The Evolution of Preclinical Alzheimer’s Disease: Implications for Prevention Trials

Sperling, Reisa A.; Mormino, Elizabeth C.; Johnson, Keith A.

doi:10.1016/j.neuron.2014.10.038

Cited by 602 publications

(525 citation statements)

References 166 publications

(221 reference statements)

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“…The well‐established pathological hallmarks of AD include plaques, consisting mainly of amyloid‐ β (A β ) peptides, and neurofibrillary tangles, consisting of phosphorylated tau (p‐tau) protein 2. Prior to the manifestation of symptoms and clinical diagnosis, the neurodegenerative processes have already progressed to a relatively advanced stage with marked synaptic loss and neuronal damage 3. A recent study by Rajan et al has shown that impairment in cognition starts almost 18 years before AD dementia could be clinically diagnosed 4.…”

Section: Introductionmentioning

confidence: 99%

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

Sengupta

Portelius

Hansson

et al. 2017

Ann Clin Transl Neurol

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ObjectiveWith an increasing incidence of Alzheimer's disease (AD) and neurodegenerative tauopathies, there is an urgent need to develop reliable biomarkers for the diagnosis and monitoring of the disease, such as the recently discovered toxic tau oligomers. Here, we aimed to demonstrate the presence of tau oligomers in the cerebrospinal fluid (CSF) of patients with cognitive deficits, and to determine whether tau oligomers could serve as a potential biomarker for AD.MethodsA multicentric collaborative study involving a double‐blinded analysis with a total of 98 subjects with moderate to severe AD (N = 41), mild AD (N = 31), and nondemented control subjects (N = 26), and two pilot studies of 33 total patients with AD (N = 19) and control (N = 14) subjects were performed. We carried out biochemical assays to measure oligomeric tau from CSF of these patients with various degrees of cognitive impairment as well as cognitively normal controls.ResultsUsing a highly reproducible indirect ELISA method, we found elevated levels of tau oligomers in AD patients compared to age‐matched controls. Western blot analysis confirmed the presence of oligomeric forms of tau in CSF. In addition, the ratio of oligomeric to total tau increased in the order: moderate to severe AD, mild AD, and controls.ConclusionThese assays are suitable for the analysis of human CSF samples. These results here suggest that CSF tau oligomer measurements could be optimized and added to the panel of CSF biomarkers for the accurate and early detection of AD.

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Section: Introductionmentioning

confidence: 99%

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

Sengupta

Portelius

Hansson

et al. 2017

Ann Clin Transl Neurol

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“…As noted, aging is key risk factor for AD, and studies have suggested that AD has a long preclinical stage from aging to the emergence of clinical symptoms (Sperling et al 2014). In general, mild cognitive impairment (MCI), especially amnesiac MCI, is accepted as an intermediate state between normal aging and dementia.…”

Section: Introductionmentioning

confidence: 99%

“…In general, mild cognitive impairment (MCI), especially amnesiac MCI, is accepted as an intermediate state between normal aging and dementia. The AD neuropathology is an age-dependent progressive process that perhaps lasts decades before the neuropathological diagnostic criteria can be met; it ultimately leads to synaptic loss and neuronal damage in cortical areas of the brain essential for cognitive functions (Sperling et al 2014;Swerdlow 2007). It has been shown that the accumulation of amyloid-β (Aβ), hyperphosphorylation of tau protein, and circuitspecific changes of synaptic connections, such as changed synaptic proteins, appear contribute to AAMI (Chen et al 2007b;Clinton et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory insult during pregnancy accelerates age-related behavioral and neurobiochemical changes in CD-1 mice

Wang

Chen

et al. 2016

AGE

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Data shows that inflammation during pregnancy significantly exerts a long-term influence on offspring, such as increasing the risk of adult cognition decline in animals. However, it is unclear whether gestational inflammation affects the neurobehavioral and neurobiochemical outcomes in the motherself during aging. In this study, pregnant CD-1 mice intraperitoneally received lipopolysaccharide (LPS) in two doses (25 and 50 g/kg, respectively) or normal saline daily during gestational days 15-17. At the age of 15 months, a battery of behavioral tasks was employed to evaluate their species-typical behaviors, sensorimotor ability, anxiety levels, and spatial learning and memory abilities. An immunohistochemical method was utilized preliminarily to detect neurobiochemical indicators consisting of amyloid-β, p h o s p h o r y l a t e d t a u , p r e s y n a p t i c p r o t e i n s synaptotagmin-1 and syntaxin-1, glial fibrillary acidic protein (GFAP), and histone-4 acetylation on the K8 site (H4K8ac). The behavioral results showed that LPS exposure during pregnancy exacerbated a decline in 15-month-old CD-1 mice's abilities to nest, their sensorimotor and spatial learning and memory capabilities, and increased their anxiety levels. The neurobiochemical results indicated that gestational LPS exposure also intensified age-related hippocampal changes, including increased amyloid-β 42 , phosphorylated tau, synaptotagmin-1 and GFAP, and decreased syntaxin-1 and H4K8ac. Our results suggested that the inflammatory insult during pregnancy could be an important risk factor for the development of Alzheimer's disease, and the H4K8 acetylation might play an important role in the underlying mechanism. This study offers a perspective for improving strategies that support healthy development and successful aging.

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“…Several prevention trials have begun to use biomarkers as outcome measures [33,34,[78][79][80], but predominantly as secondary rather than primary outcome measures because no AD biomarker has yet been validated as a surrogate endpoint [81,82].…”

Section: Endpointsmentioning

confidence: 99%

Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

2015

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Alzheimer's disease (AD) is the most common form of dementia and is a major cause of disability and dependency amongst older people. AD drugs approved so far are symptomatic treatments and are not thought to affect the underlying disease process. Trials conducted with agents aiming to slow or stop disease progression in patients with AD have all failed, perhaps because they were tested too late in the disease process. Therefore, there has been a move towards prevention of AD. This paper presents an overview of trials testing pharmacological interventions for sporadic AD prevention. Those tested to date were initially developed for the treatment of AD or for the treatment of other conditions, rather than being specifically developed for AD prevention. Associated issues, such as evidence of 'proof-of-concept,' doses and safety, are discussed. A major shift has taken place in the methodology of AD prevention trials since the results of the first trials were published in the 1990s. New directions that are currently being considered in ongoing or future prevention trials are discussed, in terms of endpoints, target populations, and study design. The use of AD-specific drugs to prevent AD in high-risk individuals is currently limited by a lack of validated predictive and surrogate markers. Population approaches, such as lifestyle changes, are an alternative strategy that could be of public health interest, but may provide only limited benefits for individuals. The best chance of preventing AD may come from a combination of individual and population prevention approaches. Key PointsFollowing the failure of treatment trials in symptomatic Alzheimer's disease (AD), there has been a move towards prevention of AD.To date, no specific pharmacological intervention has been developed for sporadic AD prevention and trial results have been disappointing.A major shift has taken place in the methodology of AD prevention trials and new directions are being considered in terms of endpoints, target populations, and study design.

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The Evolution of Preclinical Alzheimer’s Disease: Implications for Prevention Trials

Cited by 602 publications

References 166 publications

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

Inflammatory insult during pregnancy accelerates age-related behavioral and neurobiochemical changes in CD-1 mice

Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

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