Dementia is a disease of old age, and the risk of developing dementia increases with age, along with the increased likelihood of aging-related diseases and changes in the brain. Problems with memory, speech and behavior are typical when someone has dementia, and people can be under-diagnosed as simply having typical age-related changes, or over-diagnosed as having a psychiatric disorder. There are no drugs currently available specifically to treat all-cause dementia, but symptoms can sometimes be addressed successfully, and a range of support is available for people with dementia and for their caregivers. (Caringkind)
Alzheimer’s disease (AD) is the most common cause of dementia. It involves severe
neurodegenerative pathology, and promising efforts are in the pipeline to develop effective treatment and prevention strategies. There are already drugs that can dissolve beta-amyloid, but their clinical benefits are modest.(Bocharov)
“Plaque” and “tangles” are the physical signs or biomarkers in the brain that are
associated with Alzheimer’s disease. Beta-amyloid, also called amyloid beta or Aβ, describes the clumps of protein that comprise “plaque”, and abnormal accumulations of tau, another protein, make up what are described as “tangles”. For simplicity’s sake, in this article we will use the term “amyloid” to refer to both biomarkers of AD.

Clumps of beta-amyloid plaque in the human brain

Neurofibrillary tangles of tau protein in the human brain
Until the last twenty years, the diagnosis of AD could only be confirmed with an autopsy. Aloysius (Alois) Alzheimer was a Bavarian physician, born in 1864, who studied the human brain. In a 1906 talk he described “an unusual disease of the cerebral cortex” that he discovered when he conducted an autopsy on a woman who died at age fifty. Her brain showed “senile” plaque (previously only seen in older people), and neurofibrillary tangles that had never previously been described. The importance of this discovery led to the disease being named after Alzheimer in 1910.
It is only relatively recently that it has become possible for clinicians to accurately
measure the accumulation of amyloid in live patients, and this promises to provide a wealth of information from research that can now follow and re-test people periodically as they age.
Three major steps made live diagnosis possible.
1. In 2004, the Alzheimer’s Disease Neuroimaging Initiative was launched to study brain
changes in people with AD while they are alive, eventually leading to successful
diagnostic studies using MRI, CT, and PET scans.
2. A 2018 article reported the successful use of a lumbar puncture to measure amyloid and tau levels in cerebrospinal fluid, offering another way to accurately identify AD in live people. (Tariciotti).
3. In 2020, the first study that successfully used a blood test to accurately diagnose AD was conducted in Sweden (Palmqvist).
One direction of current research is based on evidence that the amyloid deposits
accumulate in some brains for as long as ten to fifteen years before people exhibit symptoms of cognitive impairment. When amyloid appears as the disease progresses, it is presently unclear whether the plaque is causing the brain damage or is simply a response to it. (Jia) In other people, cognitive changes occur before significant levels of amyloid have accumulated.
Using the new ability to observe the living brain, two new drugs, lecanemab and
donanemab, were developed and recently approved by the FDA to treat AD. These drugs are able to dissolve some of the amyloid plaque, but they have fairly modest clinical benefits. They will not improve a person’s memory, require a burdensome commitment of time and money, and have a high risk of troubling and possibly serious side effects. Drug regulators in several countries have declined to approve these drugs out of concern that the risks outweigh the modest benefits, and several major US healthcare institutions have restricted their use. Still, being able to detect
and dissolve amyloid in the brain is an exciting beginning that may lead to more effective and less hazardous treatments. The new drugs are not currently recommended for cognitively unimpaired individuals, even if a blood test reveals that they are amyloid positive.
How the new diagnostic blood tests should be used in clinical care is of great concern, mainly because these blood tests may show that some cognitively normal people have the AD
biomarkers, but the statistical likelihood that they will develop AD is relatively small. Related research cites the lifetime risk of a 65-year-old man who is amyloid biomarker positive as 21.9%, only 1.7% higher than the risk of an individual of a similar age who is amyloid negative (Brookmeyer). Diagnostic blood tests are not currently recommended for cognitively unimpaired people, other than for research studies. (Lindquist)
An international working group (Dubois et al, 2024) cautioned against defining AD
simply by the presence of the biomarkers because they do not always indicate loss of cognitive functioning. The current recommendation is that cognitively normal people who are biomarker positive should not be labeled as having AD, but rather simply as being at risk for developing AD. There are new efforts to identify cognitive impairment at the earliest point and then to follow those individuals, re-testing them periodically for many years, to learn about what and when changes in the brain occur. Early detection seems to be the key to developing effective interventions that will eventually prevent or delay further decline.
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