Alzheimer’s How changes in a brain can result in its ultimate catastrophic collapse
For a general reference about Alzheimer’s Disease, written for the informed layperson, see Coste JK, Butler R (2004) Learning to Speak Alzheimer’s: A Groundbreaking Approach for Everyone Dealing with the Disease. Houghton Mifflin, Boston; for a poignant first-person account of losing the Person that you are, to AD, see DeBaggio T (2003) Losing My Mind: An Intimate Look at Life with Alzheimer’s. Free Press, New York; or for a controversial but informative book that is wrong in one of its grand conclusions (that we should adjust to losing our way in older life) but full of provocative insights, read Whitehouse PJ, George D (2008) The Myth of Alzheimer’s: What you Aren’t Being Told About Today’s Most Dreaded Diagnosis. St. Martin’s Griffin, New York. On the other hand, I appreciate Whitehouse’s main point, which is that AD is not really a ‘disease’, but an expected final stage of a not-very-well-ordered life.
Every standard neurology textbook spends lots of time talking about AD and its dementia-causing cousins. For an authoritative perspective, see Bradley’s Neurology in Clinical Practice (2012; Daroff RB et al., eds; Elsevier, Philadelphia)
Methods for visualizing and quantifying the AD pathology in living brains, which have greatly facilitated studies of its origins, were developed by a University of Pittsburgh research team about a decade ago. See Klunk WE et al (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound B. Ann Neurol 55:306. Over this decade, several thousand studies have used this method to document the status of pathology in many “normal” and AD patient cohorts—illustrating the point, over and over again, that many of who think we’re completely normal aren’t.
The poisoning of the brain by amyloid has been documented by recording neural activity in the neighborhood of plaques, or in areas in which there is measured (or injected) soluble amyloid. Note that brain cells can be either less or more active than normal—but in this latter case, greater activity is generally interpreted as being induced by a reduction of the excitability of inhibitory neurons—with the net result that there is a growth in local cortical network “chatter” (process noise). See, for example, Busche MA et al (2008) Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321:1686. For a good description of the paradoxical effects of amyloid on increasing and decreasing local brain cell excitability, see Palop JJ, Mucke L (2010) Amyloid-Beta induced neuronal dysfunction in Alzheimer’s disease: From synapse toward neural networks. Nat Neurosci 13:812. Amyloid also directly engenders synapse loss. See, for example, Snyder EM et al (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nature Neurosci 8:1049; Shankar GM et al (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27:2866; or Bredesen DE (2009) Neurodegeneration in Alzheimer’s disease: Caspases and synaptic element interdependence. Mol Neurodegen 4:27. Note that these studies indicate that the release of beta-amyloid subserves an important natural role in synapse weakening and elimination; but in AD, this elimination has “gone wild.” [Note that there is a chicken/egg issue in play, i.e., do factors contributing to rapid synapse loss (like a decoupling resulting in a sharp down-regulation of neural activity) engender lots of amyloid; or vice versa?]Similarly, “tangle”-filled cells have been shown to be functionally disabled in a number of model studies. And similarly, ‘tangle’ formation has been convincingly argued to be an exaggerated consequence of a natural, protective immune-system-driven response to debris-filled brain tissue.It might be noted that a recent study conducted by a Stanford research team (Kurnellas MP et al, 2013, Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation. Sci Transl Med 5:179ra41. Doi: 10.1126/scitranslmed.3005681) argues that beta-amyloid has a PROTECTIVE function. Inject some, and you slow down the progression toward AD in mice. At the same time, there is a large body of evidence that shows that beta-amyloid clearing via up-regulating immune response slows down pathological progression. The amyloid story has another chapter or two to go.
There is compelling evidence that shows that the up-regulation of the immune response can result in a more rapid clearing of cellular debris and of soluble and crystallized amyloid. There is little question that immune system dysregulation is in play in the genesis and expression of the disease. At the same time, its role is complicated by the fact that it has been argued a) to contribute to pathology origin—and b) to be the basis of preventing it! For a discussion of these issues, you might begin with Cohen RM (2009) The role of the immune system in Alzheimer’s disease. FOCUS 7:28. Then, on one side of the fence, try Jones B (2012) Alzheimer Disease: TREM2 linked to late-onset AD. Nat Rev Neurol 9:5 (which shows that if you have poor inherited immune responses, AD is in your future); and on the other side, Heneka MT et al (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674 (which shows that if you block a particular aspect of the inflammatory reaction in a mouse model, AD pathology develops more slowly than expected).
I have earlier described the many references documenting the deterioration of coordination power in aging (animals, humans), and the weakening of somatostatin/parvalbumin (largely chandelier cell) inhibitory neuron power supporting that coordination.
There are a number of studies showing that the progression of AD pathology in animal models can be blocked by giving the animal a more exciting and challenging life. For example, Lazarov O et al (2005) Environmental enrichment reduces A-beta levels and amyloid deposition in transgenic mice. Cell 120:701; Hu YS et al (2010) Complex environment experience rescues impaired neurogenesis, enhances synaptic plasticity, and attenuates neuropathology in familial Alzheimer’s disease-linked APPswe/PS1DeltaE9 mice. FASEB 24:1667; Berardi N et al (2007) Environmental enrichment delays the onset of memory deficits and reduces neuropathological hallmarks in a mouse model of Alzheimer-like neurodegeneration. J Alzheimers Dis 11:59; Lahiani-Cohen I et al (2011) Moderate environmental enrichment mitigates tauopathy in a neurofibrillary tangle mouse model. J Neuropathol. Ex Neurol 70:610.Yao ZH et al (2012) Enriched environment prevents cognitive impairment and tau hyperphosphorylation after chronic cerebral hypoperfusion. Curr Neurovasc Res 9:176.Some investigators have failed to see a reduction of amyloid or tau in their mouse models. In some cases, it would appear that the farther along the pathological progression, the lower the potential for reversing amyloid deposition or tauopathy. On the other hand, even in mice in which amyloid is growing apace, the cognitive performances of animals can be sustained or even improved by giving them a more interesting and challenging life. For example, see Arendash GW et al (2004) Environmental enrichment improves cognition in aged Alzheimer’s transgenic mice despite stable beta-amyloid deposition. Neuroreport 15:1751.
For contemporary arguments that the default system is disconnected in older brains, see, for example, Ferraira LK, Busatto GF (2013) Resting-state functional connectivity in normal brain aging. Neurosci Biobehav Rev (epub ahead of print); Zhu DC et al (2013) Alzheimer’s disease and amnestic mild cognitive impairment weaken connections within the default-mode network: A multi-modal imaging study. J Alzheimers Dis (epub ahead of print); Hafkemeier A et al (2012) Imaging the default mode network in aging and dementia. Biochim Biophys Acta 1822:431. There are innumerable extensions of this class of study documenting changes in connectivity on many other conditions in which brain function and cognition are compromised. See, for example, Grecius M, Resting-state functional connectivity in neuropsychiatric disorders. Curr Opin Neurol 21:424.Resting-state connectivity studies were preceded by earlier demonstrations that cerebral blood flow and glucose metabolism reflecting brain activity levels were also reduced in these same “highest level” brain regions. See, for example, Bentourkia M et al (2000) Comparison of regional cerebral blood flow and glucose metabolism in the normal brain: effect of aging. J Neurol Sci 181:19.Resting-state connectivity-documented changes are paralleled by brain shrinkage patterns. That is expected, of course: Disconnected machinery is connectionally dis-elaborated, AND SHRINKS. See, for example, Thompson P (2003) Dynamics of gray matter loss in Azheimer’s Disease. J Neurosci 23:994 (for a video of thickness changes in AD, see http://www.loni.ucla.edu/~thompson/AD_4D/dynamic.html
It might be noted that neuropathologists (initially, Heiko Braak) have used immunocytochemical staining to identify pathological changes that presage the significant expression of pathological markers in the brain, using these strategies to define hypothetical pre-clinical stages of AD-related neurodegeneration. Using these markers (e.g., for neurofibrillary tangles, Lewy bodies, alpha-synuclein, etc), they argue that the initial recorded changes are seen sub-cortically in the limbic system (in both AD and PD) then in perirhinal structures. It should be noted that the very early emergence of pathological expressions in the locus coeruleus or posterior dorsal raphe or substantia nigra does NOT mean that the problem is fundamentally limbic — because the integrity of these neuronal populations are directly tied to the power of feed-forward and feed-back projections that clearly contribute to their vitality.
There are both direct and indirect demonstrations that brain processes are “noisier” (plagued by random noise) in brains that are older or cognitively compromised. A few examples; Anderson S et al (2012) Aging affects neural precision of speech encoding. J Neurosci 32:14156; Hommet C et al (2010) Central auditory processing in aging. Nutr Health Aging 14;751; Fu y et al (2012) Functional degradation of the primary visual cortex during early senescence in Rhesus monkeys. Cereb Cortex (epub ahead of print); Wang H et al (2006) Functional degradation of visual cortical cells in aged rats. Brain Res 1122:93; and our own de Villers-Sidani E et al (2010) Recovery of functional and structural age-related changes in the rat primary auditory cortex with operant training. PNAS 107:13900.Human studies have primarily focused on the documentation of correlated activity arising in “resting periods” in the brain, revealing, as described earlier, the integrity of connectivity in brain systems. Such studies commonly describe decrements in spontaneous activity, most prominently at higher (‘default system’) brain levels. The “chatter” in background activity that we’re describing here reflects a less visible fact: Activity in older and variously impaired brain systems is proportionally less coordinated, i.e., what activity IS expressed is progressively less useful and less reliable for resolving ‘what’s happening’. Note that ‘chatter’ grows as inhibitory processes progressively weaken. As discussed earlier, the decline in inhibitory strength and specificity is a fact of normal aging—and is recorded in most (probably when we get to them, almost all) chronic neurological and psychiatric illnesses.
Many studies have now used the imaging of AD pathology in living brains to show that pathological signs are present in a very large proportion of the asymptomatic >60 year old population. For example, see Weiner MW et al (2012)The Alzheimer’s Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimers Dement 8:S1-68; or Masdeu JC et al (2012) The neurobiology of Alzheimer disease defined by neuroimaging. Curr Opin Neurol 25:410. An earlier demonstration that the AD pathology did not always closely parallel the functional abilities of older individuals can from the examination of brains of an closely monitored older population at autopsy in what was termed “The Nun Study”. Some elderly nuns who were really doing well, in cognition and in their continuing productivity and good spirits, had brains filled with AD pathological markers—and vice versa. See, for example, Snowden D (2001) Aging with Grace: What the Nun Study Teaches Us About Leading Longer, Healthier, and More Meaningful Lives. Bantam, New York. Still, both age and amyloid levels add to the cognitive burden of older individuals, as indicated, for example, in Oh H et al (2012) Effects of age and beta-amyloid on cognitive changes in normal elderly people. Neurobiol Aging 33:2746.
The contribution of noradrenaline regulation on immune response processes clearing amyloid in Alzheimer’s models via multiple paths is well established. See, for example, Heneka MT et al (2010) Locus coeruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. PHAS 107:6058; Kong Y et al (2010) Norepinephrine promotes microglia to uptake and degrade amyloid beta peptide through upregulation of mouse formyl peptide receptor 2 and induction of insulin-degrading enzyme. J Neurosci 30:11848; Counts SE, Mufson EJ (2010) Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity. J Neurochem 113:649; Hammerschmidt T et al (2012) Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice. Biol Psychiatry (epub ahead of print).The main cortical source of noradrenaline, the midbrain locus coeruleus, is invariably degenerated in AD patients. See, for example, Weinshenker D (2008) Functional consequences of locus coeruleus degeneration in Alzheimer’s disease. Curr Alzheimer Res 5:342. Locus coeruleus degeneration is also a hallmark of Parkinson Disease and chronic epilepsies, which has led to the speculation that the pathogenesis in all three conditions is attributable to immune-response compromise attributed to its dysregulation. See, for example, Szot P (2012) Common factors among Alzheimer’s disease, Parkinson’s disease, and epilepsy: possible role of the noradrenergic nervous system. Epilepsia 53:61.
In large part because of the failure, despite a $mega-million investment, of Alzheimer’s drug trials—but also because there have been no blockbuster brain-targeted drugs licensed by the FDA over the past 20 years—most large pharmaceutical companies have greatly attenuated their research and development efforts directed toward psychiatric disease, AD, PD, et alia. The last of a long series of costly FDA trials designed to determine the safety and effectiveness for treating AD patients once again resulted in failure (see http://www.dailymail.co.uk/news/article-2205339/Leading-pharmaceutical-firms-giving-Alzheimers-treatment-series-expensive-failed-trials.html). As in earlier trials, the neuropathology was diminished by newly developed drugs, but patients did not get better. This great scientific and commercial failure stems from a fundamental misunderstanding about the nature of human cognitive abilities, and reflects the rather remarkable way that modern brain science is “siloed”. How could a multi-billion dollar investment about a brain-targeted drug proceed with teams of world-class scientists without those teams including scientists who understand the perceiving-learning-and-remembering brain?! This failure represents, to the author, a shocking example of the limitations in our human ability for dealing with complexity! All remaining large-scale efforts on developing AD-related drugs are focused on treating asymptotic patients judged, on the basis of brain imaging, as being at risk for AD onset. None of them are actually “sick.” See http://www.boston.com/2012/07/13/entry-cont/o7mFixDleEN5A9fdwfuLKL/story.html and Mullard A (2012) Sting of Alzheimer’s failures offset by upcoming prevention trials. Nature Rev Drug Disc 11:657. The drug companies shall likely stub another $mega-million toe once again. They’ll likely record an increase in resilience against AD onset, but in the broader population, far stronger and more organic effects shall be achieved by brain training at a fraction of the cost, with none of the unnatural drug-induced consequences of their pharmacologically-implemented strategy.It should be noted that there are always new lines of research that COULD lead to a different model of AD disease correction that could still lead to recovery miracles. Just don’t bet your house on it.
