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Progress in Early Detection of Alzheimers Disease

23 April 2012 | no comments | Featured Articles


Cryonics, March-April 2012

By Mike Perry

Alzheimer’s disease (AD) is the most common form of dementia. There is no cure, it worsens as it progresses, and it is uniformly fatal, though typically requiring 7-14 years to run its course from what up to now have been the first detectable, identifiable symptoms. (Symptoms may show up earlier than this but could be from other disorders.) People over 65 are mainly affected by AD, though the less-prevalent early-onset variety can appear much earlier.1 The percentage of population with the disease increases rapidly with age; one source estimates that 5.5% of Americans between age 65 and 74 have it, increasing to 17.4% for those between 75 and 84, and up to a whopping 46.2% (nearly half) for persons 85 and over.2

Because of its lengthy progression Alzheimer’s is one of those diseases that could pose a special difficulty to cryonicists, who want to be preserved with mental faculties intact. It is critically important, absent a cure for the disease, that cryopreservation occur during the earlier stages, before the disease has progressed to the point of causing dementia. In the case of faster-progressing diseases such as many cancers, refusal of food and fluids has been an acceptable means of hastening clinical death to avoid the further progression of the disease and also to avoid autopsy—and this option has been exercised by some Alcor members.3 But it is not clear what would happen for an Alzheimer’s patient in the early stages of the disease who wanted to pursue this course, with catastrophic impairment still years away yet inevitable. Prospects for slowing or curing the disease meanwhile remain grim. There is concern that efforts by pharmaceutical companies to develop effective treatments may be abandoned. (There are treatments for the symptoms of AD—for example, to keep one’s mind functioning at a high level longer—but they do not slow, halt, or reverse the  disease.)

Though the outlook for slowing or stopping the disease is presently somber, it is not totally bleak, and it could substantially improve within a few years. For the best treatment it is essential that diagnosis of the disease be made as early as possible, ideally before any outward symptoms occur. Unfortunately, there is no reliable test of this sort at present, and a reliable diagnosis is possible only when mild cognitive impairment (MCI) involving difficulty remembering recent events and the like has occurred. Current diagnostic techniques involve a combination of neuropsychological testing, interviews with family members and caregivers, and methods based on brain imaging and other testing. It is essential, of course, that AD be distinguished reliably from other diseases which could present very similar symptoms (in this case, also MCI) at an early stage; the wrong treatment could be harmful or at best, ineffective.

One fairly new technique, known as PiB PET4 (“Pittsburgh compound B,” developed at Univ. of Pittsburgh, plus “positron emission tomography”5), has been developed for directly and clearly imaging Alzheimer’s beta-amyloid (Ab) deposits in vivo using a tracer that binds selectively to the Ab deposits. The PiB-PET technique uses carbon-11 PET scanning. Recent studies suggest that PiB-PET is 86% accurate in predicting which people with MCI will develop AD (with dementia that is more severe than MCI) within two years, and 92% accurate in ruling out the likelihood of developing Alzheimer’s. Though the results are encouraging, it would be desirable to extend the time interval before AD strikes in full force, so that treatments could be started as early as possible.

Studies of AD in animal models have yielded some promising results based on a kind of immunotherapy (more later). Though these results haven’t yet translated into useful human therapies, new possibilities are raised by a recent success with early detection of AD in humans6 based on biomarkers, which is the main subject of this report. The sooner the disease is detected, the less damage it will have done, which provides more opportunity for therapeutic intervention, including the sort that has already shown success in animals.

In the study referred to, 134 aging patients, initially (“baseline”) with MCI, were followed over approximately a decade by a research team at Lund University, Sweden, headed by Physician Oskar Hansson. The study focused on biomarkers—substances present in spinal fluid and linked to AD. A certain combination of markers, low levels of Aβ and high levels of the substance tau, indicate a high risk, about 90%, of developing AD dementia over a 9.2-year period. Those who had memory impairment but normal values for the markers did not run a higher risk of getting AD than healthy individuals. Oskar Hansson previously carried out a study showing that pathological changes can be seen in the brain of an AD patient five years before the diagnosis. The new study has nearly doubled this time span.7

The biochemistry of AD is still far from fully understood. Different theories compete, and deeper understanding may be needed before a cure is found. The Hansson results are encouraging, however, for the extra “lead time” we can now expect to have in studying and combating the disease as it manifests itself in different patients. A larger time window appears to be opened to try approaches that have already shown success in animals. Some further details of the study are of interest, for which a bit of additional background on AD will be useful.

The normal brain uses a substance known as amyloid precursor protein (APP) in a rapid-fire fashion in which APP molecules are created and then destroyed.8 (Just what the APP is used for is not entirely clear, perhaps for such functions as regulation of synapse formation, neural plasticity, and iron export.) By the time AD starts to develop in a patient the clearing away of the used APP molecules has somehow gone awry. Fragments known as β-amyloid or Aβ begin to pile up in aggregates or heaps known as senile plaques. More specifically these fragments take the form of the aggregation-prone 42-amino acid isoform (equivalent form) of Aβ known as Aβ42. Senile plaques average around the size of larger-size neurons (around 50 micrometers) and are thought to be neurotoxic.

In addition to senile plaques the pathologic characteristics of AD include neurofibrillary tangles: insoluble, twisted fibers found inside the neurons containing damaged (hyperphosphorylated) tau protein or P-tau. Normal, undamaged tau protein is important to stabilize microtubules in the neurons, which in turn are essential to their functioning. P-tau does not stabilize the microtubules but instead the structure collapses. Normal tau and P-tau together make up the total tau or T-Tau;  the concentrations of T-tau, P-tau and Aβ42 are important in the Hansson study reported here.

According to the amyloid cascade hypothesis, accumulation of Aβ as Aβ42 in the brain drives the neurodegenerative process in AD. This accumulation is believed to start decades before cognitive decline. It might be detected by a reduction in cerebrospinal fluid (CSF) levels of Aβ42 and elevated retention of positron emission tomography tracers for amyloid in the brain. According to this theory, the initial, asymptomatic phase of AD is followed by neuronal dysfunction and neurodegeneration, which are reflected by increasing levels of CSF tau and regional cerebral atrophy, which in turn can be visualized by magnetic resonance imaging. Direct evidence supporting this temporal sequence of events in humans affected by AD is still scarce, however, and the theory must be considered provisional. (Some very recent evidence suggests also that AD lesions, Aβ and neurofibrillary tangles, spread like an infection from one affected region of the brain to another, rather than popping up independently in different places, starting in a key memory center known as the entorhinal cortex.9)

AD patients generally undergo a period of MCI in the early or prodromal stages of the disease, before dementia (the “true,” currently diagnosable AD) sets in. There may be difficulty remembering recent events and acquiring new knowledge but the mind is otherwise largely intact and early memories are not much affected. The later dementia stages involve increasing loss of functionality and cognitive performance, including long-term memory degradation and loss of language and motor skills, leading finally to death.

Though MCI is associated with prodromal AD, it is actually a heterogeneous syndrome. Only 30%-60% of patients have prodromal AD. The rest will have a benign form of cognitive impairment, including some reversible forms (depression being one), or another neurodegenerative illness. For the 134 MCI patients involved in the Hansson study, the breakdown is as follows (rounded figures): 54% developed AD dementia, 16% developed other dementias, and the remaining 31% were cognitively stable. It should be noted that the median clinical follow-up time for the study was 9.2 years. “Given that AD is a slowly progressive disorder,” the authors note, “it probably takes at least 10 years before most patients with prodromal AD develop dementia and can be diagnosed as having clinical AD.” Their research appears to be the first that provided nearly this amount of follow-up time; previous studies having much shorter times (typically only 1 to 3 years) must have greatly underestimated the prevalence of prodromal AD.

To complete the study cerebrospinal fluid (CSF) from each patient was collected at the start (“baseline”) by lumbar puncture and stored at -80°C until all follow-ups had been completed. The CSF samples were then thawed and concentrations of three biomarkers: Aβ42, P-tau, and T-tau were determined. (Values of these concentrations ranged from tens to hundreds of nanograms per liter.) It should be emphasized that the CSF samples were taken at the beginning of the study, before the results of the follow-ups could be known. It was found that the ratio r of Aβ42 to P-tau was a very good predictor of who would develop AD. The participants (including 39 controls with no MCI along with the 134 patients) were rather sharply divided into two groups, one with r values around 10-12, the other with values about half that size or less. 91% of those with the smaller r values went on to develop AD dementia (positive predictive value), while 86% of those with the larger values did not (negative predictive value; some did develop other dementias).

The authors of the study note that, in comparing early to late converters from MCI to AD (0-5 years versus 5-10 years), there is significant variability in the baseline concentration of both P-tau and T-Tau, but levels of Aβ42 are uniformly low for both groups and distinguishable from levels for non-AD converters. (The ratio of Aβ42 to P-tau still distinguishes better than Aβ42 alone.) It appears that CSF levels of Aβ42 go low and plateau early in AD-converters whenever conversion may occur, but that levels of P-tau and T-tau, while eventually increasing for both groups, take longer to rise in late converters.

In any case, it appears that the basis of a useful diagnostic technique has been achieved, though of course more work is needed to verify and possibly refine the results. The authors note that it would be desirable for clinical use to boost the predictive accuracy to above 95% and express hope that this might be accomplished through combination with other diagnostic aids such as thorough clinical assessment and brain imaging.

Meanwhile AD still is largely untreatable. Identifying it in its early, relatively benign stages will not by itself bring about a cure but should increase the options for developing one. Starting more than a decade ago some hopeful results were obtained with animal models of AD.10 These used immunotherapeutic approaches based on vaccination with Aβ42. Vaccinated animals showed reduction in AD neuropathology though the results have so far not been carried over to humans. But as the authors of the more recent study note, this may be because of the failure, so far, to deal properly with the long developmental period of human AD. It appears that a new corner has been turned in the fight against AD, and new hopes are raised that it will fairly soon be treatable.

References and notes:

[1] “Alzheimer’s Disease,”’s_disease, accessed 31 Jan. 2012.

2 Liesi E. Hebert et al., “Alzheimer Disease in the US Population: Prevalence Estimates Using the 2000 Census,” (reprinted) Arch Neurol. 2003;60:1119-1122,, accessed (from Google Chrome) 31 Jan. 2012. (Values shown were derived from a graph and may differ slightly from unpublished values on which the graph was based.)

3 For one such public case see Linda Chamberlain, “Her Blue Eyes Will Sparkle,” Cryonics Dec. 1990, 16,, accessed 31 Jan. 2012.

4 Much of paragraph is taken, with editing, from “Alzheimer’s Disease,” Ibid., Accessed 5 Feb. 2012.

5 “Pittsburgh Compound B,”, accessed 6 Feb. 2012.

6 Peder Buchhave, MD, PhD; Lennart Minthon, MD, PhD; Henrik Zetterberg, MD, PhD; Åsa K. Wallin, MD, PhD; Kaj Blennow, MD, PhD; Oskar Hansson, MD, PhD, “Cerebrospinal Fluid Levels of b-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia,” Arch Gen Psychiatry. 2012;69(1):98-106

7, accessed 31 Jan. 2012.

8 “Amyloid Precursor Protein”, accessed 1 Feb. 2012.

9 “Alzheimer’s could be stopped from progressing after scientists find disease ‘spreads like an infection’,”, 2 Feb. 2012, accessed 6 Feb. 2012.

10 Dale Schenk, Peter Seubert, and Richard B. Ciccarelli. DNA and Cell Biology. November 2001, 20(11): 679-681. doi:10.1089/10445490152717532,, accessed 31 Jan. 2012.

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