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The present invention relates to the treatment of dementias.
It relates to the use of interferon ? (IFN-? for the manufacture of a medicament
for treatment and/or prevention of Alzheimer's disease (AD), Creutzfeld-Jakob
disease (CJD) or Gerstmann-Sträussler-Scheinker disease (GSSD). It further
relates to the use of IFN-? in combination with an Alzheimer's disease
treating agent for the manufacture of a medicament for treatment and/or
prevention of AD. It specifically relates to the use of IFN-? in combination
with cholinesterase inhibitors (ChEI). A? toxicity lowering agents, hormone
replacement agents, lipid lowering agents, secretase modulating agents,
A? aggregation inhibitors, neurofibrilator inhibitors or ?-amyloid catabolism
inhibitors for the manufacture of a medicament for treatment and/or prevention
of AD. In particular, it relates to the use of IFN-? alone or in combination
with cholinesterase inhibitors (ChEI), A? toxicity lowering agents, hormone
replacement agents, lipid lowering agents, secretase modulating agents,
A? aggregation inhibitors, neurofibrillar inhibitors or ?-amyloid catabolism
inhibitors for the manufacture of a medicament for treatment and/or prevention
of early/onset AD.
BACKGROUND OF THE INVENTION Alzheimer's Disease (AD) Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by progressive cognitive impairment (loss of memory, cognition and behavioral stability) due to neuronal loss and resulting in language disorders, problems with judgment, problem solving, planning, abstract thought, apraxia, deficits in visual function and dementia. An age-related increase in prevalence is demonstrated in AD, afflicting approximately 6-10% of the population over age 65 and up to 50% over age 85. AD is the primary cause of dementia and the fourth cause of death after cardiovascular disease, cancer and stroke. The onset of this disease is characterized by impaired ability to recall recent events, but with disease progression other intellectual skills decline. Later, erratic behavior, delusions, and a loss of control over body functions occur. The diagnosis of Alzheimer's disease is based on well-established criteria (McKhann et al. 1984): definite is reserved for disease confirmed at postmortem examination; probable, for clinical disease without associated illnesses; and possible for those individuals meeting criteria with other illnesses that may cause central nervous system dysfunction such as hypothyroidism or cerebrovascular disease. The clinical diagnosis of disease is based on a combination of the neurological and mental status examination and is reasonably accurate. At death, the most frequent pathological manifestations in brain include specific neuropathological lesions in the limbic and cerebral cortices characterized by intracellular paired helical filaments (PHF) and extracellular amyloid plaques. The primary pathological feature of the disease is the extracellular deposition of fibrillar amyloid and its compaction into senile plaques. Hence, intra- and extracellular amyloid deposits called neurofibrillary tangles and senile plaques (deposits of fibrillar aggregates), respectively, are associated with Alzheimer's disease. Together with extensive neuronal loss (neurons as well as synapses), they are the hallmark neuropathological features of the disease and are still the only means of confirming diagnosis post-mortem. Neurofibrillary tangles consist primarily of hyperphosphorylated tau (a microtubule assembly protein), while the major fibrillar component of senile plaques is the amyloid-? peptide (A?), a 40-42-amino acid fragment of the Alzheimer precursor protein (APP). Analysis of genetic mutations that are responsible for very rarer familial forms of the disease has led to the development of the amyloid cascade hypothesis. It is characterized by the formation and deposition of amyloid fibrils by the normally soluble A? peptide, as a result of its overproduction by aberrant proteolytic events and its interactions with pathological chaperones such as Apolipoprotein E and antichymotrypsin. They are minor constituents of senile plaques and have allalic variants that are capable of increasing the proclivity of A? to assemble into amyloid fibrils. The senile plaque is the focus of a complex cellular reaction involving the activation of both microglia and astrocytes adjacent to the amyloid plaque, leading to neuronal damage. In fact, microglia are the most abundant and prominent cellular components associated with these plaques. Plaque-associated microglia exhibit a reactive or activated phenotype. Through the acquisition of a reactive phenotype, these microglia respond to various stimuli, as is evidenced by the increased expression of numerous cell-surface molecules, including major histocompatibility complex (MHC) class II antigens and complement receptors. Mutations in three genes, the amyloid precursor protein
(APP) gene on chromosome 21, the presenilin 1 (PS1) on chromosome 14, and
the presenilin 2 (PS2) on chromosome 1, have been found in families with
an autosomal dominant Alzheimer's disease with onset as early as the third
decade of life. An allelic variant of apolipoprotein-E (APOE) ?4 has also
been associated with sporadic and familial disease with onset usually after
age 65 years. Mutation in ?2-macroglobulin has been suggested to be linked
to at least 30% of the AD population. Mutations in the genes causing early-onset
disease elevate levels of amyloid B peptide (A?1-40 and A?1-42). The variant
APOE allele may be involved in the removal or degradation of amyloid ?.
Thus, a common pathway leading to the pathogenesis has been identified
by the systematic investigation of families with Alzheimer's disease.
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