Background A rare missense APOE variant (L28P; APOE*4Pittsburgh) has been reported to be a risk factor for Alzheimer’s disease (AD). However, sinceL28P has been observed only among APOE*4 carriers, its independent genetic association is uncertain. In this study, we re‐evaluated this association in a large case‐control sample of 15,762 U.S. Whites aged ≥60 years and investigated its independent effect. Method Samples were derived from three sources: University of Pittsburgh, Alzheimer’s Disease Sequencing Project and the Gingko Evaluation Memory Study. Due to variation in the age distribution between cases and controls in the three studies, each study sample was analyzed separately, and the results then combined by meta‐analysis. To distinguish the independent effect of L28P from APOE*4, we restricted the analysis to subjects with the APOE 3/4 genotype, as L28P has been observed only in the heterozygous state in the APOE*4‐background and 3/4 is the most common genotype containing the APOE*4 allele. Result A total of 80 L28P heterozygotes were observed in the combined case‐control sample, all in those containing only the APOE*4 allele, confirming the complete linkage disequilibrium between the two sites. The age‐ and sex‐adjusted meta‐analysis odds ratio (OR) was 2.87 (95% CI: 1.34 – 6.13; p = 0.0066). There were a total of 4,138 cases and controls with the 3/4 genotype. The age‐ and sex‐adjusted meta‐analysis OR was 1.53 (95% CI: 0.70 – 3.36; p = 0.28). The lack of significance is mainly due to the low power with the ∼4,100 sample size (12% power at α = 0.80), as compared to the required sample size of ∼151,000 to detect an OR of 1.5 at α = 0.80. Conclusion Even with non‐significant p‐value, the OR of 1.53 among 3/4 subjects suggests that the effect of L28P on AD risk is independent of APOE*4. Our genetic finding is reinforced by an earlier experimental finding showing that this mutation leads to significant structural and conformational alterations in ApoE and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress (J Biol Chem 2014; 289:12931). Additional studies in cell‐based systems and animal models will help to delineate its functional significance in the AD etiology.

BackgroundGenome‐wide association studies (GWAS) have identified more than 40 genetic loci associated with Alzheimer’s disease (AD). Although vascular dementia (VaD) is the second most common type of dementia after AD, the genetic contribution to VaD is understudied. We hypothesize that common forms of dementia will share genetic risk factors. We conducted the largest trans‐ancestral GWAS of "all‐cause dementia" (ACD), VaD, and examined the underlying biological mechanismsMethodDonors from 16 population‐based CHARGE cohorts, two national case‐control consortia (ADGC, MEMENTO), and the UKBB contributed 46,533 and 4,078 cases of ACD and VaD, respectively. The overall sample (475,577) included European, African, Asian, and Hispanic ancestry. We conducted ancestry‐specific and trans‐ancestral meta‐analyses using METAL and MR‐MEGA, respectively. We explored the shared genetics of ACD with related disease traits and risk factors. Using a Bayesian approach, the level of polygenicity is explored across dementia and closely related traits, followed by a multi‐trait GWAS including ACD with traits of identical polygenic background. Finally, genome‐wide (GW) signals were functionally prioritized using a TWAS study.ResultFor ACD, we replicated ten known AD loci, including regions near APOE and BIN1. We found novel suggestive loci near SEMA4D, ANO3, AJAP1, HBEGF, and RBFFOX1. These loci were previously associated with energy transport throughout the brain (SEMA4D), neuronal excitability (ANO3), amyloid plaques (RBFOX1), and cerebral small vessel disease (‐cSVD‐, HBEGF). For VaD, one locus near APOE reached GW significance along with 22 suggestive, including SPRY2, FOXA2, AJAP1, and PSMA3, previously associated with hypertension, diabetes, and neuron maintenance. In addition to the genetic overlap with neurodegenerative processes, genetic risk loci for ACD exhibited overlap with vascular risk factors (T2D, blood pressure, lipid levels) and MRI markers of cSVD. Adjusting for SNP effects from traits with similar polygenic backgrounds revealed risk loci implicated in regulating cholesterol metabolism and maintaining neuronal mRNA levelsConclusionWe leveraged data from 19 cohorts and population‐based studies to assess the genetic contribution to ACD and VaD. GW suggestive signals included genes implicated in various brain activities. Bioinformatic parsing of the identified loci pointed to a genetic overlap of ACD with vascular risk factors and MRI markers of cSVD.

BackgroundThe APOE 2/3/4 polymorphism is the greatest risk factor for Alzheimer’s disease (AD). This polymorphism is also associated with variation in plasma ApoE levels and explains about 20‐25% of its genetic variance; while APOE*4 lowers, APOE*2 increases ApoE levels. Lower plasma ApoE levels have also been reported to be a risk factor of future AD and all dementia, independent of the APOE 2/3/4 polymorphism (Ann Neurol 2015;77:301). To our knowledge, no genome‐wide association study (GWAS) has been reported on plasma ApoE levels. This study was aimed to identify novel genetic factors affecting plasma ApoE levels as well as to confirm if baseline plasma ApoE levels predict future AD dementia in an older and longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study.MethodBaseline plasma ApoE levels were measured using an immunoturbidimetric assay in 3,031 older subjects (aged 72 to 96 years; 94.1% White). Genome‐wide genotype was performed on the available 2,737 DNA samples (96% White). Due to the small number in other ethnicities, we only included the 2,852 White subjects (2,412 cognitively normal, 440 with incident AD dementia) for plasma ApoE analysis. GWAS analysis on plasma ApoE levels was performed on 2,580 White subjects where both genotype and ApoE level data were available.ResultAs expected, the risk for AD increased from E2/2 through to E4/4 genotypes (p for trend =1.7E‐10). There was no significant difference in plasma ApoE levels between cognitively normal and AD dementia subjects (p=0.55). GWAS analysis revealed the expected associations of APOE*2 (β= 1.12; p= 3.57E‐79) and APOE*4 (β= ‐0.35; p= 2.21E‐11) with plasma ApoE levels. In addition, we observed 5 novel genome‐wide significant associations on chromosomes 1 (β= 0.921; p= 5.36E‐10), 4 (β= 0.796; p= 4.31E‐08;), 7 (β= 0.722; p= 9.64E‐09), 11 (β= 0.268; p= 2.58E‐08), and 20 (β= 1.379; p=8.25E‐09).ConclusionWe have identified multiple novel associations affecting plasma ApoE levels in addition to the established APOE association. However, we could not replicate the reported association of plasma ApoE levels with future AD, probably because of the older nature of our cohort.

BackgroundAlzheimer’s disease (AD) is an irreversible neurodegenerative brain disease with varying disease progression rates among individuals. This study aims to identify possible underlying genetic variants associated with AD progression using a whole‐genome sequencing approach.MethodWhole‐genome sequencing at 30x coverage was performed on 416 late‐onset AD patients (mean baseline age ± sd) = 76.47 ± 6.10) having at least two Mini‐Mental State Examination (MMSE) scores ranged from 0 to 30. Since the study subjects had varying time points of visit and MMSE records, we defined AD progression phenotypes in four ways, including differentially specified progression rates and time to pre‐defined events in genome‐wide association analyses. Genetic association analyses between single‐nucleotide variants (SNVs) and phenotypes were adjusted for baseline age, sex, year of education, baseline MMSE measures, and the first four principal components.ResultSix novel genome‐wide statistically significant associations (p<5E‐08) were observed in our study. Two associations were detected with the same SNVs on chromosomes 2 (SLC4A10/rs13036052) and 7 (chr7:58053009[Hg38] near ZNF716) with overall progression rates. One genetic variant on chromosome 6 (chr6:3127309[Hg38] near BPHL) was associated with annual progression rate. In addition, three associations were seen on chromosomes 1 (rs199560872), 14 (chr14:9600158[Hg38] near TUNAR), and 18 (rs34718969) with time‐to‐event phenotypes. All top variants were present either in introns or intergenic regions.ConclusionOur initial whole‐genome sequencing analyses have identified several independent associations with AD progression, which need to be confirmed in larger sequencing samples.

Background Cognition is a highly complex polygenic trait. A limited number of studies have explored the genetic basis of cognitive decline in aging populations using cognitive domain specific measures. Method To identify genetic markers for cognitive decline, we conducted a genome‐wide association meta‐analysis and gene‐based tests on five different cognitive domains (attention, language, executive function, visuospatial abilities, memory) and global cognition on 3,068 older individuals (≥65 years) of European ancestry derived from three prospective cohorts: Gingko Evaluation Memory Study (GEMS), Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) and Monongahela Valley Independent Elders Survey (MoVIES). All subjects completed a comprehensive neuropsychological battery of tests covering the examined domains. A linear mixed effects model was used to estimate the longitudinal decline in cognitive scores after adjusting for sex, baseline age and education. Global cognitive decline was defined as a decline in average performance in neuropsychological tests across the five domains. Result Genome‐wide significant association of APOE*4 was observed with decline in the memory domain (p= 8.93E‐09) and global cognitive function (p= 2.69E‐08).We identified a novel locus for decline in the attention domain on chromosome 9 in an intergenic region between RASEF / FRMD3 (p = 3.17E‐08). Gene‐based analysis identified TMPRSS11D as the top gene for decline in global cognition (Bonferroni corrected p= 2.48E‐06). TMPRSS11D plays a role in host‐defense system and recent studies have shown that it activates spike protein of SARS‐CoV‐2 and facilitates viral entry to cell ( Viruses 2021;13:384; J Biol Chem 2021; 296:100135). Conclusion We have identified a novel locus for longitudinal decline in the attention domain, replicated the association of APOE*4 with the global and memory domains, and potentially implicated the role of TMPRS11D in cognitive decline through gene‐based analysis. The association of TMPRSS11D with cognitive decline might help to explain cognitive impairment observed in some patients after COVID‐19 infection ( Br J Anaesth 2021; 25:e54; JAMA Netw Open 2021; 4(10):e2130645 ). While functional studies might help to understand the underlying molecular mechanism of the associated loci, cognitive decline studies with larger samples are essential to establish these findings.