimulación Acústica , Anciano , Apolipoproteínas E/genética , Estudios de Cohortes , Función Ejecutiva , Femenino , Humanos , Trastornos del Lenguaje/etiología , Masculino , Persona de Mediana Edad , Examen Neurológico , Pruebas Neuropsicológicas , Desempeño Psicomotor , Índice de Severidad de la Enfermedad , Percepción Espacial/fisiología , Encuestas y Cuestionarios , Aprendizaje VerbalRESUMEN
APOE is the major known genetic risk factor for late-onset Alzheimer's disease. Though relationships between APOE-encoded apolipoprotein E and ß-amyloid are increasingly well described, mounting evidence supports wide-ranging effects of APOE on the brain. Specifically, APOE appears to affect brain network activity and closely related neuroenergetic functions that might be involved in vulnerability to neurodegenerative pathophysiology. These effects highlight the salience of further investigation into the diverse influences of APOE. Therefore, this article reviews the interplay between APOE and neuroenergetics and proposes areas for further investigation. This research might lead to the identification of novel therapeutic targets for the treatment and/or prevention of Alzheimer's disease.