Background: Cognitive decline is a major characteristic of aging and neurogenerative diseases such as Alzheimer's disease (AD), Parkinson's disease and other dementias. With worldwide increases in life-expectancy and elderly population, cognitive decline is a major public health concern. Understanding genetic contributors to age-related decline in cognition may facilitate identification of the molecular mechanisms of cognitive decline. Method: To discover genetic influences on cognitive decline, we conducted genomewide meta-analyses on longitudinal performance of five cognitive domains (attention, language, executive function, visuospatial, memory) and the global domain, constructed from five domains, using 3068 individuals aged 65 and above across three longitudinal cohorts: the Gingko biloba Memory Evaluation Study (GEMS), Monongahela-Youghiogheny Healthy Aging Team (MYHAT) and Monongahela Valley Independent Elders Survey (MoVIES). A linear mixed effect model was used to find individual specific slopes by adjusting for baseline age, years of education and sex. Results: APOE*4 (rs429358), a well-known risk factor for AD, demonstrated a genomewide significant association with the memory (P= 1.37E-09) and global (P= 9.26E-10) domains. Previous studies have also reported APOE*4 's association with memory decline. In addition to APOE*4, multiple suggestive associations of gene loci with cognition were also observed for each domain as follows: attention on chromosome 9 near RASEF/FRMD3 (P = 8.29E-08), memory on chromosome 6 near ID4/MBOAT1(P = 1.27E-07), visuospatial function on chromosome 11 near PAMR (P = 2.74E-07), language on chromosome 9 near PSAT1 (P = 4.08E-07), executive function on chromosome 4 near SNHG27 (P = 6.49E-07), and global function on chromosome 4 near LINC00290 (P=8.80E-07). Conclusion:Our result suggests that in addition to APOE, multiple genetic loci affect cognitive decline in older individuals. These findings may offer new insights into understanding the genetic architecture of cognitive decline.

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.

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.

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INTRODUCTIONCognitive abilities have substantial heritability throughout life, as shown by twin‐ and population‐based studies. However, there is limited understanding of the genetic factors related to cognitive decline in aging across neurocognitive domains.METHODSWe conducted a meta‐analysis on 3045 individuals aged ≥65, derived from three population‐based cohorts, to identify genetic variants associated with the decline of five neurocognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive decline. We also conducted gene‐based and functional bioinformatics analyses.RESULTSApolipoprotein E (APOE)4 was significantly associated with decline of memory (p = 5.58E‐09) and global cognitive function (p = 1.84E‐08). We identified a novel association with attention decline on chromosome 9, rs6559700 (p = 2.69E‐08), near RASEF. Gene‐based analysis also identified a novel gene, TMPRSS11D, involved in the activation of SARS‐CoV‐2, to be associated with the decline in global cognitive function (p = 4.28E‐07).DISCUSSIONDomain‐specific genetic studies can aid in the identification of novel genes and pathways associated with decline across neurocognitive domains.Highlights rs6559700 was associated with decline of attention. APOE4 was associated with decline of memory and global cognitive decline. TMPRSS11D, a gene involved in the activation of SARS‐CoV‐2, was implicated in global cognitive decline. Cognitive domain abilities had both unique and shared molecular pathways across the domains.