β-amyloid and Alzheimer disease: recent progress

: Alzheimer disease is the dominant form of elderly dementia. Today all clinical trials that target β-amyloid have failed to indicate that β-amyloid may not be a causative agent in AD pathogenesis. Thus there is a need to search for alternative ways to treat AD patients. : Neuronal store-operated calcium entry is a fine-tuning mechanism that regulates intracellular Ca2+ content. Recent evidence suggests that store-operated calcium channels may be targeted with pharmacological agents in order to prevent synapse loss, recover long-term potentiation and change behavior. : Current mini-review discusses basic chemical structures that modulate intracellular calcium dysbalance via targeting store-operated calcium channels and their applicability as anti-AD pharmacological agents.

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Crossed Hemispheric Accumulation of β-Amyloid and Tau Protein in a Patient With Typical Alzheimer Disease

Alzheimer Disease & Associated Disorders ◽

10.1097/wad.0000000000000460 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Hyung-Ji Kim ◽

Sungyang Jo ◽

Sunju Lee ◽

Minyoung Oh ◽

Jae-Hong Lee

Keyword(s):

Alzheimer Disease ◽

Tau Protein ◽

Β Amyloid

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Plasma tau correlates with basal forebrain atrophy rates in people at risk for Alzheimer disease

Neurology ◽

10.1212/wnl.0000000000008696 ◽

2019 ◽

Vol 94 (1) ◽

pp. e30-e41 ◽

Cited By ~ 4

Author(s):

Enrica Cavedo ◽

Simone Lista ◽

Marion Houot ◽

Andrea Vergallo ◽

Michel J. Grothe ◽

...

Keyword(s):

Older Adults ◽

At Risk ◽

Alzheimer Disease ◽

Basal Forebrain ◽

Large Scale ◽

Carrier Status ◽

Annual Percent Change ◽

Β Amyloid ◽

T Tau ◽

Cognitively Intact

ObjectiveTo investigate whether baseline concentrations of plasma total tau (t-tau) and neurofilament light (NfL) chain proteins are associated with annual percent change (APC) of the basal forebrain cholinergic system (BFCS) in cognitively intact older adults at risk for Alzheimer disease (AD).MethodsThis was a large-scale study of 276 cognitively intact older adults from the monocentric INSIGHT-preAD (Investigation of Alzheimer's Predictors in Subjective Memory Complainers) cohort. Participants underwent baseline assessment of plasma t-tau and NfL concentrations as well as baseline and 24-month follow-up MRI scans. Linear models with and without influential observations (calculated using the Cook distance) were carried out to investigate the effect of plasma NfL and t-tau concentrations, and their interaction effect with β-amyloid status and APOE genotype, on the APC of the whole BFCS and its anterior (Ch1/2) and posterior (Ch4) subdivisions separately.ResultsHigher plasma t-tau concentrations at baseline were associated with higher BFCS rate of atrophy (model without influencers: n = 251, F value = 4.6815; p value = 0.031). Subregional analyses showed similar results for both the APC of the Ch1/2 (model without influencers: n = 256, F value = 3.9535, p corrected = 0.047) and Ch4 BFCS sectors (model without influencers: n = 253, F value = 4.9090, p corrected = 0.047). Baseline NfL, β-amyloid load, and APOE ε4 carrier status did not affect APC of the BFCS.ConclusionIncreased concentrations of baseline plasma t-tau may predict in vivo structural BFCS atrophy progression in older adults at risk for AD, independently of β-amyloid status and APOE genotype.

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Association of APOE4 and clinical variability in Alzheimer disease with the pattern of tau- and amyloid-PET

Neurology ◽

10.1212/wnl.0000000000011270 ◽

2020 ◽

pp. 10.1212/WNL.0000000000011270

Author(s):

Renaud La Joie ◽

Adrienne V. Visani ◽

Orit H. Lesman-Segev ◽

Suzanne L. Baker ◽

Lauren Edwards ◽

...

Keyword(s):

Alzheimer Disease ◽

Linear Models ◽

Rating Scale ◽

Standardized Uptake Value ◽

Cortical Atrophy ◽

Amyloid Pet ◽

Clinical Dementia Rating ◽

Clinical Variables ◽

Β Amyloid

ObjectiveTo assess whether Alzheimer disease (AD) clinical presentation and APOE4 relate to the burden and topography of β-amyloid and tau pathologies using in vivo PET imaging.MethodsWe studied 119 β-amyloid-positive symptomatic patients aged 48–95 years, including 29 patients with logopenic variant primary progressive aphasia (lvPPA) and 21 with Posterior Cortical Atrophy (PCA). PIB- (β-amyloid) and Flortaucipir (tau)-PET standardized uptake value ratio (SUVR) images were created. General linear models assessed relationships between demographic/clinical variables (phenotype, age), APOE4, and PET (including global cortical and voxelwise SUVR values) while controlling for disease severity using the clinical dementia rating scale sum of boxes.ResultsPIB-PET binding showed a widespread cortical distribution with subtle differences across phenotypes and was unrelated to demographic/clinical variables or APOE4. Flortaucipir-PET was commonly elevated in temporo-parietal regions, but showed marked phenotype-associated differences, with higher binding observed in occipito-parietal areas for PCA, in left temporal and inferior frontal for lvPPA, and in medial temporal areas for other patients with AD. Cortical Flortaucipir-PET binding was higher in younger patients across phenotypes (r = −0.63, 95%CI [−0.72, −0.50)]), especially in parietal and dorsal prefrontal cortices. The presence of APOE4 was associated with a focal medial temporal Flortaucipir-SUVR increase, controlling for all other variables (entorhinal: + 0.310 SUVR 95%CI [0.091, 0.530]).ConclusionsClinical phenotypes are associated with differential patterns of tau but not amyloid pathology. Older age and APOE4 are not only risk factors for AD but also seem to affect disease expression by promoting a more MTL-predominant pattern of tau pathology.

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O3-10-01: DIFFERENT EFFECTS OF APOE ε4 ALLELE ON THE RELATIONSHIP BETWEEN TAU AND β-AMYLOID IN EARLY-ONSET AND LATE-ONSET ALZHEIMER DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.2825 ◽

2006 ◽

Vol 14 (7S_Part_19) ◽

pp. P1039-P1040

Author(s):

Young Noh ◽

Tae Sung Lim ◽

Sang-Yoon Lee ◽

Kee Hyung Park ◽

Dong Jin Shin ◽

...

Keyword(s):

Alzheimer Disease ◽

Early Onset ◽

Late Onset ◽

Apoe Ε4 ◽

Ε4 Allele ◽

Β Amyloid ◽

The Relationship

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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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Infiltrating Hematogenous Macrophages Aggregate Around β-Amyloid Plaques in an Age- and Sex-Dependent Manner in a Mouse Model of Alzheimer Disease

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa093 ◽

2020 ◽

Vol 79 (11) ◽

pp. 1147-1162

Author(s):

Natalie Kozyrev ◽

Shawn Albers ◽

Jennifer Yang ◽

Vania F Prado ◽

Marco A M Prado ◽

...

Keyword(s):

Alzheimer Disease ◽

Chronic Inflammation ◽

Time Course ◽

Fluorescent Protein ◽

Dependent Manner ◽

Macrophage Activity ◽

Cellular Environment ◽

Β Amyloid ◽

5Xfad Mice ◽

Age And Sex

Abstract β-Amyloid (Aβ) plaques can trigger chronic inflammation in the cellular environment that recruits infiltrating macrophages during the course of Alzheimer disease (AD). Activated macrophages release pro-inflammatory cytokines that increase neurotoxicity associated with AD. A major impediment to investigating neuroinflammation involving macrophage activity is the inability to discriminate resident microglial macrophages (mMϕ) from hematogenous macrophages (hMϕ), as they are morphologically and phenotypically similar when activated. To distinguish between mMϕ and hMϕ and to determine their respective roles in chronic inflammation associated with the progression of amyloidosis, we used lys-EGFP-ki transgenic mice that express enhanced green fluorescent protein in hMϕ, but not in mMϕ. These mice were crossed with 5XFAD mice. The offspring demonstrated robust AD pathology and enabled visual discrimination of mMϕ from hMϕ. Mutant mice demonstrated robust increases in Aβ1–42, area of Aβ plaques, gliosis and deficits in spatial learning by age 5 months. The time-course of Aβ accumulation, paralleled by the accumulation of hMϕ around Aβ plaques, was more robust in female compared with male mice and preceded behavioral changes. Thus, the accumulation of infiltrating hMϕ around Aβ plaques was age- and sex-dependent and preceded cognitive impairment.

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