We studied small vessel disease (SVD) pathology in Familial
Alzheimer's disease (
FAD) subjects carrying the
presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic
Alzheimer's disease (SAD) as a positive control for Alzheimer'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.