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Background Genetic associations with Alzheimer’s disease (AD) age at onset (AAO) have revealed genetic variants with the potential for therapeutic application. Such studies in late onset AD are limited by population heterogeneity and co-morbidities associated with aging. Studies to date in ADAD (autosomal dominant AD) have been limited by their small sample size. The large Colombian kindred presented here provides a unique opportunity to discover AAO genetic associations. Methods A genetic association study was conducted for AAO in 344 individuals with the PSEN1 E280A mutation via array imputation and whole genome sequencing in a subset of 80 individuals. Scrambled age conditions were used as a control, and replication was assessed using three studies on AD age of onset, age of onset survival, and meta-analysis. Results The proportion of variance explained (+/-95% CI) was 56% (+/-15%). 29 loci reached genome-wide significance, of which 23 had a GWAS hit from the NHGRI-EBI catalog within 500 kb relevant to neurodegeneration. Hits included a new variant in the CLU locus, rs35980966, (which replicated), a variant in a locus on a separate chromosome previously associated with plasma clusterin (rs138295139), and a missense variant in SORBS3 (rs34059820). Former GWAS index variants at the CLU locus also replicated in this cohort (rs4236673, rs9331896). APOE e4 (rs429358) and APOE e2 (rs7412)-associated variants exhibited modest (less than 3 years) associations with earlier and later age of dementia onset, respectively. Other nominal associations included coding variants in IL34 (rs4985556), TSPAN10 (rs6565617, rs7210026), STIM2 (rs1457401458), HTT (rs1473464204), and KCNT1 (rs557219607). Interpretation A large proportion of the variability in AAO was explained by genetic variation at numerous loci. The unique demography of this population as a tri-continental admixture that passed through a bottleneck about 500 years ago might predict that drift would uncover rare variants with a large effect size on AAO. Indeed, candidates for large contributions from rare alleles were observed. Common variation, presumably ancestral to the bottleneck, was also associated with AAO. The detection of these effects in the presence of a strong mutation for ADAD reinforce the potentially impactful role of the identified variants.

Working alongside physicists made me a better science communicator, says Ken Kosik, and helped me to clarify knowledge gaps in my own field. Working alongside physicists made me a better science communicator, says Ken Kosik, and helped me to clarify knowledge gaps in my own field.

The literature on GWAS (genome-wide association studies) data suggests that very large sample sizes (for example, 50,000 cases and 50,000 controls) may be required to detect significant associations of genomic regions for complex disorders such as Alzheimer's disease (AD). Because of the challenges of obtaining such large cohorts, we describe here a novel sequential strategy that combines pooling of DNA and bootstrapping (pbGWAS) in order to significantly increase the statistical power and exponentially reduce expenses. We applied this method to a very homogeneous sample of patients belonging to a unique and clinically well-characterized multigenerational pedigree with one of the most severe forms of early onset AD, carrying the PSEN1 p.Glu280Ala mutation (often referred to as E280A mutation), which originated as a consequence of a founder effect. In this cohort, we identified novel loci genome-wide significantly associated as modifiers of the age of onset of AD (CD44, rs187116, P=1.29 × 10−12; NPHP1, rs10173717, P=1.74 × 10−12; CADPS2, rs3757536, P=1.54 × 10−10; GREM2, rs12129547, P=1.69 × 10−13, among others) as well as other loci known to be associated with AD. Regions identified by pbGWAS were confirmed by subsequent individual genotyping. The pbGWAS methodology and the genes it targeted could provide important insights in determining the genetic causes of AD and other complex conditions.

The C-terminus Hsp70 interacting protein (CHIP) has dual function as both co-chaperone and ubiquitin ligase. CHIP is increasingly implicated in the biology of polyglutamine expansion disorders, Parkinson's disease and tau protein in Alzheimer's disease. We investigated the involvement of CHIP in the metabolism of the beta-amyloid precursor protein and its derivative beta-amyloid (Abeta). Using immunoprecipitation, fluorescence localization and crosslinking methods, endogenous CHIP and betaAPP interact in brain and cultured skeletal myotubes as well as when they are expressed in stable HEK cell lines. Their interaction is confined to Golgi and ER compartments. In the presence of the proteasome inhibitor with MG132, endogenous and expressed betaAPP levels are significantly increased and accordingly, the interaction with CHIP enhanced. Concurrently, levels of Hsp70 were most consistently induced by proteasome inhibition among the various heat shock proteins (HSPs) tested. Thus, complexes of CHIP, Hsp70 and holo-betaAPP (as well as C-terminal fragments) were stabilized by the action of MG132. Moreover, CHIP itself is shown to both increase cellular holo-betaAPP levels and protect it from oxidative stress and degradation. Interestingly, CHIP also promotes the association of ubiquitin with betaAPP, implying that a smaller pool of betaAPP is destined for proteasomal processing. In neuronal cultures, CHIP and Hsp70/90 expression reduce steady-state cellular Abeta levels and hasten its degradation in pulse-chase experiments. The functional significance of CHIP and HSP interactions, especially with Hsp70, was tested using siRNA and in neuronal cells where protection from Abeta-induced toxicity is shown. We conclude that CHIP, as a bimolecular switch, interacts with HSP to stabilize normal holo-betaAPP on the one hand while also assisting in the ubiquitination of a subpopulation of betaAPP molecules that are destined for proteasome degradation. CHIP also hastens the clearance of Abeta in a manner consistent with its known neuroprotective properties.

© 2015 Macmillan Publishers Limited We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer’s disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0±5.2 years compared with 41.1±7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.Molecular Psychiatry advance online publication, 1 September 2015; doi:10.1038/mp.2015.131.

Genetic linkage studies place a gene causing early onset familial Alzheimer's disease (FAD) on chromosome 14q24.3 (refs 1–4). Five mutations within the S182 (Presenilin 1: PS–1) gene, which maps to this region, have recently been reported in several early onset FAD kindreds5. We have localized the PS-1 gene to a 75 kb region and present the structure of this gene, evidence for alternative splicing and describe six novel mutations in early onset FAD pedigrees all of which alter residues conserved in the STM26 (Presenilin 2: PS-2) gene.