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- de Rojas, I., et al.
(author)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 4. |
- Kovacs, Gabor G, et al.
(author)
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Neuropathology of the hippocampus in FTLD-Tau with Pick bodies : A study of the BrainNet Europe Consortium
- 2013
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In: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 39:2, s. 166-178
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Journal article (peer-reviewed)abstract
- Aims: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurons. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. Methods: We evaluated immunoreactivity for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. Results: Mean age at death was 68.2 years (range 49 to 96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of FTD, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein immunoreactivity was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurons. Aβ immunoreactivity was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. Conclusions: 1) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; 2) even minor deviation from these morphological criteria suggests a different disorder; and 3) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.
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- Wallin, Anders, 1950, et al.
(author)
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Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease
- 2018
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In: Journal of Alzheimer's Disease. - 1387-2877. ; 62:3, s. 1417-1441
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Research review (peer-reviewed)abstract
- Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer's disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.
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