Sex Differences in Risk for Alzheimer’s Disease Related to Neurotrophin Gene Polymorphisms: The Cache County Memory Study

Abstract

Neurotrophins, including nerve-growth factor and brain-derived neurotrophic factor, have been implicated in Alzheimer's disease (AD). Associations between AD and neurotrophin signaling genes have been inconsistent, with few studies examining sex differences in risk. We examined four single-nucleotide polymorphisms (SNPs) involved in neurotrophin signaling (rs6265, rs56164415, rs2289656, rs2072446) and risk for AD by sex in a population-based sample of older adults. Three thousand four hundred and ninety-nine individuals without dementia at baseline [mean (standard deviation) age = 74.64 (6.84), 58% female] underwent dementia screening and assessment over four triennial waves. Cox regression was used to examine time to AD or right censoring for each SNP. Female carriers of the minor T allele for rs2072446 and rs56164415 had a 60% (hazard ratio [HR] = 1.60, 95% confidence interval [CI] = 1.02-2.51) and 93% (HR = 1.93, 95% CI = 1.30-2.84) higher hazard for AD, respectively, than male noncarriers of the T allele. Furthermore, male carriers of the T allele of rs2072446 had a 61% lower hazard (HR = 0.39, 95% CI = 0.14-1.06) than male noncarriers at trend-level significance (p = .07). The association between certain neurotrophin gene polymorphisms and AD differs by sex and may explain inconsistent findings in the literature.

Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice

“…Lastly, females appear to be more vulnerable to AD than males [ 71 , 72 , 73 ] thus future studies should examine the effect of Pg/gingipain in female mice also.…”

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

“…LDLR, low-density lipoprotein receptor; LRP1, LDLR-related protein 1; NMDAR, N-methyl-D-aspartate receptor. (Lehmann et al, 2003) BDNF rs6265 Female-specific association with LOAD, LOAD endophenotypes (cognitive dysfunction, CSF tau and Aβ, atrophy) and reduced BDNF expression in the brain (Li et al, 2017;Matyi et al, 2017) Female-specific association with LOAD, CSF total tau and neurofibrillary tangle density (Deming et al, 2018) IL10* rs1800896 Increased risk in females; epistasis with CYP19A1 polymorphism (Medway et al, 2014) KIBRA* (WWC1) rs3733980 Increased risk in males; epistasis with TLN2 polymorphisms; colocalization of KIBRA with TLN2 in LOAD brains and modulation of tau toxicity (Gusareva et al, 2018) rs1477307…”

“…rs13115400 Female-specific association with LOAD and Aβ42 levels (Deming et al, 2018) MCPH1 rs13259125 Increased risk in males; protection in females (Prokopenko et al, 2020) MPO rs2333227 Increased risk in females, reduced risk in males (Reynolds et al, 1999) NGFR rs2072446 Increased risk in females (Matyi et al, 2017) RELN rs528528 Increased risk in males (Fehér et al, 2015) rs607755…”

BDNF Val66Met Polymorphism and Gamma Band Disruption in Resting State Brain Functional Connectivity: A Magnetoencephalography Study in Cognitively Intact Older Females

“…This is an important issue because the reduced dependent release of BDNF could vary from 18% for one Met allele to 29% in the Met/Met homozygous cases (Chen et al, 2006 ). In addition, analyzing additive or gene-gene interactions (Kauppi et al, 2014 ; Kennedy et al, 2014 ), ethnicity (Brooks et al, 2014 ; Lin et al, 2014 ), other BDNF's SNPs (e.g., rs56164415 or rs2072446) (Matyi et al, 2017 ), their epigenetic modulation, and gender differences, could also contribute to clarify BDNF's role in human brain functioning and neurodegeneration (Boulle et al, 2012 ; Honea et al, 2013 ).…”

“…However, it is well-known that BDNF production decreases with age (Mattson and Magnus, 2006 ) and more importantly, with the emergence of Alzheimer's Disease (AD)-related neuropathology (Qin et al, 2017 ). With this background in mind, recent literature (Matyi et al, 2017 ) has focused on exploring the association between several BDNF single nucleotide polymorphisms (SNPs) and this neurodegenerative disorder, providing additional evidence in support of the interest of further studying this relationship.…”