Christine Van Broeckhoven

A Major Genetic Factor at Chromosome 9p Implicated in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD)

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative diseases for which effective therapies aiming at delaying, halting or preventing the disease are lacking. ALS is the most common motor neuron disorder (Rowland & Shneider, 2001) and FTLD has a prevalence close to that of Alzheimer disease in the population below age 65 years (Rosso et al., 2003). They are considered as both extremes of a spectrum of clinically and pathologically overlapping disorders (Lillo & Hodges, 2009). In addition, there is emerging evidence that FTLD and ALS also share common genetic aetiologies, suggesting that overlapping disease mechanisms are involved in both diseases. Clinically, ALS patients show reduced control of voluntary muscle movement expressed in increased muscle weakness, disturbances of speech, swallowing or breathing, as a result of progressive upper and lower motor neuron degeneration in motor cortex, brainstem and spinal cord, and up to 50% of ALS patients shows mild disturbances in executive functions while a minority also develop overt FTLD (Lomen-Hoerth et al., 2003; Ringholz et al., 2005). FTLD symptoms include behavioural, personality and language disturbances, and also cognitive dysfunctions, due to affected frontal and temporal cortical neurons in the brain. FTLD patients may additionally present with typical clinical signs of ALS in a later stage of the disease (Neary et al., 1998). Pathologically, although in different neuronal cells, TAR DNA-binding protein-43 (TDP-43) is a major constituent of neuronal deposits in both ALS and TDP-43 positive FTLD (FTLD-TDP), the most common pathological FTLD subtype (Arai et al., 2006; Neumann et al., 2006). Five to 10% of ALS patients and up to 50% of FTLD patients has a positive familial history of disease with a Mendelian mode of inheritance indicating a significant contribution of genetic factors in disease aetiology. Although the exact biochemical pathways involved in ALS or FTLD are still unknown, several molecular components were identified in the last twenty years through molecular genetic studies in familial and sporadic patients, which are most likely part of a complex network of cellular mechanisms. Since these genes explain only a minority of patients, further unraveling the

Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease

Systematic epistasis analyses in multifactorial disorders are an important step to better characterize complex genetic risk structures. We conducted a hypothesis-free sex-stratified genome-wide screening for epistasis contributing to Alzheimers disease (AD) susceptibility. We identified a statistical epistasis signal between the single nucleotide polymorphisms rs3733980 and rs7175766 that was associated with AD in males (genome-wide significant pBonferroni-corrected=0.0165). This signal pointed toward the genes WW and C2 domain containing 1, aka KIBRA; 5q34 and TLN2 (talin 2; 15q22.2). Gene-based meta-analysis in 3 independent consortium data sets confirmed the identified interaction: the most significant (pmeta-Bonferroni-corrected=9.02*10-3) was for the single nucleotide polymorphism pair rs1477307 and rs4077746. In functional studies, WW and C2 domain containing 1, aka KIBRA and TLN2 coexpressed in the temporal cortex brain tissue of AD subjects (β=0.17, 95% CI 0.04 to 0.30, p=0.01); modulated Tau toxicity in Drosophila eye experiments; colocalized in brain tissue cells, N2a neuroblastoma, and HeLa cell lines; and coimmunoprecipitated both in brain tissue and HEK293xa0cells. Our finding points toward new AD-related pathways and provides clues toward novel medical targets for the cure of AD.

APOE \epsilon 4 and Alzheimer's disease : positive association in a Colombian clinical series and review of the Latin-American studies

OBJECTIVEnAs the strength of the association between the APOE epsilon4 allele and Alzheimers disease (AD) varies across ethnic groups, we studied if there was such an association in Colombian patients.nnnMETHODnWe performed apolipoprotein E (APOE) genotyping in a clinical sample of 83 unrelated AD patients, predominantly late-onset (>65 yrs) including familial ( n =30) and sporadic AD cases (n= 53) diagnosed according to NINCDS-ADRDA criteria and assessed by a multi-disciplinary team. Control subjects (n = 44) had no significant cognitive impairment by medical interview and neuro-psychological testing.nnnRESULTSnWe found a high association (OR= 5.1 95%CI 1.9 -13.6) between APOE epsilon4 and AD, in this series with predominantly late-onset cases with familial aggregation in 24 cases (28.9%). A significant negative association was found between epsilon2 and AD (OR= 0.2 95% CI 0.05-0.75).nnnCONCLUSIONnFurther population-based surveys in Colombia are warranted to precise a possible dose effect of APOE epsilon4.