@article {1645469,
	title = {Evidence of beta amyloid independent small vessel disease in familial Alzheimer{\textquoteright}s disease},
	journal = {Brain Pathol},
	volume = {32},
	number = {6},
	year = {2022},
	month = {2022 Nov},
	pages = {e13097},
	abstract = {We studied small vessel disease (SVD) pathology in Familial Alzheimer{\textquoteright}s disease (FAD) subjects carrying the presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic Alzheimer{\textquoteright}s disease (SAD) as a positive control for Alzheimer{\textquoteright}s pathology and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) bearing different NOTCH3 mutations, as positive controls for SVD pathology. Upon magnetic resonance imaging (MRI) in life, some FAD showed mild white matter hyperintensities and no further radiologic evidence of SVD. In post-mortem studies, total SVD pathology in cortical areas and basal ganglia was similar in PSEN1 FAD and CADASIL subjects, except for the feature of arteriosclerosis which was higher in CADASIL subjects than in PSEN1 FAD subjects. Further only a few SAD subjects showed a similar degree of SVD pathology as observed in CADASIL. Furthermore, we found significantly enlarged perivascular spaces in vessels devoid of cerebral amyloid angiopathy in FAD compared with SAD and CADASIL subjects. As expected, there was greater fibrinogen-positive perivascular reactivity in CADASIL but similar reactivity in PSEN1 FAD and SAD groups. Fibrinogen immunoreactivity correlated with onset age in the PSEN1 FAD cases, suggesting increased vascular permeability may contribute to cognitive decline. Additionally, we found reduced perivascular expression of PDGFRβ AQP4 in microvessels with enlarged PVS in PSEN1 FAD cases. We demonstrate that there is Aβ-independent SVD pathology in PSEN1 FAD, that was marginally lower than that in CADASIL subjects although not evident by MRI. These observations suggest presence of covert SVD even in PSEN1, contributing to disease progression. As is the case in SAD, these consequences may be preventable by early recognition and actively controlling vascular disease risk, even in familial forms of dementia.},
	keywords = {Alzheimer Disease, Amyloid beta-Peptides, CADASIL, Fibrinogen, Flavin-Adenine Dinucleotide, Humans},
	issn = {1750-3639},
	doi = {10.1111/bpa.13097},
	author = {Littau, Jessica Lisa and Velilla, Lina and Hase, Yoshiki and Villalba-Moreno, Nelson David and Hagel, Christian and Drexler, Dagmar and Osorio Restrepo, Santiago and Villegas, Andres and Lopera, Francisco and Vargas, Sergio and Glatzel, Markus and Krasemann, Susanne and Quiroz, Yakeel T and Arboleda-Velasquez, Joseph F and Kalaria, Rajesh and Sepulveda-Falla, Diego}
}
