The Genetic Characterization of Dementia

Dementia is a condition of declining mental abilities, especially memory. Dementia can occur
at any age but becomes more frequent with age, with a prevalence of 5%-10% in people over 65
and 20% in people over 80. Dementia affects the rate of information processing, short term
memory is affected before long term memory. It is difficult to diagnose between even the
three most common types: Alzheimers disease, Lewy Body disease and multi infarct dementia.

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. It is the most
common form of dementia, accounting for about 50-70% of typical, late onset cases of
dementia. To date, mutations in three genes (APP, PSEN1, PSEN2) have been described to cause
familial early-onset AD. In addition, a common polymorphism in the gene encoding
apolipoprotein E (APOE) has been associated with the more common late-onset form of the
disease. Genetic variability at the APOE locus is a major determinant of late onset Alzheimer
s disease. Recent estimates suggest that these four established genes account for less than
30% of the genetic variance in age of onset for AD and predict that numerous AD genes may
exist.

Lewy Body Disease includes a range of disorders: Parkinson s Disease, Dementia with Lewy
bodies, and Parkinson s dementia, among others. Dementia with Lewy bodies (DLB) accounts for
20% of all cases of dementia in old age. Clinically DLB is characterized by cognitive
impairment, visual hallucinations, and parkinsonism. Lewy bodies are neuronal inclusions
comprised of abnormally truncated and phosphorylated neurofilament proteins, alpha-synuclein,
ubiquitin and associated enzymes. Mutations in the alpha synuclein gene were first discovered
in 1996 in a family with autosomal dominant Lewy body parkinsonism. However, most lewy body
parkinsonism is not due to a variant in the alpha-synuclein gene. The importance of
alpha-synuclein is attributed to the finding of antibodies to alpha -synuclein stain Lewy
bodies in brains of all Lewy body disease cases. The ability to identify underlying genetic
influences that result in different synuclein pathologies is key to understanding these
disorders.

The first aim of this protocol is to collect families with a history of dementia in an
attempt to clone the causative gene defect(s) via linkage and positional cloning. Our
experience with the cloning of the Amyloid Precursor Protein mutations in Alzheimer s disease
shows that this approach leads to a better understanding of the biochemical and physiological
processes underlying the disease.

It is clear there are numerous forms of dementia where disease does not appear to be
inherited in a Mendelian manner. Whilst these may be caused by environmental effects it is
also reasonable to hypothesize that disease may be caused by complex genetic interactions.
Furthermore, the susceptibility to environmental influence may be affected by genetic
predisposition. As a second aim in this protocol, we will investigate the association between
genetic polymorphisms and dementia. This will be performed by a candidate gene approach,
assessing the contribution of genes already associated with familial forms of disease, likely
candidates (for example involved in the cholinergic system, cell survival or Beta Amyloid
processing) or genes within a genetic region previously linked to disease. Although
significant association does not imply a causal relationship between the presence of the
variant and disease, the pathophysiologic significance should be studied further. The
inevitable problem of false positives within this type of analysis is a real one, which may
be addressed by independent replications and tightly controlled experiments. Undeniably the
analytical effort needed to differentiate positives from false positives is considerable, and
as can be readily seen in Alzheimer s disease, the literature is scattered with positive
associations and subsequent refutations. However, it is important that research groups
continue to identify and replicate these studies.

- INCLUSION CRITERIA:

Previous diagnosis of Dementia by neurologist, other medical care provider, or researcher
accompanied by sufficient clinical and/or laboratory evidence

Clinical confirmation of Dementia by the investigator and his associates either by exam
and/or review of medical records

Family member of diagnosed dementia patient

Healthy controls

EXCLUSION CRITERIA:

Individuals with any movement disorder secondary to a specific environmental exposure,
birth injury, metabolic disorder, or brain infection such as encephalitis.