Alzheimer’s disease (AD) is a neurodegenerative disease affecting approximately 10% of individuals over the age of 65 and nearly one-third of those over 85, making it the most common cause of dementia. Over 300 billion dollars are spent on Alzheimer's care each year.
AD patients suffer a range of symptoms, usually initially presenting as short -term memory loss above and beyond that attributable to normal aging. As the disease progresses, patients often experience confusion, mood swings, loss of language, reclusion, and eventually the loss of bodily function with the average survival time from diagnosis being seven years.
The disease is often described as being either early onset or late onset. Early onset familial Alzheimer’s Disease (EO-FAD), usually seen before a patient is 60, accounts for only a small percentage of cases and typically shows a strong inheritance pattern. Late onset Alzheimer’s (LOAD) appears to be sporadic, without the familial clusters seen in EOAD, but also involves various susceptibility genes.
The etiology of AD has been a complex puzzle for researchers. Imaging studies in AD patients show atrophy in particular areas of the brain. These include the hippocampus and related regions, as well as the association cortices in the frontal, temporal, and parietal lobes; the parts of the brain involved in long-term and visual memory, language processing, and integrating sensory information. Additionally, the autopsied brains of patients have beta-amyloid plaques and neurofibrillary tangles. Beta amyloid plaques can form when particular fragments of the amyloid precursor protein (APP), cleaved by the enzymes, beta- and gamma-secretase, clump together. Beta amyloid plaques concentrate in this space and affect the neuron’s health and the communication between neurons. They also drive the formation of the other the two hallmark AD pathologies, neurofibrillary tangles and neuroinflammation.
Neurofibrillary tangles are a result of alterations in tau proteins. Tau proteins have an important role in maintaining the cell’s microtubules, which act as transport cables in a cell. In AD patients the tau proteins are altered and begin to stick together, causing tangles to form. The tangles are thought to disrupt transport in the neurons and cause cell death. Both plaques and tangles can also be found in the brains of aged non-AD-afflicted individuals as well, but they are fewer in number and tend not to be as widely distributed in the brain as those in AD patients. Brain imaging studies have shown that plaque and tangles may precede cognitive symptoms of dementia by a decade or more. In studies at MIND, the third key pathology of AD, neuroinflammation, has been shown to kill even more neurons than the initial plaque and tangles.
Early-onset familial AD (EO-FAD) is most often caused by any of over 200 mutations in the genes for APP, presenilin 1, and presenilin 2. All three genes were co-discovered at MIND in the 1980’s and 90’s. The EO-FAD mutations in APP directly influence the production of beta-amyloid proteins while EO-FAD mutations in the presenilin-1 and presenilin-2 proteins directly affect the gamma secretase cleavage of APP to produce beta-amyloid proteins.
LOAD typically has an age of onset after 65. A genetic factor that increases the risk for LOAD is a particular version of apolipoprotein E (APOE), APOEe4. In the brain, the APOE protein transports cholesterol to neurons but also affects the deposition of beta-amyloid in the brain. For individuals carrying the APOEe4 version of APOE, there is a dose-dependent influence on the likelihood of AD onset, with two copies of this version of the gene moving average disease onset earlier and more likely than one copy. In addition to APOE4, over 30 other AD genes have been identified based on whole genome screens, many of which were carried out at MIND. These includes genes involved with neuroinflammation, beta-amyloid, cholesterol, and synaptic function. Besides genetic risk factors, other factors such as obesity, hypertension, and diabetes have also been associated with higher incidence of sporadic dementia, likely as a concurrent brain disease that amplifies AD damage.
There is currently no cure for AD. Many of the treatment options focus only on temporarily slowing disease progression and managing symptoms. Five FDA-approved drugs currently exist and work by either of two mechanisms. The first, cholinesterase inhibitors, act by inhibiting the breakdown of the neurotransmitter, or neuron-to-neuron chemical messenger, acetylcholine. Acetylcholine is in increasingly short supply as the death of cholinergic neurons in the AD patient’s brain progresses. The other type of drug acts by competitively inhibiting the glutamate NMDA receptors in the neurons from taking up glutamate, a neurotransmitter that is released by the AD-damaged cells that can damage cells by disrupting calcium balance.
Research toward a better understanding of AD that would inform more effective therapeutics is ongoing and multi-pronged. This research includes identifying additional genes associated with disease incidence in order to identify potential drug targets. Additionally, scientists are discovering improved techniques to image the diseased brain for closer study, as traditionally AD has been diagnosed only in autopsy when the plaques and tangles could be examined. There is also research into approaches that can clear brain plaques, such as antibody-based vaccines, with the hope of concomitant diminishment in cognitive impairment. At MIND, miniature human brain organoid models of AD have been pioneered to accelerate drug discovery, some of which have already been entered into clinical trials in patients.
Progress in our understanding of the causes and mechanisms of AD continues to inform our search for effective therapies to manage and cure the disease. Advances in imaging live brains and the identification of additional players in AD pathology contribute to our cache of potential drug targets and therapies.