New pharmacological possibilities in Alzheimer's disease

Alzheimerova bolest (AB) progresivna je degenerativna bolest središnjeg živčanog sustava te je najčešća neurodegenerativna bolest i najčešći uzrok demencija u osoba starijih od 65 godina. S obzirom na to da se AB javlja u starijoj životnoj dobi predstavlja sve veći javnozdravstveni problem na globalnoj razini zbog produljenja životnog vijeka i porasta udjela starije populacije. Složena i nepoznata etiopatogeneza bolesti usporavala je pronalazak uspješne terapije. Prvi lijekovi na tržištu se pojavljuju krajem devedesetih godina prošlog stoljeća. Njihovo djelovanje temeljilo se na otkriću da kod AB dolazi do propadanja kolinergičkih neurona i manjka acetilkolina u bazalnim jezgrama mozga. Lijekovi koji povećavaju koncentraciju acetilkolina inhibirajući enzim acetil-kolinesterazu su: donepezil, rivastigmin i galantamin. Na tržištu je dostupan i memantin koji je antagonist N-metil-D-aspartat (NMDA) -receptora. Ovi lijekovi nisu pokazali adekvatnu uspješnost u liječenju te se AB godinama liječila simptomatski, a incidencija je kroz to vrijeme porasla. Nove spoznaje i razumijevanje u području patogeneze i dijagnostike neurodegenerativnih bolesti otvorile su tijekom zadnjih nekoliko godina potpuno nove smjerove u razvoju lijekova. Histološki nalaz kod AB karakteriziran je prisutnošću ekstracelularnih amiloidnih (senilnih) plakova (građenih od β-amiloida) te unutarstaničnih neurofibrilarnih snopića (nakupina fosforiliranog tau-proteina). Nova terapijska istraživanja usmjerena su na metabolizam nakupljanja ovih proteina specifičnih za AB. Najveći uspjeh ostvaren je s lijekovima koji djelovanje temelje na uklanjanju β-amiloidnih plakova. Veliki iskorak napravljen je s lecanemabom, monoklonalnim protutijelom specifičnim za amiloidne plakove koji je početkom 2023. godine odobren od Food and Drug Administration (FDA). Lijekovi usmjereni na smanjenje nakupljana tau-proteina nalaze se u ranim fazama kliničkih istraživanja. Osim navedenih lijekova, dio istraživanja usmjeren je na mogućnosti lijekova koje se primjenjuju kod drugih kliničkih stanja te njihova prvotna namjena nije bila usmjerena za liječenje AB.Alzheimer's disease (AD) is a progressive degenerative disease of the central nervous system and is the most common neurodegenerative disease and the most common cause of dementia in people over 65 years of age. Given that AD occurs in older age, it represents an increasing public health problem at the global level due to the increase in life expectancy and the increase in the proportion of the elderly population. The complex and unknown etiopathogenesis of the disease slowed down the finding of a successful therapy. The first drugs appeared on the market at the end of the nineties of the last century. Their action was based on the discovery that in AD there is a deterioration of cholinergic neurons and a lack of acetylcholine in basal nucleus of the brain. Drugs that increase concentrations of acetylcholine by inhibiting acetylcholinesterase enzyme are: donepezil, rivastigmine and galantamine. Memantine, which is an N-metil-D-aspartat (NMDA) receptor antagonist, is also available on the market. AD was treated symptomatically for years, although these drugs did not show adequate success in treatment. New knowledge and understanding in the field of pathogenesis and diagnostics of neurodegenerative diseases have opened during the last few years completely new directions in the development of new drugs. Histological findings in AD are characterized by the presence of extracellular amyloid (senile) plaques (accumulations of β-amiloid) and intracellular neurofibrillary tangles (accumulations of phosphorylated tau protein). New therapeutic research is focused on the metabolism of the accumulation of these AD-specific proteins. The greatest success was achieved with drugs whose action is based on the removal of β-amyloid plaques. A major breakthrough was made with lecanemab, a monoclonal antibody specific for amyloid plaques that was approved by Food and Drug Administration (FDA) at the beginning of 2023. Drugs aimed at reducing accumulation of tau-protein are in the early stages of clinical studies. In addition to the mentioned drugs, part of the research is focused on the clinical relevance of pharmacological substances that are used in treating other clinical conditions, so their original purpose was not aimed for treatment of AD