ALZHEIMER'S DISEASE

By Douglas F. Watt, Ph.D. 

Adjunct Professor, Graduate Department of Psychology Lesley University 

Clinical Neuroscience Advisor, 9th Dimension Biotech, Inc. 

Highlights:

• THE HISTORY OF MISCONCEPTIONS AND CORRECTIVE REVISIONS OF ALZHEIMER'S DISEASE (AD)
• CHANGES IN HOW AD IS DIAGNOSED 
• PATHOGNOMONIC HISTOPATHOLOGY AND BIOMARKERS
• COGNITIVE PHENOTYPES

In this introductory review, we will cover the history of misconceptions and corrective revisions about what Alzheimer's disease might be, the substantial changes in how it's diagnosed over the last three decades, and its pathognomonic histopathology and biomarkers, including how various types of functional neuroimaging have significantly expanded our biomarker toolkit but also the critical promise of and need for pathognomonic serum biomarkers which might finally allow widespread screening of elderly cohorts at elevated risk.  Diagnosis by biomarkers is slowly but surely taking over the diagnostic process, displacing, or at least complementing, a traditional emphasis on cognitive impairment and its phenotypes.  Early diagnosis however is still unusual, with most patients still diagnosed at a mild to moderate dementia stage.

We will discuss those cognitive phenotypes, particularly the classic amnestic phenotype but others as well, including the sequential staging of cognitive impairment and types of impairment through the disease trajectory, and how cognitive impairment indexes synaptic loss and regionally specific tangling and its progression, and while tangling and synaptic loss are not synonymous they are hugely regionally overlapping.  The concept of a complex and very long-term (30-40 year) disease trajectory, with much of the disease under the waterline so to speak (meaning preclinical and asymptomatic stages which can be as long as two decades) will set the table for the subsequent discussions of neurodegenerative mechanism(s). 
We will also explore the possibility of a ‘pre-preclinical stage’, not currently described in the literature, but characterized by virtually invisible intracellular accumulation of amyloid, in the context of failing autophagy.  However despite considerable progress with biomarkers and the availability of good screening instruments to establish cognitive phenotypes, widespread elderly cohort screening is largely not recommend or even actively discouraged by opinion leaders.  We will examine this troubling Catch-22 and the assumptions behind it in some detail.  

Widespread assumptions that “nothing can be done about Alzheimer's disease” encourage both diagnostic and clinical passivity.  This is deeply regretful, given evidence that in the context of early diagnosis, we can at least intercept and mitigate several known accelerants, including a number that are classically iatrogenic emerging from clinical ignorance.  Unfortunately, widespread ignorance about Alzheimer's disease and the special clinical vulnerabilities of patients in cognitive decline is sadly pervasive within many clinical professions in the healthcare system, including even in psychiatry, neurology and neuropsychology.

By Dr. Douglas Watt, Ph.D.

Adjunct Professor, Graduate Department of Psychology Lesley University

Clinical Neuroscience Advisor, 9th Dimension Biotech, Inc.

Highlights:

• MOLECULAR AND CELLULAR COMPLEXITIES OF NEURODEGENERATION
• THE PROBLEM OF AUTOPHAGY
• THE ROLES OF INFLAMMATION AND TANGLING

In part II, we will dive headlong into the molecular and cellular complexities of neurodegeneration, examining first the traditional villain of the story, beta amyloid, in terms of its canonical processing pathways, and the evidence for physiological roles for beta-amyloid, as well as products from the competing pro-plasticity alpha pathway.  

We will examine the problem of autophagy in considerable detail, as the neglected underbelly of the amyloidosis storyline.  Both familial AD mutations (presenilin 1/2) and APOE4 disrupt autophagy.  Amyloid itself may also present intrinsically difficult challenges for the autophagy systems, suggesting its unique status as ‘agent provocateur’ in the complex loops and sequences driving neurodegeneration.  Amyloid oligomers also interact pathogenically with a host of cell receptor systems including those for classic neuromodulators, which may have significant consequences in terms of a basic neuroplasticity challenge, and may lead or at least contribute potently to processes driving tangling and the hyper phosphorylation of tau proteins.  As cells fill up with proteinaceous trash, several compensatory mechanisms are recruited, and as neurons discharge this trash or undergo programmed cell death, the extracellular space is progressively littered with proteinaceous trash, ushering in the next player in the neurodegenerative process, glial activation.  Glial systems largely fail to clear up the debris for uncertain reasons as there is no lack of glial system ‘attention’ to plaque in most individuals – perhaps an example again of failing compensation, and indeed just like neurons, glial cells may even undergo ‘autophagy fatigue’, and transition from a resting and homeostatic/neuroprotective phenotype to neuro-predatory/inflammatory phenotypes, as well as becoming dystrophic (echoing the ultrastructural and morphological changes in neurons earlier in the disease) and even become senescent, at which point they contribute significantly to the problems rather than relieving them.   

Both increasing inflammation and the regional network spreading of tangling, which may in part be fostered by a prion like synaptic mechanism involving tau oligomers, characterize the clinical stages of the disease.  Evidence is compelling that removal of amyloid, particularly extracellular plaque and fibrils, may offer little to nothing once clinical stages of the disease have been initiated, suggesting that although amyloid may initiate some aspects of the neurodegenerative process, that other players sustain and even deepen the destruction of the brain's networks.

By Dr. Douglas Watt, Ph.D.

Adjunct Professor, Graduate Department of Psychology Lesley University

Clinical Neuroscience Advisor, 9th Dimension Biotech, Inc.

Highlights:

• CLINICAL STAGES OF NEURODEGENEARTION 
• THE ROLES OF TAUOPATHY AND INFLAMMATION IN CELLULAR SENESCENCE
• THE VALUE OF PREVENTION AND CR MIMETICS

In part II, we took our first dive into the complexities of the early stages of neurodegeneration by examining failing autophagy and amyloidosis, which involved some degree of synaptic loss from amyloid oligomers.  This brings us to the more downstream and clinical stages of neurodegeneration where synaptic loss accelerates to the point of first subjective or minimal cognitive impairment, then MCI (mild cognitive impairment typically amnestic) and then the stages of dementia proper, with these clinical stages characterized by the emergence of tauopathy and destructive forms of inflammation.  Once clinical stages are engaged, removing amyloid appears to offer little if any value (raising questions about the application of popular amyloid antibodies to anyone in a clinical stage and the recent approval of Aducanumab for such patients).  

Both tauopathy and inflammation contribute to an emerging and spreading cellular senescence, which further exacerbates both neuroplasticity challenges and more destructive forms of inflammation, perhaps particularly the progressive engagement of the complement system.  Although amyloidosis initiates a neuroplasticity challenge for the brain (and where CNS infection may be an initiating or potentiating event), synaptic loss accelerates in clinical stages and appears proportional to tauopathy and not amyloidosis.  Once again, as with amyloid, tau oligomers appear more destructive of synaptic function than large-scale aggregations of phosphorylated tau (neurofibrillary tangles), and tau oligomers appear to spread synaptically, possibly explaining the progressive nature of tangling as we saw in Part I.  

Relationships between amyloid in different assembly states, hyper-phosphorylation of tau, various forms of inflammation, and how all of the above contribute to and drive synaptic loss remain to be fully clarified.  In any case, tauopathy constitutes an additional challenge for autophagy systems in the CNS, and evidence argues that they also fail to clear this problematic protein.  In any case, synaptic loss appears to accelerate during clinical stages, and while MCI might last five years, stages of dementia proper (mild, moderate, etc.) almost never do.  This suggests a tipping point process in which positive feedback between these various destructive processes and subsequent erosion of neuroplasticity accelerate at the initiation of clinical stages.  Approved treatment options for clinical stage patients are at best modestly effective, underscoring the importance of prevention, which is systematically neglected in our healthcare system, and further research into synaptic loss and its several drivers.  Will CR mimetics help fill these sizeable treatment gaps?