Alzheimer’s Research After 1945 and Reorientation After 1976

This post is part 2 of a series. Part 1 can be found here.

Alzheimer’s disease (AD) is a complex age-related brain disease. Amid all the discussions of whether recently announced anti-amyloid therapies that target the amyloid beta peptide in the brain (lecanemab, donanemab) are a breakthrough or a cause for disappointment, it may be worthwhile to take a look back and go over some of the earlier AD research papers.

During the research for my book,¹ which I have already introduced (see part 1) it became obvious that many highly interesting findings were already reported in the research phase following the invention of the label "Alzheimer’s disease" (by Emil Kraepelin) in 1910 until the late 1970s. Most of these findings, however, were not adequately acknowledged, perhaps due to the fact that, at that time, "Alzheimer’s disease" had not yet been recognized as one of our most pressing medical exigencies (as opposed to cancer). Moreover, the field had not much to propose in terms of a possible cause of Alzheimer’s dementia. The decades of AD research driven by various evidence-based disease hypotheses were only just starting.

From today’s standpoint, however, publications from the 1950s and 1960s already offered highly interesting first attempts to explain AD pathogenesis. A little later, in 1976, an editorial by Robert Katzman significantly changed the course of Alzheimer’s research. I elaborate on this extensively in my book¹ (where you can also find all full references); here, I would like to spotlight some key points.

An early view on the cause of neurodegeneration in Alzheimer’s

In 1953, Louis Goodman from the University of Pittsburgh published an article entitled “Alzheimer’s disease, a clinico-pathological analysis of twenty-three cases with a theory on pathogenesis,” which was essentially a transcript of his talk held five years before at the 104th annual meeting of the American Psychiatric Association (APA) in Washington, D.C. (May 17-20, 1948).² After reading this 70-year-old, almost forgotten and rarely cited article from today’s standpoint, it should no doubt be called visionary and groundbreaking in many ways. Based on a histopathological examination of 23 AD patients' brains, Goodman drew initial firm conclusions on a possible cause of AD and certain disease mechanisms. While Goodman addressed both general pathological hallmarks ("plaques" and "tangles") just as introduced by the works of Alois Alzheimer and Oskar Fischer at the beginning, he also looked at both pathological alterations individually and separately and elaborated in more detail on their possible relationship.

Today, we know very well that pure AD defined by plaques and tangles (amyloid and tau) only is rare; in most cases, patients display mixed pathologies—AD as a pathological mélange of various forms of dementia. In addition, we know that (1) tangles are seen in many other pathologies, called "tauopathies" as a disease group, and are also present in most regularly aged brains, and (2) about 30 to 40 percent of the elderly with no cognitive impairment show amyloid deposits in their brain.

On the other hand, at the time when Goodman’s research came into view in the 1950s, AD was still largely regarded from a purely descriptive standpoint that was based on histopathology, and Goodman had the courage to summarize a first hypothesis to mechanistically explain the disease. He underlined the importance of a disturbed cerebral iron metabolism, which may affect microglia, leading to functional microglia insufficiency and neurodegeneration. It is perplexing why his "histogenic theory of microglial insufficiency or inhibition" and the role of a "disturbed iron metabolism" were not followed more intensively in the years after this report.

Today, microglial changes in AD are key targets after further research in 2013 identified a link between the gene TREM2 (a receptor expressed in microglia) and increased AD risk, proving the relevance of disturbed microglia function in AD pathogenesis. Moreover, the attention on the peculiar changes in iron concentrations is currently being revitalized by focusing on the iron-dependent apoptotic cell death process called "ferroptosis" in AD. One further issue Goodman’s paper from 1953 raised was the question "What is normal brain aging and what is already a pathological alteration?" Johann Wolfgang von Goethe once said, “All truly wise thoughts have been thought already thousands of times; but to make them truly ours, we must think them over again honestly, until they take root in our personal experience.” So, a thorough (re)reading of early literature could help.

Combining presenile and senile dementia in the 1980s as a decisive step

Many in the field still consider Robert Katzman’s statement in 1976 as a game changer and as the beginning of a fundamental reorientation of AD research (i.e., from being descriptive to becoming more causal). The subtitle “A major killer” in Katzman’s editorial “The Prevalence and Malignancy of Alzheimer Disease”³ shook the research community and put our society's pressing need for an AD therapy front and center. In fact, this paper prominently presented the idea to regard presenile and senile forms of dementia as one disease entity.

Based on these statements, the definition and diagnostic criteria of AD were markedly adjusted and widened, and in 1980, they ultimately entered the diagnostic catalogue, DSM (Diagnostic and Statistical Manual of Mental Disorders; the current version is DSM-5). Taken together, the proposal to combine the two general forms of Alzheimer’s dementia and regard them as a single disease entity truly had tremendous consequences. For some in the field, way too many, who saw a once rare form of presenile dementia now being upgraded (or rather inflated) to the level of the age-related cognitive decline seen in a huge fraction of the elderly. Without speculating on the motivation of this 1976 proposal, one has to ask whether it was strictly science-driven or if other reasons also played a role.

Dementia Essential Reads

A Microbial Signature of Dementia

Nearly Half of Dementia Cases Can Be Prevented or Delayed

Throwing together presenile and senile forms of dementia also left the field with another major challenge that it is still facing almost 50 years after this editorial: When both disease forms are seen as one single disease, clinically and pathologically, the cause should consequently be the same. In my view, this put AD research under a lot of pressure and raised unfulfillable expectations by insinuating that the field could eventually succeed in developing one therapy approach that may work for all cases. Today, knowing that AD is a multifactorial and multigenetic disease and that many clinical trials targeting only one particular target ("amyloid beta peptide") have either failed or were not satisfying at all, an important step toward truly successful therapy and prevention approaches would be to leave this straightjacket and allow a broader look at the disease. Untangling the presenile and senile forms of AD, which were artificially forced together in the 1980s, would be a good start.

As I have learned during my book research,¹ quite a few new ideas and perspectives were introduced in the period of the recommencement of neurodegeneration research after 1945. Topics that are considered "hot" today were already addressed but, unfortunately, were not adequately followed. Leaving the plaques-and-tangle (amyloid-and-tau) only box early was missed. Today, more and more in the field are starting to do exactly that. The story of AD research and its development over the decades is a thrilling one and delivers exciting science and many surprises. To be continued…