Phosphorylated tau in neuritic plaques of APPsw/Tauvlw transgenic mice and Alzheimer disease

ObjectiveTo determine the prevalence of preclinical Alzheimer disease (AD) according to current classification systems by examining CSF from a representative general population sample of 70-year-olds from Gothenburg, Sweden.MethodThe sample was derived from the population-based H70 Gothenburg Birth Cohort Studies in Gothenburg, Sweden. The participants (n = 322, age 70 years) underwent comprehensive neuropsychiatric, cognitive, and somatic examinations. CSF levels of β-amyloid (Aβ)42, Aβ40, total tau, and phosphorylated tau were measured. Preclinical AD was classified according to criteria of the A/T/N system, Dubois 2016, National Institute on Aging–Alzheimer's Association (NIA-AA) criteria, and International Working Group-2 (IWG-2) criteria. Individuals with Clinical Dementia Rating score >0 were excluded, leaving 259 cognitively unimpaired individuals.ResultsThe prevalence of amyloid pathology was 22.8%, of total tau pathology was 33.2%, and of phosphorylated tau pathology was 6.9%. With the A/T/N system, the prevalence of A+/T−/N− was 13.1%, A+/T−/N+ was 7.3%, A+/T+/N+ was 2.3%, A−/T−/N+ was 18.9%, and A−/T+/N+ was 4.6%. When the Dubois criteria were applied, the prevalence of asymptomatic at risk for AD was 36.7% and of preclinical AD was 9.7%. With the NIA-AA criteria, the prevalence of stage 1 was 13.1% and stage 2 was 9.7%. With the IWG-2 criteria, the prevalence of asymptomatic at risk for AD was 9.7%. TheAPOEε4 allele was associated with several of the categories. Men more often had total tau pathology, A+/T−/N+, preclinical AD according to Dubois 2016, asymptomatic at risk for AD according to the IWG-2 criteria, and NIA-AA stage 2.ConclusionThe prevalence of pathologic AD markers was very common (46%) in a representative population sample of 70-year-olds. The clinical implications of these findings need to be scrutinized further in longitudinal studies.

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Strategies for the Identification of Novel Brain Specific Genes Affected in Alzheimer Disease

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100029814 ◽

1989 ◽

Vol 16 (S4) ◽

pp. 483-489 ◽

Cited By ~ 7

Author(s):

D.G. Walker ◽

B.E. Boyes ◽

P.L. McGeer ◽

E.G. McGeer

Keyword(s):

Alzheimer Disease ◽

Normal Cell ◽

Temporal Cortex ◽

Neuronal Loss ◽

Brain Regions ◽

Neuritic Plaques ◽

Substantia Innominata ◽

Expression Of Genes ◽

Preliminary Description ◽

Specific Mrna

ABSTRACT:The pathological changes that occur in Alzheimer disease (AD) brain lead to a large loss of various classes of neurons and the production of novel proteinaceous elements such as neuritic plaques and neurofibrillary tangles. For the neuronal loss to occur and these elements to arise, there must be a disturbance in the expression or regulation of genes that code for proteins required for normal cell maintenance, or perhaps even for the expression of genes unique to AD. We describe the construction of a cDNA library from the human substantia innominata and strategies for isolating genes that are expressed differentially between brain regions and which may be affected by AD. Some of the results obtained using these strategies and a preliminary description of a novel brain specific mRNA of 15.5kb, whose expression is increased in AD affected temporal cortex, are presented.

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A brief history of “Alzheimer disease”

Neurology ◽

10.1212/wnl.0000000000007583 ◽

2019 ◽

Vol 92 (22) ◽

pp. 1053-1059 ◽

Cited By ~ 14

Author(s):

David S. Knopman ◽

Ronald C. Petersen ◽

Clifford R. Jack

Keyword(s):

Alzheimer Disease ◽

Neurofibrillary Tangles ◽

Public Awareness ◽

Clinical Status ◽

Later Life ◽

Population Based ◽

Imaging Biomarkers ◽

Neuritic Plaques ◽

Β Amyloid ◽

Definition Of

The field of Alzheimer disease (AD) has a nosologic problem: The diagnostic label “Alzheimer disease” has several distinctive meanings. The term probable AD was introduced in 1984 to designate a clinically diagnosed acquired and progressive amnestic dementia for which there was no evidence for another etiology. Probable AD represented a clinicopathologic entity that assumed a specific and sensitive linkage between amnestic dementia and the neuropathology of β-amyloid-containing neuritic plaques and tau-containing neurofibrillary tangles. The clinicopathologic model represented by probable AD was adapted in abbreviated form for population-based studies and general clinical practice, although the uncertainty connoted by “probable” was often overlooked. Representing the growing public awareness of later life cognitive impairment, a vernacular meaning of AD arose out of the clinicopathologic model in which AD represented all dementia not due to another clinically apparent cause. In contrast, by the 1990s, neuropathologists settled on a definition of AD based entirely on a sufficient burden of neuritic plaques and neurofibrillary tangles at postmortem examination, regardless of antemortem clinical status. In the last decade, the availability of fluid and imaging biomarkers that measure β-amyloid and tau abnormalities has enabled antemortem pathobiological diagnoses, highlighting the divide between the clinicopathologic model, the vernacular usage, and the pathobiological models. Each definition has value. However, the meanings of AD as defined by each of these models are not interchangeable. The pathobiological one is the only one that is unambiguous.

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Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlz107 ◽

2019 ◽

Cited By ~ 4

Author(s):

Masataka Nakamura ◽

Satoshi Kaneko ◽

Dennis W Dickson ◽

Hirofumi Kusaka

Keyword(s):

Alzheimer Disease ◽

Dna Damage Response ◽

Corticobasal Degeneration ◽

The Other ◽

Chromosome 17 ◽

Phosphorylated Tau ◽

Pick Bodies ◽

Neuronal Nuclei ◽

Damage Response ◽

Pick Disease

Abstract BRCA1 plays an important roles in several biological events during the DNA damage response (DDR). Recently, some reports have indicated that BRCA1 dysfunction is involved in the pathogenesis of Alzheimer disease (AD). Furthermore, it has also been reported that BRCA1 accumulates within neurofibrillary tangles (NFTs) in the AD brain. In this study, we examined the immunohistochemical distribution of BRCA1 and another DDR protein, p53-Binding Protein 1 (53BP1), in AD, Pick disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration, and frontotemporal dementia with parkinsonism linked to chromosome 17. In control subjects, neither BRCA1 nor phosphorylated BRCA1 (pBRCA1; Ser1524) immunoreactivity was observed in neurons or glial cells; and that for pBRCA1 (Ser1423) and 53BP1 were slightly detected in neuronal nuclei. The immunoreactivity for both BRCA1 and pBRCA1 (Ser1423) was localized within phosphorylated tau inclusions in all tauopathies, whereas that for pBRCA1 (Ser1524) was mainly associated with Pick bodies in PiD and to a lesser extent with NFTs in AD. On the other hand, 53BP1-immunoreactive deposits tended to be increased in the nucleus of neurons in AD and PSP compared with those in control cases. Our results suggest that DDR dysfunction due to cytoplasmic sequestration of BRCA1 could be involved in the pathogenesis of tauopathies.

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