Any terminal illness is a terrible thing; but to a cryonics member, a brain-destroying neurodegenerative disease is the worst contemporary medical “death sentence” one can receive. There are several flavors of neurodegenerative disorders, many of which primarily affect the patient’s movement, strength, coordination, or the peripheral nervous system. And there are numerous contributory mechanisms in the causation of neurodegeneration, including prion infection and toxin related disease. But the most common – and the most feared – neurodegenerative disease is one that affects not movement, but cognition.

Of course, I am speaking of Alzheimer disease (AD). Originally described in a 51- year old woman by the Bavarian psychiatrist Alois Alzheimer in 1906, neuropathologists have increasingly recognized that AD is also the most common basis for latelife cognitive failure. Culminating in neuronal dystrophy and death leading to the progressive loss of memory and other cognitive functions (i.e., dementia), and affecting individuals of both sexes and of all races and ethnic groups at a rate of occurrence in the U.S. ranging from approximately 1.3% (age 65-74) to 45% (age 85-93), it is easy to see why AD has generated so much intense scientific interest in recent years.

In the recently published work “The Biology of Alzheimer Disease” (2012), most of what is known about AD today is described in detail in the various chapters covering topics such as the neuropsychological profile and neuropathological alterations in AD, biomarkers of AD, the biochemistry and cell biology of the various proteins involved in AD, animal models of AD, the role of inflammation in AD, the genetics of AD, and treatment strategies. The editors’ selection of contributions has resulted in the most up-to-date compendium on Alzheimer disease to date.

The book culminates in a chapter called Alzheimer Disease in 2020, where the editors extol “the remarkable advances in unraveling the biological underpinnings of Alzheimer disease…during the last 25 years,” and yet also recognize that “we have made only the smallest of dents in the development of truly disease-modifying treatments.” So what can we reasonably expect over the course of the next 7 years or so? Will we bang our heads against the wall of discovery, or will there be enormous breakthroughs in identification and treatment of AD?

Though a definitive diagnosis of AD is only possible upon postmortem histopathological examination of the brain, a thorough review of the book leads me to believe that the greatest progress currently being made is in developing assays to diagnose AD at earlier stages. It is now known that neuropathological changes associated with AD may begin decades before symptoms manifest. This, coupled with the uncertainty inherent in a clinical diagnosis of AD, has driven a search for diagnostic markers. Two particular approaches have shown the most promise: brain imaging and the identification of fluid biomarkers of AD.

Historically, imaging was used only to exclude potentially surgically treatable causes of cognitive decline. Over the last few decades, imaging has moved from this minor role to a central position of diagnostic value with ever-increasing specificity. The ability to differentiate AD from alternative or contributory pathologies is of significant value now, but the need for an earlier and more certain diagnosis will only increase as disease-modifying therapies are identified. This will be particularly true if these therapies work best (or only) when initiated at the preclinical stage. Improvements in imaging have also greatly increased our understanding of the biology and progression of AD temporally and spatially. Importantly, the clinical correlations of these changes and their relationships to other biomarkers and to prognosis can be studied.

The primary modalities that have contributed to progress in AD imaging are structural magnetic resonance imaging (MRI), functional MRI, fluorodeoxyglucose (FDG) positron emission tomography (PET), and amyloid PET. Structural MRI, which is used to image the structure of the brain, has obvious utility in visualizing the progressive cerebral atrophy characteristic of AD. Such images can be used as a marker of disease progression and as a means of measuring effective treatments (which would slow the rate of atrophy). Functional MRI, on the other hand, measures changes in blood oxygen leveldependent (BOLD) MR signal. This signal, which can be acquired during cognitive tasks, may provide the clinician with a tool to compare brain activity across conditions in order to assess and detect early brain dysfunction related to AD and to monitor therapeutic response over relatively short time periods.

FDG PET primarily indicates brain metabolism and synaptic activity by measuring glucose analog fluorodeoxyglucose (which can be detected by PET after labeling it with Fluorine-18). A large body of FDG-PET work has identified an endophenotype of AD – that is, a signature set of regions that are typically hypometabolic in AD patients. FDG hypometabolism parallels cognitive function along the trajectory of normal, preclinical, prodromal, and established AD. Over the course of three decades of investigation, FDG PET has emerged as a robust marker of brain dysfunction in AD. Imaging of β-amyloid (Aβ) – the peptide that makes up the plaques found in the brains of AD patients – is accomplished via amyloid PET to determine brain Aβ content. Historically, this has only been possible upon postmortem examination, so the utility of amyloid imaging is in moving this assessment from the pathology laboratory to the clinic. Because amyloid deposition begins early on, however, amyloid PET is not useful as a marker of disease progression.

The well-known hallmarks of AD, the plaques and neurofibrillary tangles first described by Alouis Alzheimer in 1906, were discovered in 1985 to be composed primarily of β-amyloid and hyperphosphorylated tau protein, respectively. Advances in our knowledge of Aβ generation and tau protein homeostasis have led to substantial research into disease-modifying drugs aimed at decreasing overall plaque and tangle load in an effort to halt neurodegeneration. Such treatments will likely be most effective if started early in the disease process, making sensitive and accurate fluid biomarkers of Aβ and tau especially important.

Outside of imaging, progress in AD diagnostics stems primarily from the assessment of fluid biomarkers of AD. These biomarkers are generally procured from the cerebrospinal fluid (CSF) and blood plasma and include total tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of of β-amyloid (Aβ42). These core biomarkers reflect AD pathology and have high diagnostic accuracy, which is especially useful in diagnosing AD in prodromal and mild cognitive impairment cases.

Because the CSF is in direct contact with the extracellular space of the brain, biochemical changes in the brain can be detected in the CSF. Assays to detect Aβ42 led to the discovery that Aβ42 in AD is decreased to approximately 50% of control levels, making the measurement of Aβ42 a useful clinical tool. Measurements of T-tau (around 300% of control in AD patients) and P-tau biomarkers (a marked increase in AD patients) in combination with Aβ42, however, provide an even more powerful diagnostic assay.

Fluid biomarkers for AD other than Aβ and tau have been posited, but positive results have been difficult to replicate. Novel biomarkers with the most promise inlcude the amyloid precursor proteins sAPPβ and sAPPα, β-site APP cleaving enzyme-1 (BACE1), Aβ oligomers, and other Aβ isoforms. Additionally, neuronal and synaptic proteins as well as various inflammatory molecules and markers of oxidative stress may prove valuable as CSF biomarkers. Studies of plasma biomarkers such as those investigating plasma Aβ have yielded contradictory results, but promising novel blood biomarkers for AD may be found in certain signaling and inflammatory proteins.

Taken together, progress in brain imaging and identification of fluid biomarkers hold great promise in improved diagnosis of AD cases. When combined with expected drug therapies we may be able to delay the onset of neurodegeneration and associated cognitive impairment significantly. In the meantime, early diagnosis is helpful in stratifying AD cases, monitoring potential treatments for safety, and monitoring the biochemical effect of drugs. For cryonicists, early diagnosis can help guide treatment and end-of-life care decisions in order to optimize cryopreservation of the brain.

So – back to the original question. What can we predict about the AD landscape in 2020?

Besides continued progress in early diagnosis through brain imaging and fluid biomarkers, the authors anticipate that advances in whole-genome and exome sequencing will lead to a better understanding of all of the genes that contribute to overall genetic risk of AD. Additionally, improved ability to sense and detect the proteins that aggregate in AD and to distinguish these different assembly forms and to correlate the various conformations with cellular, synaptic, and brain network dysfunction should be forthcoming in the next few years. Lastly, we will continue to improve our understanding of the cell biology of neurodegeneration as well as cell-cell interactions and inflammation, providing new insights into what is important and what is not in AD pathogenesis and how it differs across individuals, which will lead, in turn, to improved clinical trials and treatment strategies.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, April, 2013