Cognitive problems occur before abnormal amyloid

Cognitive impairment precedes abnormal amyloid in the progress to dementia

Dementia and Alzheimer's disease research over the past decade has been dominated by the hypothesis that the process of cognitive impairment begins with deposition of abnormal levels of beta-amyloid in the brain. A paper now published in the journal Neurology provides evidence that cognitive problems begin prior to the accumulation of abnormal levels of amyloid. And they further documented other degenerative changes in the brain associated with frank cognitive impairment. This highlights the principle that chronic conditions like dementia are not explained by a simple linear process but are a complex constellation of causesthat vary with the individual. Immune polarization and neuroinflammation, metabolic and hormonal dysregulation, vascular and oxidative processes are among the aspects that must be considered for which clinical tools are available.

What comes first leading to dementia?

The authors sought to determine abnormal beta-amyloid deposition could be demonstrated to be the primary cause in the development of cognitive impairment; their intent was:

To determine the temporal sequence of objectively defined subtle cognitive difficulties (Obj-SCD) in relation to amyloidosis and neurodegeneration, the current study examined the trajectories of amyloid PET and medial temporal neurodegeneration in participants with Obj-SCD relative to cognitively normal (CN) and mild cognitive impairment (MCI) groups.

In their study 747 subjects (305 CN, 153 Obj-SCD, 289 MCI) were examined by neuropsychological testing and serial amyloid PET and structural MRI imaging over four years. Those with subtle thinking and memory changes may have started with the same levels of amyloid as normal subjects but exhibited a more rapid accumulation down the road. Interestingly, the people with mild cognitive impairment had more amyloid at first but did not have faster subsequent accumulation compared with the normals, yet they showed evidence of other brain degenerative changes.

Brain thinning and atrophy

Moreover, showing that other factors are in play, those with subtle cognitive changes had faster thinning of the cortex and the MCI group showed faster atrophy of the hippocampus, the center for short-term memory and adrenocortical circadian regulation, than the normal subjects.

Amyloid accumulation was faster in the Obj-SCD group than in the CN group; the MCI and CN groups did not significantly differ from each other. The Obj-SCD and MCI groups both demonstrated faster entorhinal cortical thinning relative to the CN group; only the MCI group exhibited faster hippocampal atrophy than CN participants.

DG News- General Medicine quotes lead author Kelsey R. Thomas, PhD, of the VA San Diego Healthcare System, San Diego, California:

Our research was able to detect subtle thinking and memory differences in study participants and these participants had faster amyloid accumulation on brain scans over time, suggesting that amyloid may not necessarily come first in the Alzheimer’s disease process...Much of the research exploring possible treatments for Alzheimer’s disease has focused on targeting amyloid. But based on our findings, perhaps that focus needs to shift to other possible targets.

The authors of an editorial in the same issue of Neurology with the subtitle 'Cart Before the horse' remark on the finding that cognitive deficits turn out to precede accumulating rates of amyloid deposition:

Over the last decade, a hypothesized model of dynamic sequential biomarker changes dominated the Alzheimer disease (AD) research field. The model, informed by the amyloid hypothesis,1 proposed a prototypical cascade, lasting up to decades, in which brain β-amyloid initiates acceleration of tau pathology, which in turn drives neurodegeneration and associated cognitive symptoms. In this issue of Neurology®, Thomas et al.2 tested the specific hypothesis that if amyloid deposition occurs long before downstream detectable effects on cognition, the presence of cognitive deficits should not precede accumulating rates of amyloid deposition. They found, however, that they do: in a large cohort of older adults without dementia, a subgroup with objectively defined subtle cognitive difficulties identified on neuropsychological testing at baseline showed increasing brain amyloid deposition on PET imaging over 4 years, despite having baseline amyloid levels that were similar to those characterized as cognitively normal.

Multiple causes involved

Clinicians and the public should bear in mind that there are multiple factors involved in the failure to maintain the neuronal health and synaptic plasticity required for high functioning longevity. Immune polarization and neuroinflammation; metabolic and hormonal integrity including insulin and glucose regulation; autonomic nervous system balance; mitochondrial function and reactive oxygen species; vascular health and oxygen perfusion; and others can be significant factors that determine how well an individual's brain functions and ages. One valuable tool for screening and assessment that deserves wider recognition and clinical application is the Alzheimer's LINX panel from Cyrex Laboratories. It includes quantitative antibodies to brain proteins (including beta-amyloid and tau), nerve growth factors, enteric nerve peptides; pathogens, chemicals, and foods that cross react to neurological peptides or beta-amyloid, and blood brain barrier and neurofilament proteins. Including this within the matrix of a systems biology/functional medicine assessment helps to bring focus to the condition of a person's brain at any age.

The authors conclude:

Relative to CN participants, Obj-SCD was associated with faster amyloid accumulation and selective vulnerability of entorhinal cortical thinning, whereas MCI was associated with faster entorhinal and hippocampal atrophy. Findings suggest that Obj-SCD, operationally defined using sensitive neuropsychological measures, can be identified prior to or during the preclinical stage of amyloid deposition. Further, consistent with the Braak neurofibrillary staging scheme, Obj-SCD status may track with early entorhinal pathologic changes, whereas MCI may track with more widespread medial temporal change. Thus, Obj-SCD may be a sensitive and noninvasive predictor of encroaching amyloidosis and neurodegeneration, prior to frank cognitive impairment associated with MCI.