Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-ß precursor protein processing, amyloid-ß aggregation, lipid metabolism and microglial function in AD.

Amyloid-ß PET and CSF in an autopsy-confirmed cohort.

OBJECTIVE: Accumulation of amyloid-ß is among the earliest changes in Alzheimer's disease (AD). Amyloid-ß positron emission tomography (PET) and Aß42 in cerebrospinal fluid (CSF) both assess amyloid-ß pathology in-vivo, but 10-20% of cases show discordant (CSF+/PET- or CSF-/PET+) results. The neuropathological correspondence with amyloid-ß CSF/PET discordance is unknown. METHODS: We included 21 patients from our tertiary memory clinic who had undergone both CSF Aß42 analysis and amyloid-ß PET, and had neuropathological data available. Amyloid-ß PET and CSF results were compared with neuropathological ABC scores (comprising of Thal (A), Braak (B), and CERAD (C) stage, all ranging from 0 [low] to 3 [high]) and neuropathological diagnosis. RESULTS: Neuropathological diagnosis was AD in 11 (52%) patients. Amyloid-ß PET was positive in all A3, C2, and C3 cases and in one of the two A2 cases. CSF Aß42 was positive in 92% of ≥A2 and 90% of ≥C2 cases. PET and CSF were discordant in three of 21 (14%) cases: CSF+/PET- in a patient with granulomatosis with polyangiitis (A0B0C0), CSF+/PET- in a patient with FTLD-TDP type B (A2B1C1), and CSF-/PET+ in a patient with AD (A3B3C3). Two CSF+/PET+ cases had a non-AD neuropathological diagnosis, that is FTLD-TDP type E (A3B1C1) and adult-onset leukoencephalopathy with axonal spheroids (A1B1C0). INTERPRETATION: Our study demonstrates neuropathological underpinnings of amyloid-ß CSF/PET discordance. Furthermore, amyloid-ß biomarker positivity on both PET and CSF did not invariably result in an AD diagnosis at autopsy, illustrating the importance of considering relevant comorbidities when evaluating amyloid-ß biomarker results.

Diagnostic utility of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) in asymptomatic subjects at increased risk for Alzheimer's disease.

PURPOSE: To assess the clinical utility of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) for detection of early signs of neurodegeneration in conditions of increased risk for Alzheimer's disease (AD) as defined by: subjective cognitive decline (SCD), evidence of cerebral amyloid-pathology, apolipoprotein E (APOE) ε4-positive genotype, or autosomal dominant forms of AD (ADAD) in asymptomatic stages. METHODS: A comprehensive literature search was conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on three different diagnostic scenarios. RESULTS: The level of empirical study evidence for the use of FDG-PET to detect meaningful early signs of neurodegeneration was considered to be poor for ADAD and lacking for SCD and asymptomatic persons at risk, based on APOE ε4-positive genotype or cerebral amyloid pathology. Consequently, and consistent with current diagnostic criteria, panelists decided not to recommend routine clinical use of FDG-PET in these situations and to currently mainly reserve it for research purposes. CONCLUSION: Currently, there is limited evidence on which to base recommendations regarding the clinical routine use of FDG-PET to detect diagnostically meaningful early signs of neurodegeneration in asymptomatic subjects with ADAD, with APOE ε4-positive genotype, or with cerebral amyloid pathology, and in subjects with SCD. Future prospective studies are warranted and in part already ongoing, aiming to assess the added value of FDG-PET in this context beyond research applications.