Risk of Alzheimer's disease is associated with longitudinal changes in plasma biomarkers in the multi‐ethnic Washington Heights–Hamilton Heights–Inwood Columbia Aging Project (WHICAP) cohort

Gu, Yian; Honig, Lawrence S.; Kang, Min Suk; Bahl, Aanya; Sanchez, Danurys; Reyes‐Dumeyer, Dolly; Manly, Jennifer J.; Dage, Jeffrey L.; Lantigua, Rafael A.; Brickman, Adam M.; Vardarajan, Badri N.; Mayeux, Richard

doi:10.1002/alz.13652

Cited by 4 publications

(3 citation statements)

References 83 publications

(150 reference statements)

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“…We included 7,155 Hispanics decedents from the Washington Heights-Inwood Columbia Aging Project (WHICAP)[6] and the Estudio Familiar de Influencia Genética en Alzheimer (EFIGA)[7]. The WHICAP study is an ongoing prospective, community-based, multiethnic longitudinal study of Medicare beneficiaries 65 years and older residing in northern Manhattan (Washington Heights, Hamilton Heights, and Inwood).…”

Section: Methodsmentioning

confidence: 99%

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Multi-omics Characterization of Epigenetic and Genetic Risk of Alzheimer Disease in Autopsied Brains from two Ethnic Groups

Ma,

Reyes-Dumeyer,

Piriz

et al. 2024

Preprint

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Background: Both genetic variants and epigenetic features contribute to the risk of Alzheimer disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as the hub of both the genetic and epigenetic effects, in Hispanics decedents and generalized the findings to Non-Hispanic Whites (NHW) decedents. Methods: First, we derived the dosage of the CpG site-creating allele of multiple CGSes in each 1 KB window across the genome and we conducted a sliding window association test with clinical diagnosis of AD in 7,155 Hispanics (3,194 cases and 3,961 controls) using generalized linear mixed models with the adjustment of age, sex, population structure, genomic relationship matrix, and genotyping batches. Next, using methylation and bulk RNA-sequencing data from the dorsolateral pre-frontal cortex in 150 Hispanics brains, we tested the cis- and trans-effects of AD associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we checked their enriched pathways. Results: We identified six genetic loci in Hispanics with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score=55.2, P=4.06x10-8), between VRTN (Score=-19.6, P=1.47x10-8) and SYNDIG1L (Score=-37.7, P=2.25x10-9), SPG7 (16q24.3) (Score=40.5, P=2.23x10-8), PVRL2 (Score=125.86, P=1.64x10-9), TOMM40 (Score=-18.58, P=4.61x10-8), and APOE (Score=75.12, P=7.26x10-26). CGSes in PVRL2 and APOE were also genome-wide significant in NHW. Except for ADAM20, CGSes in all the other five loci were associated with Hispanic brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P=0.08), brain methylation levels in all the other five loci affected downstream RNA expression in the Hispanics (P<0.05), and methylation at VRTN and TOMM40 were also associated with RNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and synapse (FDR<0.05). Conclusions: We identified six CpG associated genetic loci associated with AD in Hispanics, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.

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Section: Methodsmentioning

confidence: 99%

“…Cohorts included for genetic studies We included 7,155 Hispanics decedents from the Washington Heights-Inwood Columbia Aging Project (WHICAP) [6] and the Estudio Familiar de Influencia Genética en Alzheimer (EFIGA) [7].…”

Section: Study Descriptionmentioning

confidence: 99%

Multi-omics Characterization of Epigenetic and Genetic Risk of Alzheimer Disease in Autopsied Brains from two Ethnic Groups

Ma,

Reyes-Dumeyer,

Piriz

et al. 2024

Preprint

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“…Therefore, use of Cox proportional hazards models is widespread in the AD risk literature (see e.g. [ 24 , 43 , 65 ]). We similarly used Cox regression models in the present study.…”

Section: Methodsmentioning

confidence: 99%

Subjective cognitive concerns, APOE ε4, PTSD symptoms, and risk for dementia among older veterans

Neale,

Fonda,

Miller

et al. 2024

Alz Res Therapy

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Background Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer’s disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups. Methods Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older. Results PTSD symptoms (B = 0.50–0.52, p < 1E-250) and probable TBI (B = 0.05–0.19, p = 1.51E-07 – 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13–1.21), APOE ε4 (HR = 1.73–2.05) and SCC (HR = 1.18–1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18). Conclusions The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.

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Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups

Ma,

Reyes-Dumeyer,

Piriz

et al. 2024

Acta Neuropathol

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Genetic variants and epigenetic features both contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10 –8 ), the intergenic region between VRTN and SYNDIG1L (Score = − 37.67, P = 2.25 × 10 –9 ), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10 –8 ), PVRL2 (Score = 125.86, P = 1.64 × 10 –9 ), TOMM40 (Score = − 18.58, P = 4.61 × 10 –8 ), and APOE (Score = 75.12, P = 7.26 × 10 –26 ). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20 , CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L ( P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH ( P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-024-02778-y.

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Risk of Alzheimer's disease is associated with longitudinal changes in plasma biomarkers in the multi‐ethnic Washington Heights–Hamilton Heights–Inwood Columbia Aging Project (WHICAP) cohort

Cited by 4 publications

References 83 publications

Multi-omics Characterization of Epigenetic and Genetic Risk of Alzheimer Disease in Autopsied Brains from two Ethnic Groups

Multi-omics Characterization of Epigenetic and Genetic Risk of Alzheimer Disease in Autopsied Brains from two Ethnic Groups

Subjective cognitive concerns, APOE ε4, PTSD symptoms, and risk for dementia among older veterans

Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups

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