"...determining whether a given pathological structure drives the disease, is a neutral bystander, or just represents an unsuccessful repair attempt remains challenging"--Martin Citron , Eli Lilly
I will continue to discuss individual studies and their contributions or lack of impact on the science surrounding advances in neurodegenerative diseases. The big objection I have is the lack of thoughtful engagment around the data. The media continue to report premature assumptions that a cure is eminent and exaggerates correlations that mislead not only the scientific community but caregivers and patients as well
What we know with reasonable certainty...(quotes from article)
- Exactly how the mutated genes or different isoforms increase the risk of disease risk is not clear, and, at least in the case of APOE4, a consensus mechanism of pathogenesis has not emerged in more than a decade after the discovery of its role in AD.
- No specific environmental toxin has been found to be consistently associated with AD, and there have been no randomized clinical trials as yet to support any specific dietary intervention. epidemiological studies point to depression, traumatic head injury and cardiovascular and cerebrovascular factors (for example, cigarette smoking, midlife high blood pressure, obesity and diabetes) as increasing disease risk, while anti- inflammatory medications seem to reduce risk . Some studies even suggest a beneficial role of psychosocial factors (for example, higher education, physical exercise and mental activity)
- However, the success of treatments in an animal designed to model a pathway and drive pathology and/or behavioural changes predicts only that the treatment may successfully interfere with the pathway in patients, not that interference with the pathway will have efficacy in AD, which can only be established in clinical trials
- It also follows that for disease modification, Phase II trials with small numbers of participants can inform about safety and biomarker changes, but they cannot predict efficacy, even though they are occasionally overinterpreted that way.
One, amyloid deposits provide early pathological evidence of AD and neuritic plaques are a key diagnostic criterion. Two, in peripheral amyloidoses (unrelated to Aβ and AD), amy- loid burden drives tissue dysfunction, thereby suggesting that brain amyloid is pathogenic as well. Three, Aβ oligomers show acute synaptic toxicity effects, whereas plaque-derived Aβ fibrils have pro-inflammatory effects and cause neuronal toxicity. Four, the most important genetic risk factor, APOE4, is associated with increased amyloid burden. Five, most importantly, all muta- tions that cause familial early-onset AD increase Aβ42 production or the ratio of Aβ42 compared to the less aggregation-prone Aβ40 isoform.
Strategies aimed at reducing tau hyperphosphory- lation, which appear to be more straightforward, are more widely pursued. However, this approach faces three major questions. First, is tau hyperphosphoryla- tion really critical to tau pathology? Second, assuming that tau hyperphosphorylation is critical, which is the key pathogenic kinase that should be inhibited? So far, there is no broad consensus on the identity of this kinase.
A recent meta-analysis ultimately examined 323 articles (propspective cohort studies and retrospective case-control studies). Study methodology can be found by clicking on link in results section below.
Wei Xu and colleagues
We found grade I evidence for 4 medical exposures (oestrogen, statin, antihypertensive medications and non-steroidal antiinflammatory drugs therapy) as well as 4 dietary exposures (folate, vitamin E/C and coffee) as protective factors of AD.
We found grade I evidence showing that one biochemical exposure (hyperhomocysteine) and one psychological condition (depression) significantly increase risk of developing AD.
We also found grade I evidence indicative of complex roles of pre-existing disease (frailty, carotid atherosclerosis, hypertension, low diastolic blood pressure, type 2 diabetes mellitus (Asian population) increasing risk whereas history of arthritis, heart disease, metabolic syndrome and cancer decreasing risk) and lifestyle (low education, high body mass index (BMI) in mid-life and low BMI increasing the risk whereas cognitive activity, current smoking (Western population), light-to-moderate drinking, stress, high BMI in late-life decreasing the risk) in influencing AD risk.
We identified no evidence suggestive of significant association with occupational exposures. Conclusions Effective interventions in diet, medications, biochemical exposures, psychological condition, preexisting disease and lifestyle may decrease new incidence of AD.
- Only english language articles were selected (adjusted for publication bias)
- Adjustment for confounders limited in some studies
- Only epidemiological research included
- Risk factors could not be reported quantitatively
- Number of pooled populations were relatively small for certain risk factors (interpret with caution for grade II-B and III evidence)
As cost of care approaches a trillion dollars by the year 2030, preventative strategies need to consider biologic, neurodegenerative, and epidemiological points of intervention.
"We must initiate a global conversation about Alzheimer's disease and other dementias," said Sen. Bill Nelson of Florida, the ranking Democrat on the Senate Aging committee. Nelson notes that his state, with a large population of seniors, has been particularly hard-hit by Alzheimer's. But research funding remains inadequate, the senator says, at least partly because of a dearth of knowledge about Alzheimer's. "Despite the prevalence of the disease, it is still widely misunderstood," he said.--AARP