SignificanceAlzheimer’s disease (AD) is an age-related neurodegenerative disease. Genome-wide association studies predominately focusing on Caucasian populations have identified risk loci and genes associated with AD; the majority of these variants reside in noncoding regions with unclear functions. Here, we report a whole-genome sequencing study for AD in the Chinese population. Other than the APOE locus, we identified common variants in GCH1 and KCNJ15 that show suggestive associations with AD. For these two risk variants, an association with AD or advanced onset of disease can be observed in non-Asian AD cohorts. An association study of risk variants with expression data revealed their modulatory effects on immune signatures, linking the potential roles of these genes with immune-related pathways during AD pathogenesis.

No abstract

Alzheimer's disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. Here, we report FAM222A as a putative brain atrophy susceptibility gene. Our crossphenotype association analysis of imaging genetics indicates a potential link between FAM222A and AD-related regional brain atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-β (Aβ) via its N-terminal Aβ binding domain, and facilitates Aβ aggregation. Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation and cognitive deficits in the AD mouse model. Our data support the pathological relevance of protein encoded by FAM222A in AD.

Increased presynaptic dysfunction measured by cerebrospinal fluid (CSF) growth-associated protein-43 (GAP43) may be observed in Alzheimer's disease (AD), but how CSF GAP43 increases relate to AD-core pathologies, neurodegeneration, and cognitive decline in AD requires further investigation. Methods: We analyzed 731 older adults with baseline β-amyloid (Aβ) positron emission tomography (PET), CSF GAP43, CSF phosphorylated tau181 (p-Tau 181 ), and 18 F-fluorodeoxyglucose PET, and longitudinal residual hippocampal volume and cognitive assessments. Among them, 377 individuals had longitudinal 18 F-fluorodeoxyglucose PET, and 326 individuals had simultaneous longitudinal CSF GAP43, Aβ PET, and CSF p-Tau 181 data. We compared baseline and slopes of CSF GAP43 among different stages of AD, as well as their associations with Aβ PET, CSF p-Tau 181 , residual hippocampal volume, 18 F-fluorodeoxyglucose PET, and cognition cross-sectionally and longitudinally. Results: Regardless of Aβ positivity and clinical diagnosis, CSF p-Tau 181 -positive individuals showed higher CSF GAP43 concentrations (p < 0.001) and faster rates of CSF GAP43 increases (p < 0.001) compared with the CSF p-Tau 181negative individuals. Moreover, higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases were strongly related to CSF p-Tau 181 independent of Aβ PET. They were related to more rapid hippocampal atrophy, hypometabolism, and cognitive decline (p < 0.001), and predicted the progression from MCI to dementia (area under the curve for baseline 0.704; area under the curve for slope 0.717) over a median 4 years of follow up. Interpretation: Tau aggregations rather than Aβ plaques primarily drive presynaptic dysfunction measured by CSF GAP43, which may lead to sequential neurodegeneration and cognitive impairment in AD or neurodegenerative diseases.

A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer’s disease could be illustrated with biomarker measurement under NIA–AA framework. Clinical–neuroimaging–neuropathological studies in other cohorts are needed to validate these findings.