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.
Highlights
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]
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
Cognitive impairment among older individuals is a complex convergent trait that often occurs with mixed pathology: AD, Lewy body disease (LBD), and VBI, which each have prevalent prodromal and latent stages in addition to full clinical expression as dementia
Summary
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]. While each of these diseases exclusively can cause dementia, they commonly coexist in older patients with dementia [2]. These same brain autopsy studies commonly observed pathologic changes of AD, LBD, and/or VBI in older individuals carefully demonstrated to be cognitively normal proximate to death. 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. 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
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