Dementia, Alzheimer’s Disease (AD) in particular, is widely recognized as the next global health crisis. There are more than five million Americans of all ages living with Alzheimer’s – and, unfortunately, that number is growing. The American Academy of Neurology recently published a study that reported, based on their scoring system, a healthy lifestyle is associated with a substantially lower AD risk1. Thus, many researchers are looking into prevention methods to lower a person’s risk of developing the debilitating disease. The focus of these efforts is mainly on diet and exercise, including recommending the DASH or Mediterranean diets and/or regular physical activity. These preventative solutions aid overall health and can reduce the risk of falls and loneliness, both of which tend to hasten cognitive decline. While there is much discussion around reducing the risk of AD, there is still much that is unknown or poorly understood about dementia and how to prevent – or eventually cure – it. Some optimism about Alzheimer’s Disease prevention While initial progress has been made in searching for a solution, physicians, caretakers, and patients all are seeking a “magic bullet.” But, can we get there anytime soon, if at all? The answer is perhaps we can – or at least we can move in that direction. A recent poll by Sermo (a network of over 800K global physicians; see Sermo’s full methodology) shared that 42% of 513 respondents replied in the affirmative to the question, “Are you optimistic that an effective drug for delaying the onset of Alzheimer’s will be on the market by 2025?” The adjective “effective” does not necessarily require that the drug have “meaningful benefit,” which is one reasonable standard for new drug approval. This distinction arises with AD because of the multiplicity of endpoints that a drug developer might point to as evidence for “effectiveness.” Possible endpoints include the following: improvement in neuropathology brain imaging biomarkers improvement in biofluid-based biomarkers neuropsychological function The latter, in turn, can include various domains, such as memory, executive function, and so forth. Knowing the medical community is hopeful for a drug to enter the market in the near future, let’s look into current research around neurodegeneration and drug candidates for the disease. What works and what doesn’t when it comes to dementia prevention? First, by way of a comprehensive review of all accumulated dementia prevention trial results, a meta-analysis report was recently published that described the outcomes when interventions were employed in either prospective studies or randomized clinical trials aimed at dementia prevention2. Quoting from the abstract: “Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence education cognitive activity high body mass index in late life hyperhomocysteinaemia depression stress diabetes head trauma hypertension in midlife, and orthostatic hypotension 9 with Level B weaker evidence obesity in midlife, weight loss in late life physical exercise smoking sleep cerebrovascular disease frailty atrial fibrillation, and vitamin C In contrast, two interventions are not recommended: estrogen replacement therapy (Level A2) acetylcholinesterase inhibitors (Level B).” This represents quite a comprehensive quantitative assessment of these widely debated factors. In addition to the list of potentially beneficial interventions, the study presents evidence that estrogen replacement and acetylcholinesterase inhibition are associated with accelerated decline. This landmark paper is likely to drive practice, trials, and debate for years to come. Excitotoxicity – a mechanism for neurodegeneration? The Buck Institute work from the Campisi Laboratory strengthens the notion that excitotoxicity is probably an important mechanism for neurodegeneration. Excitotoxicity” is a phenomenon associated with the most common transmitter used in the brain, which is the amino acid glutamate. Glutamate signaling triggers the entry of calcium into the nerve cell that is being excited (i.e., the postsynaptic or downstream nerve cell). Excitotoxic mechanisms have been demonstrated in a variety of brain diseases, including, stroke traumatic brain injury Huntington’s disease amyotrophic lateral sclerosis. Alzheimer’s disease might also involve excitotoxicity, though there are more data supporting this mechanism in the other 4 diseases listed. The FDA-approved drug memantine was developed with the goal in mind of blocking calcium entry into nerve cells during glutamatergic stimulation. However, in clinical trials, the drug showed some evidence for short term symptomatic benefit but no compelling evidence for long term disease modification. If memantine truly blocked calcium-mediated excitotoxicity, one would predict that the results would be the other way around (i.e., that the drug would be better at keeping nerve cells alive than at immediate symptom control). Other strategies aimed at excitotoxicity continue to be of great interest since this mechanism has been implicated in multiple common and/or often otherwise untreatable brain diseases. This work is still very much in its early days and does not currently have actionable insights for patients or physicians. Alzheimer’s Disease drug discovery continues to target brain amyloid Much of the activity in AD drug discovery continues to target the biochemistry of brain amyloidosis. This cardinal pathological feature has been the focus of attention because The amyloid precursor protein (APP) is located in or near the Down Syndrome locus on chromosome 21 The first AD-related genetic bases can all be demonstrated in cells and mouse models enhance the accumulation of aggregated or oligomerized amyloid-ß (Aß). The bases were discovered between 1991 and 1995 and include APP, PSEN1, PSEN2, APOE4. Most Aß-reduction strategies have employed passive immunotherapy with intravenous anti-Aß antibody. Bapineuzumab One of the first and best known anti-Aß antibodies tested in AD was Pfizer’s drug, bapineuzumab. In 2010, Finnish investigators reported that extended bapineuzumab therapy could reduce Aß-related neuropathology. It also reduced both biofluid-based and brain imaging-based biomarkers. However, despite the obvious reduction in brain amyloid burden, those subjects receiving bapineuzumab experienced cognitive decline at a rate indistinguishable from those receiving placebo3. Over the ensuing decade, several companies have varied this formula slightly, but so far, all have confirmed a similar decline as reported in the original observation. Thus, therapy with one of several anti-Aß antibodies always led to the same result: reduced amyloid pathology but no impact on clinical cognitive decline. During that intervening decade, another uniform observation emerged from several groups: amyloidosis can be detected in the brains of cognitively intact subjects as early as the 5th decade of life (i.e., when the subjects were at ages in their 40s)4,5. For that reason, anti-Aß antibody trials began to require positive amyloid biomarkers. Further, they included subjects of younger and younger ages. Aducanumab While elucidation of these subtle aspects of the clinico-radiological features progressed, the anti-Aß antibody, aducanumab, joined the race. Among various approaches in mid-2020 aimed to fight AD, aducanumab is the most advanced and has generated the most attention. The aducanumab story is anything but straightforward, though. It has been characterized by incomplete dose-response presentations from the outset. And, the announcement of a topline failure that was re-analyzed by a new incoming pharmaceutical team who pronounced that there was still hope for the success of the molecule for this disease6. This reversal of misfortune now led to the claim that the highest dose of the drug candidate in one of several trials appeared to meet the statistical definition of “significant.” However, it still lacked clear evidence that this statistical significance was the harbinger of meaningful benefit. In a poll conducted by another medical media firm, dementia specialists stated that while all were pessimistic about the likelihood that aducanumab might offer meaningful benefit, they indicated that if approved, they would prescribe it7. Less than a month ago, the Food & Drug Administration (FDA) received an application for approval of aducanumab based on the single high dose group from the singleton of several trials8. Advances in the diagnosis of Alzheimer’s disease have occurred as well Beyond looking at potential drug candidates, it is key to analyze the diagnosis of Alzheimer’s as well. It is a process that remains very difficult. In fact, it only recently became possible to definitively diagnose patients antemortem (before death). Digging deeper into the medical community’s thoughts on possible diagnosis techniques, Sermo’s poll asked whether physician respondents would likely recommend a “blood Alzheimer’s test” to their patients if one was developed. 74% of 462 respondents replied in the affirmative. Such a test is likely to include a recently developed, highly sensitive blood Aß determination coupled with a highly sensitive determination of blood tau levels, specifically a form of tau with the addition of a phosphate side chain to a particular amino acid. This combination of Aß and tau has been evaluated with brain imaging biomarkers of both Aß and tau, and in the imaging version that combo looks promising9. The availability of a blood test for diagnosis, and perhaps also for the monitoring of therapies will greatly enhance clinical trials of candidate AD drugs. It should reduce the cost of the trial and circumventing the need for sophisticated brain imaging or lumbar puncture. When these blood biomarkers are supported by a clinical context of cognitive decline, this may provide antemortem confirmation of clinical suspicion of AD. But what if there is a positive blood test but intact cognition? Where a blood test like the one described above will be less useful is in the setting of intact cognitive function. This is because there is already clear precedence for the concept that full-blown neuropathological AD can occur in the absence of cognitive decline10. This is now cited as an example of “resilience,” which means that these subjects are likely to harbor genes that protect them from the toxicity of aggregated proteins and/or neuroinflammation. Our understanding of cognitive resilience is skewed by our availability of data from subjects who have undergone autopsy or molecular brain imaging. The widespread ability to screen populations with a convenient reliable blood test will enable us to identify and eventually elucidate the genetic basis for this resilience. Those genes’ underlying resilience will inform candidate drug targets, with the notion that enhanced expression of resilience genes is likely to enhance one’s prospects for successful cognitive aging. What can be done NOW to prevent dementia? Now that we have looked at disease treatment research and potential diagnostic tools, there is one question we did not answer is: “What can patients do now in an effort to prevent dementia?” The Sermo poll asked physicians their top recommendations for Alzheimer’s disease prevention. Out of 477 respondents, here is how they replied: 36% identified cognitive stimulation 22% recommended reduction of vascular risks 21% recommended aerobic exercise 12% recommended dietary changes 2% recommended yoga 1% recommended supplements The remaining 6% felt other recommendations were better suited for prevention than the previously listed options. Obviously, these are neither high risk nor mutually exclusive recommendations. Cognitive stimulation Cognitive stimulation was the most popular recommendation. However, the strongest supportive data (e.g., educational attainment) are somewhat indirect. In general, most cognitive simulations (e.g., sudoku, online memory training) tend to improve one’s performance on that particular task. However, so far none have demonstrated meaningful benefit in, e.g., independence in activities of daily living11. Reduction of vascular risk factors For preserving both lifespan and brain function, the Framingham study points to the importance of cardiovascular morbidity in one’s predisposition to cognitive decline12. The role in sustaining intact cognitive function played by the maintenance of healthy levels of body weight, blood pressure, blood sugar and/or blood cholesterol are all supported by stronger and more consistent data than are any of the other options cited by the online respondents, despite its second-place ranking. The candasartan vs. lisinopril trial In a similar vein of looking into these comorbidities, investigators at Emory University in Atlanta report the results of a study in JAMA that looked into how older adults with hypertension and executive mild cognitive impairment responded to certain treatments. The study consisted of 176 randomized participants with diversity in sex and ethnicity: mean age, 66.0 years 101 [57.4%] women 113 [64.2%] African American 87 of which were assigned take the antihypertensive drug, candesartan. And, 89 were assigned to take lisinopril, another drug used to treat hypertension13. Among these, 141 participants completed the trial, including 77 in the candesartan group and 64 in the lisinopril group. Although the lisinopril vs. candesartan groups achieved similar BP (12-month mean systolic BP: 130 mm Hg vs 134 mm Hg; P = .20; 12-month mean diastolic BP: 77 mm Hg vs 78 mm Hg; P = .52), candesartan was superior to lisinopril on the primary outcome of executive function. This was measured by something known as the Trail Making Test Part B. The effect size was −12.8. Candesartan was also superior to lisinopril on the secondary outcome of Hopkins Verbal Learning Test-Revised delayed recall and retention. These findings now get us closer to a “magic bullet” for dementia prevention. This is the case even though executive dysfunction was not prevented to an important extent. Elderly subjects with poorly controlled hypertension An important caveat is that one can cause or exacerbate cognitive decline in elderly subjects with chronic poorly controlled hypertension whose blood pressure is lowered too far or too rapidly. Presumably, in that subgroup of patients, the systemic and cerebrovascular systolic, diastolic and/or pulse pressure(s) have equilibrated to this chronic status. Cerebrovascular tone may be increased via compensatory physiological reflexes aimed at protecting the brain from the high pressures. Rapid correction of systemic blood pressure would no longer be engaged in sustaining cerebrovascular perfusion, and the unopposed downregulation of cerebral blood flow can induce symptoms14,15. Thus, while these data and endpoints all focus on the geriatric population, the most important message involves the diagnosis and medication compliance for hypertensive young and middle-aged patients. While the Emory data must be replicated and extended, even these preliminary data point to specific interventions that can be sought by patients and put into place by either primary care or specialist physicians. The bottom line for Alzheimer’s Disease prevention As medical and scientific communities work together to fight the widespread onset of AD across the globe, we must continue raising awareness about how AD affects our bodies. And, we must have an open and ongoing dialogue about prevention and potential cures for this disease. Continued collaboration, research, and tapping into the collective knowledge of physicians worldwide will set us up for success in the fight to prevent dementia and AD. My analysis in this paper just taps the surface of bringing together the widespread research being conducted globally in an effort to find a treatment – and hopefully a cure – for this devastating disease. Source
