Alzheimer’s affects nearly 50 million people worldwide and is the most common cause of dementia, accounting for more than two-thirds of cases. Though Alzheimer’s is in the name of our foundation, we also fund research to prevent and treat the other causes of dementia.
Those other causes are varied and include vascular dementia, frontotemporal degeneration, dementia with Lewy bodies, Parkinson’s disease dementia, and mixed dementia. The National Plan to Address Alzheimer’s Disease refers to these other causes as Alzheimer’s-related dementias and also includes them in its research priorities. I joined the last NIH Summit on the National Plan, during which we discussed why including the other dementias is so important. Alzheimer’s disease has underlying features (i.e., pathology) in common with other types of dementia. And in some cases, the other types have features that resemble Alzheimer’s. Due to these commonalities, a treatment that proves effective for one may work for others.
THE COMMON CAUSES
Vasculature. Our vascular system carries blood to our brains, supplying it with oxygen and nutrients necessary for the survival of our brain cells (i.e., neurons). Damage to our vasculature can contribute to Alzheimer’s and vascular dementia, which is actually a collection of diseases that includes multi-infarct dementia and inherited disorders, such as CADASIL and CARASIL. Vascular dementia is the second most common type and can be caused by strokes or cerebral small vessel disease. Symptoms vary but can include confusion, difficulty planning or making decisions, and reduced attention span.
Tau. Tauopathy is an umbrella term for diseases involving tau proteins that aggregate into tangles. This includes Alzheimer’s as well as the rare diseases progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), primary age-related tauopathy, Argyrophilic grain disease, corticobasal degeneration (CBD), and some forms of frontotemporal degeneration (FTD) and its subtype primary progressive aphasia. Tau is found inside our neurons, where it plays an important role in helping transport signals. But tau can become abnormal and start to accumulate. Recent research suggests that toxic tau spreads from one neuron to another like an infection, causing widespread damage. Symptoms of tauopathies differ depending on the location of tau tangles. PSP and CBD involve motor problems, similar to Parkinson’s disease, while other types can cause personality and behavioral changes.
Alpha-Synuclein. Like tau, alpha-synuclein proteins can become sticky, at which point they aggregate into the Lewy bodies that are implicated in Lewy body dementia. There are two kinds: Parkinson’s disease dementia and dementia with Lewy bodies (DLB). (Multiple system atrophy is also caused by alpha-synuclein accumulation, but it is not classified as a dementia.) Though the exact role of alpha-synuclein is unknown, researchers do know that it is located at the part of the neuron that sends chemical signals across synapses, the space where signals move from one neuron to another. Parkinson’s disease affects an area of the brain associated with motor functions, but can also cause dementia. DLB may first present with cognitive symptoms similar to Alzheimer’s but can also result in sleep disorders, changes in behavior, and hallucinations.
TDP-43. TAR DNA-binding protein (TDP)–43 can aggregate into toxic stress granules and insoluble inclusion bodies. It is a common protein in the brain and performs several functions, such as helping RNA encode other proteins. TDP-43 aggregates are the main pathological feature of the most common types of frontotemporal dementia and amyotrophic lateral sclerosis (ALS), and are also found in approximately a quarter of Alzheimer’s patients. Some hereditary forms of FTD and ALS also share a mutation in the C9ORF72 gene. Symptoms of these diseases may include difficulties with speech and language processing, facial recognition, muscle weakness, and other motor problems.
Mixed. Other forms of dementia have mixed or poorly understood causes. Mixed-etiology dementia includes aspects of both vascular dementia and Alzheimer’s disease. While hippocampal sclerosis, a rare disease often accompanied by a form of epilepsy, may involve both TDP-43 and vascular factors. An emerging disorder, suspected non-Alzheimer's pathophysiology (SNAP), is even more poorly understood. It includes patients who do not have the beta-amyloid plaques common in Alzheimer’s but do have other markers such as brain atrophy (i.e., shrinking) that would indicate a loss of neurons.
Because the causes of dementia are intertwined, the Alzheimer’s Drug Discovery Foundation is committed to finding effective treatments for every form of dementia. As researchers uncover new findings about the causes of these diseases, we will be there to support new drugs to tackle them.
Howard Fillit, MD is the Founding Executive Director and Chief Science Officer at the ADDF.