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Background: Late onset dementia due to Alzheimer's disease (AD) has a sex‐biased incidence with females comprising nearly two thirds of all cases. Females have a more rapid progression in cognitive decline and higher levels of known AD biomarker pathology compared to men. Genetic sequence variation does not account for the sex‐biased incidence of AD, directing attention to the emerging role of epigenetics in AD. Using whole genome methylation sequencing (WGMS), we previously reported 28,038 differentially methylated position (DMPs) within 2,707 genes between persons with and without AD. Here we report sex‐specific DNA methylation levels in AD. Method: WGMS data quantified DNA methylation levels at 25,406,945 CpG loci in 281 blood samples from 109 AD (47 female, 62 male) and 174 cognitively unimpaired (CU) individuals (90 female, 84 male) in the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention cohorts. Beta‐binomial regression models were developed to test for significant sex‐specific DNA methylation levels between CU and AD accounting for batch effects, estimated white blood cell proportions, BMI, and age. P‐values were corrected and local false discovery rates (lFDRs) were calculated. Result: 13,293 DMPs were identified in females and 20,719 DMPs were identified in males (Figure 1) when comparing CU and AD (lFDR < 0.05; mean methylation difference > 2.5%). Approximately 2% (280) of the DMPs overlap between sexes with 87 having opposite mean methylation differences. The majority of DMPs annotate to introns (55.9% females; 54.8% males) with most of the remainder intergenic (37.0% females; 37.9% males). Annotation of DMPs to genes identified 1,498 genes that are only differentially methylated in females, and 2,183 genes that are only differentially methylated in males, with 1,365 differentially methylated genes shared between females and males (Figure 2). Gene ontological analyses identified significant enrichment of pathways related to glutamate receptor and ion channel activity in shared gene sets (Figure 3). Conclusion: 33,732 unique, sex‐specific DMPs in AD were identified with more than 60% annotated to one of 5,067 genes. DMP‐associated genes have sex‐specific DNA methylation levels suggesting that these DMPs may play a role in the biased pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Background: DNA microarray‐based studies report differentially methylated positions (DMPs) in blood between cognitively unimpaired persons (CU) and persons with late‐onset dementia due to Alzheimer's disease (AD) or Mild Cognitive Impairment (MCI) but interrogate less than 4% of the human genome. Whole genome methylation sequencing (WGMS) quantifies DNA methylation levels across the entire human genome (>25 million CpG loci). Using WGMS, we previously reported 28,038 DMPs within 2,707 genes between persons with and without AD. Method: We used WGMS to measure DNA methylation levels in nuclear genes encoding proteins that participate in mitochondrial function as cataloged in the Human Protein Atlas in blood samples from participants with AD (N = 109) and MCI (N = 99) compared to CU (N = 174). DNA methylation levels were compared cross‐sectionally in the Wisconsin Alzheimer's Disease Research Center (WADRC) and the Wisconsin Registry for Alzheimer's Prevention (WRAP) cohorts. ParticipantAPOE allele and demographic information are provided in Table 1. Result: Mitochondrial‐related genes (N = 1,121) were differentially methylated (local false discovery rate [lFDR] < 0.01) in persons with AD (N = 218) and MCI (N = 421) compared to CU controls. Gene ontology pathway analyses of differentially methylated genes observed in both AD and MCI groups (N = 142) are enriched for multiple terms, including myristoyl‐CoA hydrolase, palmitoyl‐CoA hydrolase, and thiolester hydrolase activity (Figure 1). Differentially methylated genes align with differentially expressed genes that support beta‐oxidation (acyl‐CoA dehydrogenase family member 9 [ACAD9]) and fatty acid transport into mitochondria (carnitine palmitoyl transferase I [CPT1A]) in blood from persons with AD. Conclusion: Disordered pathways that participate in beta‐oxidation and fatty acid metabolism have been identified in large‐scale multi‐omic reports of AD histopathology. Present data indicate that corresponding changes in the methylome play a role in mitochondrial pathways known to contribute to the pathogenesis of AD and may serve as candidates for diagnosis and intervention. [ABSTRACT FROM AUTHOR]

INTRODUCTION: DNA microarray‐based studies report differentially methylated positions (DMPs) in blood between late‐onset dementia due to Alzheimer's disease (AD) and cognitively unimpaired individuals, but interrogate < 4% of the genome. METHODS: We used whole genome methylation sequencing (WGMS) to quantify DNA methylation levels at 25,409,826 CpG loci in 281 blood samples from 108 AD and 173 cognitively unimpaired individuals. RESULTS: WGMS identified 28,038 DMPs throughout the human methylome, including 2707 differentially methylated genes (e.g., SORCS3, GABA, and PICALM) encoding proteins in biological pathways relevant to AD such as synaptic membrane, cation channel complex, and glutamatergic synapse. One hundred seventy‐three differentially methylated blood‐specific enhancers interact with the promoters of 95 genes that are differentially expressed in blood from persons with and without AD. DISCUSSION: WGMS identifies differentially methylated CpGs in known and newly detected genes and enhancers in blood from persons with and without AD. Highlights: Whole genome DNA methylation levels were quantified in blood from persons with and without Alzheimer's disease (AD).Twenty‐eight thousand thirty‐eight differentially methylated positions (DMPs) were identified.Two thousand seven hundred seven genes comprise DMPs.Forty‐eight of 75 independent genetic risk loci for AD have DMPs.One thousand five hundred sixty‐eight blood‐specific enhancers comprise DMPs, 173 of which interact with the promoters of 95 genes that are differentially expressed in blood from persons with and without AD. [ABSTRACT FROM AUTHOR]

Background: Age is the most significant predictor of Alzheimer's disease and related dementias (ADRD). Biological age, in contrast to chronological age, is modifiable – shaped by environmental and social factors which contribute to the functional declines observed in aging. Accelerated biological aging has been observed in historically underrepresented populations in ADRD research who are at highest risk for developing ADRD. Telomere length (TL) is a marker of biological age and empirically associated with cognitive aging. However, this association has not been investigated in historically underrepresented populations such as American Indians / Alaska Natives (AI/AN). This study reports on the utility of TL to predict cognitive performance in a sample of middle‐aged and older adults from Wisconsin communities historically underrepresented in ADRD research. Method: The Wisconsin Alzheimer's Disease Research Center's (WADRC) Inclusion of Underrepresented Groups Core engages AI/AN, Blacks / African Americans (B/AA), and participants of multi‐race and ethnicity identities through community based participatory research practices. A sample (n = 188) identifying their race as AI/AN or B/AA were included if they provided whole blood and completed the Rey Auditory Verbal Learning Test (RAVLT, Trials 1‐5) and the Trails Making Test (TMT, A and B times) for verbal learning and executive functioning, respectively. DNA was extracted from whole blood and analyzed with monochrome multiplex quantitative polymerase chain reaction for TL. Multivariable linear regression analyses tested relationships between TL and cognitive test performance. Result: The participants (mean age = 60.88 ±9.06) were majority female, with 79.26% B/AA and 12.77% AI/AN (Table 1). In bivariate analyses, TL significantly correlated with all outcomes: longer telomeres correlated with better verbal learning and executive functioning performance (Figure 1A‐C). In multivariable regression models, TL significantly predicted cognitive performance for all outcomes independent of participant sex, race, age, and cognitive status (Table 2). Conclusion: These findings suggest that TL is a strong predictor of cognitive performance for historically underrepresented populations, offering potential opportunities for screening of accelerated biological aging and interventions. The community‐led research at the WADRC makes this analysis the first of its kind to include AI/AN participants. Future ADRD research should consider behavioral and socioeconomic interventions shown to modify biological aging. [ABSTRACT FROM AUTHOR]