An Update on Critical Issues for Alzheimer’s Disease

Chairs: R Anand, G Knudsen

Over 25 years have elapsed since the first approval for a New Chemical Entity (NCE) based on a neurotransmitter approach to treat the symptoms of Alzheimer’sDisease (AD).  Since that time four new treatments, also based on neurotransmitter approaches (e.g. cholinesterase inhibition, NMDA receptor blockade), have been introduced for AD patients; however, their effects have been modest, of relatively short duration, and without any impact on the course of the disease. These benefits have been achieved by agents whose daily treatment costs are affordable for most patients and society. Some of these agents have also been approved for the treatment of other neurodegenerative dementias. 

Neuropathologic and biopsy findings of beta amyloid containing plaques, a by-product of the faulty cleavage of the Amyloid Precursor Protein (APP) in the brains of AD patients, has led to efforts to develop treatments that reduce beta amyloid in the brain by reducing its synthesis, preventing its deposition in the plaque by inhibiting its aggregation, promoting plaque breakdown and its sequestration in the periphery, and increasing its clearance.

Results from multinational trials of up to 2 years in patients with mild to moderate AD to date have failed to demonstrate any statistically significant, or clinically relevant benefit on any of the key measures of cognition, activities of daily living, brain atrophy or relevant bio-markers in a priori-defined statistical analyses.  Although post hoc analyses in smaller subsets of patients indicate larger benefits in milder patients, and suggest the need to evaluate prodromal AD patients as a potential target population, no results are available in prodromal patients.   

Recent initiatives in collecting neuroimaging, psychometric, and clinical data, in conjunction with biochemical investigations of CSF markers, in a population at risk for dementias indicate that the structural and functional changes are already evident 5-10 years before the diagnosis of AD. Clinical and pathological investigations have indicated that the onset of clinical symptoms of AD predate the clinical diagnosis by approximately 3-5 years. Findings from follow-up studies in patients with genetic forms of AD, e.g. presenilin 1 mutations, indicate that clinical deterioration may start almost a decade prior to diagnosis, while changes in bio-markers, such as CSF aβ -42 and Tau, as well as subtle cognitive changes may occur well more than a decade prior to clinical signs.

It has been established that AD pathological changes originate in the entorhinal cortex and progress along synaptically connected circuits to involve the hippocampus, followed by other neocortical areas. The same mechanism of spread of Tau has been demonstrated for other degenerative dementias. It is not surprising that therapeutic strategies that have been pursued in AD and other dementias have failed to arrest or modify the progression of the disease, as the current paradigm involves testing patients with a clinical diagnosis, which represent stages where extensive brain changes have already occurred and cannot be reversed.

Perhaps, due to the emphasis on developing treatments for early AD patients, very little effort has been expended for developing treatments that would reduce the suffering of patients with moderate and severe dementia, despite evidence that these patients are living longer and are a source of concern for families and governments. There is a need to re-balance the focus in research to use scanty vital resources, not only on high-risk therapies for patients at risk for dementias, but also the millions with established disease.

The development of disease progression therapies has been difficult, expensive, and time-consuming, involving major sacrifices from patients and their caregivers. The likely cost of these treatments will most certainly be multiples of the cost of currently available symptomatic treatments for a benefit that appears elusive, and will not be used for patients whose disease state is more than mild. It is time to re-initiate neuro-chemical research for symptomatic treatments that may alleviate the impairments in cognition, behavior and function in mild to severe AD patients.

This session will bring together an international faculty of researchers from the fields of basic research, genetics and neuro-imaging, experts in public policy and regulatory affairs, and clinicians to evaluate the current status of progress and establish new priorities for AD research and development of effective treatments.