Therapeutic approach to Alzheimer's disease

Alzheimerova bolest (AB) je progresivni neurodegenerativni poremećaj koji se uglavnom javlja u starijoj životnoj dobi, a kao najčešći uzrok sindroma demencije predstavlja značajni javnozdravstveni problem. Trenutačno farmakološko liječenje AB je simptomatsko, bez mogućnosti utjecaja na uzrok bolesti. U Hrvatskoj su trenutno registrirana tri lijeka: dva inhibitora acetilkolinesteraze (donepezil i rivastigmin) koji se koriste za liječenje blagog do umjerenog oblik bolesti i jedan antagonist NMDA receptora (memantin) koji se koristi za liječenje umjerenog do teškog oblika bolesti. Primjena inhibitora acetilkolinesteraze temelji se na dokazima koji upućuju da tijekom razvoja bolesti dolazi do oštećenja kolinergičkih neurona, pa se, inhibirajući enzim koji razgrađuje acetilkolin, nastoji povisiti razina tog neurotransmitera u mozgu. Mehanizam djelovanja antagonista NMDA receptora temelji se na blokiranju ekscitotoksičnog učinka prekomjerne stimulacije receptora glutamatom. Trenutno se istražuju novi terapijski pristupi koji bi trebali imati učinak na modifikaciju tijeka bolesti, što znači da bi sprečavali daljnja oštećenja neurona i progresiju bolesti, no trenutno nijedan od tih lijekova nije pokazao adekvatnu učinkovitost u kliničkim studijama. Njihov bi učinak mogao biti najveći ukoliko bi liječenje započelo u presimptomatskoj fazi bolesti stoga je bitno razviti metode ranog dijagnosticiranja AB. Od terapije koja modificira tijek bolesti aktualno se istražuju lijekovi s potencijalnim učinkom na β-amiloid i protein tau koji se nakupljaju u mozgu (stvarajući amiloidne plakove, odnosno neurofibrilarne petlje) i ostvaruju toksične učinke. Uzimajući u obzir štetan učinak slobodnih radikala istraživale su se mogućnosti i antioksidativne terapije (npr. vitamini E i C). Postoje i različiti dodaci prehrani čija uporaba nije odobrena, ali se svejedno široko koriste u svrhu poboljšanja kognitivnih simptoma. Iako epidemiološke studije povezuju hormonsku nadomjesnu terapiju i statine sa smanjenjem rizika AB, kliničke studije nisu dokazale njihovu učinkovitost. Razvija se i genska terapija, testiraju se različiti putevi dostave gena za neuralni faktor rasta u bazalne dijelove mozga. S obzirom na to da AB uz oštećenje kognitivnih sposobnosti sa sobom nosi i psihijatrijske poremećaje i poremećaje ponašanja koji bitno otežavaju samu bolest i skrb za pacijenta, potrebno je naći i zadovoljavajuću terapiju tih simptoma, s obzirom na to da su dosadašnji oblici terapije ograničenih mogućnosti.Alzheimer's disease is a progressive neurodegenerative disorder, mostly affecting elderly people. It's the most common cause of dementia and therefore a significant public health problem. Current therapy of the disease is simptomatic, it doesn't affect the cause of the disease. Three drugs are currently registered in Croatia: two acetylcholinesterase inhibitors (donepezil and rivastigmine) which are used for mild to moderate stage of the disease and one NMDA receptor antagonist (memantine) which is used for moderate to severe form of the disease. The use of the acetylcholinesterase inhibitors is based on the evidence of marked cholinergic deficit in the brains of patients with AD. The mechanism of action of the NMDA receptor antagonists is based on blocking the excitotoxic effect of the excessive stimulation of the receptor by glutamate. New, disease-modifying therapeutic approaches which prevent further neuronal damage and the progression of the disease are being investigated at the moment, but none of those drugs has shown efficacy in clinical studies. Their effect might be the greatest in the presymptomatic phase of the disease. Therefore, it's important to biomarkers for early detection of the Alzheimer's disease. Some of the disease-modifying drugs that are currently being investigated are drugs targeting β-amyloid and tau protein which accumulate in the AD brain (forming amyloid plaques and neurofibrillary tangles) and produce toxic effects. Considering the damaging effect of the free radicals, antioxidative therapy (such as vitamins E and C) has also been tried. There are different food supplements whose use has not been approved, but are widely used to improve symptoms of dementia. Even though epidemiological studies have shown an association between estrogen replacement therapy or the use of statins with a decreased risk of Alzheimer's disease, clinical studies have not proven their efficacy. Genetic therapy is also being researched, different ways of delivering nerve growth factor gene to the basal parts of the brain are being tested. Considering the fact that Alzheimer's disease is not characterized only by cognitive damage but also psychiatric symptoms and behavioural problems which aggravate the disease and make patient care more difficult, it is necessary to find adequate treatment of those symptoms since current therapy is not satisfactory