BACKGROUND The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)

Sympathetic neuronal death induced by nerve growth factor (NGF) deprivation requires the macromolecular synthesis-dependent translocation of BAX from the cytosol to mitochondria and its subsequent integration into the mitochondrial outer membrane, followed by BAX-mediated cytochrome c (cyt c) release. The gene products triggering this process remain unknown. Here, we report that BIM, a member of the BH3-only proapoptotic subfamily of the BCL-2 protein family, is one such molecule. NGF withdrawal induced expression of BIM(EL), an integral mitochondrial membrane protein that functions upstream of (or in parallel with) the BAX/BCL-2 and caspase checkpoints. Bim deletion conferred protection against developmental and induced neuronal apoptosis in both central and peripheral populations, but only transiently, suggesting that BIM--and perhaps other BH3-only proteins--serve partially redundant functions upstream of BAX-mediated cyt c release.

, and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, wholebrain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.neuroimaging | aging | dementia | neurodegeneration | DIAN T he pathological mechanisms underlying nondominantly inherited late onset Alzheimer's disease (LOAD) remain an active area of investigation (1). According to the amyloid cascade hypothesis, the precipitating event in LOAD is an alteration of the balance between production and clearance of the metabolites of amyloid precursor protein (APP) (2). Abnormalities in APP metabolism then lead to β-amyloid (Aβ) deposition in the cerebral cortex, the formation of neurofibrillary tangles (NFTs) containing hyperphosphorylated tau protein, neuronal dysfunction, cell loss, and, ultimately, dementia. In vivo biomarkers of LOAD include cerebrospinal fluid (CSF) Aβ 42 , CSF tau, amyloid deposition imaged with Pittsburgh compound B PET (PiB PET) and other amyloid tracers, altered glucose metabolism imaged with fluro-deoxyglucose PET (FDG PET), and structural atrophy assessed by volumetric MRI. A theoretical model of biomarker changes has been proposed by Jack et al. (3) that links these Significance Beta-amyloid plaque accumulation, glucose hypometabolism, and neuronal atrophy are hallmarks of Alzheimer's disease. However, the regional ordering of these biomarkers prior to dementia remains untested. In a cohort with Alzheimer's disease mutations, we performed an integrated whole-brain analysis of three major imaging techniques: amyloid PET, [18 F] fluro-deoxyglucose PET, and structural MRI. We found that most gray-matter structures with amyloid plaques later have hypometabolism follo...

IMPORTANCE Racial differences in molecular biomarkers for Alzheimer disease may suggest race-dependent biological mechanisms.OBJECTIVE To ascertain whether there are racial disparities in molecular biomarkers for Alzheimer disease.

OASIS-3 is a compilation of MRI and PET imaging and related clinical data for 1098 participants who were collected across several ongoing studies in the Washington University Knight Alzheimer Disease Research Center over the course of 15 years. Participants include 605 cognitively normal adults and 493 individuals at various stages of cognitive decline ranging in age from 42 to 95 years. The OASIS-3 dataset contains over 2000 MR sessions, including multiple structural and functional sequences. PET metabolic and amyloid imaging includes over 1500 raw imaging scans and the accompanying post-processed files from the PET Unified Pipeline (PUP) are also available in OASIS-3. OASIS-3 also contains post-processed imaging data such as volumetric segmentations and PET analyses. Imaging data is accompanied by dementia and APOE status and longitudinal clinical and cognitive outcomes. OASIS-3 is available as an open access data set to the scientific community to answer questions related to healthy aging and dementia.