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Late-onset Alzheimer disease (LOAD) is the most common form of dementia among adults ≥65 years of age. Known risk factors include female sex, increased age, mild cognitive impairment (MCI), and LOAD-associated genetic risk alleles, most notably APOE e4. Recent evidence implicates the adaptive immune system as an important component of amyloid-β plaque clearance and suggests, in limited sample sizes, LOAD-associated immune profiles detectable in blood. We characterized somatic T-cell receptor (TCR) sequence diversity profiles from DNA extracted from blood (99%) and saliva (1%) in Ohio Amish participants with LOAD+MCI (n = 22), non-LOAD (n = 35), and an unclear diagnosis (n = 12). Sequencing was performed using Adaptive Biotechnologies immunoSEQ targeting the beta chain, resulting in >160,000 productive templates and >100,000 productive rearrangements. TCR beta chain sequences were characterized using Simpson's productive clonality, which ranges from 0 to 1 representing diverse and completely even sequences (e.g., 0) to monoclonal or single dominant clone (e.g., 1). We used productive Simpson clonality as a measure of TCR diversity in our supervised logistic regression. To assess the pairwise repertoire similarities, we focused on the Morisita-Horn index, which accounts for clonotype abundance while maintaining robustness against extreme values. We applied an unsupervised machine learning (ML) approach, fuzzy C-means clustering, to identify potential patterns specific to disease status. Participants did not differ significantly based on sex. LOAD+MCI participants were slightly older at last clinical exam than non-LOAD or unclear participants (83.9 vs 81.5 and 81.2 years, respectively; chi-square, p = 0.058). We observed significantly higher TCR sequence diversity in the non-LOAD group compared to the LOAD-MCI group (p = 0.027). However, the association was not significant after adjusting for age and sex. Clustering results showed moderate agreement with clinical diagnoses (adjusted rand index up to 0.4), and incorporating APOE genotypes enhanced the performance. The addition of age as a variable, which has been demonstrated to be related to both LOAD risk and TCR diversity, reduced the clustering agreement slightly. Decreased TCR diversity is marginally associated with having LOAD or MCI. Our ongoing work focuses on applying ML approaches to TCR CD3 amino acid sequences to identify disease-associated clonotypes and develop predictive models for LOAD diagnosis.

Background Late‐onset Alzheimer disease (LOAD) is the most common form of dementia among adults ≥65 years of age. Known risk factors include female sex, increased age, mild cognitive impairment (MCI), and LOAD‐associated genetic risk alleles, most notably APOE e4. Recent evidence implicates the adaptive immune system as an important component of amyloid‐β plaque clearance and suggests, in limited sample sizes, LOAD‐associated immune profiles detectable in blood. Method We characterized somatic T‐cell receptor (TCR) sequence diversity profiles from DNA extracted from blood (99%) and saliva (1%) in Ohio Amish participants with LOAD+MCI (n = 22), non‐LOAD (n = 35), and an unclear diagnosis (n = 12). Sequencing was performed using Adaptive Biotechnologies immunoSEQ targeting the beta chain, resulting in >160,000 productive templates and >100,000 productive rearrangements. TCR beta chain sequences were characterized using Simpson's productive clonality, which ranges from 0 to 1 representing diverse and completely even sequences (e.g., 0) to monoclonal or single dominant clone (e.g., 1). We used productive Simpson clonality as a measure of TCR diversity in our supervised logistic regression. To assess the pairwise repertoire similarities, we focused on the Morisita‐Horn index, which accounts for clonotype abundance while maintaining robustness against extreme values. We applied an unsupervised machine learning (ML) approach, fuzzy C‐means clustering, to identify potential patterns specific to disease status. Result Participants did not differ significantly based on sex. LOAD+MCI participants were slightly older at last clinical exam than non‐LOAD or unclear participants (83.9 vs 81.5 and 81.2 years, respectively; chi‐square, p = 0.058). We observed significantly higher TCR sequence diversity in the non‐LOAD group compared to the LOAD‐MCI group (p = 0.027). However, the association was not significant after adjusting for age and sex. Clustering results showed moderate agreement with clinical diagnoses (adjusted rand index up to 0.4), and incorporating APOE genotypes enhanced the performance. The addition of age as a variable, which has been demonstrated to be related to both LOAD risk and TCR diversity, reduced the clustering agreement slightly. Conclusion Decreased TCR diversity is marginally associated with having LOAD or MCI. Our ongoing work focuses on applying ML approaches to TCR CD3 amino acid sequences to identify disease‐associated clonotypes and develop predictive models for LOAD diagnosis.

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.

INTRODUCTION Cognitive SuperAgers (SAs) are individuals aged 80+ with exceptional episodic memory performance for their age, exceeding middle‐aged adult norms. This study integrates family‐ and association‐based methods to identify genetic variants associated with SAs in the Midwestern Amish population. METHODS Eighty‐three Amish SAs were grouped into 16 pedigrees for parametric and non‐parametric linkage analysis. Variants in linked regions (heterogeneity logarithm of the odds [HLOD] or Kong and Cox logarithm of the odds [LOD*] ≥ 3) were tested for association with SAs using two contrasts: SA versus Alzheimer's disease (AD; n = 40) and SA versus cognitively unimpaired (CU), age‐matched non‐SA individuals (CU80+; n = 157). RESULTS Evidence of linkage for SAs was observed on chromosomes 1, 2, 7, 16, and 20, with the strongest signal around the AD‐associated locus WDR12 on chromosome 2. Association analysis for SA versus AD identified eight variants in HIVEP3 (chromosome 1) that were nominally significant when comparing SA versus CU80+. DISCUSSION WDR12 and HIVEP3 are potential candidate genes contributing to SAs in the Amish population. Highlights Genetic linkage analysis in Amish SA pedigrees identified regions on chromosomes 1, 2, 7, 16, and 20. The strongest linkage was observed in the AD‐associated WDR12 gene on chromosome 2. Regional mapping within linked regions identified associated variants within HIVEP3 on chromosome 1. Variants in HIVEP3 have been linked to AD and AD‐related characteristics.

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.

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.

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 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.

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.