More than a century ago, a German physician named Alois Alzheimer wrote a brief case report published in 1907 that barely attracted attention. “The first symptom,” he wrote about his patient, “was that she was jealous of her husband. Soon, she developed a rapid loss of memory.” In less than two pages, Dr Alzheimer described a syndrome of early memory impairment, gradual cognitive and functional decline, terminating in death. “At the end,” he described, “the patient was lying in bed in fetal position completely pathetic, incontinent.”
After her death, Alzheimer performed an autopsy and prepared the brain for study. Using silver stains, he found that her brain was full of dying neurons packed with tangles of neurofibrils and scattered foci of staining deposits that he later sketched. Presciently, he wrote: “Considering everything, it seems we are dealing here with a special illness.” He urged future doctors to think hard about this case in the context of other, similar cases that had emerged around Europe. “It will enable us to define them clinically, in greater detail.”
Now, in the 21st century, we are still hard at work at answering Dr. Alzheimer’s initial call to classify and understand the disease that carries his namesake. Although the neurofibrillary tangles and neuritic plaques that were originally described in the 1907 abstract still make up the definitive diagnosis of Alzheimer’s disease, such histopathological studies are impractical for classification, diagnosis, and prognosis of living patients. Many believe that once neuronal plaques and tangles have developed, the disease is too advanced for therapies to work. Indeed, today’s therapeutic interventions at advanced stage provide only modest benefits, at best. Consequently, researchers have focused their aim on novel clinical, cognitive, biochemical, and radiographic biomarkers that may help to identify healthy patients early. Such research efforts aren’t easy, because it means finding a population of young individuals who may or may not go on to develop the disease – a potentially expensive and time-consuming venture. Fortunately, there is a solution to creating such a cohort – the answer lies in the genetics of Alzheimer’s disease.
The majority of the 5 million Americans with Alzheimer’s disease have a sporadic variant of the illness that presents late in life. In contrast, less than 1% of afflicted Americans have an autosomal dominant form of Alzheimer’s disease (ADAD) caused by mutations in either APP, presenilin-1, or presenilin-2, implicated in amyloid dysregulation and plaque formation. Because ADAD has an autosomal inheritance pattern, children of affected individuals are at high risk for developing the same illness, with age of onset predictably similar to their parents. Assembling these families together would create an informative cohort consisting of presymptomatic, healthy individuals – critical for researching biomarkers that may predict illness before symptoms become evident. The National Insitute of Aging has promoted just that effort, through the establishment of a large, international cohort of ADAD patients and their relatives, termed “The Dominantly Inherited Alzheimer’s Network” (DIAN). Although ADAD is rare, its downstream pathogenesis and clinical presentation appears similar to the sporadic form of disease, making the DIAN cohort a unique opportunity to study Alzheimer’s disease broadly.
Using the DIAN cohort, investigators have now published their initial results in the New England Journal of Medicine. The study performed a cross-sectional analysis on 128 individuals from pedigrees with known mutations for ADAD. Investigators performed several biochemical, radiographic, and clinical tests, hoping to determine the sequence and degree of pathophysiologic changes that occur prior to overt expression of illness. At baseline, many of the individuals in the study were healthy, asymptomatic men and women between 30-50 years of age who had inherited the mutation from their parents. Other groups in the study included those with the mutation who were already symptomatic, as well as those who had not inherited the mutation. Subjects underwent serum and CSF analyses for amyloid and tau protein, MRIs and PET scans, and neuropsychiatric and cognitive testing. Investigators were able to use the results of their biomarker assays as a proxy to create a model of the sequence of pathophysiologic changes that occur in ADAD before full expression of the disease becomes apparent [see Figure 2, from paper, below].
For example, beginning 25 years before expected symptom onset, levels of amyloid in the CSF began to drop. Fifteen years before symptom onset, PET scans revealed increased amyloid deposition in the brain and the appearance of tau protein in the CSF. Cognitive testing revealed impaired episodic memory 10 years prior, and global cognitive impairment 5 years before full blown onset of the disease.
This model suggestswe can find individuals who have already begun to demonstrate signs of disease pathogenesis, even before the symptoms of Alzheimer’s become troublingly apparent. CSF studies linked to radiologic and cognitive assessment could prove to be a powerful series of tools to identify progressive disease early and potentially provide a window to start therapy before the characteristic plaques and tangles develop. It remains unclear if such a model can be extended to sporadic Alzheimer’s disease given that their causative triggers and consequent pathogenesis may vary.
However, there is reason to be optimistic. A similar experimental paradigm was used to study patients with hyperlipidemia. By examining patients with a rare, genetic variant of the disease, called familial hyperlipidemia, investigators were able to demonstrate the efficacy of a class of drugs called statins. Now, statins are the drug of choice for all patients with hyperlipidemia to prevent the downstream complications of vascular disease, coronary artery disease, and stroke. Although the tools to identify at-risk Alzheimer’s patients are still coarse compared to lipid profiles and blood pressure measurements, this study makes significant progress in establishing a framework to conceptualize the early changes of autosomal dominant Alzheimer’s disease. Such a framework is critical to test therapies that may prevent the decline that so distressed Alois Alzheimer as early as 1901.
Related NEJM editorial, “Lifelong Management of Amyloid-Beta Metabolism to Prevent Alzheimer’s Disease”