The open access paper I'll point out today makes the case for raising the profile of mechanisms other than protein aggregation in neurodegenerative conditions. The authors focus on Alzheimer's disease, characterized by the aggregation of amyloid and tau in the brain, but the argument works just as well for most other forms of age-related dementia. That Alzheimer's disease is the result of multiple mechanisms, each of which contributes to pathology to a similar degree, is one of the better explanations for the ongoing failure of clinical trials that focus solely on amyloid clearance. One only has to look at the sizable fraction of Alzheimer's patients who are also diagnosed with vascular dementia to suspect that something of this nature might be an issue. If there are, for example, five important and somewhat independent mechanisms driving a specific medical condition, then the positive outcomes that result from partially addressing just one of those mechanisms may well get lost in the noise.
This class of issue is in fact endemic in attempts to interfere in the pathology of age-related disease at points that are distant from the root causes. The root causes of aging are limited in number, but spread out into a complex tree of descendant forms of damage and reactions to damage. If the approach to medicine takes the form of pruning the outer branches, as it were, then many of those branches (a) represent smaller individual contributions to dysfunction, and (b) are to some degree independent of one another. But further back towards the roots, an intervention might be much more effective, as it targets a form of damage that drives all of the smaller, downstream branches of damage and dysfunction.
That is the simple idealized model, and it is a very useful guide to thinking about strategy in medical research and development. Nothing is that neat and tidy in reality, sadly. Alzheimer's is a complex mix of what we might think of as fundamental damage, such as protein aggregation, and downstream changes resulting from many other forms of molecular disarray, such as inflammation and general vascular dysfunction. It all interacts. Even the fundamental types of protein aggregation appear to have some form of synergy with one another, with amyloid leading to tau aggregation, and the two being worse in combination than the individual contributions might lead one to expect. The only way to deal with Alzheimer's and other forms of late life dementia may be to fix it all: protein aggregation, inflammation, vascular dysfunction. This is actually a reasonable conclusion for any age-related disease when starting from the consideration of aging as damage accumulation and rejuvenation as damage repair.
The treatment of Alzheimer's disease (AD) is currently symptomatic and based on neurotransmitter manipulation, akin to what has been achieved in Parkinson's disease. Thus acetylcholine activity is being increased by cholinesterase inhibitors, and glutamatergic activity is being dampened by memantine action on NMDA receptors. A modest but clinically detectable response is present in many patients using such drugs alone or in combination. Unfortunately the next generation of drugs acting on AD core pathological factors such as amyloid deposition and phosphorylated tau aggregation has failed so far to delay disease progression, raising the issue of timing of these interventions along the continuum of AD neurodegeneration over time. This review wants to highlight the facts that other pathological factors are at play in AD, and deserve consideration in the full diagnostic assessment of the patients, and for treatment. These factors are vascular changes, Lewy body pathology, and neuroinflammation.
The clinical progression of AD is linked to specific neuropathological features, such as extracellular deposition of Aβ plaques, intracellular inclusions of tau protein in neurofibrillary tangles, and neuronal degeneration. Given that the presence of AD pathophysiology has been found across a broad clinical spectrum including individuals asymptomatic and with mild cognitive symptoms, biomarkers now play an important role in characterizing the trajectory of AD pathophysiology and have been incorporated in the AD diagnostic research criteria. These diagnostic research criteria recognize that the coexistence of abnormal Aβ and tau biomarkers better identify the preclinical and mild cognitive impairment (MCI) individuals who will progress to dementia over relatively short time frames of three to 5 years.
Based on histopathological and genetic evidences, fibrillar Aβ, the main constituent of Aβ plaques, has been postulated as the major driving force leading to AD dementia (Aβ cascade hypothesis). According to this hypothesis, all the resulting pathological processes are due to an imbalance between Aβ production and clearance, which would then potentiate the spread of tauopathy, leading to neurodegeneration and cognitive decline. However, the lack of consistent association between Aβ and clinical progression, and the fact that amyloid pathology has been found in cognitively normal elderly individuals challenge the Aβ hypothesis in its original form.
There is growing evidence that AD often coexists with cerebrovascular disease (CVD). They share many risk factors, leading to additive or synergistic effects on cognitive decline. Most AD patients have structural changes in their cerebral blood vessels. Imaging and pathological studies have demonstrated a high prevalence of arteriolosclerotic small vessel disease (SVD) in AD patients. Post-mortem and imaging studies demonstrate that arteriolar Aβ amyloid angiopathy, a sub-type of SVD, is more common in patients with AD than in elderly controls. The links between vascular factors and AD have been clearly confirmed both clinically and pathologically. However, there is a lack of high-quality therapeutic research to examine the extent to which vascular risk changes alter the course of AD. Further longitudinal mechanisms and therapeutic studies are needed, especially to determine whether the treatment of vascular risk factors can prevent or delay the onset of AD.
Although the accumulation of amyloid protein in plaques and tau protein in neurofibrillary tangles constitutes the core pathological feature of AD, the presence of abnormal brain aggregates of a third proteinopathy has been shown to be very prevalent in moderate and severe AD. Cytoplasmic inclusions of α-synuclein intraneuronally in Lewy bodies have been reported in up to 50% of sporadic AD cases and up to 60% of familial AD cases. Postmortem observations focusing on the influence of Lewy bodies have shown inconsistent results. However, it is worth mention that a well-powered multicenter study with a high sample size has reported that the onset of symptoms and death in AD individuals with Lewy bodies occurs at younger ages as compared to those without Lewy bodies, and that AD individuals with Lewy bodies have higher chance to be APOE ε4 carriers than AD individuals without Lewy bodies.
There is a growing body of evidence supporting neuroinflammation as an important player in the pathogenesis of AD. Neuropathological studies have shown the presence of activated microglia and inflammation related mediators in AD brains. Genetic studies show that several genes that increase the risk of sporadic AD encode factors that regulate microglial clearance of misfolded proteins and inflammatory reaction. Epidemiological studies further suggest that non-steroidal anti-inflammatory drugs (NSAIDS) can defer or prevent the onset of AD. Preclinical and post-mortem studies have consistently found that activated microglia colocalises with Aβ plaque, suggesting a close intimate relationship between microglia activation, Aβ and neuroinflammation. Several mechanisms have been hypothesised, including ongoing formation of Aβ and positive feedback loops between inflammation and amyloid precursor protein (APP) processing which compromise the cessation of neuroinflammation. Continued exposure to Aβ, chemokines, cytokines, and inflammatory mediators leads to microglia being chronically activated at the Aβ plaque site, which further contribute to Aβ production and accumulation in a vicious cycle.