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From mechanism to treatment

Let us suppose that very soon we will have developed a reasonably clear understanding of the biochemical pathways which appear to be dysregulated in typical PD with Lewy bodies. Then our task will be to try to interfere in this pathway and to design clinical trials to test these potential therapies. At that stage we will want to design small molecules to intervene in those pathways and to start to think about designing clinical trials to slow disease progression. Both of these are formidable undertakings. A comparison of AD research and PD research (Table 22.2) really shows the magnitude of this task. Mechanistic PD research started 13 years later than mechanistic AD research, and we are, optimistically, still several years away from the first mechanistic therapies for AD.

Our current problems are clearly both practical (so far we have no good animal model of the disease) and philosophical (there is no generally agreed pathway to disease). Furthermore, we should not forget that AD research has not yet led to disease-modifying treatments, and currently AD researchers are worrying that trials of mechanistic therapies will need to be long and will therefore be extremely expensive to run. Additionally therapies need to be tested in individuals who are at a very early stage in the disease, possibly even completely asymptomatic. I think, therefore, that we are facing a rather distressing paradox. It would seem likely that we are more than a decade away from mechanistic therapies. From a practical perspective this means that we have nothing to offer anyone who currently has the disease except the hope that future generations will not suffer as they are suffering. While to the patient and the caregiver it seems as if we need just one more push to cure the disease, the truth is that this goal is still beyond the horizon.

Table 22.2 Progress and problems on the road to Alzheimer disease (AD) therapies: comparison with Parkinson's disease (PD)

Year

Progress

Comment

Lesson

1984

Ap identified

a-Synuclein identified in 1997

PD started 13 years behind

1991

APP mutations identified

a-Synuclein mutations identified in 1993

1992

Amyloid hypothesis

As yet no PD equivalent

1995

Presenilin genes discovered

Many other PD genes discovered

Note that AD was defined by pathology

1995

Animal model with some pathology made

AD model was incomplete, but it did at least have plaques

As yet no generally accepted pathological model of PD has been developed

1998

Presenilins shown to be involved in APP metabolism as y-secretase

Connection between any two parkinsonism genes has yet been found

1998

Delineation of other elements of APP metabolism such as BACE as other targets for intervention

No parkinsonism equivalent as yet

1998

MAPT mutations found in FTD

Led to mice with other pathological elements being developed and eventually to heavily engineered mice with full pathology

1999

Ap immunization works in mice

Probably an accidental finding, but depended on having mice with pathology

2003

First active human vaccination trial halted because of immunogenic side effects

2008

Ambivalent phase 2 results reported on passive Ap antibody trial. Phase 3 trials of this and other agents begin

2009

Planning stages of next- generation compounds. Drug companies start to plan other approaches such as anti-tau therapies using mice with tangles

The following are the present concerns: Are the AD trials beginning early enough in the disease? Does the amyloid hypothesis relate only to the autosomal dominant form of the disease? How long should a trial be to show disease modification?

We need to be ready with cohorts of high-risk genetically defined individuals so that we can organize trials in defined and characterized individuals

Table 22.2 (continued) Progress and problems on the road to Alzheimer disease (AD) therapies: comparison with Parkinson's disease (PD)

Year

Progress

Comment

Lesson

2012

Planned reporting of passive immunization trial: phase 3 trials at least 3 years behind this

28 years from amyloid identification

Ap, amyloid-beta; APP, amyloid precursor protein; BACE, p-secretase; FTD, frontotemporal dementia.

Reprinted from Neuron, 52, Hardy J, A hundred years of Alzheimer’s disease research, 3-13, Copyright (2006), with permission from Elsevier.

 
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