Similar to most chronic diseases, Alzheimer's disease (AD) develops slowly from a preclinical phase into a fully expressed clinical syndrome. We aimed to use longitudinal data to calculate the rates of amyloid β (Aβ) deposition, cerebral atrophy, and cognitive decline.In this prospective cohort study, healthy controls, patients with mild cognitive impairment (MCI), and patients with AD were assessed at enrolment and every 18 months. At every visit, participants underwent neuropsychological examination, MRI, and a carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET scan. We included participants with three or more (11)C-PiB PET follow-up assessments. Aβ burden was expressed as (11)C-PiB standardised uptake value ratio (SUVR) with the cerebellar cortex as reference region. An SUVR of 1·5 was used to discriminate high from low Aβ burdens. The slope of the regression plots over 3-5 years was used to estimate rates of change for Aβ deposition, MRI volumetrics, and cognition. We included those participants with a positive rate of Aβ deposition to calculate the trajectory of each variable over time.200 participants (145 healthy controls, 36 participants with MCI, and 19 participants with AD) were assessed at enrolment and every 18 months for a mean follow-up of 3·8 (95% CI CI 3·6-3·9) years. At baseline, significantly higher Aβ burdens were noted in patients with AD (2·27, SD 0·43) and those with MCI (1·94, 0·64) than in healthy controls (1·38, 0·39). At follow-up, 163 (82%) of the 200 participants showed positive rates of Aβ accumulation. Aβ deposition was estimated to take 19·2 (95% CI 16·8-22·5) years in an almost linear fashion-with a mean increase of 0·043 (95% CI 0·037-0·049) SUVR per year-to go from the threshold of (11)C-PiB positivity (1·5 SUVR) to the levels observed in AD. It was estimated to take 12·0 (95% CI 10·1-14·9) years from the levels observed in healthy controls with low Aβ deposition (1·2 [SD 0·1] SUVR) to the threshold of (11)C-PiB positivity. As AD progressed, the rate of Aβ deposition slowed towards a plateau. Our projections suggest a prolonged preclinical phase of AD in which Aβ deposition reaches our threshold of positivity at 17·0 (95% CI 14·9-19·9) years, hippocampal atrophy at 4·2 (3·6-5·1) years, and memory impairment at 3·3 (2·5-4·5) years before the onset of dementia (clinical dementia rating score 1).Aβ deposition is slow and protracted, likely to extend for more than two decades. Such predictions of the rate of preclinical changes and the onset of the clinical phase of AD will facilitate the design and timing of therapeutic interventions aimed at modifying the course of this illness.Science and Industry Endowment Fund (Australia), The Commonwealth Scientific and Industrial Research Organisation (Australia), The National Health and Medical Research Council of Australia Program and Project Grants, the Austin Hospital Medical Research Foundation, Victorian State Government, The Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association.Copyright © 2013 Elsevier Ltd. All rights reserved.

Currently available evidence strongly supports the position that the initiating event in Alzheimer's disease (AD) is related to abnormal processing of beta-amyloid (Abeta) peptide, ultimately leading to formation of Abeta plaques in the brain. This process occurs while individuals are still cognitively normal. Biomarkers of brain beta-amyloidosis are reductions in CSF Abeta(42) and increased amyloid PET tracer retention. After a lag period, which varies from patient to patient, neuronal dysfunction and neurodegeneration become the dominant pathological processes. Biomarkers of neuronal injury and neurodegeneration are increased CSF tau and structural MRI measures of cerebral atrophy. Neurodegeneration is accompanied by synaptic dysfunction, which is indicated by decreased fluorodeoxyglucose uptake on PET. We propose a model that relates disease stage to AD biomarkers in which Abeta biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegenerative biomarkers become abnormal later, and correlate with clinical symptom severity.Copyright 2010 Elsevier Ltd. All rights reserved.

Increased APP (amyloid precursor protein) processing causes beta-amyloid (Ab) accumulation in autosomal dominant Alzheimer's disease (AD), but it is unclear if it also affects sporadic A beta accumulation. We tested healthy controls and patients with mild cognitive symptoms (N = 331) in the BioFINDER study, using cerebrospinal fluid (CSF) A beta 40 as a surrogate for amyloidogenic APP processing. We find that levels of brain Ab fibrils (measured by 18F-flutemetamol PET) are independently associated with high CSF A beta 40 (P<0.001) and APOE epsilon 4 (P<0.001). The association between CSF A beta 40 and brain Ab is stronger in APOE epsilon 4-negative than in positive people (P = 0.0080). The results are similar for CSF A beta 38 and for a combination of CSF A beta 38 and CSF A beta 40. In conclusion, sporadic Ab accumulation may be partly associated with increased amyloidogenic APP production, especially in APOE epsilon 4-negative subjects. The risk for sporadic AD may consequently depend on increased Ab production, in addition to decreased A beta clearance.

Sporadic Alzheimer's disease (AD) is characterised by the deposition and accumulation of specific protein aggregates. Failure of clearance could underlie this process, and recent genetic association studies point towards involvement of the phagocytosis and autophagy pathways. We developed a real-time tri-color flow cytometry method to quantitate the phagocytic function of human peripheral blood monocyte subsets including non-classic CD14(dim)CD16(+), intermediate CD14(+)CD16(+) and classic CD14(+)CD16(-) monocytes. Using this method, we have measured the phagocytic ability of fresh monocytes in a study of preclinical, prodromal and clinical AD, matched with cognitively normal healthy control subjects. Basal levels of phagocytosis in all three subsets of monocytes were similar between healthy controls and AD patients, while a significant increase of basal phagocytosis was found in subjects with high Aβ-amyloid burden as assessed by PET scans. Pre-treating cells with Copaxone (CPX, to stimulate phagocytosis) or ATP (an inhibitor of P2X7-mediated phagocytosis) showed a differential response depending on clinical or Aβ-burden status, indicating a relative functional deficit. Overall the results are consistent with a perturbation of basal and stimulated innate phagocytosis in sporadic AD.

Cerebrovascular disease and Alzheimer disease are common diseases of aging and frequently coexist in the same brain. Accumulating evidence suggests that the presence of brain infarction, including silent infarction, influences the course of Alzheimer disease. Conversely, there is evidence that beta-amyloid can impair blood vessel function. Vascular beta-amyloid deposition, also known as cerebral amyloid angiopathy, is associated with vascular dysfunction in animal and human studies. Alzheimer disease is associated with morphological changes in capillary networks, and soluble beta-amyloid produces abnormal vascular responses to physiological and pharmacological stimuli. In this review, we discuss current evidence linking beta-amyloid metabolism with vascular function and morphological changes in animals and humans.

Soluble A beta (Sa beta) is normally present at a low concentration in human plasma and cerebrospinal fluid. Although the factors involved in the regulation of Sa beta plasma levels are still unknown, we have explored its excretion in the urine as one of the possible homeostatic mechanisms. The presence of Sa beta in the urine was investigated via immunoprecipitation experiments with anti-A beta antibodies followed by detection and identification by immunoblot, MALDI mass spectrometry and sequence analysis. Soluble A beta (4.3 kDa) immunoreactivity was present in the urine of normal donors, Down's syndrome individuals as well as in patients with renal disorders exhibiting glomerular or mixed proteinuria. Edman degradation of the immunoprecipitated material yielded the intact A beta N-terminus and mass spectra analysis indicated the existence of a major component at mlz 4327, corresponding to the molecular mass of A beta1-40. Semiquantitative data obtained from the immunoprecipitation experiments indicate that under normal conditions the daily excretion of intact Sa beta in the urine represents less than 1% of the circulating pool.

To seek for a new valid biomarker using non-invasive specimens for the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI), we carried out the detection of amyloid beta (Abeta) protein in urine. Ten-millilitre urine samples were first sedimented with trichloroacetic acid, and the pellets were resuspended for further analysis by Western blotting with anti-Abeta antibody. The detection sensitivity of the method was 40pg/ml. Rates of subjects positive for monomeric Abeta according to their clinical dementia rating (CDR) were 11.1% for CDR 0, 62.5% for CDR 0.5, 83.3% for CDR 1, 54.5% for CDR 2 and 0% for CDR 3. A single Abeta band relative to the CDR score reflects an alteration in the production, solubility and clearance of Abeta in the brain. Thus, the method could be used as both a diagnostic and monitoring tool in assessing AD and MCI patients during disease-modifying therapies.

我国经济和人口的持续增长，社会结构的变化使我国成为老年人口增长最快的国家之一，老年病的预防和预后都面临巨大的挑战。阿尔茨海默病（Alzheimer's disease，AD）是最常见的老年神经变性疾病。AD的病理特征是神经原纤维缠结和淀粉样斑块长期（超过20年）的沉积，导致神经细胞的死亡或失去功能。目前临床诊断主要是基于认知心理学、影像学和脑脊液检测，这些诊断方式的复杂性和侵入性限制了其在AD早期检测中的应用。尽管血液中的淀粉样蛋白（amyloid-β） Aβ_40/42比值以及和磷酸化Tau-181和Tau-217等蛋白等生物标志物已受到广泛关注，但其应用通常仅限于疾病进展评估，因为Tau蛋白变化通常被认为是Aβ沉积的继发反应，不适合用于早期检测。尿液含有多种生物分子，其组成可以实时反映机体的生理和病理变化，这使得尿液成为生物标志物发现和疾病早期筛查的理想选择。尿液作为一种非侵入性外周代谢物生物液在AD早期检测的价值正在逐步得到推广应用，本文主要对以尿液生物标记物作为AD早期检测手段的研究进展进行总结和展望。

BackgroundCurrent diagnostic methods have limitations in early prediction of dementia.ObjectiveDevelop an early screening tool to identify persons at high risk of dementia for early intervention.MethodsWe examined amyloid-β protein precursor (AβPP) and its fragments in urine from cognitively normal controls (CNs) and patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD)-dementia using western blotting with different antibodies and developed a colloidal gold lateral flow-based qualitative strip.ResultsCompared with CNs, the amounts of various AβPP fragments with molecular weights of approximately 14, 28, 56, and 68 kDa in patients were greater. We therefore used the strip to detect urine Aβ-containing AβPP fragments and evaluated its potential in multiple aged cohorts from 11 cities in Jiangsu Province, China (n = 4418); Sichuan Provincial People's Hospital (Chengdu, China; n = 408); and the Australian Imaging, Biomarker and Lifestyle Study (AIBL; n = 367). Unitizing Aβ-binding phagocytosis-promoting peptides, the strips showed increasing positivity (9.5-16.9%) with ageing in the Jiangsu cohort and good clinical performance in the Chengdu cohort (κ = 0.704). Significant differences between CNs and patients were found in the AIBL cohort with negative Aβ-PET, those with the slope of Aβ-PET change <1 centiloid per year, those under 75 years of age, or those with a body mass index of 25-30.ConclusionsOur data indicate the high potential of urine AβPP fragments as biomarkers for MCI and dementia at an early stage and warrant further longitudinal studies.

老年人痴呆或认知障碍多由一种以上年龄相关的常见脑部疾病所致。阿尔茨海默病（Alzheimer's disease, AD）是其中最常见的神经变性疾病，且是全球前10位死因中唯一无法治愈或缺乏长期对症疗效的疾病，给个人、家庭和全球经济都带来了巨大的负担。早期及时发现和干预是对抗AD的最佳策略。在过去的 30 年中，许多研究都提出了降低痴呆风险的方法，2020年《柳叶刀》杂志的痴呆预防报告已阐明通过应对风险因素可以预防或延缓超过40%的痴呆。然而，目前全球医疗体系尚未具备早期或及时发现AD的足够能力。最近的一项研究发现，只有不到 10%的轻度认知障碍（mild cognitive impairment, MCI）是在初级医疗机构中诊断出来的。近来，抗淀粉样蛋白β（Amyloid beta，Aβ）抗体药物lecanemab和donanemab被批准上市用于早期AD治疗，以及30年的随访研究证明改善风险因素显著减少AD痴呆的发病率并延长了寿命，使得人们对AD早期识别的关注迅速增加。阿尔茨海默病防治协会（China Association for Alzheimer's Disease，CAAD）认识到居家早期和及时发现 AD 的重要性，并成立了一个由协会成员、临床医生和研究人员组成的全球 AD 多领域专家团队，就以下目标达成共识： ①为个人、家庭、社区、协会和组织提供专家指导意见；②介绍用于认知障碍和痴呆居家筛查的数字工具和可用资源，并为AD高危人群或疑似患者制定下一步应对策略；③讨论现有可用或将来可能的居家筛查适宜AD生物标志物；④为未来的改进和全球应用建立可行性框架。专家组对于当前可用的证据、工具和资源进行综述，并进一步考量其在AD 居家筛查中的价值。

Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late onset Alzheimer’s disease (AD). Studies have shown that apoE, apoE4 in particular, binds to amyloid-β (Aβ) peptides at residues 12-28 of Aβ and this binding modulates Aβ accumulation and disease progression. We have previously shown in several AD transgenic mice lines that blocking the apoE/Aβ interaction with Aβ12-28 P reduced Aβ and tau-related pathology, leading to cognitive improvements in treated AD mice. Recently, we have designed a small peptoid library derived from the Aβ12-28 P sequence to screen for new apoE/Aβ binding inhibitors with higher efficacy and safety. Peptoids are better drug candidates than peptides due to their inherently more favorable pharmacokinetic properties. One of the lead peptoid compounds, CPO_Aβ17–21 P, diminished the apoE/Aβ interaction and attenuated the apoE4 pro-fibrillogenic effects on Aβ aggregation in vitro as well as apoE4 potentiation of Aβ cytotoxicity. CPO_Aβ17–21 P reduced Aβ-related pathology coupled with cognitive improvements in an AD APP/PS1 transgenic mouse model. Our study suggests the non-toxic, non-fibrillogenic peptoid CPO_Aβ17–21 P has significant promise as a new AD therapeutic agent which targets the Aβ related apoE pathway, with improved efficacy and pharmacokinetic properties.

Beta-amyloid (Abeta) deposition is pathognomic for Alzheimer's disease (AD), but may occur in normal elderly people without apparent cognitive effect. Episodic memory impairment is an early and prominent sign of AD, but its relationship with Abeta burden in non-demented persons and in AD patients is unclear. We examined this relationship using 11C-PIB-PET as a quantitative marker of Abeta burden in vivo in healthy ageing (HA), mild cognitive impairment (MCI) and AD. Thirty-one AD, 33 MCI and 32 HA participants completed neuropsychological assessment and a 11C-PIB-PET brain scan. Multiple linear regression analyses were conducted relating episodic memory performance and other cognitive functions to Abeta burden. Ninety-seven percent of AD, 61% of MCI and 22% of HA cases had increased cortical PIB binding, indicating the presence of Abeta plaques. There was a strong relationship between impaired episodic memory performance and PIB binding, both in MCI and HA. This relationship was weaker in AD and less robust for non-memory cognitive domains. Abeta deposition in the asymptomatic elderly is associated with episodic memory impairment. This finding, together with the strong relationship between PIB binding and the severity of memory impairment in MCI, suggests that individuals with increased cortical PIB binding are on the path to Alzheimer's disease. The data also suggests that early intervention trials for AD targeted to non-demented individuals with cerebral Abeta deposition are warranted.

Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becoming more clearly defined. This Review focuses on amyloid-β (Aβ), a major hallmark of AD. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we propose that these abnormal systemic changes might not only develop secondary to brain dysfunction but might also affect AD progression, suggesting that the interactions between the brain and the periphery have a crucial role in the development and progression of AD. Such a systemic view of the molecular pathogenesis of AD could provide a novel perspective for understanding this disease and present new opportunities for its early diagnosis and treatment.

阿尔茨海默病（Alzheimer's disease,AD）的发病机理一直众说纷纭，β-淀粉样蛋白(Aβ)理论一直占据主导地位。但众多针对Aβ的治疗方法收效甚微，使得研究人员重新审视这个理论。越来越多的研究发现Aβ斑块在大脑的积累虽然和认知下降密切相关，但可能只是AD的表象，并非导致AD的根本原因。机体清除由于慢性炎症、脑部损伤等多种原因导致包括Aβ在内的蛋白积累能力的不足可能是这种疾病的更深层原因。这些重要的基础细胞生物功能包括胞吞(endocytosis)、胞饮(macropinocytosis)、天然吞噬(innate phagocytosis)和自噬(autophagy)，而为这些高耗能应用提供能量的线粒体有可能是影响这些功能的决定因素。因而仅仅清除Aβ斑块在AD的治疗中是远远不够的，更多的努力应该放在改善天然吞噬和自噬，甚至是改善线粒体的功能以提高能量供应。