The most common cause of dementia in the USA is Alzheimer's disease (AD). In 2000 there were 4.5 million persons with Alzheimer's disease in USA. Unless new discoveries facilitate prevention of Alzheimer's disease there will be 13.2 million persons with AD in 2050. About 3% of men and women ages 65 to 74 have AD. Prevalence and incidence increase with age, and nearly half of those age 85 and older have AD. Of all dementias, 70% are caused by AD, and AD is often a contributing factor when other etiologies are discovered.
The majority of AD cases occur in people older than 60 years. The exact cause of this late-onset Alzheimer's disease is not well known. Rarely, Alzheimer's disease develops in patients in their 30s, 40s, or 50s. A strong genetic component has been identified in many of these cases; and genetic transmission generally follows an autosomal dominant pattern. On the other hand, the genetic aspects of late-onset AD are much less clear. It is known that the APOE*E4 allele, is a risk factor for AD (as well as for vascular and Lewy body dementia). Beyond age and family history, other risk factors are female gender, lower educational level, and a history of head injury with loss of consciousness.
Presence of atherosclerosis is a risk factor for AD as well as vascular dementia.
Histopathologic markers of Alzheimer's disease include senile plaques (aggregations of abnormal amyloid protein), neurofibrillary tangles (hyperphosphorylation of tau protein), and brain cell death. Neurofibillary tangles are preferentially distributed in the medial temporal lobe, hippocampus, and amygdala, whereas senile plaques are widely scattered throughout the cerebral cortex.
Many neurotransmitters including norepinephrine, serotonin, somatostatin, and various neuropeptides show significant abnormalities in AD. The most exuberant neuro-chemical defect seems to be a deficiency in the enzyme choline O-acetyltransferase, resulting in a deficit of acetylcholine. Alterations in neuro-chemistry probably contribute to the associated psychiatric symptoms of AD such as depression, anxiety, agitation, and psychoses.
Overall, the researches for effective disease-modifying therapies for AD bring us frustration and disappointment. A strong etiopathogenic/pathophysiologic concept is that amyloid-ß peptide (Aß) struggles the neuropathology of AD, and so anti-amyloid therapies are expected to slow AD progression efficiently. Deposition of amyloid-ß (Aß) in the brain is a neuropathological hallmark of AD and a potential cause of neuronal damage. The molecule believed to initiate the process is the 42-amino-acid peptide Aß42, which is found in soluble oligomeric forms and in neuritic and diffuse plaques.
Tarenflurbil is a selective Aß42-lowering drug which modulates ?-secretase activity and reduces production of Aß42 without effect on production of Aß40. Tarenflurbil was the first gamma-secretase modulator to be tested in a phase 3 trial. Chemically, tarenflurbil is the single enantiomer of the racemate NSAID flurbiprofen (at proposed and tested therapeutic dosage, this drug lacks anti-inflammatory activity, hence not inhibiting neither COX-1 nor COX-1; since only the S-enantiomers of arylpropionic acid of NSAID molecules can potently inhibit COX, while on the contrary, the R-enantiomers exert almost no COX activity).
Tarenflurbil has failed its large phase 3 trial. Patients who received an 800-mg dose twice daily exhibited virtually the same declines in cognition and function as did those who received placebo. Tarenflurbil had a reasonably promising phase 2 trial, denoted just last spring. In that study of 207 patients, those taking tarenflurbil experienced significant improvements in global functioning and activities of daily living, and near-significant improvements in cognition. However, disappointingly, such benefits failed to occur in the phase 3 trial, which engaged 1,653 patients with mild AD and progressed at 133 sites across USA. After 18 months of treatment, both the active and placebo groups lost 7 points on the Alzheimer’s Disease Assessment Scale–Cognition (ADAS-Cog). In a secondary cognitive measure, the Clinical Dementia Rating scale sum of boxes, both groups lost 2.5 points. A similar pattern appeared on the ADAS-ADL scale.
