Neuroprotective properties of estrogen have poorly translated to reduced neurodegeneration in clinical trials of systemic estrogen replacement therapy. To more directly assess biological processes ass Show more
Neuroprotective properties of estrogen have poorly translated to reduced neurodegeneration in clinical trials of systemic estrogen replacement therapy. To more directly assess biological processes associated with brain estrogen (estrone, estradiol) levels, we recruited 81 women (42 non-white) and 28 men (13 non-white) for cerebrospinal fluid (CSF) hormone, targeted proteomic, and volumetric brain analysis. In the mostly post-menopausal women, we found CSF estrogen levels to only modestly correlate with their corresponding plasma levels, and were additionally influenced by body mass index or age. CSF estrone was also correlated with a marker of Alzheimer’s disease (AD) neuropathologic change (CSF Aβ42/Aβ40), but this was not the case for the more biologically active CSF estradiol. Aptamer-based proteomic analysis of 1,075 CSF markers for inflammation, proteolysis, signaling, and DNA/RNA regulation revealed CSF estrogen levels to associate with alternative complement pathway proteins, and shifts observed in AD (apoE, RAGE). Parallel MRI analysis correlated higher CSF estrogen with smaller volumes of the brain somatosensory and posterior-medial networks without influence from cognition or neurodegeneration. Analysis using plasma estrogens only partially reproduced CSF estrogens’ biochemical correlates but provided inconclusive relationships with brain volume correlates. These findings highlight the association between CSF levels of the more biologically active estradiol and CSF inflammatory pathways involving AD risk genes as potential mechanisms linking hormone status to AD risks, and suggest caution in using CSF estrone or plasma estrogens when interpreting treatment or preventive studies. The online version contains supplementary material available at 10.1186/s12974-025-03657-3. Show less
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding var Show more
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Show less