The CAA-HERITAGE study: Hereditary Cerebral Amyloid Angiopathy-Dutch type; Investigating Genealogy and Disease Course

Cerebral Amyloid Angiopathy (CAA) is the most common cause of lobar, primary
intracerebral hemorrhage (ICH) in the elderly. CAA-related vascular damage is
caused by accumulation of the Amyloid-β (Aβ) peptide in small and medium-sized
vessels in the brain. Aβ is derived from the larger amyloid precursor protein
(APP). CAA occurs in a prevalent sporadic form (sCAA) and rare hereditary
forms. Hereditary Cerebral Hemorrhage with Amyloidosis Dutch type (HCHWA-D) is
a rare, familial variant of CAA caused by a genetic mutation in the APP gene on
chromosome 21. There are no available treatment options and the burden of the
disease in the affected families is tremendous. Because of its similarities
with sCAA, HCHWA-D can serve as a monogenetic model for sCAA and offers the
opportunity to study different stages of Aβ accumulation and its relation with
clinical symptoms.
Until recently, HCHWA-D has mainly been described in several large families in
two coastal villages in the Netherlands. However, mutation carriers that have
moved to other parts of the country are being increasingly identified. It is
unknown how many mutation carriers there are in the Netherlands. Patients with
HCHWA-D suffer from recurrent ICH and dementia starting around the 5th decade
of life, often leading to an early death. The disease course varies between
different families and among subjects from the same family. There is only
little known about risk factors that contribute to a more aggressive or more
benign disease course. The main goal of the study is to set up an extensive
database to identify all (possible) mutation carriers and to study the natural
history of HCHWA-D. In addition, we aim to get insight in possible other
genetic, environmental and vascular rsik factors that may influence the natural
disease course. Furthermore, this study proposal will serve as the basis for
future follow-up studies (not this proposal).

1. To investigate the size of the HCHWA-D population by identifying all
(possible) mutation carriers and their relatives.
2. Study the genealogy and natural disease history of these carriers.
3. Get insight in possible genetic, environmental and vascular risk factors
that may influence their natural disease course.

This study is an observational family-based study. The disease course and
possible risk factors will be studied retrospectively.

Proband and relatives: completion of a questionnaire. Probands will be asked to
ask in their families who would like to participate in the study, subsequently
provide an address list of relatives who want to participate and to draw a
pedigree chart of the family.
Studying HCHWA-D can contribute significantly to the worldwide CAA research, as
the Dutch population is the largest and best documented hereditary CAA
population. With HCHWA-D we have a monogenic model for CAA which makes it
possible to study presymptomatic carriers. Identifying factors that influence
the disease course would be valuable to both asymptomatic and symptomatic
mutation carriers. Ultimately we hope that a better understanding of HCHWA-D
will enable us to define new therapeutic and preventive strategies for sporadic
and hereditary CAA.