IVIG and Alzheimer’s Disease: Could It Work Where Everything Else Has Failed?

“God God gave us memory so that we might have roses in December.”

— JM Barrie

THE DREADED PROSPECT of an Alzheimer’s disease diagnosis is more feared than cancer by many. Alzheimer’s slowly robs its victims of everything: the ability to think abstractly and solve problems, perform familiar tasks, remember names and events and have conversations. Unique personality traits eventually disappear, which are often replaced by anxiety, depressive symptoms or inappropriate behaviors. In the end, most sufferers are unable to recognize familiar surroundings or close family members.

This isn’t a normal part of aging. Alzheimer’s is an insidious degenerative disease that incapacitates or kills billions of neurons as it literally shrinks its victims’ brains. At autopsy, one finds more telltale detritus: hard insoluble plaques made of a protein called beta amyloid (Abeta) and twisted masses of a normal structural nerve cell protein called “tao” that form what pathologists describe as neurofibrillary tangles.

More than five million people in this country have Alzheimer’s disease, including one in eight persons aged 65 and older.¹ With the leading edge of the baby boom generation set to double the over-65 population during the next 20 years,Alzheimer’s has long been a leading target for development of potentially disease-modifying drugs.

Drug Candidates Keep Falling Short

But up to now, the pharmaceutical industry has managed to produce only a large and costly graveyard of failed Alzheimer’s drug candidates. Throughout just the last decade, more than 20 investigational agents that reached Phase III trials were shown to be ineffective; a few were actually harmful.

Some of these drugs were intended to address known aspects of Alzheimer’srelated damage, such as oxidative damage, inflammation or mitochondrial dysfunction. Some have been designed to clear existing amyloid plaques, prevent Abeta formation or deposition, or disassemble neurofibrillary tangles.

In each case, hopes have been pinned to a narrowly defined theory of Alzheimer’s pathophysiology that neatly dovetails with the mechanism of action of the drug candidate. For example, Pfizer recently decided to investigate an antihistamine called Dimebon, which acts to help stabilize cellular mitochondria and showed seemingly promising results in a Russian Phase II trial. Severe mitochondrial dysfunction is welldocumented in Alzheimer’s brain cells. The drug failed to work in a large Phase III trial.

Earlier, the Canadian firm Neurochem touted the prospects of a small molecule dubbed Alzhemed that crosses the blood-brain barrier, binds to soluble Abeta monomers and appears to interfere with formation of amyloid plaques. In a randomized pivotal trial involving more than 1,000 Alzheimer’s patients, Alzhemed had no discernible effect on cognitive decline.

The list of dead and moribund Alzheimer’s drug candidates is long and keeps getting longer.

What Causes Alzheimer’s: New Theories, Opportunities, Questions

Exactly what goes wrong to begin with in Alzheimer’s disease remains a mystery that lengthens the odds of finding an effective drug. But more and more evidence points to single Abeta 42 peptide “monomers” linking together into highly toxic “oligomers” that disrupt nerve synapses and various nerve cell functions. People with Alzheimer’s seem to produce much less of the antibody that normally binds and clears these neurotoxic oligomers before they can do their damage. Lots of other mayhem is going on as well, including damaging chronic inflammatory activity and those changes to tao protein that disable axonal transport and create the hallmark tangles.

These days, the “beta amyloid theory” to explain Alzheimer’s has the most adherents and is the leading focus of Alzheimer’s drug research and development activity. A recent landmark study has at last discovered a “signature” profile of Abeta 42 peptide and pair of tao proteins in the cerebrospinal fluid (CSF) of persons with mild cognitive impairment. With results from a simple spinal tap, physicians may soon be able to predict with nearly 100 percent accuracy who will advance to clinical Alzheimer’s disease. 2 The implications are obvious: An early lab test-based diagnosis creates an opportunity to intervene with a therapeutic to delay or potentially even halt the disease process years before it progresses to full-blown dementia. Now all we need is that effective drug.

Meanwhile, new unanswered questions continue to challenge Alzheimer’s researchers. Why do CSF Abeta levels first increase in the years before a clinical diagnosis is made, and then decline? What’s the normal functional role of Abeta in the first place? Are Abeta monomers actually neuroprotective as some recent research suggests?³ What do we make of new evidence that Abeta is an important antimicrobial peptide in the brain?⁴ Why do certain investigational anti-Abeta vaccines and monoclonal antibodies clear Abeta in some subjects, while causing inflammatory arthritis and brain swelling in others?

Given all we don’t know about why people do or do not develop Alzheimer’s, the notion that a single agent with narrowly directed activity can effectively slow this complex disease might be bordering on wishful thinking.

Alzheimer’s, Immunology and IVIG

What, then, about all the interest in intravenous immunoglobulin (IVIG) for Alzheimer’s disease? Let’s step back and consider a few background points relating to the aging immune system, Alzheimer’s and experimental immunotherapy with human IVIG:

• Our ability to generate antibodies to defend against infectious or toxic threats and effectively regulate cellular immunity begins a long decline that starts around age 65 and accelerates in our 70s and 80s.
• Most Alzheimer’s cases occur after age 65; the incidence of the disease climbs sharply as people reach their late 70s and 80s.
• Levels of natural CSF and plasma antibodies directed against Abeta (including Abeta oligomers) are significantly lower in patients with Alzheimer’s compared with healthy individuals.⁵
• IVIG administration lowers CSF Abeta levels in Alzheimer’s patients, implying that infused anti-Abeta antibodies are binding Abeta peptide and facilitating its clearance. An in vitro model has demonstrated that IVIG facilitates microglial phagocytosis of Abeta peptide.⁶
• Anti-Abeta human antibodies in IVIG have been shown to prevent Abeta oligomer-induced neurotoxicity in an in vitro neuroblastoma cell model.⁷
• Recent evidence implicates inflammation secondary to nerve cell death and dysfunction as a distinct harmful component of the Alzheimer’s disease process.^8,9 While incompletely understood, potent anti-inflammatory and other immunoregulatory functions of IVIG have been widely cited to explain its established efficacy both in certain autoimmune inflammatory neuropathies^10,11 and in an experimental model of ischemic stroke.¹²
• Findings from several early-stage human trials of IVIG,^13,14,15 as well as retrospective analyses of older adults without Alzheimer’s or other dementias,^16,17 offer very encouraging early signals that IVIG may slow or delay cognitive decline.

Consider that the risk of developing Alzheimer’s disease doubles every five years after age 65. While heredity clearly plays a role and certain lifestyle factors might have some influence on disease risk, there is no known underlying “cause” for most cases of Alzheimer’s other than getting older.

Should IVIG ultimately prove effective in slowing progression of this disease, the fundamental therapeutic principle is straightforward: IVIG is restoring some array of critical protective antibodies that the senescent immune system can no longer make enough of on its own. We may never understand what those antibodies are or precisely how IVIG works, but that won’t be anything new. No one really knows, for example, how IVIG works in chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Kawasaki disease or mucocutaneous blistering diseases. But this ignorance doesn’t seem to bother neurologists, rheumatologists and other specialists who prescribe IVIG products every day.

Several trials being planned or now in progress should soon reveal whether IVIG modifies the course of mild to moderate Alzheimer’s disease or joins the graveyard of once-promising drug candidates.

IVIG: Random Book or Kitchen Sink?

Understandably, there are IVIG skeptics. Dr. Lawrence Honig, a Columbia University researcher evaluating Pfizer’s humanized anti-Abeta monoclonal antibody called bapineuzumab, suggested a few years ago that trying IVIG to treat Alzheimer’s disease is “like picking a random book off the shelf and hoping it’s the one you want to read.” His center and several hundred other clinical study sites are currently evaluating bapineuzumab in Phase III trials. “This more targeted approach makes a lot more sense,” he said in an interview with WebMD.¹⁸

Dr. Norman Relkin at Weill Cornell Medical College, who is the lead investigator for current Phase III trials of Baxter’s IVIG product, offers a decidedly different homespun perspective on the rationale for testing IVIG. “It is a kind of ‘kitchen sink’ approach to immunotherapy [that] throws all the antibodies in the human repertoire at the patient, hoping that those which target the amyloid pathology and those which exert an immunomodulatory effect will be of benefit,” he said in a recent interview.¹⁹

I’m not a scientist, but honestly, a monoclonal antibody like bapineuzumab that zeroes in on a single target on the N-terminal end of an Abeta peptide seems the better fit for Honig’s “random book off the shelf” analogy. On the other hand, Relkin’s “kitchen sink” metaphor about IVIG works pretty well for me. After all, IVIG is essentially a concentrate of half of the circulating human immune system. Each vial contains a myriad of natural, fully functional human antibodies collected from healthy adult donors.

Now that’s something worth thinking about.