Alzheimer’s disease (AD) is a complex neurodegenerative disorder influenced by various factors, including genetic and exposure-related. Certain combinations of these factors may promote AD more substantially than others. APOE4 is the strongest genetic risk factor for AD. Traffic-related air pollution (TRAP) and infections are important exposure-related AD risk factors. Here we investigated how the interplay between a history of infections and chronically high exposure to TRAP (highTRAP) impacts the subsequent risk of AD and other dementias (AD+) in carriers and non-carriers of APOE4 in UK Biobank (UKB) participants aged 60–75 years. HighTRAP was approximated by the proximity (50 meters or less) of a participant’s primary residence to a major road. Chi-square, Wilson score interval, Wald interval, Wald risk ratio, Welch tests, and regression were used to examine statistical significance. We found that UKB participants with a history of various infections (by ICD-10 codes), but without highTRAP, had a 54% increase in AD+ risk. HighTRAP alone did not significantly influence AD+ risk. Individuals with both a history of infections and highTRAP had a 164% higher risk of AD+ compared to those without either factor. That risk was much higher (349%) in non-carriers of APOE4 but became non-significant in APOE4 carriers. We conclude that avoiding high exposure to TRAP may significantly reduce the risk of AD in non-carriers of APOE4 with a history of infections but not in carriers. One potential explanation could be that APOE4 is a stronger AD risk factor, whose AD-promoting effects may outweigh those of other risk factors.

Introduction:Alzheimer's disease (AD) is a complex disorder influenced by many factors. The rs6859 polymorphism in the NECTIN2 gene has been consistently linked to AD risk. The NECTIN2 is involved in vulnerability to infections, which could contribute to neurodegeneration. We hypothesized that hippocampal volume (HV), a biomarker of neurodegeneration, may mediate the connection between the NECTIN2 polymorphism and AD. Methods:The analysis was conducted using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Linear mixed models were used to evaluate the association between SNP rs6859 and normalized hippocampal volumes over time. Multivariable linear and logistic regression models were used to estimate the associations between SNP rs6859 and median hippocampal volumes, and between SNP rs6859 and median hippocampal volumes and AD, adjusting for potential confounders. Causal mediation analyses (CMA) were performed using previously fitted logistic and linear models to estimate the mediating role of hippocampal volumes in the association between rs6859 and AD. Results:We found that smaller HV significantly mediates the association between rs6859 in NECTIN2 and AD risk. Carrying the rs6859 risk allele (A) was associated with lower right HV (β = -0.16, p = 0.03), left HV (β = -0.14, p = 0.04), and total HV (β = -0.15, p = 0.04) in linear mixed models. These associations were significant only in males. The mediated effects for the right and left HV were 42.75 and 49.76%, respectively. Discussion:Our results indicate that hippocampal atrophy may mediate the association between NECTIN2 polymorphism and AD risk, although the borderline significance of these associations warrants confirmation in other populations.

Erythropoiesis is the most replication-intensive process in the body. Its lifelong replicative demands may erode hematopoietic cells' replicative capacity, leading to a decline in erythrocyte count (EC) in older adults and limiting their lifespan. We examined the relationship between EC and mortality among 1,620 participants aged ≥70 years in the Long Life Family Study and found that lower EC further augmented the exponential, age-dependent rise in mortality. We identified an EC threshold (ECT) (3.8×1012/L) below which mortality was amplified (p=9.3×10-6). As EC declined with age (p=8.2×10-18), it fell below this threshold in many participants, sharply increasing their mortality risk. This mortality-based ECT emerged from modeling, independent of the World Health Organization anemia definition, which is based on statistical thresholds (5th centiles) of hemoglobin distribution in populations ≤ 65 years. Thus, declining EC may be one of the biological factors imposing a natural lifespan limit on many older adults.

Weight loss has been associated with Alzheimer’s Disease (AD), suggesting the possibility that overweight may be protective against AD. Mendelian Randomization (MR) is a common method of revealing causal relationships in observational studies. Our recent MR analysis using the Health and Retirement Study (HRS) data found that overweight has a causal protective effect on late-onset-AD. Here we expand this strategy to two other cohorts, the Long Life Family Study (LLFS) and Framingham Heart Study (FHS), to examine causal role of overweight in AD in these data. For this MR study, we created two binary variables: ‘exposure’ (group-1 “overweight” BMI 25-30 vs. group-0 “normal weight” BMI 18.5-25, at ages 65-75) and ‘outcome’ (group-1 “no AD” vs. group-0 “AD onset after age 75”), using FHS original cohort (N = 610) and LLFS (N = 1979) data on individuals who survived age 75. To identify instrumental variables ( IVs ), we implemented a recently developed new strategy. We selected SNPs in eight obesity-related genes (ADIPOQ, FTO, LEP, LEPR, INSIG2, MC4R, PCSK1, PPARG) and paired them with each other, then summed their minor alleles to create new ‘composite’ SNPs as candidate IVs . This strategy improved the MR effectiveness due to the exponentially increased number of to-be-tested IVs . R-package MendelianRandomization was used. Analyses were stratified by sex. The relatedness of samples was addressed by using mixed model to calculate statistics. Causal effect was evaluated using weighted median and Inverse-Variance Weighted (IVW). MR-Egger regression was employed to address potential pleiotropy. Being overweight at ages 65-75 had significant causal protective effect on AD onset after age 75 in LLFS White females (N_IV = 61, weighted median causal estimate = 1.15, p-value = 1.44E-4; IVW causal estimate = 0.57, p-value = 1.33E-2) and FHS White males (N_IV = 12, weighted median causal estimate = 1.22, p-value = 2.71E-2; IVW causal estimate = 0.90, p-value = 1.33E-2). MR-Egger regression intercepts in both cases were not distinct from the origin. Our MR study found causal protective effect of overweight on late-onset-AD in White participants of FHS and LLFS, in line with previous findings in HRS data. To confirm these findings in other race/ethnic groups, MR study of datasets with larger numbers of individuals of diverse backgrounds is warranted.

Background:Impaired brain glucose metabolism is a preclinical feature of neurodegenerative diseases such as Alzheimer's disease (AD). Infections may promote AD-related pathology. Therefore, we investigated the interplay between infections and APOE4, a strong genetic risk factor for AD. Methods:We analyzed data on 1,509 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database using multivariate linear regression models. The outcomes were rank-normalized hypometabolic convergence index (HCI), statistical regions of interest (SROI) for AD, and mild cognitive impairment (MCI). Marginal mean estimates for infections, stratified by APOE4 carrier status, were then computed. Results:Prior infections were associated with greater HCI [β=0.15, 95% CI: 0.03, 0.27, p=0.01]. The combined effects of infections and APOE4 carriers on HCI levels were significantly greater than either variable alone. Among APOE4 carriers, the estimated marginal mean was 0.62, rising to 0.77, with infections (p<0.001), indicating an interaction effect. Carriers with multiple infections showed greater hypometabolism (higher HCI), with an estimate of 0.44 (p=0.01) compared to 0.11 (p=0.08) for those with a single infection, revealing a dose-response relationship. The estimates for the association of infections with SROI AD and SROI MCI were β=-0.01 (p=0.02) and β=-0.01 (p=0.04), respectively. Conclusion:Our findings suggest that infections and APOE4 jointly contribute to brain glucose hypometabolism and AD pathology, supporting a "multi-hit" mechanism in AD development.

A growing body of research suggests a connection between Alzheimer’s disease (AD) and prior infections, although the mechanisms are not well understood. We recently reported a significant association between a history of adult infections and smaller brain hippocampal volume (HV), a major biomarker of neurodegeneration, in female participants of the UK Biobank (UKB). Here we further investigate this connection, taking into account the rs6859 polymorphism in the NECTIN2 gene, an established genetic risk factor for AD that is also involved in vulnerability to infections. We estimated the associations between adult history of infections and HV assessed later in life, at ages 65-80 years, in the presence and absence of the AD risk variant (A) of rs6859, using the UKB subsample with respective information (N=11,765; 48% women). Infectious disease diagnoses were based on ICD-10 codes. The left/right HV was measured by magnetic resonance imaging (MRI) in cubic millimeters (mm 3 ) and normalized. Analysis of variance (ANOVA), Tukey’s test, Welch test, and regression were used to examine statistical significance. Prior infections and carrying the AD risk variant rs6859 (A) were synergistically associated with a significant reduction in the left HV by ∼2.1% (p-value=0.03) and in the right HV by ∼2.2% (p-value=0.01) in women aged 65-80 years. Results for men did not reach statistical significance. Results of our study suggest that prior infections and rs6859 in the NECTIN2 gene synergistically contribute to neurodegeneration in older women. A potential explanation of this effect could be that carrying the rs6859 (A) may aggravate AD-related brain pathology triggered by infections because this genetic risk factor for AD also increases the brain’s vulnerability to infections. This hypothesis needs confirmation in biomedical research. The observed sex difference may reflect a higher vulnerability of the female brain to infection-related factors due to hormonal or other differences between males and females, which deserves further investigation.

Infections may contribute to neurodegeneration, including Alzheimer's disease (AD). Polymorphism in the NECTIN2 gene has been linked to both AD and vulnerability to infections. We hypothesized that neurodegeneration may mediate the connection between this polymorphism and AD. To test this hypothesis, we conducted a causal mediation analysis (CMA) using the Alzheimer's Disease Neuroimaging Initiative (ADNI) data. We found that smaller hippocampal volume (HV), a biomarker of neurodegeneration, significantly mediated the association between rs6859 in NECTIN2 and AD risk. For the right HV, the mediated effect was 42.75%, while for the left HV, it was 49.76%. In linear mixed models (LMM), carrying the rs6859 risk alleles (A) was associated with a reduction in right HV (β = -0.16, p = 0.03), left HV (β = -0.14, p = 0.04), and total HV (β = -0.15, p = 0.04). In this data, the rs6859 (A) was a risk factor for AD only in men. Our results suggest that hippocampal atrophy may substantially mediate the association between NECTIN2 polymorphism and AD risk.

Results of recent analyses indicate that axon demyelination may play an important role in AD pathology. The MBP gene encodes a myelin basic protein involved in axon myelination in the nervous system including the central nervous system. Polymorphisms in this gene, as well as variations in expression, have been associated with multiple sclerosis (MS). Evidence of the involvement of this gene in Alzheimer’s disease (AD) is emerging. The EIF2B5 gene codes for a subunit of eukaryotic translation initiation factor 2B (eIF2B), a master regulator of translation. Recent studies connected EIF2B5 and its polymorphisms with various health disorders including MS and AD, as well as hypomyelination. The latter was also associated with reduced MBP. Considering this, and that both MBP and EIF2B5 have been associated with AD, we hypothesized that the interplay between these two genes might also be associated with AD. To test this hypothesis, we analyzed data on genotyped individuals (males and females combined) from the Health and Retirement Study using a logistic regression model with the interaction term. Education, smoking status, sex, and the first five principal components were included as observed covariates. The binary AD trait was defined as “0” if AD onset was observed at any age, and as “1” if a person survived to age 85 and did not get AD during their life. Linkage disequilibrium (LD) test and SNP-clumping procedures were used to reduce the number of tests in SNPxSNP interaction analysis and make Bonferroni correction less conservative. We found a statistically significant positive association of the interaction between intronic rs12959006 in MBP gene and missense variant rs843358 in the EIF2B5 gene with AD. The rs12959006 was associated with MS and rs843358 in survival from cancer in the literature. Several other SNPs that are in high LD with the SNPs found in this study have also been separately associated with health traits in the literature. The results of this study support the hypothesis that the interaction between MBP and EIF2B5 variants is significantly associated with AD. Our finding implies that regulation of translation and axon demyelination jointly contribute to AD.

Using whole-genome sequencing (WGS) might offer insights into rare genetic variants associated with healthy aging and extreme longevity (EL), potentially pointing to useful therapeutic targets. In this study, we conducted a genome-wide association study using WGS data from the Long Life Family Study and identified a novel longevity-associated variant rs6543176 in the SLC9A2 gene. This SNP also showed a significant association with reduced hypertension risk and an increased, though not statistically significant, cancer risk. The association with cancer risk was replicated in the UK Biobank and FinnGen. Metabolomic analyses linked the rs6543176 longevity allele to higher serine levels, potentially associated with delayed mortality. Our findings warrant further investigation of SLC9A2’s role in both longevity and cancer susceptibility, and they highlight the need for careful evaluation in developing anti-aging therapies based on EL-associated alleles.

Studying the relationships between longitudinal changes in omics variables and event risks requires specific methodologies for joint analyses of longitudinal and time-to-event outcomes. We applied two such approaches (joint models [JM], stochastic process models [SPM]) to longitudinal metabolomics data from the Long Life Family Study, focusing on the understudied associations of longitudinal changes in lysophosphatidylcholines (LPCs) with mortality and aging-related outcomes. We analyzed 23 LPC species, with 5,066 measurements of each in 3,462 participants, 1,245 of whom died during follow-up. JM analyses found that higher levels of the majority of LPC species were associated with lower mortality risks, with the largest magnitude observed for LPC 15:0/0:0 (hazard ratio: 0.71, 95% CI (0.64, 0.79)). SPM applications to LPC 15:0/0:0 revealed that the JM association reflects underlying aging-related processes: a decline in robustness to deviations from optimal LPC levels, higher equilibrium LPC levels in females, and the opposite age-related changes in the equilibrium and optimal LPC levels (declining and increasing, respectively), which lead to increased mortality risks with age. Our results support LPCs as biomarkers of aging and related decline in biological robustness, and call for further exploration of factors underlying age-related changes in LPC in relation to mortality and diseases.

IntroductionEmerging evidence suggests a connection between vulnerability to infections and Alzheimer’s disease (AD). The nectin cell adhesion molecule 2 (NECTIN2) gene coding for a membrane component of adherens junctions is involved in response to infections, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as NECTIN2.Materials and methodsWe conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer’s disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer’s disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor).ResultsThe increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p < 0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p < 0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect.ConclusionThis study reported a new potential causal relationship between pTau-181 and AD. We found that the association between rs6859 in the NECTIN2 gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Our finding sheds light on the complex interplay between genetic susceptibility, protein aggregation, and neurodegeneration in AD. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the NECTIN2 gene and AD.

Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683, p = 2.52 × 10−8; rs880179, p = 4.83 × 10−8) mapped to the CMYAS gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10−5 < p < 7.35 × 10−3), of which two were replicated (p < 3.10 × 10−3). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.

Overweight, defined by a body mass index (BMI) between 25 and 30, has been associated with enhanced survival among older adults in some studies. However, whether being overweight is causally linked to longevity remains unclear. To investigate this, we conducted a Mendelian randomization (MR) study of lifespan 85+ years, using overweight as an exposure variable and data from the Health and Retirement Study and the Long Life Family Study. An essential aspect of MR involves selecting appropriate single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs). This is challenging due to the limited number of SNP candidates within biologically relevant genes that can satisfy all necessary assumptions and criteria. To address this challenge, we employed a novel strategy of creating additional IVs by pairing SNPs between candidate genes. This strategy allowed us to expand the pool of IV candidates with new 'composite' SNPs derived from eight candidate obesity genes. Our study found that being overweight between ages 75 and 85, compared to having a normal weight (BMI 18.5-24.9), significantly contributes to improved survival beyond age 85. Results of this MR study thus support a causal relationship between overweight and longevity in older adults.

INTRODUCTION:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by declines in cognitive and functional severities. This research utilized the Clinical Dementia Rating (CDR) to assess the influence of tilavonemab on these deteriorations.METHODS:Longitudinal Item Response Theory (IRT) models were employed to analyze CDR domains in early-stage AD patients. Both unidimensional and multidimensional models were contrasted to elucidate the trajectories of cognitive and functional severities.RESULTS:We observed significant temporal increases in both cognitive and functional severities, with the cognitive severity deteriorating at a quicker rate. Tilavonemab did not demonstrate a statistically significant effect on the progression in either severity. Furthermore, a significant positive association was identified between the baselines and progression rates of both severities.DISCUSSION:While tilavonemab failed to mitigate impairment progression, our multidimensional IRT analysis illuminated the interconnected progression of cognitive and functional declines in AD, suggesting a comprehensive perspective on disease trajectories.Highlights:Utilized longitudinal Item Response Theory (IRT) models to analyze the Clinical Dementia Rating (CDR) domains in early-stage Alzheimer's disease (AD) patients, comparing unidimensional and multidimensional models.Observed significant temporal increases in both cognitive and functional severities, with cognitive severity deteriorating at a faster rate, while tilavonemab showed no statistically significant effect on either domain's progression.Found a significant positive association between the baseline severities and their progression rates, indicating interconnected progression patterns of cognitive and functional declines in AD.Introduced the application of multidimensional longitudinal IRT models to provide a comprehensive perspective on the trajectories of cognitive and functional severities in early AD, suggesting new avenues for future research including the inclusion of time-dependent random effects and data-driven IRT models.

Abstract Lysophosphatidylcholines (LPC) are phospholipids involved in apoptosis and demyelination, among other functions. They have been linked to cancer, atherosclerosis, and neurodegeneration (with potential trade-offs) and explored as early markers of Alzheimer’s disease (AD) and accelerated aging. However, relationships between longitudinal changes in LPC levels and AD risk remain poorly understood. We applied statistical approaches for joint analyses of longitudinal and time-to-event outcomes, joint models (JM) and stochastic process models (SPM), to study longitudinal dynamics of LPC in relation to AD incidence in the Long Life Family Study (LLFS) participants. In total, 4,017 measurements of 23 LPC species in 2,858 LLFS participants from the U.S., who had 93 incident AD cases and up to two LPC measurements per individual, were analyzed. In JM applications, we found sex-specific relationship (for males only) between the dynamics of LPC species and AD incidence in the model adjusted for baseline age, education, smoking, medication use, and two genetic principal components. The strongest association was found for LPC(14:0/0:0) in males (regression coefficient: 0.739, p=2.3e-23). In SPM applications, we demonstrated that various hidden biomarkers of aging, embedded within the model’s structure and indirectly evaluated from individual LPC trajectories and data on AD incidence, significantly contribute to the associations between LPC and AD. We also observed sex differences in ‘optimal’ and ‘equilibrium’ LPC trajectories, as well as in vulnerability to LPC deviations from these trajectories, and in how these relations change with age. Our findings call for further investigation into the biological mechanisms underlying the observed associations.

The ε4 allele of the APOE gene (APOE4) is known for its negative association with human longevity; however, the mechanism is unclear. APOE4 is also linked to changes in body weight, and the latter changes were associated with survival in some studies. Here, we explore the role of aging changes in weight in the connection between APOE4 and longevity using the causal mediation analysis (CMA) approach to uncover the mechanisms of genetic associations. Using the Health and Retirement Study (HRS) data, we tested a hypothesis of whether the association of APOE4 with reduced survival to age 85+ is mediated by key characteristics of age trajectories of weight, such as the age at reaching peak values and the slope of the decline in weight afterward. Mediation effects were evaluated by the total effect (TE), natural indirect effect, and percentage mediated. The controlled direct effect and natural direct effect are also reported. The CMA results suggest that APOE4 carriers have 19%–22% (TE p = 0.020–0.039) lower chances of surviving to age 85 and beyond, in part, because they reach peak values of weight at younger ages, and their weight declines faster afterward compared to non-carriers. This finding is in line with the idea that the detrimental effect of APOE4 on longevity is, in part, related to the accelerated physical aging of ε4 carriers.

Background: Better physical robustness and resilience of long-lived siblings compared to sporadic long-livers has been demonstrated in several studies. However, it is unknown whether long-lived siblings also end their lives better. Objective: To investigate end-of-life (EoL) events (dementia diagnosis, medication, hospitalizations in the last 5 years of life), causes of death, and location of death in long-lived siblings compared to matched sporadic long-livers from the Danish population. Methods: Long-lived siblings were identified through three nationwide Danish studies in which the inclusion criteria varied, but 99.5% of the families had at least two siblings surviving to age 90 + . Those who died between 2006 and 2018 were included, and randomly matched with sex, year-of-birth and age-at-death controls (i.e., sporadic long-lived controls) from the Danish population. Results: A total of 5,262 long-lived individuals were included (1,754 long-lived siblings, 3,508 controls; 63% women; median age at death 96.1). Long-lived siblings had a significantly lower risk of being diagnosed with dementia in the last years of life ( p = 0.027). There was no significant difference regarding the number of prescribed drugs, hospital stays, days in hospital, and location of death. Compared to controls, long-lived siblings presented a lower risk of dying from dementia ( p = 0.020) and ill-defined conditions ( p = 0.030). Conclusions: In many aspects long-lived siblings end their lives similar to sporadic long-livers, with the important exception of lower dementia risk during the last 5 years of life. These results suggest that long-lived siblings are excellent candidates for identifying environmental and genetic protective factors of dementia.

Accumulating evidence suggests that infections may play a major role in Alzheimer's disease (AD), however, mechanism is unclear, as multiple pathways may be involved. One possibility is that infections could contribute to neurodegeneration directly by promoting neuronal death. We explored relationships between history of infections and brain hippocampal volume (HV), a major biomarker of neurodegeneration, in a subsample of the UK Biobank (UKB) participants. Infectious disease diagnoses were based on ICD10 codes. The left/right HV was measured by the magnetic resonance imaging (MRI) in cubic millimeters and normalized. Analysis of variance (ANOVA), Welch test, and regression were used to examine statistical significance. We found that HV was significantly lower in women aged 60–75, as well as 65–80, years, with history of infections, compared to same age women without such history. The effect size increased with age faster for the left vs. right HV. Results for males didn't reach statistical significance. Results of our study support a major role of adult infections in neurodegeneration in women. The detrimental effect of infections on HV became stronger with age, in line with declining resilience and increasing brain vulnerability to stressors due to aging. The faster increase in the effect size observed for the left vs. right HV may indicate that female verbal memory degrades faster over time than visual-spatial memory. The observed sex difference may reflect a higher vulnerability of female brain to infection-related factors, which in turn may contribute to a higher risk of AD in women compared to men.

Background Functional decline associated with dementia, including in Alzheimer’s disease (AD), is not uniform across individuals, and respective heterogeneity is not yet fully explained. Such heterogeneity may in part be related to genetic variability among individuals. In this study, we investigated whether the SNP rs6859 in nectin cell adhesion molecule 2 (NECTIN2) gene (a major risk factor for AD) influences trajectories of cognitive decline in older participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Methods We retrospectively analyzed records on 1310 participants from the ADNI database for the multivariate analysis. We used longitudinal measures of Mini-Mental State Examination (MMSE) scores in participants, who were cognitively normal, or having AD, or other cognitive deficits to investigate the trajectories of cognitive changes. Multiple linear regression, linear mixed models and latent class analyses were conducted to investigate the association of the SNP rs6859 with MMSE. Results The regression coefficient per one allele dose of the SNP rs6859 was independently associated with MMSE in both cross-sectional (-2.23, p < 0.01) and linear mixed models (-2.26, p < 0.01) analyses. The latent class model with three distinct subgroups (class 1: stable and gradual decline, class 2: intermediate and late decline, and class 3: lowest and irregular) performed best in the posterior classification, 42.67% ( n = 559), 21.45% ( n = 281), 35.88% ( n = 470) were classified as class 1, class 2, and class 3. In the heterogeneous linear mixed model, the regression coefficient per one allele dose of rs6859 – A risk allele was significantly associated with MMSE class 1 and class 2 memberships and related decline; Class 1 (-2.28, 95% CI: -4.05, -0.50, p < 0.05), Class 2 (-5.56, 95% CI: -9.61, -1.51, p < 0.01) and Class 3 (-0.37, 95% CI: -1.62, 0.87, p = 0.55). Conclusions This study found statistical evidence supporting the classification of three latent subclass groups representing complex MMSE trajectories in the ADNI cohort. The SNP rs6859 can be suggested as a candidate genetic predictor of variation in modeling MMSE trajectory, as well as for identifying latent classes with higher baseline MMSE. Functional studies may help further elucidate this relationship.