Alzheimer's drug trials have failed 99.5% of the time
Billions of dollars have gone into Alzheimer's research, yet in clinical trials 99.5% of attempted treatment strategies have failed. Wrong doses, wrong targets and poorly chosen volunteers share the blame. Meanwhile dementia cases are projected to rise from 55 million worldwide in 2019 to 139 million by 2050.
Neurodegenerative diseases share one grim feature: neurons are lost progressively, and nothing yet reverses the damage, so the conditions count as incurable. The family includes Alzheimer's, Parkinson's, Huntington's, ALS and prion diseases. Oxidative stress and inflammation are the two main drivers identified so far, and at the level of the cell many of these illnesses look alike, with misfolded proteins clumping together. That overlap raises hope that a breakthrough against one could help others. One recent review proposes a threshold model: ordinary ageing slowly piles up damaged proteins until the cell's clean-up capacity gives way.
Alzheimer's, the most common, shrinks the temporal and parietal lobes. Its signature is plaques built from amyloid beta, peptides of 39 to 43 amino acids snipped by enzymes from a larger membrane protein, together with tangles of tau. Diagnosis remains poor, with about a fifth of cases misdiagnosed. Parkinson's, the second most common, kills dopamine-producing cells in the midbrain's substantia nigra for reasons still unknown; age is its main risk factor, and loss of smell is a frequent but debated clue.
Other conditions follow their own routes. Huntington's, caused by an expanded stretch in the huntingtin gene, first ravages the striatum and produces jerky involuntary movements called chorea. In ALS, upper and lower motor neurons both die; a 1993 discovery linked mutations in the enzyme SOD1 to some family cases, and lab work suggests those mutations harm neurons via neighbouring astrocytes, implicating non-neuronal cells. Multiple sclerosis is driven by immune attack on myelin, and about 15% of patients face steady decline from the outset.
Some forms have striking origins. Variant Creutzfeldt-Jakob disease comes from eating beef infected with mad cow disease. Chronic traumatic encephalopathy follows repeated blows to the head, even ones too mild to concuss, leaving tau clustered around small blood vessels deep in the folds of the cortex.
Source: Neurodegenerative disease
