Amyloid pathology and vascular disease in focus: exploring interaction in two pathways towards neurodegeneration

Central to the quest for the etiology of Alzheimer*s disease is insight into
how the two prevailing pathways, amyloid-* pathology and vascular pathology,
influence disease development in its earliest stage. These pathways could act
as independent processes leading to dementia, or alternatively, they may
directly influence each other, interact and cause an accelerated disease
process. Evidence from the two pathways influencing each other comes from both
experimental studies and patient-based studies. Yet, there is a void of studies
that use an integrated approach to study both pathways simultaneously, in
particular in a preclinical setting. Technical developments in imaging
amyloid-* deposition non-invasively with use of radioactive PET tracers has
greatly advanced the possibility to study amyloid-* pathology in vivo,
directly, in presumed healthy individuals. This proposal will make use of the
existing infrastructure within The Rotterdam Study, a large on-going
population-based study with extensive multiple time-point data (including brain
magnetic resonance imaging), enabling a detailed assessment of vascular
pathology.

To study in a population-based setting, in persons free of dementia, the
interplay between amyloid-* pathology and vascular pathology. We hypothesize
that higher overall load and progression of vascular pathology will relate to a
higher burden of amyloid-* pathology.

Moreover, we will examine if both pathologies interact in their effect on
(decline in) cognitive functioning, by investigating if amyloid pathology leads
to a greater cognitive decline in the presence of vascular pathology, or if
amyloid deposition and vascular pathology are indirectly related to cognition
and cognitive decline. We will in a secondary objective furthermore examine
whether Apolipoprotein E4 (APOE4) affects these relations.

In a sample of 700 persons from the Rotterdam Study, brain amyloid PET imaging
will be acquired. To ensure a good representation of different stages of
vascular brain pathology, these 700 participants will be selected by random
sampling from quartiles of the distribution of white matter lesion volume load,
as quantified on previous brain MRI.

The main reason to participate in this study would be the contribution to
scientific research. This study is particularly relevant as vascular factors
are potentially modifiable and thus could prove preventive targets for
Alzheimer*s disease, especially when shown to modify amyloid-* pathology. Risks
include radiation exposure and potential adverse reactions to the injection of
the radionuclide, but are deemed acceptable.