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INTRODUCTION: Alzheimer's disease (AD) remains a debilitating condition with limited treatments and additional therapeutic targets needed. Identifying AD protective genetic loci may identify new targets and accelerate identification of therapeutic treatments. We examined a founder population to identify loci associated with cognitive preservation into advanced age. METHODS: Genome‐wide association and linkage analyses were performed on 946 examined and sampled Amish individuals, aged 76–95, who were either cognitively unimpaired (CU) or impaired (CI). RESULTS: A total of 12 single nucleotide polymorphisms (SNPs) demonstrated suggestive association (P ≤ 5 × 10−4) with cognitive preservation. Genetic linkage analyses identified > 100 significant (logarithm of the odds [LOD] ≥ 3.3) SNPs, some which overlapped with the association results. Only one locus on chromosome 2 retained significance across multiple analyses. DISCUSSION: A novel significant result for cognitive preservation on chromosome 2 includes the genes LRRTM4 and CTNNA2. Additionally, the lead SNP, rs1402906, impacts the POU3F2 transcription factor binding affinity, which regulates LRRTM4 and CTNNA2. Highlights: GWAS and linkage identified over 100 loci associated with cognitive preservation.One locus on Chromosome 2 retained significance over multiple analyses.Predicted TFBSs near rs1402906 regulate genes associated with neurocognition. [ABSTRACT FROM AUTHOR]

Introduction: Lowering blood pressure (BP) reduces the risk for cognitive impairment and the progression of cerebral white matter lesions. It is unclear whether hypertension control also influences plasma biomarkers related to Alzheimer's disease and non‐disease‐specific neurodegeneration. Methods: We examined the effect of intensive (< 120 mm Hg) versus standard (< 140 mm Hg) BP control on longitudinal changes in plasma amyloid beta (Aβ)40 and Aβ42, total tau, and neurofilament light chain (NfL) in a subgroup of participants from the Systolic Blood Pressure Intervention Trial (N = 517). Results: Over 3.8 years, there were no significant between‐group differences for Aβ40, Aβ42, Aβ42/Aβ40, or total tau. Intensive treatment was associated with larger increases in NfL compared to standard treatment. Adjusting for kidney function, but not BP, attenuated the association between intensive treatment and NfL. Discussion: Intensive BP treatment was associated with changes in NfL, which were correlated with changes in kidney function associated with intensive treatment. Trial Registration: clinicaltrials.gov Identifier: NCT01206062 [ABSTRACT FROM AUTHOR]

Introduction: Apathy is common in neurocognitive disorders (NCD) but NCD‐specific diagnostic criteria are needed. Methods: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health‐care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019. Results: The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. Discussion: These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research. [ABSTRACT FROM AUTHOR]

Background: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate (MPH) was modestly efficacious is treating apathy in Alzheimer's disease (AD) with 66% response (> = 4 point decrease on Neuropsychiatric Inventory – apathy (NPI‐A). Here, we evaluated if blood‐based biomarkers potentially associated with treatment‐limiting neuronal damage predicted the probability of treatment response. Method: ADMET 2 participants with baseline and endpoint (6 month) NPI‐A and baseline concentrations of (i) neuronal damage: neurofilament light (NFL) and S‐100B, (ii) inflammation: interleukin (IL)‐6, IL‐10, Tumor Necrosis Factor‐alpha (TNFα), and (iii) oxidative stress: lipid hydroperoxide (LPH), 4‐hydroxynonenal (4‐HNE), 8‐isoprostane (8‐ISO) were included. Biomarkers were normalized by log transformation and pareto scaling. Univariate models examined whether each biomarker interacted with the treatment condition to predict a change of at least 2 points on the NPI‐A. Next, biomarkers with significant associations were included in a multivariate logistical regression model that was used to predict treatment response to MPH and placebo. The index score (difference between response probabilities for MPH and placebo) of each participant indicated their favourability for MPH treatment. Participants were grouped into quartiles by their index score with confidence intervals estimated using non‐parametric bootstrapping. Result: Forty‐nine participants (placebo = 26, MPH = 23, age = 75.4 years (standard deviation [SD] = 7.6), 57% males, Mini Mental State Examination = 19.7 [SD = 4.6]) were included. MPH was more efficacious than placebo in those with higher baseline NFL (‐5.8, t = ‐3.1, p = 0.003), and less efficacious in those with higher LPH (2.0, t = 1.48, p = 0.15). Apathy worsened in participants with high TNFα (2.71, t = 1.94, p = 0.06) in both MPH and placebo groups. Participants in the top quartile of the biomarker index score (66.7% on MPH) were more likely to respond to MPH than placebo (index score = 0.58, 95%CI: 0.48, 0.69). Conclusion: Individuals with greater neuronal injury were more likely to respond to MPH, suggesting that MPH supplementation provides more benefit when neuronal injury is more severe. Combining blood biomarkers yielded a prediction score where participants with high NFL and low LPH levels were more likely to respond to MPH. This approach utilizes biomarkers to address heterogeneity in treatment response to MPH. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) reflects cognitive deficits without significant functional decline in activities of daily living (1). MCI subtypes correspond to phenotypic cognitive impairment patterns in memory, attention, language, executive, and visuospatial compared to age‐adjusted norms: Amnestic single domain (ASD) or multi‐domain (AMD), Nonamnestic single domain (NASD), or Nonamnestic multi‐domain (NAMD). Previous studies have suggested nonamnestic subtypes are more likely to represent non‐AD prodromes, but conclusions have been limited by small sample sizes (1). Method: Using the National Alzheimer's Coordinating Center (NACC) database (grant U24 AG072122), we selected all initial Uniform Data Set (UDS) assessments diagnosed as MCI with subtyping. The NACC data was collected from 37 participating Alzheimer's disease Research Centers. Baseline clinical features, primary etiology and associated medical conditions were collected. Results: 9852 individuals with MCI on baseline UDS visits were analyzed: 45.6% were diagnosed with AD (Table 1). AD was the most common primary etiology in all subtypes, more frequent in amnestic than nonamnestic subtypes (AMD 54.1%; ASD 50.5%; NAMD 20.0%; NASD 18.8%). Overall, 6% were diagnosed with DLB and 3.1% with PD; NAMD and NASD were more frequent than AMD or ASD. The most frequently associated medical conditions were hypercholesterolemia, HTN, depression, anxiety, sleep apnea and diabetes (table 2). The highest percentage of depression and anxiety were in nonamnetsic subtypes. Recent stroke was most frequent in NAMD. Conclusion: MCI is a heterogeneous disorder, and its classification by subtypes is essential in understanding prodromal stages and neurodegenerative neuropathology. Dementia risk modulation and prevention is linked to identification and treatment of associated medical conditions including frequent neuropsychiatric comorbidity (2). [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) reflects cognitive deficits without significant functional decline in activities of daily living. MCI subtypes correspond to phenotypic cognitive impairment patterns in memory, attention, language, executive, and visuospatial compared to age‐adjusted norms: Amnestic single domain (ASD) or multi‐domain (AMD), Nonamestic single domain (NASD), or Nonamnestic multi‐domain (NAMD). Previous studies have suggested Nonanmestic subtypes demonstrate more likely represent non‐AD prodromes, but conclusions have been limited by small sample sizes. The present study attempts to see correlates of htese proposed differences as evident by cognitive testing battery. Method: Using the National Alzheimer's Coordinating Center (NACC) database (grant U24 AG072122), we selected all initial Uniform Data Set (UDS) assessments diagnosed as MCI with subtyping. The NACC data was collected from 37 participating Alzheimer's disease Research Centers. Baseline demographic, clinical features, Neuropsychiatric symptoms, and AD biomarkers were collected. One‐way ANOVA analyses were used to compare cognitive performance on all UDS cognitive tests across MCI subtypes. Result: 9852 individuals with MCI on baseline UDS visits were analyzed: 45.4% AMD, 33.7% ASD, 12.6% NASD, 8.2% NAMD. There were significant differences (P<.001 or greater) on all measures which is not unexpected given large sample size. Notable differences between ASD/AMD, NASD/NAMD were prominent on Trails B, Craft story immediate and delayed recall, and Benton immediate recall minus delayed recall. See table for complete summary of scores.Trails B, mean (SD) times were ASD (113±62), AMD (157±82), NASD (143±78),NAMD (171±83). Craft story showed clear differences between groups on immediate recall (ASD14.9 (6.4)/AMD 14.2 (6.76)/NASD 18.0 (8.0/NAMD 17.9 (6.9)) and delayed recall (ASD 9.9 (7.0)/AMD 10.1 (6.7)/NASD 15.2 (6.4)/NAMD 15.5 (6.2)). Benton immediate minus delayed recall differences were ASD 8.1/AMD 7.9 versus NASD 4.2, NAMD 4.9) Conclusion: Nonamnestic MCI subtypes are characterized by lower performance on executive tasks such as Trails B. Conversely, memory tasks show lower performance in NACC UDS participants with amnestic subtypes of MCI. This would support the concept that Nonamnestic MCI may represent prodromal stages of non‐AD dementia more frequently. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) reflects cognitive deficits without significant functional decline in activities of daily living. MCI subtypes correspond to phenotypic cognitive impairment patterns in memory, attention, language, executive, and visuospatial compared to age‐adjusted norms: Amnestic single domain (ASD) or multi‐domain (AMD), Nonamnestic single domain (NASD), or Nonamnestic multi‐domain (NAMD. In this study, we explore frequencies of domain impairment by MCI subtype, and frequency of each combination of (memory ±) all combinations of Language, Attention, Executive and Visuospatial impairment in the NACC database. This is of practical importance for both localization of amyloid or tau deposition as well as relative localization of areas of deficit. Method: Using the National Alzheimer's Coordinating Center (NACC) database (grant U24 AG072122), we selected all initial Uniform Data Set (UDS) assessments diagnosed as MCI with sub‐typing. The NACC data was collected from 37 participating Alzheimer's disease Research Centers. 9852 individuals with MCI on baseline UDS visits were analyzed: 45.4% AMD, 33.7% ASD, 12.6% NASD, 8.2% NAMD. Result: Figure one shows the distribution overall of domain specific impairment by MCI subtype. Except for ASD, Executive function was the most common domain affected, and visuospatial was the least common. NAMD had higher percentages affected for all domains compared to AMD. In Figure 2, all combinations of language, executive, attention and visuospatial are compared. The most frequent combination was Language‐Executive, and the least common combination was Language‐Attention‐Visuospatial. The mean absolute percentage difference between AMD and NAMD was 2.2%. The Spearman's rho of AMD vs. NAMD was 0.845. Conclusion: Within an MCI subtype, there is substantial variability in the frequency of individual domains. However, comparison of AMD and NAMD shows striking uniformity in frequency of combinations of individual domains with very correlation. The latter findings suggests that Amnestic and Nonamnestic multidomain subtypes may be closely related in pathophysiology but show greater heterogeneity within a MCI subtype. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) is a leading cause of death in the US, with limited treatment options. Most studies assess risk factors for AD; however, protective mechanisms demonstrate higher success rates as therapeutic targets. Here, we examine the genetics of Amish individuals maintaining cognitive preservation into advanced age, aiming to uncover protective mechanisms against AD. Method: Our dataset consisted of individuals of Amish descent, between 76 – 95 years of age and cognitively unimpaired (CU) with at least one first‐degree relative determined to be either CU or cognitively impaired (CI). 946 Amish individuals met our criteria, were genotyped across their genomes, and incorporated into a single 13‐generation pedigree containing 8,222 individuals. Their complex familial relationships were considered in linkage and genome‐wide association analyses (GWAS). GENESIS was used for GWAS, with XWAS used for the X chromosome. Several parametric and non‐parametric linkage analyses were also performed utilizing MERLIN software for the autosomes and MINX for the X chromosome. Result: 106 SNPs (representing 64 loci) reached an initial significance threshold (LOD≥3.3) in linkage analyses. Adjusting for number of independent SNPs in our dataset, no SNPs reached significance after GWAS (P≤6.4×10−7), but 12 loci were suggestive (P≤5×10−4). No loci were suggestive/significant on the X chromosome. For a locus to be further investigated, 1) a significant or suggestive LOD score was required in two or more linkage analyses or 2) one significant LOD score and a suggestive GWAS association within a 10 Mb region were required. After applying these criteria, 8 loci, on chromosomes 1, 2, 3, 7, 11, and 17, were selected for further evaluation. Loci on chromosomes 7 and 11 are within 10 Mb of known AD risk and protective loci, EPHA1 and PICALM, respectively. Significant LOD score results on chromosomes 7, 11, and 17 overlap with coding regions for TBXAS1, DLG2, and SPNS3, respectively. These three loci have been implicated in cognitive impairment relating to neurological disorders. Conclusion: We identified 8 loci potentially harboring genes promoting cognitive preservation. These are under further investigation and represent potential therapeutic targets but require experimental studies identifying their specific mechanisms in relationship to AD. [ABSTRACT FROM AUTHOR]

Background: Informed decisions to enroll in clinical investigations of Alzheimer's disease and related dementias (ADRD) require careful consideration of complex risks and uncertain benefits. Decisions regarding scope of research participation and whether to receive information about biomarker status are complicated by lack of scientific consensus regarding biomarkers as surrogate end points for Alzheimer's disease. This Delphi protocol aims to establish stakeholder consensus regarding the content and features of ethically optimal informed consent support for ADRD research. Method: This consensus‐building Delphi protocol consists of three rounds of online surveys conducted with three stakeholder groups: Alzheimer's disease research experts (including ethicists, research oversight specialists, and clinical trialists), Alzheimer's disease research participants, and study partners of individuals enrolled in ADRD research. Participants will be administered questionnaires developed from a synthesis of researcher‐ and participant‐endorsed decisional needs identified in published literature and a decisional needs assessment conducted with support from an Alzheimer's Association Research Grant. Participants will also be asked their views on the design, content, and implementation of a decision support tool. ≥70% agreement will be required to achieve consensus. Response rates, level of agreement, medians, interquartile ranges, and group rankings will be analyzed. Following each round of data collection, our research team will undertake qualitative content analysis of open‐ended responses and forum interactions. Result: This protocol will develop consensus regarding priorities for decision support for ADRD research participants and the key features and content of ethically optimal informed consent support interventions. The Delphi technique is appropriate to develop consensus between diverse stakeholders because of its ability to offer anonymity to other participants and minimize bias. Conclusion: Findings will contribute to the development of a digital health research infrastructure that is inclusive of diverse individuals and attentive to the needs of cognitively vulnerable patient populations and their caregivers. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are the among the most common neuropathologies. Amyloid and tau biomarker changes are often incorporated in the clinical diagnosis of AD. The current DLB criteria does not include robust biofluid biomarkers. However differences in amyloid plaque and CSF neurogranin in DLB has been of interest based on neuropathology and prior CSF reports. Our objective was to determine if Abeta modifications Abeta 3‐42 and Abeta 1‐42 along with neurogranin could be used to differentiate DLB from AD. Method: This cohort study among 45 MCI stage of AD meeting NIA/AA 2011 criteria and 15 DLB participants meeting the 2017 Mc Keith criteria. We evaluated the CSF levels of Abeta 3‐42, Abeta 1‐42 by Liquid chromatography‐mass spectrometry (LC‐MS/MS) techniques and CSF neurogranin by standard ELISA to explore the differences between groups. Two sample t‐tests both without and with data imputation for samples not meeting lower levels of detection and linear regression models by considering the confounding variables of age, sex and education were assessed. Result: Mean age 67.67 (SD5.13) years, 33% Female. Mean neurogranin levels in DLB 325.9 (SD 200.34 were lower than in MCI‐AD 707.7 (SD 489.94) pg/ml, (p = 0.0006 from two‐sample t‐test). Mean levels of Abeta 3‐42 were 51.63(SD = 19.6) and 43.63(SD = 13.5)fmol/l, and Abeta 1‐42 848.7 (SD = 248.4) fmol/l and 981.5(SD = 265.0) in DLB and MCI‐AD, respectively and were not significantly different. The ratio of Abeta 3‐42/Abeta 1‐42 was higher in DLB 0.06 (SD = 0.02) than MCI‐AD 0.04 (SD = 0.01) (p = 0.008 from two‐sample t‐test). In the multivariable regression models after adjusting for confounding variables the ratio of Abeta 3‐42/Abeta 1‐42 (Est = 67.19,SE = 29.62, p = 0.02) and neurogranin (Est = ‐0.0069,SE = 0.0026,p = 0.009) were significant discriminators between DLB and MCI‐AD. Conclusion: Higher ratio of CSF Abeta 3‐42/Abeta 1‐42 and lower CSF levels of neurogranin were noted in the DLB group compared to MCI‐AD. Lower levels of CSF neurogranin in DLB has been reported, while higher ratio of CSF Abeta 3‐42/Abeta 1‐42 in DLB is a novel biomarker finding. Differences in Abeta species in DLB could be potential biomarkers in separating DLB from AD. [ABSTRACT FROM AUTHOR]

Background: As plasma biomarker assays have become more widely available, they are increasingly being used to characterize AD and related dementias. The Old Order Amish are a cultural and genetic isolate in the US that have participated in genetic studies for decades. This study investigated plasma phosphorylated tau at threonine‐181 (pTau181) in an Old Order Amish cohort to determine if the association with cognitive status is reproducible in this population. Method: Old Order Amish individuals over age 65 (n=467, mean age = 81.3, 60.6% female) in Indiana and Ohio were examined using a modified Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery. Each individual was assigned Impaired (n=155, mean age = 82.5, 56.8% female) or Unimpaired (n=312, mean age = 80.8, 62.5% female) cognitive status via consensus review of these examination results. The level of plasma pTau181 was measured using the pTau181 Advantage V2 assay from Quanterix. Genetic Risk Scores (GRS) were calculated using genome‐wide significant variants from Kunkle et al. (2019), weighted by log odds ratio estimates. A t‐test was used to compare plasma pTau181 levels between the Impaired and Unimpaired groups. Logistic regression was then used to model the contribution of age, sex, GRS, and plasma pTau181 on cognitive status. Result: We found that the average level of plasma pTau181 was significantly higher in the Impaired group (2.46 pg/mL) compared to the Unimpaired group (2.01 pg/mL) at p<0.0001. A multivariable model found increasing age (OR=1.10, p=0.0002), male sex (OR=1.60, p=0.04), increasing GRS (OR=1.97, p<0.0001), and increasing plasma pTau181 (OR=1.46, p=0.001) associated with impaired cognitive status. The effect of GRS is mostly attributable to APOE. Conclusion: The result of these analyses indicates that pTau181 is associated with impaired cognitive status in the Old Order Amish, adding additional information beyond the known genetic risk factors for AD. [ABSTRACT FROM AUTHOR]

Background: Mosaic loss of chromosome Y (mLOY) refers to acquired aneuploidy in a fraction of somatic cells. In aging men, has been suggested as a possible biomarker for increased risk of numerous diseases, including Alzheimer's disease (AD). We investigated mLOY as a risk factor for AD in the Mid‐Western Amish, a founder population with homogeneous lifestyle, reducing the effect of confounding environmental factors. Method: The median of the log R ratio (mLRRY) from SNP array data within the male‐specific region of chromosome Y was used to measure the degree of mLOY. A mLRRY value lower than the 99% confidence limit of the experimental distribution was scored to estimate the frequency of mLOY. The cognitive status was assigned via consensus review of cognitive examination results. Men in 3 age groups (65‐74, 75‐84, >=85) were included. The linear mixed model with a polygenic component to account for relatedness and a transformation to address non‐normality was used to estimate familial correlations and heritability. A likelihood ratio test of association was performed with age at blood sampling and age of cognitive exam as covariates. Result: After extensive QC, 533 participants (mean age=75.42±6.17) were included and 39 (7.9%) had a detectable level of mLOY. mLOY frequency increased with age (p<1.0x10‐6): 1.0% (65‐74; n=103), 8.4% (75‐84; n=334) and 14.3% (85+; n=96). Heritability of mLOY was 0.53 and the residual sibling correlation was 0.27 (n=201, p<1.0x10‐2). A subset of 423 individuals were assigned to the cognitively impaired (n=134) or unimpaired (n=289) groups and mLOY was significantly higher in the cognitively impaired group (p<0.0001).. Conclusion: The sibling correlation was significant for mLOY. We observed the same trend as reported in other European descent populations: mLOY increased with age and was more frequent in cognitively impaired individuals. The frequency of mLOY in Amish was lower than reported, overall and in each age stratum. Our results along with the lower prevalence of AD in Amish reinforces as a promising biomarker for the risk of AD. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial dysfunction is an important feature of Alzheimer's Disease (AD) pathogenesis. Reduced glucose utilization and increased oxidative stress are intermediates through which impaired mitochondria may promote AD‐associated brain changes. Association between groups of variants ("haplogroups") in the mitochondrial genome and AD have been reported for haplogroups U, J, and K. To test these effects in the Amish, we looked for evidence of association between AD‐associated haplogroups and cognitive impairment in a sample of aged Amish individuals. Method: Cognitive status in adult Amish participants (n=670) with whole‐genome sequence (WGS) data was determined based on modified mini‐mental status exam results (3MS). An outcome of cognitively impaired (CI) was assigned to individuals with an education‐adjusted 3MS < 87 at any age. A status of cognitively unimpaired (CU) was assigned to those aged ≥ 75 scoring ≥ 87 on the 3MS. Mitochondrial variants detected by WGS were used to derive broad haplogroups for each sample using Haplogrep2. Mixed model association testing was performed in GENESIS with CI as the outcome, and haplogroup (U, J, or K), APOE ε4 carrier status (ε4 vs no ε4), sex, and age as predictors. Based on reports of sex‐specific haplogroup U effects on AD, a sex‐stratified analysis was conducted. A random‐effect kinship matrix was used to account for relationships. Result: Association between mitochondrial haplogroups U, J, or K and CI was not observed at a 5% significance level. The sex‐stratified analysis showed the strongest association of CI with haplogroup U (OR 1.8, 95% CI 0.92‐3.5) among women. Among men, the estimated effect was 0.77 (95% CI 0.37‐1.62). The overall direction of association was opposite in men and women, though neither was statistically significant at 5%. Conclusion: Although significant evidence of a haplogroup effect on cognitive status was not observed, the moderate sex‐dependent effect of haplogroup U on impairment warrants further examination in an expanded dataset.Previously, haplogroup U was proposed as an AD risk factor among men, whereas it appears as a risk factor for CI in women in the present study. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD), the most common type of dementia, has a complex etiology with a strong genetic component. Many genetic risk variants for AD have been identified including APOE, the largest known genetic risk factor. However, most of this research has examined only broad populations of individuals with European ancestry and there is mounting evidence that effect sizes vary by population. Here, we investigate the transferability of polygenic risk scores (PRSs), including a network‐specific PRS, in the midwestern Amish and across diverse ancestries. Method: Data from 1,091 Amish adults with AD diagnosis by consensus were considered for analysis from the Collaborative Amish Aging & Memory Project. Genotype data (Illumina GSA and MEGAEX) were imputed using the Haplotype Reference Consortium panel. We also analyzed 15,745 individuals from the Alzheimer's Disease Sequencing Project (ADSP) r3 with three predominant race/ethnicity groups: African American (AA; n=2,937), Hispanic (n=3,047), and non‐Hispanic White (NHW; n=9,708). An AD network‐specific PRS was constructed by including variants from AD‐implicated molecular networks in the Kyoto Encyclopedia of Genes and Genomes. A comprehensive pruning and thresholding PRS considering all variants was calculated for comparison. Effect estimates from Kunkle et al. (2019) were used. PRS‐only models, sex and age covariate‐only, and full models were constructed for each group and the full ADSP data. Result: We observed that PRS‐only predictive ability was similar between the comprehensive PRS (AUC=0.56) and the network‐specific PRS (AUC=0.55) in the full ADSP r3 data. Network‐specific PRS performance was similar in the Amish (AUC=0.55). However, we observed better predictive ability with the comprehensive PRS compared to the network‐specific PRS in each of the subgroups (Amish AUC: 0.61 vs. 0.55; NHW: 0.70 vs. 0.53; AA: 0.56 vs. 0.53, Hispanic: 0.61 vs. 0.56). These trends were consistent after inclusion of sex and age covariates. Conclusion: We demonstrated that a network‐specific PRS performed similarly to a comprehensive PRS in a combined diverse population and the Amish but confers less predictive ability when investigating individual subgroups. Thus, the network‐specific PRS has potential as a component of a risk model in diverse populations because it may successfully account for effects that are consistent across subgroups. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) is the most common form of dementia and has limited treatments. While AD risk has a large genetic component, under 50% of the genetic risk has been identified. By focusing on identifying genetic variants that delay or prevent the onset of AD, our goal is to identify new associated genes and variants. To detect such loci, we studied cognitive preservation in the Midwestern Amish, a genetically and culturally isolated population of European descent. Methods: We studied 946 Amish individuals (ages 76‐95) from Ohio and Indiana. Participants were classified as cognitively impaired (33.8%) or cognitively unimpaired (66.2%) by consensus review of cognitive examinations. These individuals were all connected in a 15‐generation 8,222‐person pedigree. This pedigree was divided into 104 sub‐pedigrees via PedCut for linkage analysis. MERLIN was used for autosomal linkage analysis, while MINX was used for X‐chromosome linkage analysis. The association analysis, corrected for genetic relationship, used GENESIS for autosomes and XWAS for the X chromosome. Results: Over 250,000 SNPs were used for association and two‐point linkage analyses, and a subset of 5,294 uncorrelated SNPs was used for multipoint linkage analyses. on 15 different chromosomes, with the highest two‐point heterogeneity LOD score (HLOD = 5.85) on chromosome 2 (∼79Mb) and highest multipoint HLOD (3.55) on chromosome 12 (∼25Mb), neither overlapping with known AD genes. Two linkage results overlapped with known AD genes (Chr 6: CD2AP; Chr 11: PICALM) and do not overlap with association results. Significant (p ≤ 6.4x10‐7) and suggestive (p ≤ 1x10‐4) thresholds for association were determined using SimpleM. While no significant associations were found, suggestive associations were found for 103 SNPs (11 loci) across 10 chromosomes. Three of these (chr 11: MS4A2; chr 14: SLC24A4; chr 16: IQCK) fall near known AD genes. These significant and suggestive regions are being followed up currently with fine mapping. Conclusion: Preliminary analyses suggest that using cognitive preservation as our phenotype of interest identifies both known AD loci and novel regions that warrant further evaluation and may lead to a further understanding of both AD and cognitive preservation. [ABSTRACT FROM AUTHOR]

Background: Apathy is the most common neuropsychiatric symptom in Alzheimer's disease (AD), however there are no approved treatments. In the recent Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), methylphenidate treatment resulted in a significant reduction in apathy with a small to medium effect size. Given these results and the clinical heterogeneity of apathetic AD patients, we assessed the heterogeneity of response to methylphenidate in ADMET 2 to identify individuals who may benefit particularly from this treatment. Method: In this multicenter, randomized, placebo‐controlled clinical trial of 177 AD patients with clinically significant apathy, participants were randomized to receive methylphenidate or placebo for 6 months. Twenty‐one unplanned potential predictors of treatment outcomes were assessed. Predictors were chosen for multivariate modeling based on estimated effect difference, difference of change in the Neuropsychiatric Inventory (NPI)‐apathy subscale of two or more at the 6 month visit. Participants were then grouped into 10 subgroups by their index scores, which were constructed based on the predictors with the biggest difference in effect. Result: Of the 21 predictors, six were chosen for multivariate modelling based on having an effect difference of 2 or more in the NPI apathy score. Four of these predictors had a significant interaction with the treatment. Methylphenidate was more effective in participants less likely to have baseline anxiety (‐3.1, 95% CI ‐5.7 ‐ ‐0.5, p = 0.023) or agitation (‐3.6, 95% CI ‐6.1 ‐ ‐1.1, p = 0.005) as measured by the NPI, taking a cholinesterase inhibitor (‐4.1, 95% CI ‐6.7 ‐ ‐1.3, p = 0.004), taking at least one AD medication (‐4.0, 95% CI ‐6.9 ‐ ‐1.1, p = 0.008), highly educated (‐2.1, 95% CI ‐5.4 – 1.3, p = 0.231), and low functional capacity (‐2.6, 95% CI ‐5.55 – 0.26, p = 0.076) as measured by the Activities of Daily Living scale. Conclusion: Individuals who were less anxious or agitated, more highly educated, on treatment for Alzheimer's disease, and with low functional capabilities were more likely to benefit from methylphenidate when compared to placebo. Consistent with its potential activating effects, methylphenidate may be particularly beneficial for subgroup of apathetic AD participants with lower baseline anxiety and agitation. [ABSTRACT FROM AUTHOR]

Background: Apathy is one of the most common and debilitating neuropsychiatric symptoms of Alzheimer's Disease (AD). Two previous trials that suggested methylphenidate was safe and efficacious involved only 60 participants each, followed for 6 weeks. A larger, longer‐lasting trial was required to confirm those promising findings. Methods: ADMET 2 was a phase III, placebo‐controlled, 6‐month, multi‐center, randomized (1:1, 20 mg methylphenidate per day or placebo) clinical trial that randomized 200 participants with AD and apathy. Primary outcomes included: (1) the mean difference on the Neuropsychiatric Inventory Apathy (NPI‐A) subscale scores measured as change from baseline to 6 months, and/or (2) the odds of a rating of improvement on the modified AD Cooperative Study Clinical Global Impression of Change (ADCS‐CGIC) at month 6 compared with baseline. Secondary outcomes included change in cognition, safety, and cost‐effectiveness measured monthly for up to 6 months. Results: 200 individuals were randomized (65.8% were males; 34.2% were females; avg age=76 years; 75.3% had some college education or greater; mean Mini‐Mental State Examination score at baseline was 18.9). There was a larger difference in the methylphenidate group compared with the placebo group in NPI‐A score from baseline to 6 months using a mixed model (Mean difference = ‐1.25; 95% CI: ‐2.03, ‐0.47, p = 0.002) with the largest change observed during the first two months. At 6 months, the ADCS‐CGIC showed that 43.8% (39/89) of participants in the methylphenidate group improved compared with 35.2% (32/91) of study participants in the placebo group (odds ratio 1.90 (95% CI: 0.95, 3.84), favoring methylphenidate, but not reaching statistical significance (p = 0.071)). There were no significant differences in other assessments. The safety profile was similar between the two groups. Conclusion: ADMET 2 showed a small to medium benefit for methylphenidate in the treatment of apathy in AD. The effect was observed at 2 months and was sustained throughout the 6 months of the study. Adverse events were mild. These results support previous observations in smaller studies. Methylphenidate offers a viable treatment for patients suffering from apathy in AD. [ABSTRACT FROM AUTHOR]

Background: Previous studies have identified genetic risk factors for Alzheimer Disease (AD). In the Amish community, many individuals maintain normal cognitive function at older ages, despite having relatively high genetic risk of AD. These individuals may carry protective alleles that buffer the genetic risk. To find such loci, we utilized the Amish family structures to apply a modified genetic linkage analytical tool that considered genetic risk of AD. Method: Cognitive status in adult Amish subjects (n=1,855) was assigned using the modified mini‐mental status exam (3MS). Individuals aged ≥ 75 with 3MS ≥ 87 were classified as CN. Those with 3MS < 87 were classified impaired (CI), regardless of age. Genome‐wide genotypes were used to impute ∼7 million variants using the HRC imputation reference panel. For genome‐wide linkage analysis, we selected 2,167 SNPs and analyzed 110 sibships with ≥ 2 CN members. Adjusting for known genetic risk, we applied ordered subsets analysis (OSA) to rank families by mean Genetic Risk Score (GRS) of CN members. GRS was derived from 27 genome‐wide AD loci (Kunkle et al, 2019). Regions with significant increases in linkage (LOD*) were assessed by mixed model genetic association testing. Result: Ranking sibships by high‐to‐low mean GRS, significant increases in the LOD* after OSA were observed at ∼40 Mb on chromosome (Chr) 19 (peak LOD*=2.176, p=0.009) and ∼49 Mb on chr 18 (peak LOD*=2.23, p=0.03). While linkage to chr 19 may result from known AD loci, the observed linkage to chr 18 does not overlap known risk loci. Mixed model association testing within a 5 Mb region of the peak linkage to chr 18 was performed in 1,036 SNPs with minor allele frequency ≥ 0.01. Individuals with a GRS ≥ 3.65, corresponding to the GRS in the 17 families with the strongest LOD* increase, were considered (n=236). The strongest association occurred at rs12969463 (p=0.002, OR = 2). Conclusion: This study detected increased evidence of linkage and association for protective AD loci on chr 18, considering CN individuals with the highest risk from known AD loci. One or more protective alleles that buffer this increased risk may be located in this region. [ABSTRACT FROM AUTHOR]

Background: While studying cognition in the Amish, we have observed strong performance on the constructional praxis delayed recall (CPDR) as compared to other cognitive tests, independent of overall cognitive status. This may indicate a preferential preservation of visuoconstructive memory in this population. Here, we investigate this by comparing the CPDR to the word list delayed recall (WLDR) while controlling for relationship, genetic risk of Alzheimer disease, and other covariates. Method: Amish individuals > 65 years of age (mean age=82) in Indiana/Ohio were examined (n=512) and assigned by consensus review to Normal, MCI/Borderline, or Impaired cognitive status. Paired t‐tests were used to compare the CPDR and WLDR Z‐scores. Using genome‐wide genotype data, a kinship matrix and principal components (PCs) estimating population substructure were calculated. Genetic Risk Scores (GRS) were also calculated using genome‐wide significant variants from Kunkle et al. (2019), weighted by log odds ratio estimates. Using linear regression adjusting for relatedness, we modeled the contribution of GRS, PC1, PC2, cognitive status, age, sex, and education level to the difference between the CPDR and WLDR Z‐scores. Result: We found a significantly better performance on CPDR over WLDR in every cognitive status group, with this difference between Z‐scores being 1.02 units for Normal, 1.72 units for MCI/Borderline, and 1.58 units for Impaired. Linear regression of this difference in Z‐scores found significant associations with age, sex, and cognitive status. The effect size of cognitive status was 0.65 units for MCI/Borderline and 0.50 units for Impaired, with Normal as the reference category. This indicates that MCI/Borderline and Impaired individuals have a significantly larger gap between CPDR and WLDR Z‐scores than Normal individuals. Conclusion: These results suggest that the Amish may preserve memory of constructional praxis relative to word list, especially in MCI/Borderline and Impaired individuals. This indicates that impaired Amish individuals, including those with Alzheimer disease, may decline at a slower rate in visuoconstructive memory than other domains. Genetic Risk Score was not significantly associated with this preferential preservation of constructional praxis, suggesting that it may not be explained by known risk genes. This warrants further studies to identify genetic and other factors associated with this preferential preservation. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease is the most prevalent type dementia and has a strong genetic component. Much of AD genomic research has focused on identifying risk variants, primarily in European ancestry populations. After immigration to the United States, the Amish experienced a genetic bottleneck, making it likely that their underlying genetic architecture is different from the broader European ancestry population. Here, we compare the genetic risk for Alzheimer's disease in an Amish and general European ancestry population using genetic risk scores (GRSs). Method: 1,981 adults were recruited from Amish communities in Indiana and Ohio. A non‐Amish population of 2,470 adults were recruited from clinics in Tennessee, North Carolina, and Florida as a comparison group. Subjects were screened for cognitive impairment and further evaluated for AD and dementia. Genotype data were collected using Illumina genotyping chips. Imputation was performed based on a 1,000 Genomes reference panel. GRSs were generated using genome‐wide significant variants from Kunkle et al., (2019), weighted by their log‐odds ratios. We compared the GRSs by source population and case status. Further, we evaluated their predictive ability on AD status with and without sex, age, and APOE genotype covariates. Result: The results indicated that there exists less variation in GRSs among the Amish population. This is evident in how the four highest GRSs belonged to non‐Amish individuals. The median GRS of Amish cases was also moderately lower overall among Amish cases (0.0163) compared to non‐Amish cases (0.0171). In the Amish population, area under curve (AUC) of the GRS model was strengthened considerably from 0.541 to 0.872 by inclusion of the sex and age covariates and slightly (AUC=0.883) by further inclusion of APOE genotype. In the non‐Amish group, inclusion of sex and age improved AUC from 0.583 to 0.697 and to 0.817 by subsequent inclusion of APOE genotype. Conclusion: These results suggest that the Amish have a different genetic architecture than a general European‐ancestry population, manifesting itself in less overall variation but also a lower relative importance of APOE. Since the prevalence of dementia in the Amish is similar to the general European population, this suggests the Amish may harbor unique AD genetic risk variants. [ABSTRACT FROM AUTHOR]

Background: Most studies on Alzheimer Disease (AD) have focused on the identification of variants associated with increased risk. The Amish is a genetically homogeneous population ideal to investigate susceptibility genes for complex traits such as AD. This study aims to use family‐based linkage and association approaches to identify genetic variants that protect against the development of cognitive impairment (CI), the central feature of AD. Method: A total of 800 adults from Amish communities in Indiana and Ohio were screened for CI using the 3MS test. Individuals were classified as cognitively normal (CN) if the 3MS score was ≥87 at age 75 and cognitively impaired if < 87 at any age. Samples were genotyped on the Illumina Infinium Global Screening or Expanded Multi‐Ethnic Genotyping Array. Over 7 Million common and rare variants were then imputed using the HRC reference panel. For the linkage analysis 75 nuclear families containing at least two CN individuals were analyzed using Merlin to fit multipoint non‐parametric linkage models and parametric affected‐only (AO) dominant and recessive models using a map of more than 40,000 genotyped markers. The genome‐wide association study (GWAS) of imputed variants utilized the program Genesis to fit a logistic regression model 426 CN to 360 CI, associating each variant with cognitive status while adjusting for sex, pc1, pc2 and relatedness. Result: The top linkage peaks were seen in the parametric multipoint AO dominant model: Chr3 (HLOD = 2.6) ∼3.9 mb region (21.0 mb – 24.9 mb) and Chr11 (HLOD 2.1) ∼6.5 mb (11.0 mb – 17.5 mb). In the GWAS analysis, no variants reached genome wide significance (5 × 10−8). However, using a lower significance threshold for regional association under a linkage peak (p < 10−5), 7 associated variants were identified in two regions under the Chr11 peak. Conclusion: We identified a 6.5 mb area of interest on chromosome 11 associated with preserved cognitive function in Amish adults over age 75, which is near OTOG a previously reported gene associated with AD. This region merits further investigation for functional variants that might slow or prevent the development of cognitive impairment in older adults. [ABSTRACT FROM AUTHOR]

Background: Most genetic studies on Alzheimer's disease (AD) have focused on finding risk genes and variants. Taking into account the 30+ loci identified to increase risk of AD, still only around 40‐50% of the estimated heritability of AD is explained. Our goal is to identify genetic variants that delay the onset or protect against the development of AD and to find novel gene interactions or pathways associated with AD. Method: Our study focuses on the Amish communities in Ohio and Indiana due to their homogeneous genetics and environment. Studying genetics in the Amish increases our ability to find rare protective variants for AD that do not exist at a detectable frequency in the general population. Our focus is to identify individuals who are cognitively normal (CN), but at high risk for developing AD (i.e. have an affected sibling). Each of these individuals is retested every two years to assess their cognition status. Results: Using the extensive genealogical data of families in the Amish population, we have generated a large ∼5,000 person, 13‐generation pedigree. As of January 2020, we have ascertained 652 individuals and are examining over 300,000 SNPs that were retained after preliminary QC. Out of the recently adjudicated enrollments, 55 percent are cognitively normal, 33 percent are borderline or cognitively impaired, and the remainder have been sampled and are awaiting a consensus diagnosis. The frequency of the APOE‐e2 allele in our enrollments is at 5%, while the APOE‐e4 allele is at 14%, is lower than the general European population. We are currently using KING and GENESIS software to QC the data since they take into account more relatedness in a population structure, which is needed for working with the Amish. Association and linkage analyses, taking into account the complex pedigree relationships, is ongoing. Conclusion: We are using a founder population to have an increased chance of finding protective genetic variants in AD. We are specifically targeting individuals who are at high risk for developing AD, but seem to be resilient. This is important in discovering novel pathways in which AD functions, which can lead to further functional and pharmaceutical studies. [ABSTRACT FROM AUTHOR]

Background: The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated a significant reduction in the occurrence of mild cognitive impairment (MCI) for adults with hypertension randomly assigned to intensive systolic blood pressure (SBP) lowering and a similar but non‐significant effect on incidence of dementia.. Given that individuals with MCI are at greater risk of progressing to dementia, an open question from the trial is the frequency of progression in cognitive status subsequent to an adjudication of MCI, and whether this associates with intensive SBP lowering. Method: Randomized trial of community‐dwelling adults (≥50 years) with hypertension. Participants were randomized to a SBP goal of <120 mm Hg (intensive treatment; n=4678) or <140 mm Hg (standard treatment; n=4683). Adjudication of MCI or dementia followed standardized procedures by a panel of expert clinicians. Multistate survival models were used to examine transitions in cognitive status between normal cognitive function, MCI, and dementia, accounting for the competing risk of death. Result: Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 91.5% completed at least 1 follow‐up cognitive assessment over a median follow‐up of 5.1 years. Based on multistate modeling, from a state of normal cognitive function, the risk of transitioning to dementia in the next 2 years was 1.1% [95% Confidence Interval (CI): 1.0% to 1.3%]), with 2.3% [95% CI: 2.1% to 2.5%] of participants dying over that same interval. Subsequent to an adjudication of MCI, the probability of progressing to dementia in the next 2 years increased to 6.4% [95% CI: 5.3% to 7.8%], with the risk of death increasing to 8.2% [95% CI: 6.9% to 9.7%]. We did not observe any significant associations between treatment groups and transition risk within the multistate model, though power for these analyses was likely limited given the focus on complex transitions between multiple outcomes. Conclusion: An adjudication of MCI in SPRINT was associated with an increased risk of progression to dementia and death in the following 2 years, highlighting the relevance of MCI as an outcome both within SPRINT and for future prevention trials of cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a progressive neurological disease that leads to atrophy of the brain and cognitive decline. There are many factors that play a role in the risk of AD, such as age, smoking, gender, and genetics. the genetic influence on AD is strong, with heritability estimates between 40‐60%. Identifying genetic factors that either increase or decrease AD risk are critical in the understanding of this disease. Here, we studied a homogeneous, isolated population – the Ohio and Indiana Amish – to identify protective genetic factors for AD. Our previous studies in the Amish documented numerous individuals who are cognitively normal at advanced ages. Method: Here, we have completed a genome wide association study (GWAS) on Amish individuals who are at high risk for AD (i.e., have an affected sibling and are over 76 years of age), but are cognitively normal. We have genotypes on 2096 individuals, 921 of which are being analyzed for association, in which we have a complex 5,000‐person, 13‐generation pedigree to help inform our results. MEGAex and GSA chips were used for genotyping. Both KING and GENESIS software were used for quality control and association analyses since they control for both population structure and kinship in evaluating association via a generalized linear mixed model (GLMM). Result: We included 601 cognitively normal (CN), 320 cognitively impaired (CI) individuals. Association analysis was done on a total of 921 individuals, with 256,978 SNPs. We had a total of four SNPs reach a significance threshold of p ≤ 5 x 10‐5 to also include suggestive association loci in our examination. (Nearest genes: DISC1, IQGAP2, and LOC401478 on chromosomes 1, 5 and 8. One SNP on chromosome 13, rs1556774, has no gene association currently known, and no known gene within 80kb.) These loci are currently under further examination. Conclusion: We studied cognitively resilient individuals from a founder population to identify potential protective genetic variants for AD. We identified four SNPs associated with CN in at‐risk adults over 75. These loci might influence cognitive resilience. Here we have shed some light on possible genetic factors that may contribute to protection from cognitive decline. [ABSTRACT FROM AUTHOR]

Background: The Modified Mini‐Mental State (3MS) is a widely used measure of global cognition. The Old Order Amish are both genetically and environmentally homogeneous, with similar years of formal education across the population. Here, we investigated the longitudinal course of cognitive function as measured by the distribution of 3MS in the Mid‐Western Amish. Method: After extensive QC, the 919 subjects with both baseline 3MS and AD status were analyzed. The change from 1st to 2nd measurement was used as the main longitudinal trait of interest. Mean decline differences in 4 baseline age groups (<70, 70‐80, 80‐90, >=90) were assessed. The differences in the average longitudinal decline of 3MS between AD cases and controls was assessed using Kolmogorov‐Smirnov tests and ANCOVA adjusted for age at exam and sibship. Result: The overall baseline mean 3MS score was 89.52 [42, 100] at the mean age of exam 75.52 [60, 99]. The overall annual rate of decline was ‐0.3 [‐5, 5] from 1st to 2nd measurement (n=242) and ‐0.6 [‐2.1, 1.3] from 2nd to 3rd measurement (n = 23). The annual rate of decline was ‐0.96 [‐4, 1.7] in AD cases (n=18), ‐0.01 [‐5, 5] in AD controls (n=180) and ‐1.08 [‐5, 0.7] in an 'Unclear' group (n = 44). The most rapid annual decline of the 3MS was in age 80 to 90 group and the decline rate was significant (p‐value=0.004) compared to the lowest age group (<70) overall and in AD cases. In the Unclear group, the rate of decline was greatest in age 70 to 80. However, in the control group, cognition improved, with a 1.29 [‐1, 5] annual increase in age 80 to 90. The age and sibship adjusted differences in decline were significant (p‐value<2e‐10) between AD cases vs. controls as well as between Unclear vs. controls. Conclusion: We explored the changes of 3MS scores over time and demonstrated different patterns of decline by age and AD status in the Amish. Our study is the first in this homogeneous Amish population, providing a better understanding and insight into the cognitive decline examining the change in 3MS over time. [ABSTRACT FROM AUTHOR]