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Title: Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias}
Article:
Abstract:
Alzheimer's disease( AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4, 914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD( neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy( CAA), Lewy body disease( LBD), hippocampal sclerosis of the elderly( HS), and vascular brain injury( VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene( APOE). GalNAc transferase 7( GALNT7), ATP-Binding Cassette, Sub-Family G( WHITE), Member 1( ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2( KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
Introduction:
Studies of brain aging with brain autopsy endpoint have repeatedly demonstrated that dementia in older individuals most often derives from three common diseases: Alzheimer's disease( AD), vascular brain injury( VBI) especially small vessel disease, and Lewy body( LB) disease( LBD)[1]. Importantly, while each of these diseases exclusively can cause dementia, they commonly co-exist in older patients with dementia[2]. These same brain autopsy studies also commonly observed pathologic changes of AD, LBD, and/or VBI in older individuals carefully demonstrated to be cognitively normal proximate to death. Indeed, it was these observations from cognitively intact “controls” that first led to the hypothesis of cognitive reserve, the idea of excess functional capacity that can mask clinical expression of disease. Biomarker and molecular neuroimaging studies also have observed abnormal changes in cognitively normal individuals that typically occur in patients with dementia, and have demonstrated with longitudinal observation that some of these changes are pathologic[3]. Thus, dementia in older individuals is a syndrome that derives most commonly from the idiosyncratic convergence of three chronic disease processes, AD, VBI, and/or LBD, that each appear to have prevalent latency prior to clinical expression. The suffering to patients and loved ones and cost to health care systems from the global burden of dementia are staggering, and projected to increase markedly in the coming 20 years[4]. While interventions exist to mitigate some types of VBI, the major unmet medical needs are disease-modifying therapies for AD and LBD. Many efforts are underway to achieve this therapeutic imperative, although none yet has met with reproducible success in clinical trials. One response to these setbacks is to revise the approach to existing therapeutic targets, such as using existing experimental interventions in earlier stages of disease or in selected subgroups. Another approach is to increase the repertoire of therapeutic targets by expanding our knowledge of the molecular drivers of disease; this rationale animates the several recent genome-wide association studies( GWAS) for AD[5]–[11]. Given the pathologic complexity of AD and related dementias, and the prevalence of latent disease, we hypothesized that direct analysis of neuropathologic features might align known genetic risk loci with specific diseases processes as well as identify novel genetic variants associated with specific neuropathologic features. To test these hypotheses the Alzheimer's Disease Genetics Consortium( ADGC) assembled a set of 4, 914 samples with genome-wide genotyping data and neuropathologic data, and performed genome-wide association tests of AD and related diseases. We performed both genome wide association and analyses focused on known AD dementia genetic risk loci while using three approaches to the neuropathologic data: a clinico-pathologic definition of AD dementia or controls, focus on the core neuropathologic features of AD, i. e., neurofibrillary tangles( NFTs) and neuritic plaques( NPs), in cases and controls combined, and inclusion of commonly co-morbid neuropathologic features observed in older individuals with dementia, i. e., cerebral amyloid angiopathy( CAA), LBD, hippocampal sclerosis in the elderly( HS), and VBI.
Discussion:
Cognitive impairment among older individuals is a complex convergent trait that often occurs with mixed pathology: AD, LBD, and VBI, which each have prevalent prodromal and latent stages in addition to full clinical expression as dementia. Indeed, approximately 95% of subjects without dementia in this age group have some pathologic evidence of at least one of these three diseases. These facts as first discovered in neuropathologic studies of brain aging and subsequently validated in part by neuroimaging and biomarker studies present serious challenges to diagnose accurately and comprehensively the diseases that cause an individual's dementia based exclusively on clinical data, and clearly demonstrate that age-matched control populations are variably, and potentially extensively, “contaminated” with latent disease. Virtually all previous GWAS of AD have been based on cases and controls defined exclusively by clinical criteria. To address this limitation, we undertook a GWAS of dementia that focused on neuropathologic data( i) to test the hypothesis that clinico-pathologic characterization of cases and controls could be used to strengthen previous genetic associations with AD made by clinical criteria,( ii) to test the hypothesis that genetic associations for AD dementia will selectively align with specific neuropathologic features, and( iii) to discover new genetic associations with neuropathologic features of AD and related dementias. Although we assembled a large brain autopsy cohort, it is still a relatively modest number of samples for GWAS compared to the larger IGAP GWAS where subjects were primarily clinically diagnosed cases and controls. The reduction in statistical power due to a smaller sample must be balanced against improved phenotypic homogeneity. With this balance in mind, our study confirmed 12 of the 21 previously reported loci as significantly associated with AD dementia. Our association with clinico-pathologic AD dementia was strengthened for 9 of these 12 loci( ABCA7, BIN1, CASS4, CD33, MEF2C, MS4A6A, PICALM, SORL1, and ZCWPW1), essentially unchanged for CLU and PYK2B, and diminished for CR1 to unity with increasingly stringent pathologic criteria. CR1 also is the only locus that we confirmed as associated with AD dementia that was not significantly associated with a specific neuropathologic feature. One possible explanation is that previous associations of CR1 with AD dementia may be related more to clinical expression of disease rather than to the accumulation of NPs and NFTs; it is of note though that CR1 has been associated with NPs and CAA previously[15]. The same may be true for the other 9 loci that were not confirmed in our clinico-pathologic case-control analysis; however, lack of confirmation also may be the result of limitations of smaller sample size outweighing the potential advantages of reduced phenotypic heterogeneity or perhaps even spurious associations in previous studies. Clinical expression of dementia encompasses at least several processes that include disease mechanisms that produce stress and injury, response to injury, physiologic compensation, and cognitive reserve. Our second major goal was to determine the alignment between AD dementia genetic risk loci and specific neuropathologic features that are core to( NPs and NFTs) or co-morbid with( LBD, VBI, HS, CAA) AD in an attempt to clarify the relevant molecular mechanisms that underlie these characteristic lesions that are related to injury and response to injury. Association tests for NFTs and NPs were significant for five of the previously reported loci that were validated in our clinico-pathologic GWAS( ABCA7, BIN1, CASS4, MEF2C, and PICALM); NFTs were specifically associated with CLU, SORL1, and ZCWPW1, and NPs were specifically associated with MS4A6A and CD33. In all instances the effect sizes for NPs or NFTs were in the same direction as the previously reported effects for AD dementia. Effects sizes for LBD were increased with SORL1 and decreased with MEF2C, and HS was associated with PTK2B; no significant association was observed between previously reported AD dementia loci and VBI or CAA. Association of LBD with SORL1 locus is novel and, interestingly, the effect size was in the direction opposite to its association with NFTs. The SORL1 locus has not been identified in previous studies of Parkinson's disease( PD), another LBD, but these were investigations of PD defined by its movement disorder rather than LBD in the context of AD dementia as we have done here; this unexpected association will require replication and further investigation. We analyzed NPs and NFTs as binary( any vs. none) and finer graded( ordinal) phenotypes; stronger associations were observed with binary analyses perhaps because of variation in assigning histopathologic stages to these characteristic AD lesions. We observed a linear correlation between the previously reported AD dementia effect sizes and the effect sizes for NPs and NFTs determined in our cohort whether we included all 21 IGAP loci or limited our analysis to the 12 loci confirmed in our clinico-pathologic investigation. We do not think this is a foregone conclusion. Indeed, the literature is replete with commentary that one or both of the core AD lesions are a product of brain aging rather than AD. Our results strongly support the view that the molecular drivers underlying the accumulation of NPs and NFTs in brain are largely shared with the molecular drivers of severely impaired cognitive function. Interestingly, there was not a significant correlation with CAA, suggesting that this other form of amyloidosis has a different genetic risk profile than NP accumulation. Using the same approach, correlation of effect sizes for IGAP loci with effect sizes for LBD was at best weakly positive, and for VBI was negative. This last observation was unexpected and, if validated, might indicate that the genetic risk architecture for AD and VBI are inversely related, an intriguing possibility that stimulates speculation over why this may be. It also suggests a possible approach to genetic stratification of risk for two of the most common causes of cognitive impairment and dementia in older individuals. Our third goal was genome-wide discovery of associations with the six neuropathologic features to gain additional insights into the molecular drivers of these characteristic lesions. As expected, there was a very strong association of the APOE locus with our clinico-pathologically defined AD dementia. We observed a strong association between the APOE locus and NFTs, NPs, CAA, and LBD, but not with HS or VBI. While the association of APOE with both core features and a secondary neuropathologic feature of AD is expected from ascertainment bias, the association with LBD may not be so simple. Indeed, an association between APOE and Dementia with Lewy bodies( DLB) has been varyingly supported or refuted in several smaller studies that did not include pathologic evaluation to exclude contribution from unknown and likely varying amounts of AD. However, in a recent large study of DLB and PD dementia that included pathologic evaluation, we demonstrated that inheritance of APOE ε4 allele is a significant risk factor for DLB even in the absence of AD[16]. In addition, our GWAS showed a genome-wide significant association between NPs and ABCG1, a locus previously implicated in AD[17]. The association of NPs with GALNT7 is novel and potentially reinforces existing genetic associations with other genes that encode for members of this family of transferases. Indeed, alteration in the O-glycosylation pattern of amyloid beta peptides and NPs has been reported in AD[18]–[20]. Finally, we made a novel association of HS with a variant of KCMNB2, which encodes a subunit of a Ca++-gated K+ channel that is key to neuronal excitability and is highly expressed by hippocampal pyramidal neurons in sector CA1. Although this discovery requires validation, it may have significance beyond AD dementia since HS also occurs frequently in some forms of fronto-temporal dementia. While additional replication datasets are ideal for these novel loci, we do note that the meta-analysis approach here is a type of replication, and that all of the novel variants with support from multiple datasets had no signs of heterogeneity of effect size. In summary, this genetic association study of autopsy brain enhanced some and diminished other known genetic risk loci for AD dementia, highlighted a subset of the loci previously associated with AD dementia as potential molecular drivers of specific neuropathologic features of AD, and discovered new genetic loci associated with specific neuropathologic features. These novel results provide new insights into new candidate therapeutic targets for AD and related dementias that will require validation and functional investigation.
Alzheimer's disease ( AD ) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis . We performed a genome-wide association study ( GWAS ) , as well as an analysis of known genetic risk loci for AD dementia , using data from 4 , 914 brain autopsies . Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases . Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample . Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear . Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias .