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Background Late‐onset Alzheimer Disease (LOAD) shares multiple pathologic features and genetic risk factors with Age‐related Macular Degeneration (AMD). Amyloid‐beta (Ab) forms amyloid plaques in the brain and aggregates with other proteins and lipids to form drusen deposits in the retina of AMD eyes. CFH and HTRA1, genes coding for Ab‐processing complement proteins, are the strongest genetic risk factors for AMD, but the association with LOAD has been equivocal. In addition, the APOE e4 allele, LOAD's strongest genetic risk factor, has the opposite effect (e.g. is protective) for AMD. Therefore, we investigated whether the strongest genetic risk factors for AMD, CFH and ARMS2/HTRA1 also influence risk of LOAD. Method Utilizing our large dataset of mid‐Western Amish individuals, we performed single nucleotide polymorphism (SNP) association analysis on the ARMS2/HTRA1 and CFH loci to determine their association with LOAD. This analysis included 152 LOAD cases and 746 cognitively unimpaired controls, all evaluated by consensus review of clinical test results. Those with known AMD were excluded from this study. Result Our preliminary results found no significant association between LOAD and the individual SNPs defining the CFH or ARMS2/HTRA1 loci. As these genes are in regions of strong linkage disequilibrium, these SNPs define a small set of extended haplotypes, which have known differential impact on AMD. Conclusion Single SNP association analyses did not expose any significant associations between LOAD and single SNPs at the CFH or ARMS2/HTRA1 loci. Examining the haplotype association with LOAD will allow for increased power and better understanding of the risk these two loci confer to LOAD.

Cognitive preservation is observed in older individuals who are at high risk of cognitive decline but remain cognitively unimpaired (CU). Identifying rare variants (RVs) associated with cognitive preservation may address the missing heritability of Alzheimer Disease (AD). Furthermore, RVs are likely to be enriched to higher frequencies through genetic drift in founder populations, making them easier to detect. This study utilized whole genome-sequencing (WGS) data from the Mid-Western U.S. Amish to search for RVs and their associated genes that are associated with cognitive preservation. Our study included 868 Amish individuals (age 62.5-101.8, mean = 82.6). Of these, 518 were CU and considered as cognitively preserved (mean age 81.5), and 350 were cognitively impaired (CI) (including mild cognitively impaired (mean age 83.6), cognitively impaired but not AD (mean age 85.0), and AD (mean age 84.9)). Cognitive status was determined based on adjudication of neurocognitive and physical exams by clinical experts. Gene-based genome-wide RV association tests were conducted against the binary cognitive status (CU vs CI) to test for RVs associated with cognitive preservation. Variants with minor allele frequency (MAF) < 1% in the general European population and MAF < 5% in the Amish were included in the study. To detect RVs in the coding regions, RVs annotated as having high or moderate impact on protein function by SNPEff were aggregated and analyzed using SKAT-O tests. RVs in the non-coding regulatory regions were grouped and tested following the STAARpipeline. All association tests accounted for age, sex, study center, and relatedness. We observed suggestive associations (significant p threshold = 3.96x10 ) of three coding RVs with cognitive preservation mapped in two genes: B3GNT9 (SKAT-O p = 5.07x10 ) and RANBP10 (SKAT-O p = 6.59x10 ). All three RVs are missense variants with moderate impact on protein function. In addition, grouping of 14 RVs in the promoter DNAase I hypersensitive site of C1QL4 revealed another suggestive signal (STAAR-O p = 7.00x10 , significant p threshold = 4.05x10 ). Our gene-based genome-wide RV association analyses identified suggestive associations with cognitive preservation in the Amish. These results underscore the potential significance of RVs in elucidating the full genetic architecture of AD.

Background Cognitive preservation is observed in older individuals who are at high risk of cognitive decline but remain cognitively unimpaired (CU). Identifying rare variants (RVs) associated with cognitive preservation may address the missing heritability of Alzheimer Disease (AD). Furthermore, RVs are likely to be enriched to higher frequencies through genetic drift in founder populations, making them easier to detect. This study utilized whole genome‐sequencing (WGS) data from the Mid‐Western U.S. Amish to search for RVs and their associated genes that are associated with cognitive preservation. Method Our study included 868 Amish individuals (age 62.5‐101.8, mean = 82.6). Of these, 518 were CU and considered as cognitively preserved (mean age 81.5), and 350 were cognitively impaired (CI) (including mild cognitively impaired (mean age 83.6), cognitively impaired but not AD (mean age 85.0), and AD (mean age 84.9)). Cognitive status was determined based on adjudication of neurocognitive and physical exams by clinical experts. Gene‐based genome‐wide RV association tests were conducted against the binary cognitive status (CU vs CI) to test for RVs associated with cognitive preservation. Variants with minor allele frequency (MAF) < 1% in the general European population and MAF < 5% in the Amish were included in the study. To detect RVs in the coding regions, RVs annotated as having high or moderate impact on protein function by SNPEff were aggregated and analyzed using SKAT‐O tests. RVs in the non‐coding regulatory regions were grouped and tested following the STAARpipeline. All association tests accounted for age, sex, study center, and relatedness. Result We observed suggestive associations (significant p threshold = 3.96x10‐6) of three coding RVs with cognitive preservation mapped in two genes: B3GNT9 (SKAT‐O p = 5.07x10‐5) and RANBP10 (SKAT‐O p = 6.59x10‐5). All three RVs are missense variants with moderate impact on protein function. In addition, grouping of 14 RVs in the promoter DNAase I hypersensitive site of C1QL4 revealed another suggestive signal (STAAR‐O p = 7.00x10‐6, significant p threshold = 4.05x10‐7). Conclusion Our gene‐based genome‐wide RV association analyses identified suggestive associations with cognitive preservation in the Amish. These results underscore the potential significance of RVs in elucidating the full genetic architecture of AD.

Background In aging men, mosaic loss of chromosome Y (mLOY) is a possible biomarker for increased risk of disease, including Alzheimer disease (AD). We previously reported mLOY increased with age and carriers of mLOY had an increased risk of AD. We also found plasma Aβ42/p‐tau181 ratio (APR) was significantly lower among AD Amish individuals compared to cognitively‐unimpaired (CU) individuals. We now examine how these two biomarkers interplay with cognitive status in Amish males. Method mLOY was determined using the Mosaic Chromosomal Alterations(MoChA) pipeline. Extensive QC was done for both mLOY and plasma biomarker measures. Consensus review of medical history and neuropsychological testing categorized individuals into AD, Mild‐cognitive‐impairment (MCI) or Cognitive‐impairment‐not‐AD (CINAD) or CU. The cognitively‐impaired (CI) group combined AD, MCI and CINAD. We compared 1) CI to CU and 2) AD to CU. Correlation between APR and mLOY were estimated accounting for relatedness. Receiver operating characteristic analysis was performed to evaluate the discriminatory ability of the two biomarkers compared to the baseline model with age and presence/absence of APOE ε4 alleles. p‐value <0.05 was noted as statistically significant. Result 249 males (mean age=82.89±5.57) had measurements for both biomarkers. Of these, a subset had consensus diagnoses AD (n = 30; mean age=85.63±5.31), CINAD, MCI or CU (n = 105; mean age=82.01±5.36). The mean age of 82 CI individuals was 84.34±4.73. mLOY was observed in 20.1% of CU vs. 29.3% of CI (p‐value=0.23). APR was significantly negatively correlated with CI and AD as expected, was positively correlated with mLOY but not significantly and remained positively correlated when stratified, with the stronger correlation in AD. For AD, the area under the curve (AUC) improved from 0.70 to 0.82 with the inclusion of APR, with mLOY showing little effect. For CI, AUC improved from 0.63 to 0.68 by including mLOY, with no independent effect of APR. When including both in the model, AUC improves from 0.63 to 0.69. Conclusion We observed two promising biomarkers of AD, mLOY and APR, both contribute discriminating AD and CI but differently. This and the stringer correlation in AD may indicate they are more specific to AD than non‐specific CI.

Late-onset Alzheimer Disease (LOAD) shares multiple pathologic features and genetic risk factors with Age-related Macular Degeneration (AMD). Amyloid-beta (Ab) forms amyloid plaques in the brain and aggregates with other proteins and lipids to form drusen deposits in the retina of AMD eyes. CFH and HTRA1, genes coding for Ab-processing complement proteins, are the strongest genetic risk factors for AMD, but the association with LOAD has been equivocal. In addition, the APOE e4 allele, LOAD's strongest genetic risk factor, has the opposite effect (e.g. is protective) for AMD. Therefore, we investigated whether the strongest genetic risk factors for AMD, CFH and ARMS2/HTRA1 also influence risk of LOAD. Utilizing our large dataset of mid-Western Amish individuals, we performed single nucleotide polymorphism (SNP) association analysis on the ARMS2/HTRA1 and CFH loci to determine their association with LOAD. This analysis included 152 LOAD cases and 746 cognitively unimpaired controls, all evaluated by consensus review of clinical test results. Those with known AMD were excluded from this study. Our preliminary results found no significant association between LOAD and the individual SNPs defining the CFH or ARMS2/HTRA1 loci. As these genes are in regions of strong linkage disequilibrium, these SNPs define a small set of extended haplotypes, which have known differential impact on AMD. Single SNP association analyses did not expose any significant associations between LOAD and single SNPs at the CFH or ARMS2/HTRA1 loci. Examining the haplotype association with LOAD will allow for increased power and better understanding of the risk these two loci confer to LOAD.

Background Studies of older adults with exceptional cognitive performance can enhance understanding of the mechanisms that protect against Alzheimer's disease (AD). Cognitive SuperAgers (SA) are individuals aged 80 and above with above‐average episodic memory performance exceeding norms for middle‐aged adults. This study integrates family‐ and association‐based analytical approaches to identify genetic variants associated with SA in the Midwestern Amish population. Methods A comprehensive neuropsychological evaluation was conducted among adult Amish participants (N = 515). SA were defined as those aged ≥ 80 with episodic memory task performance at or above the mean for ages 35‐44, and non‐episodic memory tasks within one standard deviation of the mean or better for the participant's age (N = 83). SA were grouped into 16 pedigrees for parametric and non‐parametric linkage analysis allowing for locus heterogeneity in MERLIN. Variants located in regions exhibiting HLOD or LOD* scores ≥ 3 were tested for association with SA in GENESIS. Comparison groups included cognitively unimpaired, age‐matched non‐SA individuals (CU 80+, n = 157) and individuals with AD (n = 40). Significance thresholds for each region were determined using SimpleM, which estimates the number of independent tests in the presence of high linkage disequilibrium. Results Linkage analysis identified HLOD scores > 3 on chromosomes 1 (HLOD = 3.10, GRCh38 44.6 Mb), 2 (HLOD = 3.92, 202.9 Mb), 7 (HLOD = 3.14, 30.2 Mb), 16 (HLOD = 3.18, 22.7 Mb), and 20 (HLOD = 3.71 16.7). Regional analysis revealed significant associations for eight correlated variants in the HIVEP3 gene on chromosome 1, comparing SA to AD (peak signal at rs12734651, OR = 0.24, p = 6.46 x 10‐6). These variants were nominally associated when comparing SA to CU 80+ (rs12734651, OR = 0.61, p = 0.032). Conclusions This study identified variants in HIVEP3 associated with SA. Previous studies have linked variants in HIVEP3 to increased risk of AD, as well as with hippocampal volume and cognitive trajectories in unimpaired adults, suggesting that variants in HIVEP3 may influence both AD risk and cognitive performance in unimpaired individuals. These findings indicate that HIVEP3 represents a plausible candidate for further investigation into the mechanisms promoting exceptional cognitive performance in older adults.

Studies of older adults with exceptional cognitive performance can enhance understanding of the mechanisms that protect against Alzheimer's disease (AD). Cognitive SuperAgers (SA) are individuals aged 80 and above with above-average episodic memory performance exceeding norms for middle-aged adults. This study integrates family- and association-based analytical approaches to identify genetic variants associated with SA in the Midwestern Amish population. A comprehensive neuropsychological evaluation was conducted among adult Amish participants (N = 515). SA were defined as those aged ≥ 80 with episodic memory task performance at or above the mean for ages 35-44, and non-episodic memory tasks within one standard deviation of the mean or better for the participant's age (N = 83). SA were grouped into 16 pedigrees for parametric and non-parametric linkage analysis allowing for locus heterogeneity in MERLIN. Variants located in regions exhibiting HLOD or LOD* scores ≥ 3 were tested for association with SA in GENESIS. Comparison groups included cognitively unimpaired, age-matched non-SA individuals (CU 80+, n = 157) and individuals with AD (n = 40). Significance thresholds for each region were determined using SimpleM, which estimates the number of independent tests in the presence of high linkage disequilibrium. Linkage analysis identified HLOD scores > 3 on chromosomes 1 (HLOD = 3.10, GRCh38 44.6 Mb), 2 (HLOD = 3.92, 202.9 Mb), 7 (HLOD = 3.14, 30.2 Mb), 16 (HLOD = 3.18, 22.7 Mb), and 20 (HLOD = 3.71 16.7). Regional analysis revealed significant associations for eight correlated variants in the HIVEP3 gene on chromosome 1, comparing SA to AD (peak signal at rs12734651, OR = 0.24, p = 6.46 x 10 ). These variants were nominally associated when comparing SA to CU 80+ (rs12734651, OR = 0.61, p = 0.032). This study identified variants in HIVEP3 associated with SA. Previous studies have linked variants in HIVEP3 to increased risk of AD, as well as with hippocampal volume and cognitive trajectories in unimpaired adults, suggesting that variants in HIVEP3 may influence both AD risk and cognitive performance in unimpaired individuals. These findings indicate that HIVEP3 represents a plausible candidate for further investigation into the mechanisms promoting exceptional cognitive performance in older adults.

INTRODUCTION Genetic factors promoting cognitive preservation in high‐risk older adults for Alzheimer's disease (AD) risk remain understudied. Among Midwestern Amish with elevated AD genetic risk, we hypothesized ranking sibships by mean genetic risk scores during linkage analysis would reveal loci influencing preserved cognition. METHODS We evaluated 1855 Amish adults (≥75 years) using the Modified Mini‐Mental Status Exam (3MS), classifying individuals with education‐adjusted scores ≥87 as cognitively unimpaired (CU) and lower scores as impaired (CI). Non‐parametric linkage analysis (NPL) on 143 sibships with ≥ 2 CU was combined with ordered‐subsets analysis (OSA) to incorporate 25 known European AD risk loci. RESULTS NPL‐OSA and association identified linkage on chromosome 2 (rs6719884) within LINC01122 (logarithm of odds [LOD]* = 3.08) and a significant interaction on chromosome 12 (rs11063479 near KCNA5), suggesting synergy with genetic risk. DISCUSSION These findings implicate long intergenic non‐coding RNAs (lincRNAs) and potassium channel genes in maintaining cognition despite high AD risk, informing future research on protective genetic mechanisms. Highlights Non‐parametric linkage and ordered‐subsets analysis in sibships enriched with cognitively unimpaired older adults found significant evidence of linkage on chromosome 2 within the lincRNA LINC01122, along with suggestive evidence at additional loci. Association mapping within significant and suggestively linked regions revealed a significant single nucleoride polymorphism (SNP) x AD genetic risk scores (GRS) interaction effect on chromosome 12, near the potassium channel gene KCNA5. LINC01122 is primarily brain‐expressed, while KCNA5 has been linked to multiple cardiovascular phenotypes, supporting their potential role in cognitive function.

Background Plasma amyloid‐beta (Aβ) 42/40 ratio and phosphorylated tau 181 (pTau181) are promising blood biomarkers for AD. Compared to heterogenous clinical phenotypes, they are more objective and proximal to the pathological hallmarks of Aβ plaques and tau tangles. Biomarker‐guided clustering using Aβ42/40 and pTau181 can potentially establish subpopulations that share similar mechanisms of AD and treatment responses. Method Plasma biomarkers were measured using Simoa™ Neuro‐3Plex, 4Plex, and pTau181 Advantage V2 assays. To eliminate potential confounding effects, age, sex, and study center were regressed out of Aβ42/40 and pTau181 using a quadratic regression model. Adjusted biomarkers were then normalized for unsupervised K‐means clustering, with the optimal number of clusters determined by the elbow method and Silhouette score. To interpret the cluster profiles, we explored the differences in demographics and clinical features between clusters. We also examined the association between clusters and neuropsychological tests adjusting for age, sex, study center, APOE e4 alleles, and diagnosis. Result We analyzed plasma biomarkers from 593 Amish individuals (age ³ 60 years old) living in Ohio and Indiana. 62% were females, and the average age was 81.7 ± 5.7 years. Utilizing plasma Aβ42/40 and pTau181, the clustering approach yielded six distinct clusters (N = 92, 95, 94, 152, 75, and 85) whose composition was driven by varying burdens of amyloid and tau pathology. There was no significant difference in proportion of cognitive impairment or of family structure across clusters. As expected, the low Aβ42/40 and high ptau cluster (Cluster 6) featured a significantly higher proportion of APOE e4 carriers than other clusters combined (51% vs 22%, p = 0.002). No significant associations were found between clusters and neuropsychological tests. Conclusion The integrated analysis of plasma Aβ42/40 and pTau181 in the Amish established six clusters with varying levels of amyloid and tau burden, suggesting possible differences that need to be further explored. Examination of potential genetic or pathophysiological differences across the clusters are underway.

Mosaic loss of chromosome Y (mLOY) refers to acquired aneuploidy in a fraction of somatic cells. In aging men, this has been suggested as a possible biomarker for increased risk of numerous diseases, including Alzheimer's disease (AD). We investigated mLOY estimated from whole genome sequencing (WGS) as a risk factor for AD in the Midwestern Amish, a founder population with homogeneous lifestyle, reducing the effect of confounding environmental factors. The calling of mLOY was performed using the Mosaic Chromosomal Alterations (MoChA) pipeline, utilizing long-range phase information to search for imbalances between maternal and paternal allelic fraction in a cell population. A loss was called when the slope of coverage over allelic deviation was -0.94. The cognitive status of each individual was assigned via consensus review of medical history and neuropsychological testing. The cognitively-impaired (CI) group combined AD, MCI and Unclear individuals and compared to the cognitively-unimpaired (CU) group. Individuals in 3 age groups (65-74, 75-84, ≥85) were included. To evaluate the association between mLOY and risk of developing CI in follow-up, we fit a Cox proportional hazards model associating mLOY to years of disease-free follow-up within individuals for whom blood was sampled prior to CI diagnosis. After extensive QC, 457 males (mean age = 80.48±5.12) were included. mLOY frequency increased with age (p = 0.029): 18.75% (65-74; n = 48), 31.86% (75-84; n = 317) and 39.13% (85+; n = 92). A subset of 372 males were assigned to the CU (n = 202) or CI (n = 170) group and mLOY was slightly higher in the CI group (26.2% in CU vs. 34.1% in CI; p = 0.099). Within 217 males for whom blood was sampled a priori, there were 48 subsequent CI events. mLOY was associated with an increased risk of CI diagnosis with hazard ratio (HR) = 1.90 (1.03-3.56, p = 0.04). After adjusting for the age of sampling, HR increased to 2.31 (1.23-4.36, p = 0.009). We assessed the impact of mLOY in males on the risks of CI. We observed the same trend as reported in other European descent populations: mLOY increased with age and the higher sensitivity with WGS data compared with array-based data. We found that carriers of mLOY had an increased risk of impairment.