Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles

Abstract

The bulk of AD research during the last 25 years has been Aβ-centric based on a strong faith in the Amyloid Cascade Hypothesis which is not supported by the data on humans. To date, Aβ-based therapeutic clinical trials on sporadic cases of AD have been negative. Although most likely the major reason for the failure is that Aβ is not an effective therapeutic target for sporadic AD, initiation of the treatment at mild to moderate stages of the disease is blamed as too late to be effective. Clinical trials on presymptomatic familial AD cases have been initiated with the logic that Aβ is a trigger of the disease and hence initiation of the Aβ immunotherapies several years before any clinical symptoms would be effective. There is an urgent need to explore targets other than Aβ. There is now increasing interest in inhibiting tau pathology, which does have a far more compelling rationale than Aβ. AD is multifactorial and over 99% of the cases are the sporadic form of the disease. Understanding of the various etiopathogenic mechanisms of sporadic AD and generation of the disease-relevant animal models are required to develop rational therapeutic targets and therapies. Treatment of AD will require both inhibition of neurodegeneration and regeneration of the brain.

Keywords: Abnormal hyperphosphorylation of tau; Aβ; Neurofibrillary tangles; Neuroregeneration; Plaques; Protein phosphatase-2A; Tauopathies.

Figure 1. Neuropathology of Alzheimer disease (AD) and related conditions

Both AD and adults with Down syndrome (DS) are neuropathologically characterized by β-amyloidosis and phosphotau neurofibrillary degeneration. While familial AD is caused by certain mutations in βAPP, presenilin 1 (PS1) and PS2 proteins, the exact causes of sporadic AD, which accounts for over 99% of the cases, are not yet established. Besides normal aged cases, around 30% of whom have as much Aβ plaque load in their brains as in a typical case of AD, extensive β-amyloidosis in the absence of neurofibrillary pathology is a hallmark of hereditary cerebral hemorrhage with amyloidosis of Dutch origin (HCHWA-D) and sporadic cerebral congophilic angiopathy (SCCA). Conversely, several tauopathies such as corticobasal degeneration (CBD), Pick disease (PiD), progressive supranuclear palsy (PSP), dementia pugilistica/traumatic brain injury (DP/TBI) and Guam Parkinsonism dementia complex (Guam PDC) are characterized by phosphotau neurofibrillary pathology in the absence of Aβ plaque. Moreover, several intronic and extronic mutations in tau gene in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17 tau) cause phosphotau neurofibrillary pathology. Tau pathology in the neocortex in tauopathies is associated with dementia. Neurofibrillary degeneration is a slow chronic progressive process which is seen as retrograde degeneration and takes place over a period of several months to years.