A Brief Update on Alzheimer's Diagnosis and Treatment

I had the opportunity to interview Dr. Ariel Gildengers about the state of the art in diagnosis and treatment of Alzheimer's and related conditions. Dr. Gildengers is Professor of Psychiatry at the University of Pittsburgh School of Medicine. He is an active clinician, educator, and scientist. Over the past 20 years, Dr. Gildengers’ research has focused on understanding the long-term effects of bipolar disorder and its comorbidities on cognitive function and brain integrity in older adults, improving the treatment of older adults with bipolar disorder (OABD) and preventing depression and cognitive deterioration in older adults with mild cognitive impairment.

What is Alzheimer’s disease exactly, and what is causing the dementia? Alzheimer’s disease (AD) is the most common cause of dementia, accounting for more than half of dementia in the U.S. and worldwide. AD is typically characterized by loss of memory due to damage that begins in the medial temporal lobes of the brain and spreads to other parts of the brain as the disease progresses. AD is thought to begin decades before there are any observable symptoms. Over 6 million people in the U.S. have Alzheimer’s disease at an estimated $355 billion (2021) in costs to society (National Institute on Aging). Slowing disease progression would result in many fewer people living with AD in its most advanced stages, which require the highest level of care and incur the greatest cost.

While the pathology of AD has not been fully elucidated, central to the disease process is the abnormal accumulation of amyloid protein, which sets off a pathological cascade that leads to abnormal accumulations of tau protein, resulting in neuronal damage and dysfunction. Brain atrophy follows, with impaired memory and overall cognitive decline. Cognitive decline is associated with impaired everyday function.

Since the disease process likely begins decades before overt symptoms, there may be many points to intervene to prevent neurodegeneration. And this is critical. AD therapies need to prevent neuronal damage before cognitive symptoms become apparent. Once AD-induced neuronal death occurs, investigators believe it is too late to reverse the damage.

Current research is directed at identifying preclinical AD (evidence of brain amyloid accumulation without cognitive symptoms) and prodromal AD (evidence of brain amyloid accumulation with mild cognitive symptoms) and intervening at these earlier disease stages to alter the trajectory of neurodegeneration. Investigators are studying whether slowing down, stopping, or removing amyloid or tau accumulation can prevent the development of AD.

How to detect Alzheimer’s disease when there are no obvious signs of illness? Until the early 2000s, amyloid accumulation in the brain could only be confirmed at autopsy. Then researchers developed Pittsburgh Compound B (PiB), a radioligand that binds to brain amyloid, making it possible to visualize amyloid accumulation in vivo using positron emission tomography (PET).

The PiB breakthrough has enabled investigators to identify individuals at earlier and earlier stages of AD to test anti-amyloid interventions. Newer methods of identifying individuals with high levels of brain amyloid have focused on examining biomarkers from cerebral spinal fluid and blood plasma, obtained via lumbar puncture and venipuncture, respectively, for amyloid beta or phospho-tau.

Investigators believe that in the next one to two years, there will be commercially available blood tests that will be highly accurate in identifying individuals who have AD without clinically overt symptoms. The availability of these blood tests will enable screening for AD the way that we screen for diseases like diabetes mellitus, heart disease, and cancer.

What is the role of anti-amyloid interventions? In 2022 and 2023, the FDA approved disease-modifying anti-amyloid interventions, including aducanamab and lecanemab. Both aducanamab and lecanemab are monoclonal antibodies directed at removing amyloid-beta (Aβ). The abnormal accumulations of Aβ include those that are circulating in the body (soluble) and those that are deposited in the brain (insoluble). Aducanamab and lecanemab work by crossing the blood-brain barrier, binding to soluble and insoluble Aβ to varying degrees, and removing it. By removing Aβ, scientists believe it disrupts the disease process and stops the pathological cascade.

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To date, the effects have been modest and there is controversy in the scientific community about the effectiveness of these interventions, especially surrounding the FDA approval process of aducanamab. While it is clear that these interventions remove Aβ, to a greater or lesser extent, it is unclear how effective they are at stopping AD.

In the case of lecanemab, intervention with the anti-amyloid monoclonal antibody will delay disease progression by five to seven months if started in the earliest phases of the illness. Five to seven months of preserving cognitive function is substantial and a breakthrough in treatment, but the risks of intervention are significant, including risk of death from brain inflammation. Plus, the treatments involve monthly or twice-monthly infusions that may not be widely available; the costs are high ($20-$30,000), and many people may be excluded due to pre-existing general medical illness (e.g., people on blood thinners). Hence, while anti-amyloid interventions are a breakthrough, the scientific community is looking for treatments that are beyond amyloid.

Are there any other ways to mitigate dementia beyond antibody therapies? Anti-amyloid therapies have only a modest impact on AD, so investigators are looking for interventions to complement them. One drug that has drawn considerable interest is lithium, which may prevent amyloid and tau accumulation as well as prevent inflammatory or oxidative damage to neurons.

Since the FDA approved lithium for treatment of bipolar disorder (BD) in 1970, it has been one of the most effective interventions for BD mood episodes. In Alzhemier's disease and related dementias (AD/ADRD), investigations of lithium range from animal to human to epidemiological studies. Animal models of AD/ADRD have shown that lithium can improve cognitive function, reduce Aβ and tau pathology, and increase the number of neurons in the hippocampus.

An epidemiological study in Denmark showed that in areas of the country where there are naturally higher concentrations of lithium in the water supply, there are lower rates of dementia. A study conducted in Brazil in older adults with amnestic moderate cognitive impairment (MCI), lithium slowed cognitive decline. In short, there are a number of published studies that have suggested that lithium may prevent AD.

However, to date, the data are not yet definitive, and importantly, there are significant safety and tolerability concerns about lithium, including toxicity in elders and long-term concerns about kidney damage. Lithium should be used only under the supervision of a qualified physician. Nonetheless, if lithium is shown to prevent or slow down AD, it would be an important addition to the available treatments because it is inexpensive and could be given widely to older adults.

For more information on AD, please visit the Alzheimer's Association website.