Neuropathology of preclinical and clinical lateonset Alzheimer's disease

Troncoso, Juan C.; Cataldo, Anne M.; Nixon, R.; Barnett, Jody L.; Lee, Michael K.; Checler, Frédéric; Fowler, David; Smialek, John E.; Crain, Barbara J.; Martin, Lee J.; Kawas, Claudia H.

doi:10.1002/ana.410430519

Cited by 80 publications

(66 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A very different type of mechanism was implicated when it was recognized that neurofibrillary tangles comparable to those found in AD occur in young adults with Niemann-Pick's type C disease (17)(18)(19), a single gene mutation resulting in partial lysosomal dysfunction. Other postmortem analyses showed that lysosomal disturbances develop in AD vulnerable neurons in advance of AD pathologies (20)(21)(22)(23). Finally, studies using cultured slices from rat brain confirmed that experimentally induced lysosomal dysfunction generates hyperphosphorylated tau fragments (24,25) and other concomitants of AD (26).…”

mentioning

confidence: 81%

Rapid induction of intraneuronal neurofibrillary tangles in apolipoprotein E-deficient mice

Yong²,

Zhou³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cultured hippocampal slices prepared from apolipoprotein E-deficient mice were exposed to an inhibitor of cathepsins B and L and then processed for immunocytochemistry using antibodies against human paired helical filaments. Dense, AT8-immunopositive deposits were found in the subiculum, stratum oriens of hippocampal field CA1, and the hilus of the dentate gyrus. This distribution agrees with that described for tangles in Alzheimer's disease. The appearance of the labeled structures fell into categories that correspond to previously proposed stages in the progression of intraneuronal neurofibrillary tangles in human hippocampus. Electron microscopic analyses confirmed that microtubule disruption and twisted bundles of filaments were present in neurons in the affected areas. These results support the hypothesis that partial lysosomal dysfunction is a contributor to Alzheimer's disease and suggest a simple model for studying an important component of the disease. N eurofibrillary tangles (NFTs) and amyloid plaques are pathological hallmarks of Alzheimer's disease (AD). Although much has been learned about the formation of plaques, the mechanisms responsible for tangles are still poorly understood. The discovery that NFTs are largely composed of hyperphosphorylated tau protein and fragments of tau (1-7) pointed to age-related changes in kinases and phosphatases as key events in their etiology (8)(9)(10)(11)(12)(13)(14)(15)(16). A very different type of mechanism was implicated when it was recognized that neurofibrillary tangles comparable to those found in AD occur in young adults with Niemann-Pick's type C disease (17-19), a single gene mutation resulting in partial lysosomal dysfunction. Other postmortem analyses showed that lysosomal disturbances develop in AD vulnerable neurons in advance of AD pathologies (20-23). Finally, studies using cultured slices from rat brain confirmed that experimentally induced lysosomal dysfunction generates hyperphosphorylated tau fragments (24, 25) and other concomitants of AD (26).Missing from hypotheses connecting lysosomes to tangles is direct evidence that disturbances of the former are followed by robust formation of the latter. Moreover, there are no results suggesting that predisposing conditions for AD interact with lysosomes, as would be expected from these hypotheses. The only predisposing condition unequivocally associated with late-onset AD is the variation of the apolipoprotein E (apoE) gene. In humans, three alleles (2, 3, and 4) of the apoE gene encode variants that differ at two residues (27, 28). ApoE4 increases the risk for late-onset familial and sporadic AD dose-dependently, whereas apoE2 and apoE3 seem to function as protective factors (29)(30)(31)(32)(33)(34). In vitro experiments showed that apoE3 but not apoE4 variants were able to form stable complexes with the microtubule-associated proteins tau and MAP2c (35). It has been hypothesized that apoE3, by binding to tau, protects tau from being hyperphosphorylated and thus prevents the generation of intracellu...

show abstract

mentioning

confidence: 81%

Rapid induction of intraneuronal neurofibrillary tangles in apolipoprotein E-deficient mice

Yong²,

Zhou³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Human Postmortem Brain Samples and Rat Tissues-Post mortem MTG samples of controls, AD, and HD (supplemental Table S1, A and B) subjects were obtained from the Department of Pathology of the Division of Neuropathology at Johns Hopkins University School of Medicine, where diagnoses were all confirmed by autopsy (37), and the samples were qualified for an exemption under 45 CFR 46.101 of the DHHS criteria. The RNA integrity of each sample was analyzed by the Agilent RNA 6000 Nano kit with Bioanalyzer (Agilent Technologies).…”

Section: Methodsmentioning

confidence: 99%

Identification of Novel GDNF Isoforms and cis-Antisense GDNFOS Gene and Their Regulation in Human Middle Temporal Gyrus of Alzheimer Disease*

Airavaara

Pletniková

Doyle

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

“…1,2 As a consequence, the long duration of preclinical AD dementia has been a major point of emphasis. [3][4][5] Although our direct knowledge of the preclinical sequences and interrelations of cognitive and pathologic events are limited, pathologic events are generally thought to begin much earlier than clinical ones.…”

mentioning

confidence: 99%

Cognitive impairment 18 years before clinical diagnosis of Alzheimer disease dementia

et al. 2015

View full text Add to dashboard Cite

Objective: To examine the relation of performance on brief cognitive tests to development of clinically diagnosed Alzheimer disease (AD) dementia over the following 18 years in a sample of African Americans and European Americans.Methods: A composite cognitive test score based on tests of episodic memory, executive function, and global cognition was constructed in a prospective population-based sample of 2,125 participants (55% African American and 61% female) aged 65 years and older residing in 4 Chicago neighborhoods. Time before AD dementia diagnosis was categorized into 6 groups corresponding to data collection periods: 0.1-0.9, 1.0-3.9, 4.0-6.9, 7.0-9.9, 10.0-12.9, and 13.0-17.9 years.Results: Of 2,125 participants without clinical AD dementia, 442 (21%) developed clinical AD dementia over 18 years of follow-up. Lower composite cognitive test scores were associated with the development of AD dementia over the duration of the study. The magnitude of association between composite cognitive test score and development of AD dementia increased from an odds ratio of 3.39 (95% confidence interval 1.72, 6.67; p , 0.001) at 13.0-17.9 years to 9.84 (95% confidence interval 7.41, 13.06; p , 0.001) at 0.1-0.9 years, per SD increment. These associations were consistently larger among European Americans than among African Americans. Performance on individual cognitive tests of episodic memory, executive function, and global cognition also significantly predicted the development of AD dementia, with associations exhibiting a similar trend over 18 years. Because of the lack of effective treatments for Alzheimer disease (AD) dementia, early preventive efforts may be more effective in slowing preclinical manifestation of AD dementia. Conclusions:1,2 As a consequence, the long duration of preclinical AD dementia has been a major point of emphasis.3-5 Although our direct knowledge of the preclinical sequences and interrelations of cognitive and pathologic events are limited, pathologic events are generally thought to begin much earlier than clinical ones.6,7 Imaging-based studies suggest an initial deficiency in limbic regions of the brain affecting episodic memory in the early stages of the disease, 8,9 that progresses to the cortical regions of the brain followed by other cognitive symptoms, and an AD dementia syndrome is noticed. [10][11][12] Much of this knowledge is from investigations confined to clinical settings rather than from the general population.

show abstract

Neuropathology of preclinical and clinical lateonset Alzheimer's disease

Cited by 80 publications

References 19 publications

Rapid induction of intraneuronal neurofibrillary tangles in apolipoprotein E-deficient mice

Rapid induction of intraneuronal neurofibrillary tangles in apolipoprotein E-deficient mice

Identification of Novel GDNF Isoforms and cis-Antisense GDNFOS Gene and Their Regulation in Human Middle Temporal Gyrus of Alzheimer Disease*

Cognitive impairment 18 years before clinical diagnosis of Alzheimer disease dementia

Contact Info

Product

Resources

About