rs5848

Clustering analysis of 495 autopsied NACC subjects with TDP-43 proteinopathy identified four distinct neuropathologic and clinicopathologic groups differing by age at death and Alzheimer's disease neuropathologic changes severity. Genetic analysis of 114 subjects examined five TDP-43 disease risk SNPs, finding a suggestive trend for C9orf72 rs3849942 T allele association with earlier disease onset cluster (p=0.095).

This neuropathological study of 244 non-FTLD brains with TDP-43 pathology identified two distinct types based on inclusion morphology and neuronal context. TDP typeα (n=131) showed widespread TDP-43 deposition, higher prevalence of hippocampal sclerosis (60% vs 15%, p<0.001), and significant atrophy in amygdala (-10.6%, p=0.003) and hippocampus (-14.4%, p<0.001) compared to typeβ. Genetic analysis showed differences in TMEM106B haplotypes (rs3173615, p=0.01), with protective GG haplotype enriched in typeβ (24% vs 8%), supporting biological distinction between TDP-43 types.

Multi-cohort study investigating progranulin (GRN) mRNA expression in peripheral blood across Alzheimer's disease (AD), mild cognitive impairment (MCI), and control subjects. Progranulin expression was 13% higher in AD and MCI patients in the UCSF-MAC cohort (p=3.7×10⁻⁵) and replicated in AddNeuroMed (21% higher in AD, p=5.6×10⁻⁶), but not in ADNI. The rs5848 T-allele predicted 12.3% lower progranulin expression (p=0.02), and APOE4 showed independent positive association with expression.

This is the first genome-wide association study (GWAS) of hippocampal sclerosis of aging (HS-Aging), a common neuropathology in elderly individuals. The study analyzed 363 HS-Aging cases and 2,303 controls from multiple autopsy cohorts and identified that rs704178:G in the ABCC9 gene (ATP-binding cassette, sub-family C member 9, also known as sulfonylurea receptor 2) is associated with HS-Aging pathology with genome-wide significance (p = 1.4 × 10⁻⁹, OR = 2.13 in recessive mode). The authors also confirmed previously identified associations with rs5848 (GRN, OR = 1.16) and rs1990622 (near TMEM106B, OR = 1.22). Additionally, sulfonylurea drug exposure in elderly subjects (n = 624, age ≥85 at death) was associated with increased HS-Aging risk (p = 0.03), identifying a potentially targetable dementia risk factor.

This study analyzed 9 uric acid-regulating SNPs and 5 progranulin-regulating SNPs in 1,061 Parkinson's disease patients and 754 controls. A cumulative genetic risk score from 8 SNPs (SLC2A9 rs734553, ABCG2 rs2231142, SLC17A1 rs1183201, SLC22A12 rs505802, GCKR rs780094, PDZK1 rs12129861, LRRC16A/SCGN rs742132, SLC16A9 rs12356193) was significantly associated with increased PD risk (OR=1.55, p=0.012). The TMEM106b rs1020004 variant showed association with PD risk (p=0.003), and SORT1 rs646776 was associated with serum progranulin levels and PD-dementia risk.

Genome-wide association study of hippocampal sclerosis of aging (HS-Aging) pathology in 363 cases and 2,303 neuropathologically confirmed controls found that rs704178 in the ABCC9 gene (sulfonylurea receptor 2) was significantly associated with HS-Aging (p = 1.4 × 10⁻⁹, OR = 2.13 recessive). Sulfonylurea drug exposure was also associated with HS-Aging risk (p = 0.03) in elderly individuals age 85+. Previously reported SNPs rs5848 (GRN) and rs1990622 (TMEM106B) showed trends toward association with similar effect sizes.

A case report of a 63-year-old female patient (GS) with sporadic corticobasal syndrome (CBS) due to FTLD-TDP pathology. Genetic testing showed no mutations in MAPT or PGRN genes, but the patient was homozygous for the T allele of rs5848 (PGRN). Brain autopsy demonstrated ubiquitin and TDP-43 pathology consistent with FTLD-TDP, the first reported case of sporadic CBS-FTLD-TDP without a PGRN mutation.

This review article summarizes recent advances in amyotrophic lateral sclerosis (ALS) research, covering molecular genetics, environmental factors, phenotypic heterogeneity, prognostic factors, diagnostic challenges, neuroimaging, and clinical management. Key genetic findings include mutations in SOD1, TARDBP, FUS, MATR3, C9orf72 (the most common cause accounting for >1/3 of familial ALS and ~7% of sporadic cases), TBK1, CHCHD10, PFN1, and TUBA4A genes. The paper identifies UNC13A rs12608932 as a risk factor for ALS and a modifier of disease progression in Spanish and Italian populations.

This narrative review examines the role of microRNAs (miRNAs) in neuropsychiatric disorders including schizophrenia, bipolar disorder, major depression, Alzheimer's disease, and Parkinson's disease. The paper synthesizes studies on miRNA expression alterations in peripheral tissues and genetic variants in miRNA-related genes (SNPs in miRNAs, miRNA target genes, and miRNA processing genes), highlighting the potential of miRNAs as biomarkers for diagnosis and prognosis of brain diseases.

This functional study investigates how progranulin (PGRN) deficiency affects amyloid-beta dynamics and microglial responses in 5XFAD mouse models of Alzheimer's disease. PGRN deficiency reduced amyloid-beta and APP levels in young male mice but not females, while increasing lysosomal dysfunction and inflammatory markers (galectin-3, GPNMB, TREM2, CD68) in plaque-associated microglia, suggesting PGRN regulates neuroinflammation through lysosomal homeostasis.