Is Alzheimer’s prevention possible today?

In the absence of disease modifying therapies, clinicians face an urgent need to be aware of potential interventions to reduce risk, delay onset, and at least in some cases prevent Alzheimer’s disease (AD). While there is no “magic pill” to prevent AD, evolving evidence can assist in answering a common question from patients: “Is there anything that I can do to reduce my risk?” (1–2). In THE PREVENTION OF ALZHEIMER’S DISEASE: LESSONS LEARNED AND APPLIED, Galvin eloquently and comprehensively provides a practical scientific overview for clinicians whose patients will inevitably ask how they can protect their brain health over time. Galvin appropriately makes the case that while the field waits for successful pharmacologic interventions, it is prudent to apply interventions that influence the multiple genetic, pathological and biological pathways that may lead to AD while testing hypotheses related to risk reduction and mitigation. Based on the evidence to date, efforts to slow cognitive decline and prevent dementia may be more successful with multimodal interventions directed toward at-risk individuals based on their personal health profile, rather than the more common “one-size-fits-all” approach.

As Galvin makes clear, a common methodological constraint of randomized controlled trials, even those that have demonstrated positive outcomes, is their experimental focus on homogeneous study cohorts that make it difficult to generalize results to the unique patient sitting in front of a clinician. Confirmation studies in real-world clinic settings are needed to test the efficacy and ecological validity of modifiable risk factor reduction strategies in at-risk individuals, especially in those at the asymptomatic pre-clinical stage of AD.

To this end, over the last few years, it has become more common for clinicians to practice in the field of Alzheimer’s prevention. Aligned with Galvin’s rigorous, evidence-based and comprehensive personalized framework, there are now several clinics in United States that focus on AD risk assessment and early intervention. In 2013, the Alzheimer’s Prevention Clinic (APC) at Weill Cornell Medicine and NewYork-Presbyterian was founded, providing direct clinical care to asymptomatic patients with a family history of AD (4). In 2014, the Alzheimer’s Risk Assessment and Intervention Clinic at the University of Alabama in Birmingham began, followed by the Alzheimer’s Prevention Program at Cedars Sinai Medical Center in Los Angeles in 2015, and the Alzheimer’s Prevention Clinic and Research Center in San Juan, Puerto Rico in 2016 (in research collaboration with Weill Cornell). Similarly, the Cardiology Cognitive Clinic at the Rush Heart Center for Women in Chicago maintains the same philosophy of care toward early protection of brain health. These programs have applied the best available evidence in varied ways to provide care and educate patients in the absence of definitive preventative treatments, and several have utilized novel strategies via an effectiveness-proven online AD prevention course (www.AlzU.org) to communicate a sound and balanced message to patients and family members (15).

From a practical clinical perspective, applying lessons learned from observational studies can help to target a range of modifiable risk factors (1–3). Population-attributable risk models estimate that one out of every three cases of AD may be preventable (3), leaving ample time for patients at risk to make lifestyle changes in an effort toward both primary and secondary (pre-symptomatic) AD prevention. In one report, the projected effect of risk factor reduction on AD prevalence found that a modest (10–25%) reduction in seven risk factors (diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity) could potentially prevent as many as 1.1 to 3.0 million AD cases worldwide, and 184,000 to 492,000 cases in the US (12).

Clinicians and patients have two options: to passively face the challenges of AD, or to intervene based on the mounting scientific evidence for a direct relationship between lifestyle and vascular-related risk factors and future dementia. Fortunately, most of these changes are balanced in terms of risk versus benefit and, especially when under physician supervision, grounded in safety (5).

Yet, there remains substantial confusion for practicing physicians. With each passing week, more and more studies are published on either side of the fence which can both help and hinder. Most commonly in medical practice, treatment plans are designed for the “average patient” based on the best available evidence, incorporating a broad spectrum of data from heterogeneous cohorts that may, or may not, be directly applicable (11). It may be most practical to provide patients with an individualized, detailed plan (fortified with qualifiers) for reducing the risk of dementia after an extensive evaluation of their medical history, lifestyle factors, body composition, laboratory and cognitive assessments. As a practicing AD prevention physician, the concept that prevention is not possible could be interpreted to mean, “There is nothing you should do. You don’t have to exercise; you don’t have to eat healthy; you don’t have to engage your brain; you don’t have to socialize because it won’t help your brain.”

Some of the most robust and applicable evidence comes from the landmark FINGER trial. Published in the Lancet in 2015, this large 2-year study established that an evidence-based program combining a brain-healthy diet, exercise, cognitive training, and vascular risk monitoring helped to improve or maintain cognitive functioning in elderly people at risk for AD (6). Differential effects have also been reported in carriers vs. non-carriers of the APOE4 gene, with the multi-domain intervention being preferentially effective in APOE4 positive subjects (7). Conversely, the MAPT trial, published in Lancet Neurology 2017, did not find significant effects of multi-modal lifestyle interventions, Omega-3 DHA supplementation, or the combination of the two, on episodic memory performance (8). It is instructive to postulate why the FINGER and MAPT studies demonstrated divergent outcomes. Considerations include the cognitive outcomes selected, or the older age, greater frailty, more impaired baseline cognitive function, and a nutrition pattern that was considerably higher in carbohydrate intake in MAPT subjects. In addition, using a “one-size-fits-all” approach with respect to supplementation with the Omega-3 fatty acid DHA without first assessing their RBC-DHA levels in MAPT is one example of an intervention inconsistent with an individually tailored approach.

Along these lines, according to the National Institutes of Health, precision medicine is defined as “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person” (9). The most accurate term to describe a prudent way forward toward AD prevention may be what has been termed clinical precision medicine, whereby the use of an expanded clinical history (e.g., neurodevelopment, academic trajectory, past and current lifestyle patterns, environmental exposures, and lifecourse events) is combined with past medical history and physical/neurological examination, and then interpreted in conjunction with anthropometric, blood biomarkers (including genetics), and cognitive performance. (4, 10) A comprehensive, multi-modal management plan can then be carefully crafted by cross-referencing each point of data, and the patient is followed longitudinally to evaluate the effectiveness of this clinical precision medicine intervention. Galvin suggests conducting these types of “N-of-1” trials to evaluate the effectiveness of targeted evidence-based intervention strategies in effort to validate this approach in a real-world clinical setting.

In the end, much of the argument may come down to a matter of semantics. Is it really possible to absolutely prevent a heart attack or a stroke? No. But, decades of evidence favors the potential for significant risk reduction (13–14). While the totality of the evidence in AD prevention is not yet as robust, the opportunities to apply emerging evidence in the clinic today are burgeoning. Preliminary results from the APC cohort have shown that the clinical practice of AD prevention is feasible, and significant improvements in cognition and laboratory markers of AD risk have been demonstrated over time (10). Based on the totality of evidence and early experiences in the clinical management of AD prevention, we anticipate the continued growth of this medical specialty. Further research is indeed warranted, and Galvin provides a roadmap ahead for like-minds to follow.