In this phase I-II parallel design, randomized, double-blind clinical trial we will
determine if 3,000 or 30,000 units ingested hrIFN-a prevents deterioration of cognitive
functioning in patients with dementia of Alzheimer's type (AD) and whether ingested hrIFN-a
treatment decreases acute phase reactants and pro-inflammatory cytokine IL-6 in mild to
moderate AD. We predict that the novel anti-inflammatory agent ingested human recombinant
interferon alpha (hrIFN-a) will modulate inflammation and inhibit the natural history of AD
progression. If you are eligible, you will receive Aricept for 5 weeks (donezepil) and
thereafter in addition to Aricept either placebo (inactive substance) or interferon alpha at
3,000 or 30,000 units every day for 12 months.
Inflammatory mechanisms contribute to neurodegeneration in AD. Acute phase proteins such as
the antichymotrypsin (a1ACT), pro-inflammatory cytokines IL-6 and IL-1, and activated
microglial cells are all associated with neuritic plaques. a1ACT levels are elevated in AD,
correlate with cognitive decline and serve as a biological marker of intervention. a1ACT is
intimately associated with the 42-AA b peptide (Ab) in filamentous amyloid deposits and
stimulates the polymerization of Ab into amyloid filaments. IL-6 is found in AD cortices
prior to the onset of neuritic change, serum and stimulated PMNC IL-6 levels are higher in
AD, and may induce b-amyloid protein deposition. Microglia, CNS resident inflammatory cells,
produce IL-6 within the adult human brain, are IL-1a +, and are a prominent component of the
neuritic plaque. Because the pathogenesis of AD appears in part immune mediated, we propose
testing directly in humans whether ingested IFN-a can ameliorate AD. Because there is no
good model for inflammation in animal models of AD, we will directly determine in humans 1)
if 3,000 or 30,000 IU hrIFN-a inhibits the natural history rate of cognitive decline in mild
to moderate AD using neuropsychological instruments as primary and secondary outcome
measures that 2) correlates with inhibition of acute phase reactants and pro-inflammatory
IL-6. If this novel anti-inflammatory agent inhibits the natural history rate of cognitive
decline in AD in this pilot phase II trial, this would provide the preliminary data to
submit a phase III clinical trial.
IFNs administered by the oral route show a systemic effect. Oral IFN-a caused neutropenia
in mice. In contrast to their i.p. administration, oral IFN-a did not result in the presence
of detectable levels of IFNs in the blood. Circulating specific antibody to IFN blocked the
neutropenic effects of i.p. IFN, but did not block the neutropenic effects of the oral IFNs
(2). Therefore, we examined the expression of antiviral MxA message, a type 1 IFN-specific
induced signal, as a sensitive marker for type 1 IFN interaction with lymphoid cells in the
gut-associated lymphoid tissue (GALT) using semi-quantitative RT-PCR on splenocytes from
mice and PMNC from man after IFN-a ingestion. Both mice and man demonstrated inducible
levels of Mx mRNA after ingesting IFN-a. Murine spleen T cells and CD8+ T cells also
demonstrated upregulation of Mx mRNA. Therefore, ingested IFN-a acts via established
pathways of type 1 IFN signalling (3). Elevated levels of activated T cells, mainly of the
CD8+ (cytotoxic/suppressor) phenotype, are found in AD brains in contact with microglial
cells (4). Interestingly, peripheral CD8+ T cells are depleted in AD patients (5).
Lymphocytes bearing T helper and T cytotoxic/suppressor cell antigens are found in
hippocampus and temporal cortex in AD (6,7). The data above suggest that lymphocytes are
part of inflammation in AD, and potential immunomodulatory T and CD8+ T cells that contact
ingested non-absorbed IFN in the GALT could migrate to the brain and decrease inflammation.
Males and females, age 50 or greater. Possible or probable dementia of the Alzheimer Type
defined by NINDS-ARDA criteria with dementia of at least one year duration.
Folstein MMSE Score 10-24 inclusive. Vision, hearing, speech, motor function and
comprehension must be adequate for compliance with all testing procedures.
Absence of a reliable caregiver. Clinical or radiological evidence for other neurological
disorders such as Parkinson's disease, normal pressure hydrocephalus, multi-infarct
dementia, idiopathic seizure disorder, CNS infectious disease.
History of major psychiatric disorders; schizophrenia and unipolar or bipolar depression.
Presence of any significant medical disorder which might cause or contribute to dementia
such as B12 or folic acid deficiency, untreated hypothyroidism, history of significant
alcohol abuse (within the past 10 years).
Patients with recent (< 2 years) hematologic/oncologic disorders (other than basal or
squamous cell carcinoma of the skin.
Patients with recent (< 3 months) myocardial infarction, poorly controlled CHF, surgery
for peripheral vascular disease, or coronary artery bypass surgery.
Evidence of clinically significant or unstable active GI, hepatic or pulmonary disease.
History of documented stroke or more than one confirmed TIA. Any condition which would
make the patient or caregiver, in the opinion of the principal investigator unsuitable for
Patients with known hypersensitivity to Donezepil HCL or other piperidine containing