Aug 2026· Frontiers in Aging Neuroscience· Vol 18· 0 citations· 69 references
Medicine
TL;DR
Rare and common variants in AD- and neurodegenerative biomarker-associated genes with increased frequency in India compared to other populations may impact blood levels of neurodegenerative biomarkers in South Asians.
Abstract
Background Alzheimer’s disease (AD) and related dementias are a growing health and economic burden in India. Blood levels of amyloid beta (Ab), tau, and other proteins marking neuronal injury are biomarkers of AD risk and are potentially important for AD prevention. Methods In 2,224 participants from the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD), we performed gene-based analyses on (1) missense/loss-of-function (LoF) single-nucleotide variants (SNVs) and (2) brain-specific promoter/enhancer SNVs across 84 genes selected from AD GWAS and 25 gene-biomarker pairs selected from biomarker GWAS. We used variant-Set Test for Association using Annotation infoRmation (STAAR) across 7 neurodegenerative biomarkers measured in blood: Ab40, Ab42, Ab42/Ab40, total tau (tTau), tau phosphorylated at threonine 181 (pTau), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). We adjusted for age, sex, and genetic ancestry, with random intercepts for genetic relatedness and biomarker plate. Analyses incorporated weighted annotation scores (e.g., deleteriousness). Significant results (FDR-q < 0.1) were followed up with single variant analysis. Genes were also assessed for sex- and age-interactions using iSKAT. Results Missense/LoF variants in 6 AD-associated genes (ECHDC3, CLU, APOE, EPHA1, ICA1L, CASS4) and 1 biomarker-associated gene (APOE) were associated with Ab40, Ab42/Ab40, pTau, and/or GFAP (FDR q < 0.1), with the most significant SNVs tending to be rare/low-frequency (MAF ≤ 0.05) and potentially deleterious. Promoter/enhancer variants in 1 AD-associated gene (CCDC6) were associated with Ab42/Ab40, with the index SNV being a potentially deleterious common variant (MAF = 0.27). Several associated variants appeared to have higher frequency in India compared to other global populations. Missense/LoF SNVs in two AD genes (EPHA1, MS4A6A) had sex-specific effects on Ab42 and/or tTau, and promoter/enhancer SNVs in four AD genes (DGKQ, MS4A6A, MS4A4A, JAZF1) had sex-specific effects on tTau and/or pTau. Missense variants in 12 AD genes and promoter/enhancer variants in two AD genes showed interaction with age on at least one biomarker, primarily GFAP and NfL with genetic effects tending to be stronger at older ages. Conclusion Rare and common variants in AD- and neurodegenerative biomarker-associated genes with increased frequency in India compared to other populations may impact blood levels of neurodegenerative biomarkers in South Asians.
A stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.
Keun You Kim, Hyunsun Ham, E. Yoon et al.· The journal of prevention of...· 0 citations
In cognitively unimpaired older adults, elevated blood p-tau217 was linked to faster shrinkage in AD-specific brain regions, whereas NfL and GFAP were associated with more widespread atrophy, with NfL also associated with accelerated WMH accumulation.
Martina Valletta, D. L. Vetrano, E. Laukka et al.· Annals of Neurology· 0 citations
In low- and middle-income countries, Alzheimer’s disease (AD) constitutes a growing public health burden. However, AD biomarkers research remains underrepresented in African populations. This study assesses core biomarkers of AD and their relevance in the African context as potential aid in clinical diagnosis. Nigerian older adults from VALIANT cohort (n = 967) underwent biomarker quantification in plasma (p-tau217, GFAP, NfL, Aβ42 and Aβ40) employing both the Single Molecule Assay (Simoa, Quanterix) and Nucleic acid-Linked Immuno-Sandwich Assay (NULISA, Alamar). Biomarkers were associated with disease severity in clinical-diagnostic and clinical-biological groups, with stepwise increases of p-tau217, NfL and GFAP from cognitively unimpaired to dementia (p < 0.05). Results were consistent across platforms. Comparison between sexes showed higher biomarker levels in male participants across diagnostic groups. A significant effect of apoE-E4 proteotype on p-tau217 levels, after adjusting for age and sex was identified. These findings support the application of plasma AD biomarkers in the African context and the relevance of further AD biomarker research in diverse populations.
T. Akinyemi, I. Pola, K. Tan et al.· npj Dementia· 0 citations
ABSTRACT Background In Alzheimer's disease (AD), neurodegeneration is primarily attributed to the accumulation of tau neurofibrillary tangles. However, the distribution patterns of both tau pathology and neurodegeneration vary across different brain regions and among individuals. Moreover, multiple factors may influence the relationship between tau burden and neurodegenerative processes. Identifying the genetic architecture associated with deviation in the tau‐neurodegeneration relationship can provide deeper mechanistic insights and guide the development of precision medicine strategies. Methods Here, I perform a genome‐wide association study (GWAS) of cortical tau and thickness quantified by positron emission tomography (PET) and magnetic resonance imaging (MRI) in 794 participants from two cohorts of Alzheimer's disease Neuroimaging Initiative (ADNI) and A4. Results A GWAS was identified between the Tau/Neurodegeneration residual and two novel loci on chromosomes 7 and 14, with two SNPs (rs9323573 and rs9784993) exceeding the genome‐wide significance threshold (p ≤ 5 × 10−8). SNP rs9323573 is located in STXBP6 on chromosome 14, while rs9784993 is in AKAP9 on chromosome 7, both of which were directly genotyped. The minor allele G of both SNPs (rs9323573, MAF = 0.221, p = 2.60 × 10−8; rs9784993, MAF = 0.197, p = 4.92 × 10−8) was associated with lower Tau/Neurodegeneration residuals, indicating higher‐than‐expected neurodegeneration given tau levels. Conclusion GWAS of tau‐related neurodegeneration identified two novel genetic variants in the loci AKAP9 and STXBP6 leading to higher than expected regional neurodegeneration given the tau level. Identifying genetic factors involved in tau‐neurodegeneration mismatch may improve our understanding regarding the potential mechanistic downstream leading to susceptibility or resilience to tau pathology.
F. Nabizadeh, Hanieh Mohamadi· CNS Neuroscience & Therapeut...· 0 citations
Introduction Hippocampal atrophy is frequently observed in neurodegenerative diseases such as Alzheimer’s disease (AD) or hippocampal sclerosis of aging (HS-aging). Volume loss in the hippocampus is described as prodromal stage of dementia and has been associated with AD polygenic risk score (PRS). CA1 and subiculum atrophy have been suggested to be a promising in vivo biomarker for HS-aging. Recent studies suggest that some loci associated with AD may be more related to other brain diseases concomitant with AD. We aimed to find which significant single nucleotide polymorphisms (SNPs) in the latest AD genome wide association studies (GWAS) could be potentially related with early atrophy of specific hippocampal subregions related to HS-aging. Materials and methods We used regression models to assess the relation of the AD-PRS, and genome-wide significant AD variants, with CA1 and subiculum volumes assessed by magnetic resonance imaging (MRI) in 1,859 participants without dementia (with mild cognitive impairment or cognitively healthy). Co-regulatory network analyses and over-representation enrichment analyses were conducted to identify biological pathways enriched with co-regulatory networks of genes associated with hippocampal subregion volumes. We meta-analyzed data from seven cohorts to associate their AD-PRS with AD in the presence of concomitant brain pathologies. Results Reduced volumes of CA1 and subiculum show association with higher levels of AD-PRS and with variant rs5848 in GRN. This variant was enriched in immune-related pathways. AD-PRS showed no significant association with AD pathology alone, but was strongly associated with AD in the presence of concomitant neurodegenerative pathologies, with HS-aging showing the largest effect size. Discussion Specific AD-SNPs enriched in immune-brain axis pathways rather than Aβ related processes, were associated with reduced volumes of CA1 and subiculum prior to dementia onset. This supports that AD-PRS may capture genetic susceptibility to concomitant neurodegenerative diseases frequently misdiagnosed as AD. Given that AD-PRS is most strongly associated with AD in cases with HS-aging, and that CA1 and subiculum are promising in vivo biomarker for HS-aging also linked with rs5848 in GRN, our findings are consistent with HS-aging related vulnerability. This insight links early hippocampal subfields atrophy to shared genetic mechanisms and biological pathways of interest.
C. Olivé, Itziar de Rojas, Linda Zhang et al.· Frontiers in Aging Neuroscie...· 0 citations
Increased serum p-tau217 and decreased ApoE levels were significantly associated with greater AD severity, suggesting that both biomarkers may serve as complementary noninvasive indicators of disease severity in Alzheimer’s disease.
Ahmed Kadom Kalaf, Khawla A. Shemran, Waleed Azeez AlAmeedy· International Journal of Nut...· 0 citations
