The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease: Perspectives from the Research Roundtable

Knopman, David S.; Haeberlein, Samantha Budd; Carrillo, María C.; Hendrix, James A.; Kerchner, Geoff; Margolin, Richard; Maruff, Paul; Miller, David S.; Tong, Gary; Tome, Maria; Murray, Melissa E.; Nelson, Peter T.; Sano, Mary; Mattsson, Niklas; Sultzer, David L.; Montine, Thomas J.; Jack, Clifford R.; Kolb, Hartmuth C.; Petersen, Ronald C.; Vemuri, Prashanthi; Canniere, Megan Zoschg; Schneider, Julie A.; Resnick, Susan M.; Romano, Gary; Harten, Argonde C. van; Wolk, David A.; Bain, Lisa J.; Siemers, Eric

doi:10.1016/j.jalz.2018.03.002

Cited by 111 publications

(109 citation statements)

References 86 publications

(93 reference statements)

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“…Although it has been recommended that risk stratification be based on more accurate neuropathological changes, several current large‐scale AD prevention studies have targeted individuals based on AD genetic risk ( APOE4 status) . Individuals with one and two APOE4 allele(s) have a 3‐ and 15‐fold increased risk of AD, respectively .…”

Section: Discussionmentioning

confidence: 99%

“…Apolipoprotein E ε4 allele ( APOE4 ) carrier status is the strongest genetic risk factor for AD and has been used and recommended for risk stratification in AD therapeutic development trials . However, recently, it has been suggested that clinical trial inclusion should target AD pathological changes of AD . Cerebrospinal fluid (CSF)‐derived or positron emission tomography (PET) imaging biomarkers express physiological changes associated with disease pathology but are invasive or cost‐prohibitive .…”

Section: Introductionmentioning

confidence: 99%

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Prediction of Alzheimer's disease diagnosis within 14 years through Aβ misfolding in blood plasma compared to APOE4 status, and other risk factors

Stocker

Nabers

Perna

et al. 2020

Alzheimer's & Dementia

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Introduction:Alzheimer's disease (AD) has a long prodromal stage and identifying high-risk individuals is critical. We aimed to investigate the ability of A misfolding in blood plasma, APOE4 status, and dementia risk factors to predict diagnosis of AD.Methods: Within a community-based cohort, A misfolding in plasma measured by immuno-infrared sensor and APOE genotype were determined at baseline in 770 participants followed over 14 years. Associations between A misfolding, APOE4, and other predictors with clinical AD, vascular dementia, and mixed dementia diagnoses were assessed. Results:A misfolding was associated with a 23-fold increased odds of clinical AD diagnosis within 14 years. No association was observed with vascular dementia/mixed dementia diagnoses. APOE4-positive participants had a 2.4-fold increased odds of clinical AD diagnosis within 14 years.Discussion: A misfolding in blood plasma was a strong, specific risk prediction marker for clinical AD even many years before diagnosis in a community-based setting.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prediction of Alzheimer's disease diagnosis within 14 years through Aβ misfolding in blood plasma compared to APOE4 status, and other risk factors

Stocker

Nabers

Perna

et al. 2020

Alzheimer's & Dementia

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“…Alzheimer's disease (AD) is an age‐related neurodegenerative disorder characterized by the development of Aβ‐plaques, neurofibrillary tangles and cognitive dysfunction . Motor dysfunction also develops in AD, and manifests as altered gait, hyperactivity and motor stereotypes .…”

Section: Introductionmentioning

confidence: 99%

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

O’Leary

Mantolino

Stover

et al. 2018

Genes Brain and Behavior

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Alzheimer's disease (AD) is a neurodegenerative disorder that leads to age‐related cognitive and sensori‐motor dysfunction. There is an increased understanding that motor dysfunction contributes to overall AD severity, and a need to ameliorate these impairments. The 5xFAD mouse develops the neuropathology, cognitive and motor impairments observed in AD, and thus may be a valuable animal model to study motor deficits in AD. Therefore, we assessed age‐related changes in motor ability of male and female 5xFAD mice from 3 to 16 months of age, using a battery of behavioral tests. At 9‐10 months, 5xFAD mice showed reduced body weight, reduced rearing in the open‐field and impaired performance on the rotarod compared to wild‐type controls. At 12‐13 months, 5xFAD mice showed reduced locomotor activity on the open‐field, and impaired balance on the balance beam. At 15‐16 months, impairments were also seen in grip strength. Although sex differences were observed at specific ages, the development of motor dysfunction was similar in male and female mice. Given the 5xFAD mouse is commonly on a C57BL/6 × SJL hybrid background, a subset of mice may be homozygous recessive for the Dysf im mutant allele, which leads to muscular weakness in SJL mice and may exacerbate motor dysfunction. We found small effects of Dysf im on motor function, suggesting that Dysf im contributes little to motor dysfunction in 5xFAD mice. We conclude that the 5xFAD mouse may be a useful model to study mechanisms that produce motor dysfunction in AD, and to assess the efficacy of therapeutics on ameliorating motor impairment.

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“…Alzheimer Disease (AD) is an age‐related progressive neurodegenerative disorder and is the most frequent form of dementia in elderly persons . Mouse models are key to understanding the progression of AD and for developing new AD treatments .…”

Section: Introductionmentioning

confidence: 99%

Whisker exploration behaviours in the 5xFAD mouse are affected by sex and retinal degeneration

Grant

Wong

Fertan

et al. 2018

Genes Brain and Behavior

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Active whisking in mice and rats is one of the fastest behaviours known in mammals and is used to guide complex behaviours such as exploration and navigation. During object contact, whisker movements are actively controlled and undergo robust changes in timing, speed and position. This study quantifies whisker movements in 6‐ to 7‐month old male and female 5xFAD mice, and their C57/SJL F1 wild‐type (WT) controls. As well as genotype, we examined sex differences and the effects of retinal degeneration (rd). Mice were filmed using a high‐speed video camera at 500 frames per second (fps), under infrared light while behaving freely in three tasks: object exploration, sequential object exploration and tunnel running. Measures of whisker position, amplitude, speed and asymmetry were extracted and analysed for each task. The 5xFAD mice had significantly altered whisker angular positions, amplitude and asymmetry during object contacts and female 5xFAD mice with rd had lower mean angular positions during object contact. There were no significant effects of genotype on sequential object exploration or on tunnel running but differences due to sex and rd were found in both tasks, with female mice making larger and faster whisker movements overall, and mice with rd making larger and faster whisker movements during object contact. There were sex differences in whisker movements during sequential object exploration and females with rd had higher whisker retraction speeds in tunnel running. These data show that measuring whisker movements can quantify genotype and sex differences and the effects of rd during exploratory behaviour in these mice.

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The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease: Perspectives from the Research Roundtable

Cited by 111 publications

References 86 publications

Prediction of Alzheimer's disease diagnosis within 14 years through Aβ misfolding in blood plasma compared to APOE4 status, and other risk factors

Prediction of Alzheimer's disease diagnosis within 14 years through Aβ misfolding in blood plasma compared to APOE4 status, and other risk factors

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

Whisker exploration behaviours in the 5xFAD mouse are affected by sex and retinal degeneration

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