No abstract

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.

Key Points Question How does lack of awareness (anosognosia) of memory impairment evolve in the Alzheimer disease (AD) trajectory? Findings In this cohort study of 2379 members of the Alzheimer’s Prevention Initiative Registry with a presenilin ( PSEN1 E280A) variant for autosomal dominant AD, awareness of memory function was increased in carriers and noncarriers approximately 14 years before their estimated median age of dementia onset (49 years). In variant carriers only, awareness of memory function was reduced in the predementia stages, reaching anosognosia 6 years before dementia onset. Meaning The findings suggest that alteration of awareness of memory function in predementia stages may inform practitioners about AD progression.

Introduction Females may have greater susceptibility to Alzheimer's disease (AD)‐pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively‐unimpaired Presenilin‐1 (PSEN1) E280A mutation carriers and non‐carriers. Methods We analyzed baseline data from 167 mutation carriers and 75 non‐carriers (ages 30 to 53) from the Alzheimer's Prevention Initiative Autosomal Dominant AD Trial, including florbetapir‐ and fludeoxyglucose‐PET, MRI based hippocampal volume and cognitive testing. Results Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory. Discussion Our findings suggest that, among cognitively‐unimpaired individuals at genetic risk for autosomal‐dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex‐specific differences in autosomal‐dominant AD is key to elucidating mechanisms of AD risk and resilience.