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Alzheimer's genetic risk is reduced in primary age-related tauopathy: a potential model of resistance?

ABSTRACT: Objective:Nearly all adults >50 years of age have evidence for neurofibrillary tau tangles (NFTs) and a significant proportion of individuals additionally develop amyloid plaques (A?) consistent with Alzheimer's disease (AD). In an effort to identify the independent genetic risk factors for NFTs and A?, we investigated genotypic frequencies of AD susceptibility loci between autopsy-confirmed AD and primary age-related tauopathy (PART), a neuropathological condition defined by characteristic neurofibrillary tau tangles (NFTs) with minimal or absent A?. Methods:General linear models assessed the odds of AD (N = 1190) relative to PART (N = 376) neuropathologically confirmed cases from two independent series: the Penn Brain Bank (PENN; AD N = 312; PART N = 65) and National Alzheimer's Coordinating Center (NACC; AD N = 878; PART N = 311). We also evaluated the odds of Braak stage NFT burden. Results:Three genotypes significantly associated with reduced AD risk relative to PART in the PENN (N = 377) and NACC (N = 1189) cohorts including APOE ?4, APOE ?2, and rs6656401 in the CR1 gene. The genotypes rs6733839 in the BIN1 gene and rs28834970 in the PTK2B gene approached significance in the PENN cohort and were significantly associated with reduced AD risk in the NACC cohort. In a combined cohort analysis (N = 1566), APOE ?4 dosage was highly associated with higher Braak stage of NFT burden in Probable PART and AD, but not Definite PART. Interpretation:The presence of genotypic differences between PART and AD suggest that PART can provide a genetic model of NFT risk and potential A? resistance to inform disease-modifying therapies.

SUBMITTER: McMillan CT

PROVIDER: S-EPMC6093846 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Alzheimer's genetic risk is reduced in primary age-related tauopathy: a potential model of resistance?

McMillan Corey T CT Lee Edward B EB Jefferson-George Kyra K Naj Adam A Van Deerlin Vivianna M VM Trojanowski John Q JQ Wolk David A DA

Annals of clinical and translational neurology 20180619 8

<h4>Objective</h4>Nearly all adults >50 years of age have evidence for neurofibrillary tau tangles (NFTs) and a significant proportion of individuals additionally develop amyloid plaques (A<i>β</i>) consistent with Alzheimer's disease (AD). In an effort to identify the independent genetic risk factors for NFTs and A<i>β</i>, we investigated genotypic frequencies of AD susceptibility loci between autopsy-confirmed AD and primary age-related tauopathy (PART), a neuropathological condition defined ...[more]

PMID: 30128317

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Project description:Alzheimer's disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer's disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer's disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer's disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer's disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer's disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0-16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer's disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer's disease and primary age-related tauopathy.

Dataset Information

Alzheimer's genetic risk is reduced in primary age-related tauopathy: a potential model of resistance?

Publications

Alzheimer's genetic risk is reduced in primary age-related tauopathy: a potential model of resistance?

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